MXPA06004961A - Once-a-day, oral, controlled-release, oxycodone dosage forms - Google Patents

Abstract

Oxycodone formulations are provided which produce substantially flat in vivo steady state plasma profiles. Tolerance levels associated with such profiles and tolerance levels associated with biphasic profiles are shown not to be statistically different. The substantially flat in vivo steady state plasma profiles are produced by dosage forms having substantially zero order in vitro release profiles. Such release profiles produce low single dose in vivo Cmax levels which can reduce the probability of adverse side effects.

Description

DOSAGE FORMS OF OXYCHODONE CONTROLLED RELEASE, ORAL, ONCE A DAY CROSS REFERENCE TO RELATED REQUESTS This application changes the benefit under United States Code 35 § 119 (e) of United States Provisional Application No. 60 / 515,880 filed on October 29, 2003, the contents of which are incorporated by reference herein. whole. This request is a continuation in part of the request of the United States No.10 / 423,454, filed on April 25, 2003, which claims the benefit under United States Code 35 § 119 (e) of United States Provisional Application No. 60 / 376,470 filed on April 29 April 2002 and published as U.S. Patent Publication No. 2004-0010000 A1 on January 15, 2004 and as WO 03/092648 on November 13, 2003, the contents of which are incorporated herein in their entirety. by reference. This application is also a continuation in part of the United States application No. 10 / 447,910 filed May 28, 2003, which claims the benefit under United States Code 35 § 119 (e) of the provisional application of United States No. 60 / 384,442 filed May 31, 2002 and which was published as United States Patent Publication No. 2003-0224051 A1 on December 4, 2003 and as WO 03/101384 on December 11. of 2003, whose contents in their entirety are incorporated herein by reference.

FIELD OF THE INVENTION This invention relates to In vitro and in vivo profiles, ie in vitro dissolution / release profiles and stable in vivo and single dose plasma profiles in vivo for the opioid analgesic, oxycodone, when orally administered using a form of controlled release dosage. In particular, the invention relates to in vitro and in vivo oxycodone profiles designed to produce effective pain management and a lower likelihood of "liking" when oxycodone is orally administered to a patient once a day.

BACKGROUND OF THE INVENTION A. Oxycodone Oxycodone, a listing II drug, is an opioid for the management of moderate to severe chronic pain, such as pain due to surgery, cancer, trauma, biliary colic, renal colic, myocardial infarction and burns. Oxycodone has been marketed as an analgesic for more than 70 years. It is currently available in immediate release (IR) forms, as well as a controlled release formulation (CR) indicated for dosing twice a day. The pharmacological and medical properties of analgesic opioids including oxycodone are described in Pharmaceutical Sciences, Remington, 17th Ed., Pp. 1099-1107 (1985), and The Pharmacological Basis of Therapeutics, Goodman and Rail, 8th Ed., Pp. 485-518 (1990). Generally, the analgesic action of oxycodone administered parenterally is evident at 15 minutes, whereas the onset of action of oxycodone administered orally is a little slower and analgesia occurs within about 30 minutes. In human plasma, the half-life of orally administered oxycodone is about 3.2 hours Physicians' Desk Reference, Thompson Heaare, 56th Ed., Pp. 2912-2918 (2002). In the past, oxycodone has been administered in conventional forms, such as immediate release tablets of rapid discharge without speed control, or by rapid discharge capsules and usually in repetitive and multiple dosing intervals throughout the day. Oxycodone is also administered twice daily with a controlled release matrix system, OXYCONTIN® (Purdue Pharma LP, Stamford, CT). However, the OXYCONTIN® therapy mode continues to lead to an initial high dose of oxycodone in the blood after administration, followed by decreased levels of oxycodone in the blood. Additionally, this maximum and residual concentration pattern occurs twice during a 24-hour period due to the dosing regimen twice a day. Differences in concentration in dosage patterns are related to the presence and absence of the drug administered, which is a major disadvantage associated with these previous dosage forms. Conventional dosage forms and their mode of operation including peak and dose valleys are discussed in Pharmaceutical Sciences. Remington, 18th Ed., Pp. 1676-01686 (1990), Mack Publishing Co.

B. Tolerance to oxycodone Previous studies in rats and mice with opioids have shown the development of tolerance to analgesia (antinociception) after bolus dosing, intermittent dosing and infusions at constant speed (Ekblom et al 1993, Gardmark et al 1993 , Ouellet &Pollack 1995, 1997, Duttaroy &Yoburn 1995). In relation to the product OXYCONTIN® employees of Purdue Pharma and its associated companies have published scientific articles in which two-phase profiles are described as better than flat profiles with respect to the development of tolerance to oxycodone. Thus, in the Journal of Pain and Symptom Management, Purdue employees wrote (Benzíger et al., 1997 on page 81): "Although the benefits of controlled-release dosage forms that allow less frequent dosing are well established, It is suggested that the maintenance of almost constant concentrations of plasma of opioids can lead to the development of tolerance.Oxycodone CR tablets under study [OXYCONTIN®] were developed to reduce the number of fluctuations Cm \ n / Cma? during the interval of 12-hour dosing coinciding with the degree of fluctuation (Cm¡n / Cmax) of oxycodone concentrations in the plasma that were observed during steady state dosing with comparable doses of oxycodone IR.When retaining the degree of fluctuation in concentrations of Plasma can reduce the possibility of lower pharmacodynamic effects over time compared to CR formulations that maintain in comparable constant blood levels "(citations omitted). Similarly, Dr. Robert Kaiko, an inventor of OXYCONTIN®, wrote in Acta Annesthesiol Scand (Kaiko 1997): "Another fundamental basis for the biphasic opioid absorption profile is to produce a maximum residual fluctuation comparable to the release opioid. Conventional Immediate Since it has been suggested that highly stable plasma opioid concentrations may lead to the development of tolerance, it is anticipated that altering the rate of fluctuation without altering the degree of fluctuation would minimize development to tolerance "(p. skip appointments). Novel teachings against flat plasma profiles and, in particular, against flat plasma profiles for once-a-day dosage forms can be found in the patent literature. Thus, U.S. Patent No. 5,478,577, assigned to Euroceltique, SA, a company related to Purdue Pharma, states (column five, lines 34-42): "It has surprisingly been discovered now that faster analgesic efficacy is achieved and increased by 24-hour oral opioid formulations that do not show a substantially flat serum concentration curve, but otherwise provide a faster initial opioid release so that the minimum effective analgesic concentration can be achieved more rapidly in many patients than they have measurable, if not significant, pain at the time of dosing. " See also the United States patent of Euroceltique No. 5,672,360, column 5 line 40-47. By virtue of these explicit warnings against flat profiles by the main manufacturer of controlled release oxycodone products, those skilled in the art have deviated from the use of oxycodone dosage forms having substantially zero order in vitro release profiles. In particular, such people would expect flat profiles to generate higher levels of tolerance than biphasic profiles. As fully discussed below (see example 8), it has been found that regardless of the teachings of Purdue Pharma, the oxycodone tolerance levels associated with biphasic profiles and flat profiles (substantially zero-order release profiles) are not, in fact, statistically different. Additionally, as illustrated in Figure 5 (see discussion below), the oxycodone release profiles substantially of zero order produce dose values Cma? low individual and that are expected to have lower levels of "liking" than profiles that are not substantially of zero order, such as biphasic profiles. As is well documented in the literature, including the popular press, the two-phase product OXYCONTIN® Purdue Pharma has serious abuse problems, substantially beyond any "liking" issue. Importantly, as illustrated by the efficacy data of Example 7 below, substantially zero-order oxycodone release profiles achieve effective pain management. Accordingly, in accordance with the invention, it has been shown that oxycodone dosage forms having substantially zero order in vitro release profiles can be used to achieve effective pain management without exaggerated problems of tolerance and with a lower likelihood of "liking" - a combination of benefits that is not previously known or expected from the existing state of the art.

BRIEF DESCRIPTION OF THE INVENTION According to a first aspect, the invention provides a controlled release oxycodone formulation for oral administration once a day to human patients comprising a D dose of: (i) oxycodone, (ii) one or more acid addition salts pharmaceutically acceptable oxycodone, or (iii) a combination of oxycodone and one or more pharmaceutically acceptable acid addition salts of oxycodone, said formulation provides (a) a maximum mean single dose concentration in plasma Cma? and (b) a mean single-dose area under a plasma concentration curve-time for 0-48 hours AUCo-8 satisfying the ratios: 3.5 x 10"4 liter'1 < Cma? / D = 6.8 x 10 '4 liter-1, and 7.6 x 10"3 hour / liter < AUC0- 8 / D < 16.7 x 10-3 hour / liter, wherein said formulation provides pain relief for about 24 hours or more after its administration to the patient. According to a second aspect, the invention provides a controlled release oxycodone formulation for oral administration once a day to human patients comprising a D dose of: (i) oxycodone, (ii) one or more acid addition salts pharmaceutically acceptable oxycodone, or (iii) a combination of oxycodone and one or more pharmaceutically acceptable acid addition salts of oxycodone, wherein: (a) the formulation provides a single-dose mean concentration profile in plasma that substantially increases monotonic to the passage of 24 hours or more; (b) the formulation provides a single dose mean area under a plasma concentration-time curve of 0-48 hours AUC0-4s satisfying the ratio: 7.6 x 10"3 hour / liter <AUC0-8 / D < 16J x 0"3 hours / liter; and (c) the formulation provides pain relief for about 24 hours or more after its administration to the patient. According to a third aspect, the invention provides a controlled release oxycodone formulation for oral administration once a day to human patients comprising a D dose of: (i) oxycodone, (ii) one or more acid addition salts pharmaceutically acceptable oxycodone, or (iii) a combination of oxycodone and one or more pharmaceutically acceptable acid addition salts of oxycodone, said formulation provides (a) an average single dose plasma concentration at 12 hours C? 2 and (b) a mean area of single dose under a plasma concentration curve-time for 0-48 hours AUC0-48 satisfying the ratios: 2.7 x 10'4 liter "1 < C? 2 / D < 5.7 x 10" 4 liter-1, and 7.6 x 10'3 hour / liter < AUC D < 16.7 x 10"3 hours / liter, wherein said formulation provides pain relief for about 24 hours or more after its administration to the patient.

According to a fourth aspect, the invention provides a controlled release oxycodone formulation for oral administration once a day to human patients comprising a D dose of: (i) oxycodone, (ii) one or more acid addition salts pharmaceutically acceptable oxycodone, or (iii) a combination of oxycodone and one or more pharmaceutically acceptable acid addition salts of oxycodone, said formulation provides average areas of steady state under a plasma concentration-time curve for 0-6 hours AUC0- 6, 6-12 hours AUC6-12, 12-18 hours AUC? 2.18, 18-24 hours AUC? 8_24, and 0-24 hours AUC0-24 satisfying ratios: AUC0-6 / AUCo-24 > 0.18; AUC6.12 / AUC0-24 > 0.18; AUC12.18 / AUC0-24 > 0.18; and AUC18.24 / AUC0-24 > 0.18; wherein said formulation provides pain relief for about 24 hours or more after its administration to the patient. According to a fifth aspect, the invention provides a controlled release oxycodone formulation for oral administration once a day to human patients comprising a dose of: (i) oxycodone, (ii) one or more acid addition salts pharmaceutically acceptable oxycodone, or (iii) a combination of oxycodone and one or more pharmaceutically acceptable acid addition salts of oxycodone, said formulation has an in vitro release profile in which: (a) 0-20% of the dose is Free in 0-2 hours; (b) 30-65% of the dose is released in 0-12 hours; and (c) 80-100% of the dose is released in 0-24 hours; wherein the release profile is determined using a USP type IV bath indexer in a constant temperature water bath at 37 ° C and wherein said formulation provides pain relief for about 24 hours or more after administration to the patient. According to a sixth aspect, the invention provides a controlled release oxycodone formulation for oral administration once a day to human patients comprising a dose of: (i) oxycodone, (ii) one or more pharmaceutically acceptable acid addition salts of oxycodone, or (iii) a combination of oxycodone and one or more pharmaceutically acceptable acid addition salts of oxycodone, wherein: (a) the dose comprises a first component for immediate release and a second component for sustained release; and (b) the weight ratio W of the first component to the sum of the first and second component is less than about 0.25. According to a seventh aspect, the invention provides a method for treating pain in humans comprising orally administering to a human patient once a day a controlled release dosage form comprising a D dose of: (i) oxycodone, (ii) ) one or more pharmaceutically acceptable acid addition salts of oxycodone, or (iii) a combination of oxycodone and one or more pharmaceutically acceptable acid addition salts of oxycodone, said dosage form providing (a) a maximum mean single dose concentration in plasma Cma? and (b) a mean single dose area under a plasma concentration-time curve for 0-48 hours AUC0-48 satisfying the ratios: 3.5 x 10"4 liter" 1 < Cma? / D < 6.8 x 10"4 liter" 1, and 7.6 x 10"3 hour / liter < AUC D < 16.7 x 10" 3 hour / liter, wherein the dosage form provides pain relief for about 24 hours or more after its administration to the patient. According to an eighth aspect, the invention provides a method for treating pain in humans comprising orally administering to a human patient once a day a controlled release dosage form comprising a D dose of: (i) oxycodone, (ii) ) one or more pharmaceutically acceptable acid addition salts of oxycodone, or (iii) a combination of oxycodone and one or more pharmaceutically acceptable acid addition salts of oxycodone, wherein: (a) the dosage form provides a median concentration profile of a single dose in plasma that increases substantially monotonously by spending 24 hours or more; (b) the dosage form provides a mean single dose area under a plasma concentration-time curve for 0-48 hours AUC0-48 satisfying the ratio: 7.6 x 10"3 hour / liter <AU r- D < 16.7 x 10"3 hour / liter; and (c) the dosage form provides pain relief for about 24 hours or more after its administration to the patient. According to a ninth aspect, the invention provides a method for treating pain in humans which comprises orally administering to a human patient once a day a controlled diversion dosage form comprising a D dose of: (i) oxycodone, (ii) ) one or more pharmaceutically acceptable acid addition salts of oxycodone, or (iii) a combination of oxycodone and one or more pharmaceutically acceptable acid addition salts of oxycodone, said dosage form providing (a) an average concentration of single dose in plasma at 12 hours? 2 and (b) a mean single dose area under a plasma concentration-time curve for 0-48 hours AUCo-48 satisfying the ratios: 2.7 x 10"4 liter" 1 < C? 2 / D < 5.7 x 10"4 liter" 1, and 7.6 x 10"3 hour / liter < AUC D < 16.7 x 10" 3 hour / liter, wherein said dosage form provides pain relief for about 24 hours or more after its administration to the patient. In accordance with a tenth aspect, the invention provides a method for treating pain in humans comprising orally administering to a human patient once a day a controlled release dosage form comprising a D dose of: (i) oxycodone, (ii) one or more acid salts Pharmaceutically acceptable addition salts of oxycodone, or (iii) a combination of oxycodone and one or more pharmaceutically acceptable acid addition salts of oxycodone, said dosage form provides steady state average areas under a plasma concentration-time curve for 0- 6 hours AUCo-6, 6-12 hours AUC6.12, 12-18 hours AUC? 2-? 8, 18-24 hours AUC12-? S, and 0-24 hours AUCo-24 satisfying relationships: AUC6-12 / AUC0-24 >; 0.18, AUC12.18 / AUC0-24 > 0.18, and AUC18.24 / AUCo-24 > 0.18, wherein said dosage form provides pain relief for about 24 hours or more after its administration to the patient. According to an eleventh aspect, the invention provides a method for treating pain in humans comprising orally administering to a human patient once a day a controlled release dosage form comprising a D dose of: (i) oxycodone, (ii) ) one or more pharmaceutically acceptable acid addition salts of oxycodone, or (iii) a combination of oxycodone and one or more pharmaceutically acceptable acid addition salts of oxycodone, said dosage form provides pain relief for about 24 hours or more after of its administration to the patient and that has an in vitro release profile in which: (a) 0-20% of the dose is released in 0-2 hours, (b) 30-65% of the dose is released in 0 -12 hours; and (c) 80-100% of the dose is released in 0-24 hours; wherein the release profile is determined using a bath indexer of the USP type VII in a water bath at constant temperature at 37 ° C.

According to a twelfth aspect, the invention provides methods for treating pain in humans comprising orally administering to a human patient once a day a controlled release dosage form comprising a D dose of: (i) oxycodone (i) ) one or more pharmaceutically acceptable acid addition salts of oxycodone, or (iii) a combination of oxycodone and one or more pharmaceutically acceptable acid addition salts of oxycodone, wherein: (a) the dose comprises a first component for immediate release and a second component for sustained release; (b) the weight ratio W of the first component to the sum of the first and second component is less than about 0.25; and (c) the dosage form provides pain relief for about 24 hours or more after its administration to the patient. The various AUC and C values referenced below can be determined by using plasma samples from people who have been administered one or more opioid antipharyngia (eg, naltrexone) or by using samples from a person who has not received an anasthogonism. . For higher dosage levels, antagonists are usually used, especially in studies involving healthy volunteers. For example, several of the numerical values set forth above are based on the pharmacokinetic data of Example 6, which used healthy volunteers and a dosage form containing 80 mg oxycodone HCl. As described in example 6, naltrexone was administered in this study. As is known in the art, naltrexone has a tendency to increase oxycodone concentrations in plasma. As a result, somewhat lower values of AUC and C may be expected if naltrexone had not been used, but the changes would not have been expected to move the mean values substantially outside of the specified scales. Further features and advantages of the invention are set forth in the detailed description that follows, and in part will be readily understood by those skilled in the art from that description or who will recognize themselves when practicing the invention as described in the present. It should be understood that the foregoing general description and the following description disclosed are merely examples of the invention and are intended to provide a panoramic or structural framework for understanding the nature and characteristics of the invention as claimed. Furthermore, the enlisted aspects of the above invention, as well as the preferred embodiments and modalities of the invention discussed below, may be used separately or in each and every one of their combinations. The attached drawings are included to provide a better understanding of the invention and are incorporated into and included in part of this specification. The drawings will illustrate various embodiments of the invention and, together with the description, serve to explain the principles and operation of the invention. The drawings and, in particular, Figures 1-4, do not pretend to indicate proportions to scale or relay of the elements shown therein. In the drawings and in the specification, equal parts in related figures are idenified with equal numbers.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 illustrates a type of dosage form that can be used in the practice of the invention. Dosage forms are shown in Figure 1 prior to administration to a subject. Figure 2 illustrates a first embodiment of the dosage form of figure 1 in open section. As shown, the dosage form comprises a pharmaceutically acceptable, pharmaceutically acceptable, oxycodone composition hosted in-house. Figure 3 illustrates a second embodiment of the dosage form of Figure 1 in open section. As shown, the dosage form comprises a therapeutic oxycodone composition. pharmaceutically acceptable inorganic form and a contact displacement composition comprising means for pushing the pharmaceutical oxycodone composition of the dosage forms. Figure 4 illustrates a dosage form that also includes an immediate release coverage of a pharmaceutically acceptable therapeutic oxycodone composition.

Figure 5 is a simulated single-dose plasma concentration chart for a zero-order substantial release rate (SZO) (curve 100), rapid release rate followed by a leny (curve 102) and a slow release rate followed of a fast one (curve 104). Figure 6 is a diagram of a preferred cumulative release scale for the dosage forms of the invention. The cumulative release in percent in the diagrams on the vertical axis of oxycodone and / or one or more of its pharmaceutically acceptable addition salts (for example,% of what is reported in the label for a dosage form that has received regulatory approval) and the time in diagram on the horizontal axis. Figures 7A and 7B are diagrams of in vitro release profiles for the dosage form of 17 mg of oxycodone HCl idenified as "rapid system" in example 1. Figure 7A (curve 106) shows the percentage released per hour (FIG. for example,% of what is manifested in% released per hour), while Figure 7B (curve 108) graphs the cumulative release in percentage (for example, accumulated% of what manifested in efiquela). Figures 8A and 8B are diagrams of in vitro release profiles for the dosage form of 17 mg of oxycodone HCl identified as "slow system" in Example 1. Figure 8A (curve 110) graphs the percentage released per hour (FIG. for example,% of what is shown on the label released per hour), while Figure 8B (curve 112) graphs the accumulated release as a percentage (for example, accumulated% of what is manifested in the label). Figures 9A and 9B are graphs of in vitro release profiles for the dosage form of 20 mg of oxycodone HCl from example 2. Figure 9A (curve 114) graphs the percentage released per hour (for example% of what was expressed in the efiqueia released per hour), while Figure 9B (curve 116) graphs the accumulated release as a percentage (for example, accumulated% of what is manifested on the label). Figures 10A and 10B are graphs of in vitro release profiles for the 80 mg dosage form of oxycodone HCl from Example 3. Figure 10A (curve 118) graphs the percentage released per hour (for example% of what is manifest in the label released per hour), while Figure 10B (curve 120) graphs the cumulative release as a percentage (for example, accumulated% of what is manifested in the label). Figure 11 is a diagram of the diameter of the pupil in millimeters (mm) with the time in hours for healthy males who received placebo (curve 122), morphine (curve 124) or the dosage form of example 2 (curve 126). Figure 12 is a diagram of the plasma concentrations in nanograms / milliliters (ng / ml) of oxycodone (curve 128) noroxycodone (curve 130) and oxymorphone (curve 132) against in time in hours for healthy male subjects who received the form of dosage of example 2.

Figure 13 is a simulated pharmacokinetic diagram, in specific single-dose plasma concentrations for a dosage (qdh) immediate release (IR) (curve 134), as well as other experimental for the dosage forms of example 2 and the curve of best suitability for those damages (curve 136). Figure 14 is a simulated pharmacokinetic diagram, in specific concentrations in stable esiable plasma for an immediate release dosage (q6h) (IR) (curve 140), biphasic dosage of OXYCONTIN (curve 138), and a dosage of substantially order zero / once a day (SZO-24) using a dosage form having the sustained release / cover release drug distribution of Example 2, ie 5% of the drug in the shell (curve 142). The y-axis in this figure shows the concentration of oxycodone. Figures 15A and 15B are plasma diagrams of oxycodone concentration profiles in vivo, immediate release (IR) dosing means (qdh) (curve 144).; n = 16), dose with the oxycodone HCl dosage form of 17 mg idenified as the "rapid system" in Example 1 (curve 146; n = 17), and dosage with the oxycodone HCl dosage form of 17 mg identified as the "slow system" in example 1 (curve 148, n = 17). Figure 15A shows the single dose profiles and Figure 15B shows the steady state profiles. The error bars associated with the data points will show the standard deviation (SD) in one direction.

Figures 16A, 16B, 16C, and 16D are diagrams of oxycodone plasma concentration profiles in vivo media for substantially zero order dosing (SZO) with the oxycodone HCl dosage form of 80 mg of Example 3 (curve 150); n = 37), and biphasic dosing with OXYCONTIN 40 mg tablets (curve 152, n = 38). Figure 16A shows steady-state and single-dose profiles, Figures 16B and 16C show single-dose profiles and Figure 16D shows a stable profile. Error bars associated with damage points show standard deviation (SD) in one direction. Figures 17A and 17B are diagrams of the damage in tables 12A and 12B, figure 17A graphs all the damages of these tables and figures 17B graphs data of day + 3 for tail whiplash test doses of 0.25. , 0.5, 0.75, and 1.0 mg / kg.

Definitions As used in this specification and in the claims, the following terms and phrases will have the following meanings. By "dosage form" a pharmaceutic composition or device comprising an acidic pharmaceutical agent, such as oxycodone and / or one or more of its pharmaceutically acceptable acid addition salts, is added, the composition or device also contains inactive ingredients; that is, pharmaceutically acceptable excipients such as suspending agents, surfactants, disinfectants, binders, diluents, lubricants, stabilizers, antioxidants, osmotic agents, colorants, plasticizers, coatings and the like, which are used to manufacture and supply active pharmaceutical agents. By "acive agent", "drug" or "compound" is meant an agent, drug or compound which has the characteristics of oxycodone and / or one or more of its pharmaceutically acceptable acid addition salts.

If desired, other analgesics, or, more generally, other medicaments, may be included in the dosage forms of the invention. By "pharmaceutically acceptable acid addition salts" is meant those salts in which the anion does not contribute significantly to the toxicity or pharmacological activity of the salt and, as such, are pharmacological equivalents of the bases of the oxycodone compound. Examples of pharmaceutically acceptable acids that are used for the purposes of salt formation include hydrochloric, hydrobromic, hydroiodic, cyclic, acyphic, benzoic, mandelic, phosphoric, niric, mucic, isiionic, palmitic and other resins. By "sustained release" the deliberately release of a predefined agent from an active agent into an environment over a prolonged period is enlisted. The "exit", "exit orifice", "supply orifice" or "drug delivery orifice" suspensions and other similar expressions as may be used herein include one or more elements selected from the group consisting of one step; An opening; a hole; and a perforation. The expressions also include orifices that are formed or are formable from a substance or polymer that erodes, dissolves or leaches from the dosage form to form there an exit orifice. A "release rate" of drug refers to the amount of drug released from a dosage form per unit of time, eg milligrams of drug released per hour (mg / hr). The rate of drug release for drug dosage forms is typically measured as an in vitro release rate; that is, a quantity of drug released from the dosage form per unit of time measured under appropriate conditions and in an appropriate fluid. The release rate tests used in the examples described here were carried out in dosage forms placed on media coils in a metal coil attached to a bath indexer of the USP type VII in a water bath at room temperature. constant at 37 ° C. Aliquots of the release rate solutions were injected into a chromatographic system to quantify the amounts of drug released during the test intervals. By "release rate assay" a standardized assay is defined to eliminate the release of the compound from a proven dosage form using a type 7 rate-release device from USP. It is understood that reagents of equivalent grade can be substituted in the assay in accordance with generally accepted procedures.

For clarity and convenience, the convention of designating the time of administration of the drug as zero hours (t = 0 hours) and the fleps after its administration in appropriate units of time, for example t = 30 minutes or = 2, is used. hours, etc. As used herein, unless otherwise specified, and "after administration" refers to the rate of drug release in vitro obtained in the specified time after the implementation of an appropriate dissolution test. The time at which a specific percentage of the drug has been released into a dosage form can be called as the "Tx" value, where "x" is the percentage of drug that has been released. For example, a commonly used reference measurement for evaluating the release of drug from dosage forms is the time at which 70% of the drug in the dosage form has been released. This measurement is known as "T o" for the dosage form. An "immediate release dosage form" refers to a dosage form that dispenses drug susfancialmenie completely within a short period after administration; that is, generally within a few minutes to about an hour. By "sustained release dosage form" is meant a dosage form that releases the drug substantially continuously for many hours (the "sustained release period"). The sustained release dosage forms in accordance with this The invention preferably exhibits T70 values of at least about 10 to 20 hours and preferably 15 to 18 hours. The dosage forms preferably continuously release the drug for sustained periods of at least about 10 hours, more preferably 12 hours or more and even more preferably 16-20 hours or more. The dosage forms according to the present invention preferably exhibit uniform release rates of oxycodone over a prolonged period within a period of sustained release. By "uniform release rate" is meant an average rate of release per hour from the core that varies positively or negatively no more than about 30% and preferably no more than about 25% and more preferably no more than 10% of the rate of average release per subsequent or preceding hour as determined by a USP type 7 release apparatus where the cumulative release is between about 25% to about 75%. By "extended period" a continuous period of at least about 4 hours, preferably 6-8 hours or more and, more preferably, 10 hours or more is enlightened. For example, the example osmotic dosage forms described herein generally begin to release oxycodone at a uniform release rate of between about 2 to about 6 hours after its administration and the uniform release rate, as described above, it continues for a prolonged period of about 25% to at least about 75% and preferably at least about 85% of the drug is released from the dosage form. Oxycodone release continues after this for several more hours although the rate of release generally decreases somewhat in relation to the uniform release rate. By "a dosage form having a substantially zero order invitro release profile" and similar phrases is meant a dosage form which as a whole has in vitro release kinetics substantially of zero order; that is, the overall release rate in vitro is substantially constant over a period of 24 hours. For example, for a dosage form that has an integral release component as an initial loading dose (initial charge component), an in vitro release profile of zero order means that the rate of in vitro release resulting from the combined release of drug from the two components is substantially sustained over a period of 24 hours. In a stable manner, a dosage form having a substantially zero-order in vitro release profile produces an in vivo plasma profile that is substantially flat in contrast to the biphasic one as with the product OXYCONTIN (see below). By "C" is meant the concentration of drug in blood plasma of a subject that is generally expressed as mass per unit volume, typically in nanograms per milliliter. For convenience, this concentration can be called at the present "plasma drug concentration" or "plasma concentration" which is intended to include the measured drug concentration in any appropriate body fluid or tissue. The concentration of drug in plasma at any time after administration of the drug is known as Ct¡empo. as in C9 ° or C24 ° etc. By "stable state" is meant the condition in which the profile of the drug present in the blood plasma of a subject does not vary significantly over a prolonged period. A pattern of drug accumulation after coninuous administration of a dosage form in dosage formlets at the end attains a "stable stage" where the maximum concentrations in plasma and residuals of plasma concentration essentially remain unchanged for each dose. dosage. Those skilled in the art agree that plasma drug concentrations obtained in individual subjects will vary due to the variability among patients in the many parameters that affect drug absorption, distribution, metabolism and excretion. For this reason, unless otherwise indicated, the mean values obtained from groups of subjects are used in the present for the purpose of comparing the damages of concentration of drug in plasma and to analyze the relationship between the dissolution rates of in vitro dosage form and plasma drug concentrations in vivo.

DETAILED DESCRIPTION OF THE INVENTION A. Dosage Forms The present invention can be practiced by using a variety of techniques known in the art to produce controlled release oral dosage forms. Non-limiting examples of such techniques include osmotic systems, diffusion systems such as reservoir devices and maize devices, dissolution systems such as encapsulated solution systems (including, for example, "micropels") and dissolution systems in malre, diffusion systems. solution in combination and resin systems with ion exchange as described in Remington's Pharmaceutical Sciences, 1990 ed., pp. 1682-1685. Oxycodone dosage forms that operate in accordance with any of these or other approaches are encompassed in the present invention to the extent that the drug release characteristics and / or the oxycodone concentration characteristics in plasma of the appended claims are achieved medianie those dosage forms either literally or equivalently. As illustrated by the examples below, particularly preferred dosage forms for use in the practice of the invention are osmotic dosage forms. The osmotic dosage forms, in general, use the osmotic pressure to generate a pulse force to imbibe fluid from a compartment formed, at least in part, by a semipermeable wall that allows the free diffusion of fluid but not of the drug or osmotic agent (s) if you are present (s). A significant source of the osmotic system is that its operation is independent of the pH and therefore continues at the speed determined osmotically over an extended period even if the dosage form transits through the gastrointestinal treatment and faces different microenvironments that have pH values. significantly different An analysis of such dosage forms is found in Santus and Baker, "Osmoíic drug delivery: a review of the patení literafure," Journal of Controlled Relay 35 (1995) 1-21, which is incorporated in its entirety by reference herein. In particular, the following countries of the U.S.A., owned by ALZA Corporafion and directed to osmotic dosage forms, are incorporated herein, in their presence: No. 3,845,770; 3,916,899; 3,995,631; 4,008,719; 4,111, 202; 4,160,020; 4,327,725; 4,519,801; 4,578,075; 4,681, 583; 5,019,397; and 5,156,850. Figure 1 is a perspective view of a modality of a conjoined release osmoic dosage form. The dosage forms 10 comprise a wall 20 that surrounds and encompasses an internal compartment (which is not seen in Figure 1). The inner compartment contains a composition comprising oxycodone and / or one or more of its pharmaceutically acceptable acid addition salts. The wall 20 is provided with at least one outlet for drug supply 60 for connecting the internal compartment to the outside environment of use. Accordingly, after oral ingestion of the dosage form 10, the fluid is imbibed from the wall 20 and the oxycodone and / or one or more of its pharmaceutically acceptable addition salts are released through the outlet 60. Although the preferred geometiric embodiment in Figure 1 illustrates a standard biconvex shaped tablet, the geometry may include a tablet in the form of a capsule and other oral dosage forms. Fig. 2 is a sectional view of Fig. 1 showing one embodiment of an osmotic release dosage form confroled with an internal compartment 15 containing a single component layer which is referred to herein as drug layer 30, comprising the drug 31; that is, at least oxycodone and / or one or more of its pharmaceutically acceptable addition salts, in a mixture with excipients selected and adapted to provide a gradient of osmotic activity to drive the fluid from an external environment through the wall. and to form a drug formulation available upon embedding the fluid. As described in more detail below, the excipients may include a suitable suspending agent, which is also known in the present as carrier of drug 32, binder 33, lubricant 34 and an osmotically active agent, osmoagenie 35. In operation, after oral administration of the Dosage form 10, the osmotic activity gradient across the wall 20 causes the gastric fluid to be imbibed through the wall 20 thus forming a drug formulation that can be delivered, i.e., a solution or suspension within the inert compartment. The drug formulation is released through the outlet 60 as the fluid continues to enter the internal compartment. As the release of the drug formulation occurs, the fluid continues to be imbibed, thus promoting continued release. In this way, the drug is released in a sustained and continuous manner for an extended period. Figure 3 is a sectional view of Figure 1 with an alternate embodiment of the internal compartment 15 which has a bilayer configuration. In this embodiment, the internal compartment 15 contains a compressed bilayer core having a first component drug layer 30 and a second component pushing layer 40. The drug layer 30, as described above with reference to FIG. 1, it comprises at least oxycodone and / or one or more of its pharmaceutically acceptable acid addition salts in a mixture with selected excipients. As described in greater detail hereinafter, the second component push layer 40 comprises osmotically active component (s) but does not contain any active agent. The components in the push layer 40 typically comprise an osmagent 42 and one or more osmopolymers 41 that have relatively large molecular weights that show swelling as the fluid is soaked up as the release of these osmopolymers through the orifice for drug delivery. 60 does not happen. Additional excipients such as binder 43, lubricant 44, antioxidant 45 and dye 46 can also be included in the thrust layer 40. The second component layer is referred to herein as an expandable or push layer, since, as the fluid, the osmopolymer (s) swells and pushes forward the drug formulation available from the first component drug layer to thereby facilitate the release of the drug formulation from the dosage form. In operation, after oral ingestion of the dosage form 10 as shown in Figure 3, the gradient of osmotic activity through the wall 20 causes the gastric fluid to be imbibed through the wall 20, thereby forming the drug layer 30 in a dispensable formulation and consequently inflating the osmopolymer (s) in the pusher layer 40. The dispensable drug layer 30 is released through the outlet 60 as the fluid continues to enter the internal compartment 15. and the push layer 40 continues to swell. As the release of the drug layer 30 occurs, the fluid continues to be imbibed and the pusher layer continues to swell, thereby promoting its continuous release. In this way, the drug is released in a sustained and continuous manner over an extended period. The drug layer 30, as described with reference to FIGS. 2 and 3, comprises oxycodone and / or one or more of its pharmaceutically acceptable acid addition salts in a mixture with selected excipients. The thrust layer 40, as described with reference to Figure 3, comprises osmioscimically compliant compound (s) but does not contain any active agent. The drug layer 30 comprises a composition formed by a pharmaceutically effective amount of oxycodone drug 31 and / or one or more of its pharmaceutically acceptable acid addition salts and a carrier 32. Oxycodone in drug comprises 4,5-epoxy-14 -hydroxy-3-methoxy-17-methylmorphinan-6-one that has analgesic therapy. Oxycodone is known in the art. The Merck Index, 11th Ed., P. 1100 (1990). The oxycodone salts are, for example, represented by one or more members of the group consisting of the following: oxycodone sulfate, oxycodone hydrochloride, oxycodone trifluoroacetyl, oxycodone thiosemicarbazone hydrochloride, oxycodone pentafluoropropionate, oxycodone p-nitrophenylhydrozone Oxycodone o-methyloxy, oxycodone iosemicarbazone, oxycodone semicarbazone, oxycodone phenylhydroazone, oxycodone hydrazone, oxycodone hydrobromide, oxycodone mucoid, oxycodone melilbromide, oxycodone oleate, oxycodone n-oxycodone aceate, phosphate Oxycodone dibasic, Oxycodone monobasic phosphate, Oxycodone inorganic salt, Oxycodone organic salt, Oxycodone trihydraphated acetate, Oxycodone bis (heptafluorobutyrazole), Oxycodone bis (methylcarbamazole), Oxycodone bis (pentafluoropropionate), Bís (pyridine-3) -carboxylate) of oxycodone, oxycodone bis (lrifluoroacetamide), oxycodone bitartrate, oxycodone chlorine hydrated and oxycodone sulfate pentahydrate.

The dosage form and the therapeutic composition in any manufacture may comprise 1 to 640 mg of oxycodone drug 31 and / or pharmaceutically acceptable salt of the oxycodone drug 31. More typically, the charge of the compound in the dosage forms, either by using Osmological or other controlled release technology, will provide compound doses to the subject in the range of 10 mg to 160 mg and more usually 20 mg to 80 mg per day. In general, if a total drug dose of more than 160 mg per day is required, multiple units of the dosage form can be administered at the same time to provide the required amount of drug. Preferably, the once-daily dosage forms of the present invention comprise a D dose of oxycodone and / or one or more of its pharmaceutically acceptable acid addition salts that are greater than or equal to about 10 mg and less than or equal to to around 80 mg. For reference, immediate release oxycodone is typically administered in a starting dose of about 10 mg, administered in two or three doses per day. The effective dose scale has been determined as generally 10 mg / day - 320 mg / day. Observations of the patient's tolerance to side effects without the need for an additional clinical effect on the starting dose often result in the dose being increased in increments of 5 mg / day to 80 mg / day. According to these observations, plasma concentrations in a subject can be determined by clinical trial to determine a relationship between tolerance to side effects, clinical effect and blood plasma concentration of the drug. Plasma concentrations of oxycodone can vary from 0.1 ng / ml to 100 ng / ml (nanograms per milliliter), more typically from 4 ng / ml to 40 ng / ml. For some dosages administered by an osmotic dosage form, it is advisable to modulate the viscosity of the hydrated drug layer in operation by adding or reducing salt in the formulation. Traditional systems that use salt in a drug formulation brought with compounds that exhibit a strong common ionic effect. This strong ionic effect common in the high drug loading allows the addition of salt to modulate the compound's solubility, allowing more salt to be released at the beginning in the supply cycle in order to produce a zero order release rate profile . These systems will show the incorporation of salt in the systems of drug loading with little or no salt in the systems of low drug loading where a salification effect is unnecessary. It has been found that oxycodone and other similar drugs that exhibit a weak common ionic effect are not similarly affected by the salts to modulate the solubility and affect the rate of release through a salting effect. Specifically, it has been found that oxycodone does not benefit from the addition of salt in higher doses, but benefits from the addition of salt in low doses. It has also been found that this addition of salt at the lower doses can modulate the viscosity of the hydrated drug layer to maintain an appropriate supply for the desired release rate profile. The amount of salt incorporated in the drug layer of the system is about 25% if a polymer of allio molecular weight is used and low doses of drug at a percentage of 0 if a polymer of low molecular weight and higher doses is used of drug. Some representative salts that can be incorporated into the drug composition include sodium chloride, potassium chloride and the like. More preferable is sodium chloride. Preferably, the viscosity of the drug layer during operation is maintained between about 50 cps and about 100 cps. Thus, products containing lower drug concentrations (5-15%) and higher drug concentrations (15-40%) can essentially be produced in such a way that they have equivalent release functionality. The viscosity of the drug layer can be achieved using any of the many hydrophilic polymers. Some examples include water soluble cellulose polymers, such as NaCMC, HPMC, etc. or polyethylene oxide polymers, such as Poiyox® or water soluble sugars, such as maltodextrin, sucrose, mannitol. Any physical or chemical property of the polymer, which can be modified to achieve the desired viscosity, is also included in this description. The carrier 32 may comprise a hydrophilic polymer represented by the horizontal stripes in Figures 2 and 3. The hydrophilic polymer provides a hydrophilic polymer particle in the drug composition that contributes to the controlled delivery of the active agent. Representative examples of these polymers are poly (alkylene oxide) with number average molecular weight of 100,000 to 750,000, including poly (ethylene oxide), poly (methylene oxide), poly (butylene oxide) and poly (oxide). hexylene); and a poly (carboxymethylcellulose) with a number average molecular weight of 40,000 to 400,000, represented by poly (carboxymethylcellulose alkaline), poly (sodium carboxymethylcellulose), poly (carboxymethylcellulose potassium) and poly (carboxymethylcellulose lithium). The drug composition may comprise a hydroxypropyl alkylcellulose with a number average molecular weight of from 9,200 to 125,000 to enhance the delivery properties of the dosage form as represented by hydroxypropylethylcellulose, hydroxypropylmethylcellulose, hydroxypropylbuylcellulose and hydroxypropylpentylcellulose; and a poly (vinylpyrrolidone) with number average molecular weight of 7,000 to 75,000 to enhance the flow properties of the dosage form. Among those preferred polymers are poly (ethylene oxide) with a number average molecular weight of 100,000-300,000. Carriers that wear out in the gasyric environment, that is, biodegradable carriers, are especially preferred. Other carriers that can be incorporated into drug layer 30 include carbohydrates that exhibit sufficient osmotic activity to be used individually or with other osmagents. Such carbohydrates comprise monosaccharides, disaccharides and polysaccharides.

Representative examples include maltodextrins (ie, glucose polymers produced by the hydrolysis of corn starch) and sugars comprising lactose, glucose, raffinose, sucrose, mannitol, sorbitol and the like. Preferred maltodextrins are those having a dextrose equivalence (DE) of 20 or less, preferably with a range of DE ranging from about 4 to about 20, and sometimes from 9-20. It has been found that maltodextrin having an ED of 9-12 is the most useful. The carbohydrates described above, preferably the maltodexirins, can be used in the drug layer 30 without the addition of an osmagent, and obtain the desired release of oxycodone and / or one or more of its pharmaceutically acceptable acid addition salts in the form of dosage, while providing a therapeutic effect during a prolonged period of time and up to 24 hours with a dosage once per day. The preferred molecular weight of the polymeric carrier used in the drug layer varies from 100,000 PM to 300,000 PM and more preferably around 200,000 PM. The drug layer 30 may further comprise a therapeutically acceptable vinyl polymer binder 33 represented by vertical stripes in Figures 2 and 3. The vinyl polymer comprises an average molecular weight of 5,000 to 350,000 represented by a member selected from the group consisting of of poly-n-vinylamide, poly-n-vinylacetamide, poly (vinyl pyrrolidone), also known as poly-n-vinylpyrrolidone copolymers, poly-n-vinyl caprolactone, poly-n-vinyl-5-meityl-2-pyrrolidone, and polyvinylpyrrolidone with a member selected from the group consisting of vinyl acetate, vinyl alcohol, vinyl chloride, vinyl fluoride, vinyl butyrate, vinyl laurate and vinyl stearate. The dosage form 10 and the εeparal composition may comprise from 0.01 to 25 mg of the agluíinanfe or vinyl polymer which serves as a binder. The different representative binders include acacia, starch and gelatin. The dosage form 30 may also comprise lubricant 34 represented by a wavy line in Figures 2 and 3. The lubricant is used during the processing to prevent adhesion to the walls of the nickel or punch faces. Iypic lubricants include magnesium stearate, sodium acetate, stearic acid, calcium acetate, magnesium oxide, oleic acid, pofasium oil, caprylic acid, sodium fumarate, and magnesium palm. The amount of lubricant present in the idérapéuíica composition can be from 0.01 to 10 mg. The drug layer 30 will normally be a dry composition formed by compression of the carrier and the drug as one layer and the push composition as the other layer in a count ratio. The drug layer 30 is formed as a mixture containing oxycodone and / or one or more of its pharmaceutically acceptable acid addition salts and the carrier which when in contact with the biological fluids in the environment of use provides a paste, solution or suspension of the compound that can be dispensed by means of the action of the thrust layer.

The drug layer can be formed from particles by spraying which produces the size of the drug and the size of the accompanying polymer used in the manufacture of the drug layer. The means for producing the particles include granulation, spray drying, sieving, lyophilization, compression, trituration, jet mill grinding, micronization and cutting to produce the proposed micron particle size. The procedure can also be carried out through the use of size reduction equipment, such as a micropulverizing mill, a fluid energy cleaning mill, a milling mill, a roller mill, a hammer mill, a mill degas by rozamienío, a fillet mill, a ball mill, a ball mill with vibration, an impact pulverizer mill, a cenyrifugal spray, a coarse tri-incubator and a fine grinder. The size of the particle can be verified by mediation, including a grill blade, a flat blade, a vibrating blade, a rotating blade, a shaking blade, an oscillating blade and an alveolar blade. The process and equipment for the preparation of drug particles and carriers are described in Pharmaceutical Sciences, Remingíon, 17a Ed., Pp. 1585-1594 (1985); Chemical Engineers Handbook. Perry, 6th Ed., Pp. 21-13 to 21-19 (1984); Journal of Pharmaceuiical Sciences. Parral, Vol. 61, No. 6, pp. 813-829 (1974): v Chemical Engineer, Hinox, pp. 94-103, (1990). The drug layer 30 may further comprise surfactant agents and disintegrants. Exemplary surfactants are those having an HLB value of between about 10-25, such as polyethylene glycol monostearate 400, polyoxyethylene-4-sorbitan monolaurate, polyoxyethylene-20-sorbitan monooleate, polyoxyethylene-20-sorbitan monopalmitate , polyoxyethylene-20 monolaurate, polyoxyethylene-40 stearaite, sodium oleate and the like. Disintegrants can be selected from starches, clays, celluloses, algines and gums and interlaced starches, celluloses and polymers. Representative disintegrants include corn starch, croscamellose potato starch, crospovidone, sodium starch glycollate Veegum HV, methyl cellulose, agar, bentonia, carboxymethyl cellulose, alginic acid, guar gum and the like. The thrust layer 40 comprises a displacement composition in a slickly disposed arrangement with the first drug layer of the component 30 as illustrated in Fig. 3. The thrust layer 40 comprises an osmopolymer 41 that absorbs an aqueous or biological fluid and it swells to push the drug composition through the device's output means. A polymer having suitable absorption properties can be referred to herein as an osmopolymer. The osmopolymers are swellable, hydrophilic polymers that interact with water and aqueous biological fluids and swell or expand to a degree, typically exhibiting a volume increase of 2 to 50 times. The osmopolymer may be entangled or non-interlaced, but in a preferred embodiment it is at least slightly entangled to create a polymer network that is too long and entangled to exit the dosage form. Thus, in a preferred embodiment, the expandable composition is retained within the dosage form during its operative lifetime. The thrust layer 40 comprises from 20 to 375 mg of osmopolymer 41, represented by "V" in Figure 3. Osmopolymer 41 in layer 40 has a higher molecular weight than osmopolymer 32 in drug layer 20. Representative fluid-absorbing displacement polymers comprise members selected from poly (alkylene oxide) having a number-average molecular weight of 1 million to 15 million, as represented by poly (ethylene oxide) and poly (carboxymethyl cellulose alkaline) with an average molecular weight in number from 500,000 to 3,500,000, where the alkali is sodium, poiasium or lithium. Examples of additional polymers for the thrust displacement composition composition comprise osmopolymers comprising polymers that form hydrogels, such as Carbopol® acid carboxy-polymer, an acrylic polymer crosslinked with a polyallyl sucrose, also known as carboxypolymethylene, and carboxyvinyl polymer which has a molecular weight of 250,000 to 4,000,000; Cyanamer® polyacrylamide; indenomalic anhydride polymers, swellable with water, entapered; Good-rife® polyacrylic acid having a molecular weight of 80,000 to 200,000; acrylate polymer polysaccharides Aqua-Keeps® condensate condensed units, such as polygluurane entangled with diester; and the similar. Representative polymers that form hydrogels are known in the prior art in the US Pat. No. 3,865,108 issued to Hartop; the patent of E.U.A. No. 4,002,173, issued to Manning; the patent of E.U.A. No. 4,207,893, issued to Michaels; and in Handbook of Common Polvmers. Scott and Roff, Chemical Rubber Co., Cleveland, OH. The push layer 40 may comprise from 0 to 75 mg, and currently from 5 to 75 mg of an osmotically effective compound, osmagent 42, represented by circles in Figure 3. The osmotically effective compounds are also known as osmagents and as osmotically solutes. effective. The osmagent 42 that can be found in the drug layer and the push layer in the dosage form are those that exhibit a gradient of osmotic activity through the wall 20. Suitable osmagents comprise a member selected from the group consisting of sodium chloride, potassium chloride, lithium chloride, magnesium sulfate, magnesium chloride, potassium sulfate, sodium sulphate, sulphate of lithium, phosphate of potassium, mannitol, urea, inositol, magnesium succinate, tartaric acid, raffinose, sucrose , glucose, lactose, sorbitol, inorganic salts, organic salts and carbohydrates. The push layer 40 may further comprise a therapeutically acceptable vinyl polymer 43 represented by the triangles in Figure 3. The vinyl polymer comprises a viscosity average molecular weight of 5,000 to 350,000, represented by a member selected from the group consisting of poly-n-vinyl amide, poly-n-vinyl acetamide, polyvinylpyrrolidone, also known as poly-n-vinylpyrrolidone, poly-n-vinylprolactone, poly-n-vinyl-5-methyl-2-pyrrolidone, and poly-n copolymers -vinyl pyrrolidone with a member selected from the group consisting of vinyl acetylate, vinyl alcohol, vinyl chloride, vinyl fluoride, vinyl butadiene, vinyl laureate and vinyl stearate. The push layer may contain from 0.01 to 25 mg of vinyl polymer. The push layer 40 may further comprise from 0 to 5 mg of a non-toxic dye or dye 46, idenified by the vertical wavy lines in Figure 3. Dye 35 includes dyes from the administration of food and drugs (FD &; C), such as blue dye No. 1 FD &C, red dye No. 4 FD &C, red ferric oxide, yellow ferric oxide, lithium dioxide, carbon black, and indigo. The thrust layer 40 may further comprise lubricant 40, idenified by circles in FIG. 3. Typical lubricants comprise a member selected from the group consisting of sodium stearate, potassium stearate, magnesium stearate, stearic acid, calcium stearate. , sodium oleate, calcium palmitate, sodium lauraio, ricinolea sodium and potassium linoleate. The lubricant concentration can be from 0.1 to 10 mg. The push layer 40 may further comprise an antioxidant 45, represented by the slanted stripes in Figure 3 to inhibit the oxidation of ingredients comprising an expandable formulation 40. The push layer 40 may comprise up to 5 mg of an antioxidant. The representative antioxidants comprise a member selected from the group consisting of ascorbic acid, ascorbyl palmiyate, butylated hydroxyanisole, a mixture of 2 and 3-butene-4-hydroxyanisole, butylated hydroxytoluene, sodium isoascorbate, dihydrogenase acid, sorbate, Sodium bisulfate, sodium metabisulfate, sorbic acid, potassium ascorbate, E vine, 4-chloro-2,6-diterc-bufio? phenol, alpha-tocopherol and propyl gallate. Figure 4 depicts a preferred embodiment of the present invention comprising a top layer 50 of drug 31 in the dosage form of Figure 3. Coverage 50 can be a fepethutic composition comprising 0.5 to 75 mg oxycodone 31 and / or one or more of its pharmaceutically acceptable acid addition salts and 0.5 to 275 mg of a pharmaceutically acceptable carrier selected from the group consisting of alkylcellulose, hydroxyalkyl cellulose and hydroxypropylalkyl cellulose. For example, the coating may contain methylcellulose, hydroxyethyl cellulose, hydroxybutyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxypropyl cellulose and hydroxypropylbutyl cellulose. Coverage 50 provides immediate therapy as coverage 50 dissolves or undergoes dissolution in the presence of gastrointestinal fluid and concurrently provides oxycodone 31 and / or one or more of its pharmaceutically acceptable acid addition salts in the gastrointestinal tract for therapy. of immediate oxycodone. Exemplary solvents suitable for the manufacture of the dosage form components comprise inert or aqueous organic solvents which do not adversely harm the materials used in the system. Solvenis broadly include elements selected from the group consisting of aqueous solvents, alcohols, ceions, esters, ethers, aliphatic hydrocarbons, halogenated solvents, cycloaliphatic, aromatic, heterocyclic solvents and mixtures thereof. Ethyl solvents include acetyl, diacefon alcohol, meianol, eneol, isopropyl alcohol, butyl alcohol, meityl acetyl, ethyl ether, isopropyl acetyl, n-buylyl acetyl, isobuyl ketone, methyl propyl, and n-hexane, n-hepfano, diethylene glycol monomethyl ether, ethylene glycol monoethylene, ethylene glycol dichloride, ethylene dichloride, propylene dichloride, carbon dioxide, nitropropane, ethylene chloride, ethyl ether, isopropyl ether, cyclohexane, cycloochane, benzene, toluene, naphtha, 1, 4-dioxane, teirahydrofuran, diglyme, water, aqueous solvents, which contain inorganic salts such as sodium chloride, calcium chloride and the like, and their natural mixtures, such as acelline and water, aceanone and meianol, acetyl and ethyl alcohol, dichloride of methylene and methanol and ethylene dichloride and methanol. The wall 20 is formed to be permeable to the passage of an exothermic fluid, such as water and biological fluids, and is subsanially impermeable to the passage of oxycodone and / or one or more of its pharmaceutically acceptable acid addition salts., osmoagenie, osmopolymer, and the like. As such, it is semipermeable. The selectively semipermeable compositions used for wall formation are not essentially wear-resistant and are substantially insoluble in biological fluids during the life of the dosage form. Representative polymers for forming the wall 20 comprise homopolymers, semipermeable, semipermeable copolymers and the like. Such materials comprise cellulose esters, cellulose ethers, and cellulose esters. The cellulosic polymers have a degree of subsitution (DS) of their anhydroglucose unit of more than 0 to 3, inclusive. The degree of substilution (DS) refers to the average number of hydroxyl groups originally present in the anhydroglucose unit that are replaced by a substituting group or converted to another group. The anhydroglucose unit can be partially or completely substituted with groups such as acyl, alkenoyl, alkenoyl, aroyl, alkyl, alkoxy, halogen, carboalkyl, alkyl carbamate, alkyl carbonate, alkyl sulfonate, alkyl sulphamate, polymer forming groups semipermeable and the like, wherein the organic radicals contain from one to twelve carbon atoms, and preferably from one to eight carbon atoms. The semipermeable compositions usually include a member selected from the group consisting of cellulose acylation, cellulose diacylate, cellulose triacylation, cellulose acetyl, cellulose diary, cellulose iron, mono-, di-, and yl-cellulose alkylamines, mono- di-, and i-alkenylates, mono-, di- and Iriaroilalos, and the like. Exemplary polymers include cellulose oil that has a DS of 1.8 to 2.3 and an acetyl content of 32 to 39.9%; diazepam of cellulose having a DS of 1 to 2 and an acefilo content of 21 to 35%; cellulose triacefaction that has a DS of 2 to 3 and an acetyl content of 34 to 44.8%; and the similar. The more specific cellulosic polymers include cellulose propionate having a DS of 1.8 and a propionyl content of 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%, an average propionyl content of 39.2 to 45%, and a hydroxyl content of 2.8 to 5.4%; buíiralo cellulose acetyl having a DS of 1.8, an acetyl content of 13 to 15%, and a buíiril content of 34 to 39%; the cellulose acetyl containing an aceyl content of 2 to 29%, a butyryl content of 17 to 53%, and a hydroxyl content of 0.5 to 4.7%; the cellulose fibers that have a DS of 2.6 to 3, such as cellulose compound, cellulose trilamate, cellulose tripalmonate, cellulose triocyanol and cellulose ionopropion; cellulose diesters that have a DS of 2.2 to 2.6, fales such as cellulose cellulose dissipation, cellulose dilation, cellulose dioxide, cellulose dicapillary and the like; and mixed cellulose esters, such as cellulose acetate valerate, cellulose acetate succinate, cellulose succinafo propionate, cellulose acetate octanoa, cellulose cellulose palmitate, cellulose acetyl cellulose and the like. Semipermeable polymers are known in the US Pat. No. 4,077,407, and can be synthesized through procedures described in Encvclopedia of Polvmer Science and Technology. Vol. 3, pp. 325-354 (1964), Iníerscience Publishers Inc., New York, NY.

The additional semipermeable polymers for the formation of the outer wall 20 comprise cellulose diacetylaldehyde dimethyl acetate; ethylcarbamazine acetyl cellulose; cellulose acetylcarboxylate; cellulose dimethylaminoacety; semipermeable polyamide; semipermeable polyureia; semi-permeable sulfonated polyesirenes; semi-permeable, semi-permeable polymers formed by the co-precipitation of an anion and a cation, as described in the patents of E.U.A. Nos. 3,173,876; 3,276,586; 3,541, 005; 3,541, 006 and 3,546,142; semipermeable polymers, as described by Loeb, ef al. in the patent of E.U.A. No. 3,133,132; semipermeable polystyrene derivatives; poly (sodium sulfonated silyrene) semipermeable; semipermeable poly (polyvinylbenzyltrimethylammonium chloride); and semipermeable polymers exhibiting a fluid permeability of 10"5 to 10" 2 (ce. 25 μm / cm hr.atm), which is expressed as by aosphere of hydrostatic or osmotic pressure differences across a semipermeable wall. The polymers are known for the technique in the E.U.A. Nos. 3,845,770; 3,916,899 and 4,160,020; and in Handbook of Common Polymers, Scoíí and Roff (1971) CRC Press, Cleveland, OH. The wall 20 also comprises a flow regulating agent. The flow regulating agent is an added compound to aid in the regulation of fluid permeability or flow through the wall 20. The flow regulating agent may be an agent that intensifies the flow or an agent that decreases the flow . The agency can be preselected to increase or decrease the liquid flow. Agents that produce a marked increase in fluid permeability such as water are sometimes essentially hydrophilic, while those that produce a marked decrease in fluids such as water are essentially hydrophobic. The amount of regulator in the wall when incorporated in this is generally about 0.01% to 20% by weight or more. The flow regulating agents may include polyhydric alcohols, polyalkylene glycols, polyalkylene diols, alkylene glycols polyesters, and the like. Typical flow enhancers include polyethylene glycol 300, 400, 600, 1500, 4000, 6000 and the like; low molecular weight glycols such as polypropylene glycol, polybutylene glycol and polyamylene glycol: the polyalkylene diols such as poly (1,3-propanediol), poly (1,4-butanediol), poly (1,6-hexanediol), and the like; aliphatic diols such as 1, 3-butylene glycol, 1,4-pentamethylene glycol, 1,4-hexamethylene glycol and the like; alkynylene triols such as glycerin, 1,2,3-buanothiol, 1,4-hexanetriol, 1,3,6-hexanetriol and the like; esters such as ethylene glycol dipropionate, ethylene glycol butyrate, butylene glycol dipropionate, glycerol acetate esters, and the like. Preferred preferred flux enhancers include the group of polyoxyalkylene copolymer difunctional block copolymers of propylene glycol known as pluronic (BASF). Representative flow-rate agents include subsitiated units with an alkyl or alkoxy group or with both alkyl and alkoxy groups such as diethyl phthalate, dimethoxyethyl phthalate, dimethyl phthalate, and [di (2-ethylhexyl) phthalaryl], aryl phthalates. such as phylalo of triphenyl, and butyl benzyl phthalate; polyvinyl acetates, trieryl citrate, eudragit; insoluble salts such as calcium sulfate, barium sulfate, calcium phosphate and the like; insoluble oxides such as titanium oxide; powdered polymers, granules and similar forms such as polysulfur, polymethyl methacrylate, polycarbonate, and polysulfone; esters such as citric acid esters esterified with long chain alkyl groups; substantially waterproof and inert waterproofing substances; Resins compatible with cellulose-based wall-forming materials, and the like. Other materials may be included in the semipermeable wall material to impart flexibility and elongation properties, to make the wall 20 less brittle and more resistant to tearing. Suitable materials include phthalate plasticizers such as dibenzyl phthalate, dihexyl phthalate, octyl phthalaryl butyl, straight chain phthalates of six to eleven carbons, diisononyl phthalate, diisodecyl phthalate, and the like. The plasfificants include non-phthalates such as triacein, diocrylic azelate, epoxidized talate, tri-sucokyl trimellylamide, uryisononyl trimelliferous, sucrose sucrose, epoxidized soybean oil, and the like. The amount of plasma in a wall when incorporated is around 0.01% to 20% by weight, or even more. The tray backing can be conveniently used to provide the complete dosage form, except for the exit orifice. In the tray coating system, the wall-forming composition for the wall 20 is deposited by successively spraying the appropriate wall composition onto the compressed single-ply or double-ply core comprising the drug layer for the core. of a single layer or drug layer and the push layer for the double layer core, accompanied by agitation in a rotating tray. A tray counter is used due to its availability on a commercial scale. Other techniques can be used to coat the compressed core. Once coated, the wall can be dried in a forced air oven or in a homo with temperature and moisture conirro to release the dosage form of the solvent or solvents used in the processing. The drying conditions will be selected conventionally based on the available equipment, ambient conditions, solvents, coatings, coating thickness and the like. Other coating techniques may be employed. For example, the wall or walls of the dosage form can be formed in a technique using the air suspension procedure. This process consists of the suspension and agitation of the compressed single-ply or double-ply core in an air stream and the semipermeable wall-forming composition, until the wall has been applied to the core. The suspension procedure in air is highly suitable for independently forming the wall of the dosage form. The air suspension procedure is described in US Pat. No. 2,799,241; in J. Am. Pharm. Assoc., Vol. 48, pp. 451-459 (1959); and, bid., Vol. 49, pp. 82-84 (1960). The dosage form can also be coated with a Wurster® air suspension pad using, for example, methanol methylene dichloride as a cosolvent for the wall-forming material. An Aeromatic® air suspension coater can be used using a cosolvenie. The dosage forms according to the present invention are prepared by standard techniques. For example, the dosage form can be made by the wet granulation technique. The wet granulation technique, the drug and the carrier are mixed using an organic solvent, such as denatured anhydrous ethanol, as the granulation fluid. The restani ingredients can be dissolved in a portion of the granulation fluid, such as the solvent described above, and this last-prepared solution is added slowly to the drug mixture with coninuous mixing in the mixer. The granulation fluid is added until a wet mixture is produced, where the wet mass mixture is then forced through a predefined starch onto oven trays. The mixture is dried for 18 to 24 hours at a temperature of 24 ° C to 35 ° C in a forced air oven. The dried granules are then sized. Subsequently, the magnesium stearate, or other suitable lubricant, is added to the drug granulation, and the granulation is placed in milling shaker containers and mixed in a shaker vessel mill for 10 minutes. The composition is compressed in a layer, for example, in a Manesty® press or a Korsch LCT press. For a two-layered core, the layer containing the drug is compressed and a similarly prepared wet mixture of the push layer composition, if included, is compressed with the layer containing the drug. The intermediate compression normally takes place under a force of around 50-100 newtons. The final stage compression normally takes place at a force of 3500 newtons or more, sometimes 3500-5000 newons. The single layer or double layer compressed cores are fed to a dry coating press, for example a Kilian® dry coating press, and subsequently coated with the wall materials as described above. One or more exit orifices are perforated at the extrude of the drug layer of the dosage form, and the optional water-soluble coatings, which may be colored (e.g., Opadry-colored overlays) or be clear (e.g. Clear Opadry), can be reversed in the dosage form to provide the finished dosage form. In another type of processing the drug and the other ingredients comprising the drug layer are mixed and compressed into a solid layer. The layer has dimensions corresponding to the internal dimensions of the area that the layer occupies in the dosage form, and also has dimensions corresponding to the second thrust layer, if included, to thereby form a conjoint arrangement. The drug and the other ingredients can also be mixed with a solvent and mixed in a solid or semi-solid form by conventional methods, such as ball milling, calendering, stirring or roller milling, and then compressed in a pre-selected form. Subsequently, if included, a layer of osmopolymer composition is placed in contact with the drug layer in a similar manner. The stratification of the drug formulation and the osmopolymer layer can be obtained by conventional two-layer pressing techniques. The compressed cores can then be coated with the semipermeable wall material as mentioned above. Another manufacturing process that can be used comprises mixing the powdered ingredients for each layer in a fluid bed granulator. After the powdered ingredients are mixed dry in the granulator, a granulation fluid, for example, polyvinylpyrrolidone in water, is sprayed onto the powders. The coated powders are then dried in the granulator. This procedure granulates all the ingredients present in it while the granulation fluid is added. After the granules are dried, a lubricant, such as stearic acid or magnesium stearate, is mixed in the granulation using a mixer, for example a V-blender or tote mixer. The granules are then compressed in the manner described above. Output 60 is provided in each dosage form. The outlet 60 cooperates with the compressed core for the uniform release of drug from the dosage form. The exit can be provided during the preparation of the dosage form or during drug delivery by the dosage form in a fluid environment of use.

The outlet 60 can include a hole that is formed or can be formed from a substance or polymer that wears, dissolves or experienced leaching from the outer wall to form an outlet hole in this manner. The susancy or polymer may include, for example, a polyglycolic acid or degassable polyacrylic acid in the semipermeable wall; a gelatinous filamenion; a polyvinyl alcohol removable with water; a leachable compound, as a removable pore former with water selected from the group consisting of inorganic and organic salt, oxide and carbohydrate. The outlet, or a plurality of outlets, may be formed by leaching a number selected from the group consisting of sorbitol, lactose, fructose, glucose, mannose, galactose, talose, sodium chloride, potassium chloride, sodium citrate and mannitol. to provide a pore outlet orifice sized for uniform release. The exit may be any shape, such as round, triangular, square, elipic and the like for the uniform measured dose release of a drug from the dosage form. The dosage form can be consumed with one or more outlets in separate relation or one or more surfaces of the dosage form. Drilling, including mechanical and laser drilling, through the semipermeable wall can be used to form the exit orifice. Such outputs and equipment for the formation of said outputs are described in the US patents. Nos. 3,916,899, by Theeuwes and Higuchi and in the patents of E.U.A. No. 4,088,864 by Theeuwes et al., Each of which is incorporated in its entirety for reference herein. Currently, it is preferred to use a single-outlet orifice. Techniques that correspond to those described above for osmotic systems are used for dosage forms that employ other confrigated release technologies. For example, mairiz systems are described in several of the panes that are related to the OXYCONTIN products of Purdue Pharma. See, for example, the country of E.U.A. Nos. 4,861,598; 4,970,075; 5,226,331; 5,508,042; 5,549,912; and 5,256,295. Based on the present disclosure, persons skilled in the art will be able to easily adapt these other controlled release technologies to produce the in vitro and in vivo profiles of the present invention.

B. Single-dose Cmgx Values One of the advantages of the preferred embodiments of the invention is the production of single-dose plasma profiles which have values of Cma? little ones. The values of Cma? which are large, are known to be undesirable for a variety of reasons. For example, it is known that aliphatic concentrations of oxycodone are associated with respiratory depression and result in high levels of C02 in the blood. See Leino et al., "Time Course of Changes in Breathing in Morphine and Oxydocodone-induced Breathing and Depression," Anaesihesia, 1999, 54: 835-840.

Although specific studies with oxycodone have not been conducted, "liking" studies have been performed using morphine and have shown higher "liking" values for higher concentrations of plasma morphine. See Marsch et al., "Effects of Infusion Rate of Intravenously Administered Morphine on Physiological, Psychomotor, and Self-Reported Measures in Humans," Journal of Pharmacology and Experimental Therapeutics, 2001, 299: 1056-1065. Marsch et al. He summarizes his findings to this respect on page 1063 of his article as follows: "These results suggest that measurements suggestive of liking for the drug may depend both on the speed and the magnitude of the changes in blood levels of the drug ..." in this way, in and of themselves, the Cmax values of single dose reduction represented an important contribution to the technique. As discussed above, the present invention provides zero-order (SZO) release profiles. The plasma oxycodone concentration profile for an oral conirrolated release dosage form with a consistant release rate of R can be modeled using the following equation: where Ka is a constant of absorption speed, ke is a constant of elimination velocity, and Vd / F is the apparent mean volume of distribution. Ke can be derived as the ratio of CL / F to Vd / F, where CL / F is the apparent mean clearance.

The concentration of oxycodone in plasma after a single oral solution administration of oxycodone, 20 mg, has been previously modeled by Mandema, J.W., R. F. Kaiko, B. Oshlack, R. F. Reder and D. R. Stanski (1996). "Characlerization and validation of a pharmacokinetic model for controlled oxycodone," British journal of clinical pharmacology 42 (747-756). The parameters used in this article are set forth in Table 1. Also included in Table 1 are the corresponding parameter values derived from the pharmacokinetic data of Examples 5 and 6 below. Using the data of Example 6 and Equation 1 above, a single dose profile is calculated for a substantially zero order release rate. The results are shown in Figure 5 through curve 100. In addition, other two release profiles are modeled, one having a fast release rate followed by a slow release and the other having a slow release rate followed by a release fast The specific release rates used are shown in Table 2. Each of these release profiles, as well as the constant release profile used to produce curve 100, releases the same amount of drug for 24 hours, ie, 80 milligrams. . The results of the simulations for the fast release rates followed by lenia and lenia release followed by rapid release are shown in Figure 5 through curves 102 and 104, respectively. As can be clearly seen in this figure, each of these curves has values more than Cma? than the curve 100. The values of Cma? for curves 102 and 104 are shown in table 2. For comparison reasons, the value of Cma? for curve 100 it is 46.5, that is, 18% less than the value of curve 102 and 24% less than the value of curve 104. Although it has not been formally proven, it is thought that the results shown in Figure 5 will be true for all other profiles, that is, all profiles that administer the same amount of drug for 24 hours but do not have a constant release rate will have a value of Cma? much greater than the one achieved with a constant release velocity. According to the first and seventh aspects of the invention discussed earlier, the CMA? for single dose is specified by the following equation: 3.5 x 10'4 liter'1 = Cmax / D < 6.8 x 10'4 liter Ec. 2 where D is the dose. The upper and lower limits specified in the ratio Cmax to dose (Cma? D) in equation (2) are based on the mean value of Cma? referred to in Table 8 for oxycodone SZO-24, plus and minus the standard deviation mentioned for Cma? - (Similarly, the upper and lower limits in the ratio AUC0.48 to dose (AUC0-48 / D) of these aspects of the invention, as well as the second, the third, eighth and ninth aspects, are based on the mean value AUCo-48 for oxycodone SZO-24 mentioned in Table 8, plus and minus its referred standard deviation). Because the data in Table 8 are for a dosage form having a substantially zero order release rate, based on the modeling of Figure 5, it is thought that the scale for the ratio Cma? D specified in equation (2) represented the lowest possible scale of the Cma? / D ratios that can be achieved by any of the oral oxycodone formulations. The provision of dosage forms that have low Cma? / D ratios is one of the important contributions to the art of the present invention.

O Profiles As discussed above, the present invention provides in vitro dissolution / release profiles and single dose in vivo and steady state plasma profiles for orally administered oxycodone and / or one or more of its pharmaceutically acceptable acid addition salts. Based on how drugs are absorbed and eliminated by the body, the shape of a steady state plasma profile of the dosage form is linked to the shape of its single dose plasma profile. In particular, for oxycodone, if one decreases the value of Cma? In the case of a single-dose dose while mani has a substantially equal AUC single-dose value, the result will be a more flat esfable plasma profile. In terms of the language of the passage quoted above from Benziger et al. 1997, this means that by decreasing the Cma? maintaining the AUC will result in "constant, comparative blood levels" of oxycodone. Based on the teachings of Purdue Pharma, blood levels should be avoided because they run the risk of developing tolerance. The AUC0-48 / D ratio specified in the first, seventh and other aspects of the invention (ie, the specification 7.6 x 10"3 hour / liter <; AUCo-48 / D < 16.7 x 10"3 hours / hour) is characteristic of how the body absorbs and eliminates oxycodone, since OXYCONTIN administers its dose incorporated during this time as the dosage form is found in the body, its ratio AUCo -4s / D is within the range for the AUCo-D relationships specified in the first and seventh aspects of the invention Specifically, as shown in Table 8, OXYCONTIN has an average ratio AUC0.48 / D of 12.6x10" 3 hours / liter ((1007.3 hr-ng / ml) / 80 mg = 12.6x10"3 hours / lire), which will be within the specified range of 7.6x10" 3 to 16.7x10"3 hours / liter. AUCo-4s / D values specified specify the value of OXYCONTIN, the upper limit specified in the Cma? / D single-dose value, ie 6.8x1 O ^ liter "1 is significantly lower than that of OXYCONTIN. Specifically, in relation to the pharmacokinetic study of Example 6, Cmax for single dose of OXYCONTIN 40 mg is found to be 41.8 ng / ml. When divided by 40 mg, the result is 1O.5x1O "4 / liter, which is clearly above the specified upper limit of 8x10" 4 / liter of the first and seventh aspects of the invention.

In this form, the first and most comprehensive aspects of the invention specify a single dose AUC value which specifies OXYCONTIN, but a lower Cmax. Based on the binding between the single-dose and steady-state profiles discussed above, it is understood that a steady state profile is generally specified to be flatter than that produced by OXYCONTIN. Figure 16D confirms that this is precisely what is observed. As can be seen in this figure, the stable state profile SZO-24 (curve 150) is almost completely flat while the profile OXYCONTIN (curve 152) clearly oscillates. Based on the foregoing, it is evident that the single dose profiles specified in the first and seventh aspects of the invention need a dosage form that is exacdy in opposition to what is claimed by Purdue Pharm, ie, that one can not use a dosage form that produces a stable state profile due to the risk of tolerance. As discussed further below (see example 8), experimentally it has been found that despite Purdue Pharm's teachings, the levels of oxycodone tolerance associated with biphasic profiles (ie, lipo profiles OXYCONTIN) and flat profiles ( that is, profiles of the SZO-24 type) are not, in fact, statistically different. This is clearly contrary to what one might expect based on Purdue Pharm's warnings regarding "comparatively constant blood levels" of oxycodone.

With the foregoing as the background, we will now address a specific discussion of the stable state in vivo, single dose in vivo and preferred in vitro release profiles of the invention. 1. In vivo profiles of plasma in steady state According to certain aspects of the invention, it has been found that effective pain management can be achieved with plasma profiles in steady state that are sufficiently flat. As discussed herein, a steady-state plasma profile is sufficiently flat to achieve the pain management benefits of the invention if the ratio of the AUC (area under the curve) for each quartile for the profile to the AUC for the complete profile, that is, the full 24-hour dosing period, is greater than 0.18 (such profile is referred to below as a "steady state profile> 18% / quartile"). As is conventional, the first quartile starts at 0 o'clock (ie, the administration time of the dosage form) and ends at 6 o'clock, the second quartile starts at 6 o'clock and ends at 12 o'clock, the third quartile starts at 12 o'clock and ends at 6 o'clock, and the fourth quartile starts at 6 o'clock and ends at 4 o'clock. As is also conventional, the plasma profiles are average profiles obtained from a population of the sample and the AUC values for the quartiles and for the complete profiles are obtained using the frapezoidal method. More particularly, the AUC relationships are determined for each individual and then these values are averaged. The samples of subjects are taken according to the selected sampling scheme to reflect the time course of the plasma profile, that is, there may be more sampling points where the profile changes rapidly with time. Preferably, the AUC ratio for each profile quartile with the AUC for the entire profile is greater than or equal to approximately 0.20. Even more preferably, the difference in the relationships between any two adjacent quartiles is less than about 0.03 and / or the difference in relationships between any two quartiles is less than about 0.05. More preferably, both criteria are satisfied, that is, the difference in the relationships between any two adjacent quartiles is less than approximately 0.03 and the difference in the relationships between any two quartiles is less than about 0.05. As shown by the present data, it has been found that steady state profiles > 18% / quartile assure an efficiency of each quartile, reducing in this way the probability of advancement of pain that has been a great permanent problem in pain management using controlled release forms. 2. Single-dose in vivo profiles According to other aspects of the invention, it has further been found that profiles in steady state > 18% / quartile are related to single dose plasma profiles that have certain preferred characteristics. A preferred feature of the single dose plasma profile is a form of the average profile that is substantially increased monophonic for a period of 24 hours or more. In certain embodiments, such an average profile that increases substantially in a monotonic manner comprises a first phase of elevation and a second phase, where the slope of the first phase is greater than the magnitude of the slope of the second phase, where the slope of a phase is defined as the slope of a straight line better adjusted to the portion of the middle profile that makes up the phase. For example, the slope of the first phase can be at least about 10 times the magnitude of the slope of the second phase. In other embodiments, the first lift phase may include a first lift subphase followed by a second lift subphase, where the slope of the first lift subphase is greater than the slope of the second lift subphase, where the slopes are defined in the same way as for the first and second phases. Generally, the transition from the first phase to the second phase occurs in about 14 hours, for example, between approximately 12 hours and approximately 16 hours, while the transition from the first sub-phase to the second sub-phase occurs in about 2 hours, for example, run about 1 hour and about 3 hours.

The single dose plasma profiles also preferably have their maximum concentration (Cma?) Values at the time (Tmax) which is greater than about 17 hours, more preferably greater than about 18 hours, and more preferably greater than about 19 hours. The single dose plasma profiles preferably also have an AUC of 12 to 24 hours which is greater than their AUC of 0 to 12 hours. In particular, the AUC ratio of 12 to 24 hours with the AUC from 0 to 12 hours is preferably greater than about 1.5, more preferably greater than 1.7, and still more preferably about 2.0. To reduce the likelihood of the dosage form having "pleasing" problems, the single dose plasma profile preferably has a ratio Cma? / (Tmax x dose) which is less than about 3x10"4 hour" 1 liter "1 , more preferably less than about 4x10"5 hour" 1 liter "1, and more preferably less than about 3x10" 5 hour "1 liter" 1. In this way, the user of the dosage form does not achieve an initial, strong bolus , of oxycodone and in this way is less likely to experience the euphoria and other effects that can lead to a pleasant response.For comparison, the commercial product OXYCONTIN, which is known to have a problem of taste, in effect, a problem of abuse, has a ratio Cma? / (Tma? x dose) of approximately 4x1 O * 4 hour "1 liter" 1 for its dosage concentration of 40 mg.

As with the steady state profiles, the single dose profiles are average profiles obtained from a study population and the sampling scheme is selected to reflect the time course of the single dose plasma profile. As discussed above, the slopes are determined from the middle profiles. However, the ratios Tmax, Cma ?, and Cma? / (Tma? X dose) are obtained for individual subjects and then averaged. 3. In vitro Release Profiles According to other aspects of the invention, it has further been found that the steady state profiles > 18% / quartile desired are related to the in vitro dissolution / release profile of the dosage form. In particular, the in vitro dissolution / release profile preferably comprises an initial charge dose component and a controlled release component. Preferably, the ratio of the amount of oxycodone in the initial loading dose to the total amount of oxycodone in the dosage form is less than 0.25, more preferably less than 0.10, and more preferably less than or equal to 0.05. The upper limit 0.25 in the initial loading dose ensures that the dosage form does not generate plasma concentrations above those produced by an immediate release dosage form administered in an equivalent daily dose, and thus the probability that the Dosage form having "liking" problems or other adverse side effects will not be worse than for an immediate release product. The levels 0.10 and 0.05 should produce this "liking" and other problems even lower. The controlled release component preferably has a substantially in vitro dissolution / release rate so that when combined with the initial loading dose, the overall dosage form has in vitro release kinetics of substantially 0 order, ie, the Global in vitro release rate is subsinarily constant over a period of 24 hours. Figures 9 and 10 are non-limiting examples of release profiles for dosage forms that employ a conical release component and an initial loading dose and exhibit in vitro release kinesics of sub-zero order, while Figure 8 is an example of a release profile for a dosage form that achieves those kinesics only with a controlled release component. Preferably, the dosage form releases 70% of marked dose of the dosage form within a period (the period T o) of between about 15 hours to about 18 hours. More particularly, the dosage form preferably has a supply dosage pattern of 0% to 20% in 0-2 hours, 30 to 65% (preferably 33 to 63%) in 0 to 12 hours, and 80 to 100% in 0 to 24 hours, as shown schematically in figure 6.

As is conventional, in vitro dissolution / release profiles are used which are determined by analysis of a set of samples of dosage forms using USP 1, 2, or 7, or comparable apparatus that can be substituted in the fuíuro. The T 0 values, however, are an average of the T 70 values for the individual dosage forms tested, and similarly the delivery dose pattern for a dosage form is determined by the average of the results for the individual dosage forms analyzed. .

D. EXAMPLES The following non-limiting examples illustrate several of the features of the invention.

EXAMPLE 1 Osmotic push-pull systems with oxycodone hydrochloride 17 mq (fast and slow) An adapted dosage form, designed and shaped as an osmotic drug delivery device is made as follows: Two granulations are carried out by the following procedure: 1479 g oxycodone hydrochloride, USP and 7351 g polyethylene oxide N80 with Average molecular weight of 2000,000 are added to a fluid bed granulator bowl. Subsequently a binder solution is prepared by dissolving 500 g of polyvinylpyrrolidone identified as K29-32 in 4500 g of water. The dry materials are granulated in a fluid bed by spraying with 1800 g of binder solution. Subsequently, the wet granulation is dried in the granulator to an acceptable moisture content. The two granulations are then sized by passing through a 7 mesh screen in the same container. The granulation is then transferred to a mixer and mixed with 3.53 g of butylated hydroxytoluene as an antioxidant and lubricated with 88 g of magnesium acetate. Further on, a push composition is prepared as follows: first, a solution is prepared agluinan. 27.3 kg of polyvinylpyrrolidone idenified as K29-32 which has an average molecular weight of 40,000 is dissolved in 182.7 kg of water. Then, 22.4 kg of sodium chloride and 1.12 kg of ferric oxide are sized using a Quadro Comil with a 21 mesh screen. Subsequently, the sieved materials and 82.52 kg of polyethylene oxide (approximately 2,000,000 molecular weight) are added to a fluid bed granulator bowl. The dried materials were fluidized and mixed while 43 kg of the binder solution was sprayed from 3 nozzles into the powder. The granulation was dried in the fluidized bed chamber at an acceptable moisture level. The granulation process was repeated four times and the granulations were mixed together during sizing. The coated granules were sized using a fluid air mill with a 7 mesh screen. The granulations were transferred to an auxiliary latch, mixed with 224 g of butylated hydroxytoluene and lubricated with 1.12 kg of stearic acid. Next, the composition of the oxycodone hydrochloride drug and the push composition were compressed into bilayer tablets. First, 113 mg of the oxycodone hydrochloride composition was added to the icarbon cavity and pre-compressed; Subsequently, 103 mg of the thrust composition was added and the layers were pressed into a standard, concave, double-layer arrangement with a diameter of 0.79 cm. The bilayer arrangements were reviewed with a semipermeable wall. The wall-forming composition comprises acetylation of 99% cellulose with a content of 39.8% acetyl and 1% polyethylene glycol comprising a viscosity average molecular weight of 3,350. The wall-forming composition was dissolved in a co-solvent of acetone: water (95: 5 p: p) to make a 5% solids solution. The wall-forming composition was sprinkled in and around the bilayer arrangements in a tray coater until approximately 20 mg of the membrane was applied to each tablet to create "fast" systems. The reversal procedure was repeated and approximately 30 mg of the membrane was applied to each tablet to create "slow" systems.

Then, a 0.64 mm exit passage was laser drilled through the semi-permeable wall to connect the drug layer to the exterior of the dosing system. The residual solvency was removed by drying at 48 to 45 ° C and humidity at 45% followed by 4 hours at 45 ° C to remove excess moisture. The dosage forms produced by this manufacture were designed to deliver 17 mg of oxycodone HCl, USP of the core containing 15.8% oxycodone hydrochloride USP, 81.68% polyethylene oxide N80 having a molecular weight of 200,000, polyvinylpyrrolidone 2 % having a molecular weight of 40,000, 0.02% butylated hydroxytoluene, and 0.5% magnesium stearate. The thrust composition comprised 73.7% polyethylene oxide comprising a molecular weight of 7,000,000, "20% sodium chloride, 5% polyvinylpyrrolidone having an average molecular weight of 40,000, 1% ferric oxide, 0.05% butylated hydroxytoluene. %, and it was 0.25% magnesium.The semipermeable wall comprised 99% acetyl cellulose of 39.8% acetyl content and 1% polyethylene glycol.The dosage forms comprised one step, 0.64 mm in the center of the drug side. The final dosage forms had an average release rate of 1.35 mg oxycodone hydrochloride, USP per hour (7.95% rh) and 0.97 mg oxycodone hydrochloride USP per hour (5.70% rh) for the "fast" and "fast" systems. "The formulation of this example is summarized in Table 3.

EXAMPLE 2 20 mq osmotic push and pull system of oxycodone hydrochloride An adapted dosage form designed and formed as an osmotic drug delivery device was manufactured as follows: 1933 g oxycodone hydrochloride, USP, 7803 g polyethylene oxide N80 with an average molecular weight of 200,000 and 200 g of polyvinylpyrrolidone idenified as K29-32 with an average molecular weight of 40,000 were added to a fluidized bed granulator fazón. Next, a binder solution was prepared by dissolving 500 g of the same polyvinylpyrrolidone in 4500 grams of water. The dry materials were granulated in a fluidized bed by spraying with 2000 grams of binder solution. Then, the wet granulation was dried in the granulator at an acceptable moisture content, and was measured by passing through a 7 mesh screen. The granulation was then transferred to a mixer and mixed with 2 g of hydroxytoluene. builated as an antioxidant and lubricated with 25 g of magnesium stearate. Then, a push composition was prepared as follows: first, a binder solution was prepared. 15.6 kg of polyvinylpyrrolidone identified as K29-32 with an average molecular weight of 40,000 was dissolved in 104.4 kg of water. Subsequently, 24 kg of sodium chloride and 1.2 kg of ferric oxide were sized using Quadro Comil with a 21 mesh screen. Then, the scanned materials and 88.44 kg of polyethylene oxide (molecular weight of approximately 2,000,000) were added to a granulator bowl of the fluidized bed. The dry materials were fluidized and mixed while 46.2 kg of binder solution was sprayed from 3 nozzles into the powder. The granulation was dried in the fluidized bed chamber at an acceptable moisture level. The coated granules were denoted using a fluid air mill with a 7 mesh screen. The granulation was transferred to an auxiliary latch, mixed with 15 g of butylated hydroxytoluene and lubricated with 294 g of magnesium stearate. Next, the oxycodone hydrochloride drug composition and the push composition were compressed into bilayer diameters. First, 113 mg of the oxycodone hydrochloride composition was added to the icarbon cavity and pre-compressed; posioriormenie, 103 mg of the push composition were added and the layers pressed into a bilayer arrangement, concave standard, round with a diamery of 0.79 cm. The bilayer arrangements were reviewed with a semipermeable wall. The wall-forming composition comprised 99% cellulose acetyl with a 39.8% acetyl content and 1% polyallylene glycol comprising an average viscosity molecular weight of 3.350. The wall-forming composition was dissolved in a co-solvent of acetone: water (95: 5 p: p) to make a 5% solids solution. The wall-forming composition was sprinkled in and around the bilayer arrangements in a tray coater until about 37 mg of a membrane was applied to each board. Then, a 1 mm exit passage was laser drilled through the semipermeable wall to connect the drug layer to the exterior of the dosing system. The residual solvent was removed by drying for 48 hours at 45 ° C, and humidity at 45%. After drilling, the osmotic systems were dried for 4 hours at 45 ° C to remove excess moisture. Next, the drilled and dried systems were coated with an immediate release drug coverage. The drug coverage was an 8% aqueous solution of solids containing 157.5 g of oxycodone HCl, USP and 850 g of hydroxypropylmethylcellulose having an average molecular weight of 11,200. The drug coverage solution was sprayed on the dry coated cores until an average wet coated weight of about 8 mg per system was achieved. Next, the drug coverage systems were covered with color. The color coverage was a suspension of 12% Opadry solids in water. The color coverage solution was sprayed in the drug coverage systems until an average wet coated weight of approximately 8 mg per system was achieved. Then, the color coverage systems were coated transparently. The lransparenie coating was a solution of 5% Opadry solids in water. The ransparent coating solution was sprayed on the color-coated cores until an average wet coated weight of approximately 3 mg per system was achieved. Next, the transverse lining systems were coated with approximately 1 g of Camuaba wax by dispersing the wax over the systems as they were rotated in the tray reverifier. The dosage form produced by this manufacture was designed to deliver 1 mg oxycodone hydrochloride USP as an immediate release from a coating comprising 15% oxycodone HCl, USP and 85% hydroxypropylmethylcellulose followed by controlled delivery of 19 mg HCl of oxycodone, USP from the core which contains 17.7% oxycodone hydrochloride USP, 78.03% polyethylene oxide having a molecular weight of 200,000, 4% polyvinylpyrrolidone having a molecular weight of 40,000, 0.02% buffered hydroxytoluene, and 0.25% magnesium stearate. The thrust composition comprised 73.7% polyethylene oxide comprising a molecular weight of 7,000,000, 20% sodium chloride, 5% polyvinylpyrrolidone having an average molecular weight of 40,000, 1% ferric oxide, 0.05% butylated hydroxytoluene. and magnesium stearate at 0.25%. The semipermeable wall comprised 99% cellulose acetate with 39.8% acetyl content and 1% polyethylene glycol. The dosage form comprised a step, 1 mm in the center of the drug side. The final dosage form contained a color, a translucent coverage and a wax coating and had an average release rate of 0.93 mg oxycodone hydrochloride, USP per hour (4.66% / hr). The formulation of this example is summarized in Table 4 and is referred to hereinafter as "the SZO-24 dosage form of Example 2".

EXAMPLE 3 80 mq Osmotic Push and Pull System of Oxycodone Hydrochloride An adapted dosage form designed and formed as an osmotic drug delivery device was manufactured in the following manner: 34.36 kg oxycodone hydrochloride, USP, 63.7 kg N150 polyethylene oxide with an average molecular weight of 200,000 and 0.02 kg of red ferric oxide, fluidized bed granulator was added to a bowl. Next, a binder solution was prepared by dissolving 5.40 kg of polyvinylpyrrolidone identified as K29-32 with an average weight of 40,000 in 49.6 kg of water. The dry materials were granulated in a fluidized bed by spraying with 33.3 kg of binder solution. Next, the wet granulation was dried in the granulator at an acceptable moisture content, and sized as it passed through a 7 mesh screen. The granulation was then transferred to a mixer and mixed with 0.02 kg of buffylated hydroxytoluene as an antioxidant and lubricated with 0.25 kg of magnesium stearate. Next, a push composition was prepared in the following manner: first, a binder solution was prepared by dissolving 7.8 kg of polyvinylpyrrolidone identified as K29-32 with an average molecular weight of 40,000 in 52.2 kg of water. Subsequently, 24 kg of sodium chloride and 1.2 kg of ferric oxide were sized using Quadro Comil with a 21 mesh screen. The dimensioned materials and 88.5 kg of polyethylene oxide (molecular weight of approximately 2,000,000) were added to a granulation bowl of the fluidized bed. The dry materials were fluidized and mixed while 46.2 kg of binder solution was sprayed from 3 nozzles into the powder. The granulation was dried in the fluidized bed chamber at an acceptable moisture level. The coated granules were sized using a fluid air mill with a 7 mesh screen. The granulation was transferred to an auxiliary latch, mixed with 24 g of butylated hydroxytoluene and lubricated with 300 g of magnesium phase. Next, the composition of the oxycodone hydrochloride drug and the push composition were compressed into bilayer tablets. First, 250 mg of the oxycodone hydrochloride composition were added to the die cavity and pre-compressed, then 192 mg of the push composition was added and the layers were pressed into a standard concave bilayer arrangement, round with a diameter of 1.3 cm.

The bilayer arrangements were coated with a semipermeable wall. The wall-forming composition comprised 99% cellulose acetate with a content of 39.8% acetyl and 1% polyethylene glycol comprising an average viscosity molecular weight of 3,350. The wall-forming composition was dissolved in a solvent mixture of acetone: water (95: 5 p: p) to make a 5% solids solution. The wall-forming composition was sprayed in and around the bilayer arrangements in a tray coater until approximately 44 mg of the membrane was applied to each tablet. Next, two 1 mm exit steps were laser drilled through the semi-permeable wall to connect the drug layer to the exterior of the dosing system. The residual solvent was removed by drying for 72 hours at 45 ° C and humidity at 45% followed by 4 hours at 45 ° C to remove excess moisture. Next, the drilled and dried systems were coated with an immediate release drug coverage. The drug coverage was an aqueous solution of 12% solids containing 1.33 kg of oxycodone HCl, USP and 7.14 kg of Opadry ™ Clear. The drug coverage solution was sprayed in the reverse systems until an average wet weight of approximately 27 mg per system was achieved. Next, the drug coverage systems were covered with color. The color coverage was a suspension of 12% Opadry solids in water. The suspension of the color coverage was sprayed in the drug coverage systems until an average wet coated weight of approximately 8 mg per system was achieved. Then, color coverage systems were checked with approximately 100 ppm Carnuaba wax by dispersing the wax on the systems as they were rotated in the tray coater. The dosage form produced by this manufacture was designed to deliver 4 mg of oxycodone hydrochloride USP as an immediate release from a coverage comprised of 15% oxycodone HCl, 85% USP and Opadry ™ Clear followed by controlled delivery of 76%. mg of oxycodone HCl, USP of the core that contains 32% USP oxycodone hydrochloride, 63.73% N150 polyethylene oxide having a molecular weight of 200,000, 4% polyvinylpyrrolidone having a molecular weight of 40,000, 0.02% buoyating hydroxyindole. %, and magnesium esierarate at 0.25%. The thrust composition comprised 73.7% polyethylene oxide comprising a molecular weight of 7,000,000, 20% sodium chloride, 5% polyvinylpyrrolidone having an average molecular weight of 40,000, 1% ferric oxide, 0.05% butylated hydroxytoluene. , and magnesium stearate at 0.25%. The semipermeable wall comprised cellulose acetate with 99% acetyl content at 39.8% and 1% poly-ethylene glycol. The dosage form comprised two steps, 1 mm equidistant in the center of the drug side. The final dosage form contained a color coverage and a wax coating and had an average release rate of 3.94 mg oxycodone hydrochloride, USP per hour (4.93% / hr). The formulation of this example is summarized in Table 5 and is referred to hereafter as the "SZO-24 dosage form of Example 3".

EXAMPLE 4 Pharmacokinetics and pharmacodynamics of oxycodone hydrochloride osmotic (fast and slow) and oxycodone hydrochloride immediate release in healthy volunteers This study investigated the pharmacokinetics and pharmacodynamics of the "fast" and "lens" oxycodone HCl systems of Example 1 and immediate release oxycodone HCl (IR) in healthy male volunteers. In particular, this pharmacokinetic / pharmacodynamic study, crossover, multiple and individual doses, three periods, three randomized trials, a single center compared to two formulations of oxycodone HCl osmoic and oxycodone HCl IR (Oxynorm capsule) ®, 5 mg supplied by Napp Pharmaceuticals, Cambridge Science Park, Milton Rd., Cambridge, UK) in healthy male subjects for four days. The pharmacodynamic portion of the study was single-blind and was used as a VAS pain registry. Eighteen subjects enrolled and fifteen completed all periods of study. Lies are operated, the oxycodone released from osmoic dosage forms of rapid release and release in a zero-order mode with different durations and no dosage form had an immediate release oxycodone coverage. Each of the subjects received three treatments in accordance with the randomly assigned sequence: • A 17 mg dose of the rapid-release dosage form (supplied for approximately 10 hours); • A 17 mg dose of the slow release dosage form (supplied for approximately 20 hours); • Four doses of 5 mg of oxycodone HCl from IR (one dose at hours 0, 6, 12 and 18 of the study period). The rapid release formulation produced a greater reduction in the pain core than the slow release formulation or oxycodone HCl of IR. The reduction in pain records with the slow release formulation were generally comparable with those observed in oxycodone HCl of IR. On average, the fast release and slow release formulations were 105% and 99 bioavailable, respectively, relative to oxycodone HCl of IR. The plasma oxycodone concentration profiles for the fast and slow formulations were consistent with their in vitro release rate data.

The profiles of oxycodone mean concentration in plasma after a single day of dosing are shown in Figure 15A. After a single dose administration, the average Cmax / (Tmá? * Dosage) ratio was 7x10"5 (h * Liter)" 1 and 4x10"5 (h * Liíro)" 1 for the fast and slow dosage forms, respectively. The profiles of oxycodone mean concentration in plasma after repeated dosing are shown in Figure 15B. The stable AUC quartile values for the formulations are set forth in Table 6. The steady-state plasma profiles for the qdh regimen of the IR product and the once-a-day regimen of the slow formulation were of the quartile type > 18% while for the once-a-day regimen of rapid formulation there was no. Based on the findings of this study, the osmotic dosage form changed to have 5% of the marked dose in the coverage to allow rapid dissolution and absorption after ingestion, and 95% of the dose marked in the nucleus for release slow during the dosing interval, that is, 24 hours. This modified design was evaluated in a phase I pharmacokinetic / pharmacodynamic study (example 5) and in a phase II dose range study in osteoarthritis pain (example 7).

EXAMPLE 5 Pilot study to evaluate pharmacodynamics of oxycodone hydrochloride SZO-24 A double-blind, randomized, single-center crossover study was conducted to compare the SZO-24 dosage form of Example 2 (2x20 mg), IV morphine (10 mg) and placebo in healthy male subjects. This study was designed to determine the dose of oxycodone HCl when administered by the SZO-24 dosage form of Example 2 which provides a statistically significant pharmacodynamic response as measured by the cold pain test. Twelve male subjects were enrolled and received fresh treatments in accordance with a randomly assigned sequence: • Placebo IV and oral placebo; • Infusion of IV morphine (10 mg for 15 minutes) and oral placebo; • SZO-24 dosage form of example 2 (2x20 mg) and placebo IV (saline). The treatment of IV morphine was intended to serve as a positive control due to the successful separation of this placebo treatment as previously reported (Van and Rolan 1996), however, in this study, this treatment was not statistically separated from a placebo. as measured by the cold pain test. The size of the pupil remained stable during the study period for the placebo treatment, and changes in pupil size for IV morphine and the SZO-24 dosage form of Example 2 were consistent with their respective pharmacokinetic profiles (see figure 11). The study generated oxycodone in single dose plasma, noroxycodone and the oxymorphone concentration profiles for the SZO-24 dosage form of example 2 (2x20 mg) (see figure 12 and table 7). The average Cma? / (Tmax * Dosage) ratio for oxycodone for this study was 2x10'5 (h * Liter). "1 A pharmacokinetic model consisting of an in-vitro release rate for the SZO-24 dosage form of the Example 2 and a first-order absorption, the first disposal model for first-order disposal was adapted to the oxycodone concentration in plasma using NONMEM, since the damages were not sensitive with the constant of absorption rate, the constancy of absorption rate was set at 6.48 h "1. The apparent average depuration of the population (C1 / F) was 67.7 L / h and the average apparent volume of population (V / F) was 556 L. The curve of best fit average underestimated the average data during the first few hours after the Dosage as shown in Table 13. The expected pharmacokinetic profile for oxycodone HCl IR, 10 milligrams, which was given every 6 hours was also simulated and included in Figure 13. The simulated steady state pharmacokinetic profiles for a regimen q6h of an IR product, a regime q12h of OXYCONTIN, and a regime qd of the dosage form SZO-24 of example 2 are depicted in Figure 14. Based on the pharmacokinetic results, this formulation (5% of the dose marked in the coverage to allow rapid dissolution and absorption after ingestion, and 95% of the marked dose in the nucleus for slow release during the entire dosage interval, that is, 24 hours, was also evaluated. in a phase II clinical trial (example 7).

EXAMPLE 6 Single-dose and multiple-dose pharmacokinetics of oxycodone hydrochloride SZO-24 and OXYCONTIN This study was a multiple-dose, single-dose crossover study of two periods, of two treatments, of an open-label, randomized, single-center study in healthy subjects. Subjects received the following treatments: • Treatment A-a single dose of the SZO-24 dosage form of Example 3 (80 mg) followed by 72 hours by a QD regimen of the same dosage form (80 mg for 5 days); • Treatment B- two doses of OXYCONTIN®, 40 mg of each dose, administered in a 12 hour interval followed by 72 hours by a regimen q12H of OXYCONTIN, 40 mg during 5 days. All subjects enrolled 50 mg of nalírexone orally starting 14 hours before dosing and every 12 hours during the periods of tramadol and 24 hours after the last day of dosage of oxycodone. There was a minimum rest period of 5 days but not more than 14 days during the period of the year. The objectives of the study were: • To determine the concentration profile of oxycodone in plasma for a single dose of the dosage form SZO-24 of Example 3 (80 mg) and the concentration profile of oxycodone hydrochloride in stable stable plasma for a QD regime of the dosage form; • Compare the oxycodone concentration profile in steady state plasma for a QD regimen of the SZO-24 dosage form of Example 3 (80 mg), and for a q12h regimen of OXYCONTIN. A total of 37 subjects completed the study. The average concentration profiles of oxycodone in plasma are given in Figure 16. The average concentration profile of oxycodone in plasma after administration of the SZO-24 dosage form of Example 3 (80 mg) can be found in Figure 16B and the same profile is plotted with the average profile after the administration of two OXYCONTIN (40 mg each) separated by 12 hours in Figure 16C. From these figures and, in particular, the 12-hour data point for the SZO-24 dosage form of Example 3 and the standard deviation for that data point, it can be seen that a single-dose plasma profile for the forms of dosage of the invention satisfies the relationship: 2. 7 x 10"4 liter" 1 < C12 / D < 5.7 x 10"4 liter" 1 For comparison, using the same 37 subjects, it was found that the b.i.d. OXYCONTIN produces an average C? 2 concentration of 15.92 ng / ml (SD = 6.88 ng / ml). Dividing this average value between 80 mg, the total OXYCONTIN dosage for 24 hours gives 2.0 x 10"4 liters" 1 which is substantially below the above scale for the once-a-day dosage forms of the invention. The plasma concentration profiles of stable state for a once a day regimen of the SZO-24 dosage form of Example 3 (80 mg) and the twice daily dosing of OXYCONTIN, (40 mg each) can be found in Figure 16D. PK data are summarized in tables 8 (single dose) and 9 (stable state). After the individual administration of the SZO-24 dosage form of Example 3, the average ratio of the area below the plasma concentration profile from 0 to 12 hours for AUC¡nf was 0.24 (0.07) and the average area ratio under the profile of drug concentration in plasma from 12 to 24 hours with 0 to 12 hours was 1.94 (0.49). A comparison of plasma oxycodone concentrations at 72 (day 3), 96 (day 4), and 120 (day 5) hours after the start of dosing during the multiple dose period showed that the stable state was reached on the day 4 of dosing in both regions. A comparison of PK parameter AUC96-? 2 on day 5 of the multiple dose period with AUC.nf after the single dose period for the SZO-24 dosage form of Example 3 demonstrated constant time kinetics for this formulation (p = 0.9). The bioavailability for the SZO-24 dosage form of Example 3 was 92% relative to OXYCONTIN as estimated by the AUC96-120 ratio. The confidence interval at 90% of this ratio fell on the 80-125% scale for the bioequivalence criterion. Thus, the amount of oxycodone provided by the oxycodone dosage form SZO-24 of Example 3 which is given once a day is bioequivalenized with that of OXYCONTIN which is given twice a day in the same total daily dose. The value Cmin for the dosage form SZO-24 of example 3 was 121% for OXYCONTIN, while the value Cmax for dosage form SZO-24 of example 3 was 78% for OXYCONTIN. The Cmax values were • significantly different (ie, the relation was significantly different from 1 (p <; 0.001)). These damages demonstrate that the oxycodone plasma profile is flatter following the process with the SZO-24 dosage form of Example 3 compared to the oxycodone with OXYCONTIN. The stable AUC quartile values for the SZO-24 dosage form of Example 3 and OXYCONTIN are set in Table 10. These data prove that the SZO-24 dosage form of Example 3 given once a day and OXYCONTIN which is given twice a day achieves profiles of oxycodone concentrations in stable stable plasma quartile of > 18% Dosing once a day, however, is more convenient for patients and is more likely to lead to better compliance. In addition, as shown in Figure 16D, the SZO-24 dosage form of Example 3 produces a stable profile profile that is clearly flatter than that produced by OXYCONTIN, which clearly remains two-phase.

EXAMPLE 7 Phase II clinical study of oxycodone hydrochloride SZO-24 A two-week, phase II placebo-controlled study was conducted using the SZO-24 dosage form of Example 2 (20 mg and 2x20 mg = 40 mg) in patients with pain from osteoarthritis of the hips and / or knees. In general, 40 mg showed significant differences for placebo in pain assessments over a two-week period, while 20 mg was greater than placebo during the first week of the trial but less during the second week, despite the fact that the study was not energized to show a statistically significant difference between the 20 mg and the placebo in any week. The results showed the general trend that 40 mg were more effective than 20 mg, as expected, although the resistance of two dosages did not show statistically different results in the majority of cases. The records of the brief pain inventory (BPI), average pain intensity, showed important results for 20 mg (p = 0.042) and 40 mg (p = 0.010) in the last week in the study medication. The results of an analysis of the total quality of sleep indicate that for the 40 mg treatment, the average increases from the baseline to the last week of treatment and was statistically superior to placebo (p = 0.0360) in improving the quality of treatment. 2.35 vs. 1.21, on a scale of 0 (very poor) to 10 (excellent).

EXAMPLE 8 Tolerance study in rats This example reports the results of the experiments conducted to determine the effect of oxycodone entry patterns on the development of tolerance in rats. The specific objective of the study was to compare the degree of antinocicepiric tolerance developed in rajas administered with oxycodone hydrochloride (HCl) over a period of three days, either through a biphasic dosing regimen (bolus / twice a day) or a regimen of SZO dosage (substantially zero / continuous order). The biphasic dosing regimen used subcutaneous infusion (SC), and the SZO regimen used ALZET® osmotic pumps implanted subcutaneously. The conírol of the vehicle for the esfudio was 0.9% saline solution. The test solutions were oxycodone HCl dissolved in saline. The whiplash test of the rodents was used to evaluate the analgesia (aníinociception). This evaluation is a well-characterized and standardized method to evaluate antinociception and tolerance to opioid drugs (Cleary 1994, D 'Armor &Smiíh 1941). In this test, the rodents are held briefly and radiant heat is applied to the tip of the tail. The time taken by the animal to provoke the tail in its tail will be recorded; A positive response in comparison to previous dosing readings are aniinocicepsion indicators. The tail-lancellation methods used in the present study were similar to those previously described in the literature for evaluating antinociception (Dutfaroy &Yobum 1995, Nielsen et al 2000) with slight modifications of the original method described by D ' Armor and Smith (1941). An IITC Model 33 tail whip analgesia meter was used to apply heat to the animal's tail (IITC Life Science, Woodland Hill, CA). The meter was programmed with the following conditions: (1) Acíiva intensity: 75% (intensity of the light of simulation during the test); (2) Triggering temperature: 30 ° C (this time allows pre-heating of the tail of the animal to allow more uniform measurements day by day and test on trial); (3) Separation time: 10 seconds (that is, the length of time from the start of the test until the unit automatically ends the test to avoid tissue damage). The animals were briefly fastened in plexiglass fasteners and radiant heat was applied to the tail tip of the animal (approximately 1-2 cm from the puncture). After the temperature reached 30 ° C, the meter increased the intensity of light provided a noxious stimulus to the tail of the animal. The time in seconds for the animal to initiate lair in its tail was recorded for each animal. If the animal does not whip its tail ten seconds (separation time) the heat stimulus is removed in order to minimize the injury to the tail. Three pre-dosing readings are taken for each animal in intervals of approximately 5-15 minutes. For the animals used in the study, these previous dosing readings do not vary more than one second for an individual animal. The average pre-dose readings for animals within the same test group do not vary more than about two seconds (scale = 2.02 seconds). In this way, the variability of measurements decreases and in this way the dynamic scale of the test increases. The values of the lagigability of the tail are converted to a percentage of the maximum possible effect (% MPE) using the following formula:% MPE = 100 x (? L /? Lm?) Where:? L = Post-dose dosage latency - Prior dosage, and? Lmax = Separation time - Pre-dosing latency. For the biphasic dosing regimen, the animals were infused subcutaneously using a computer controlled Harvard syringe pump. The STANPUMP computer program (STANPUMP 1998) was used to drive an infusion device to administer the test or control solutions as two boluses, approximately 12 hours later. The animals implanted catheters subcutaneously implanted with approximately 7 cm of PE 10 tubing. The enigma was secured with sutures and glue for sterile surgical skin to avoid accidental removal of the catheter. Before the start of the infusion, the tubing was filled with infusate (saline solutions or oxycodone). During the treatment, the animals were connected to an Instech adhesion system, which consisted of a Covance infusion arm and a double stainless steel channel mounted swingably on a counterbalanced lever arm fixed to an Instech MTANK box. This adhesion system allowed the raids. to fly freely in the boxes while protecting the caíéíres. The adhesion system is designed to protect surgically implanted catheters while providing free mobility at the rate during the delivery. During the infusion, the animals were stored individually and had free access to food and water. After approximately 72 hours of infusion, the adhesion system was disassembled, the suture was cut, and the catheter was removed. For each 24-hour period, the infusion regimen produced a biphasic profile, with two peaks (Cmax) between 2 to 4 hours and 14 and 16 hours, and two depressions (Cmin) at approximately 12 hours and 24 hours. The ratio of Cmax to Cmin was between three and four. For the SZO dosing regimen, ALZET® osmotic pumps (Model 2ML1) were implanted subcutaneously in the animals. The pumps were loaded overnight in 0.9% saline solution in an oven at 37 ° C in order for the pump to reach its steady state pumping speed at implantation (DURECT 2003). After approximately 72 hours, the pumps were removed. For the SZO dosage, the rates were not adhered. Male Sprague-Dawley (SD) rats obtained from Charles River (Hollister, CA) and weighing at least 200 g were used in the experiments. Additional animals were employed in the biphasic dosing regimen to account for damaged catheters, but only enough animals were dosed on day +3 to replace the animals with damaged catheters. The study was conducted in accordance with the animal welfare regulations of 9 CFR 1-3 and Guide for the Care and Use of Laboratory Animáis (National Research Council 1996). The animals were divided into four groups and in day -1, each group was further divided into six subgroups and administered with 0, 0.25, 0.5, 0.75, 1 or 1.5 mg / kg of oxycodone by subcutaneous injection (SC), respectively. The animals were tested for antinociception (tail whip latency) approximately 15 minutes after the injection. On day 0, the animals in each group were brought in according to Table 11. After approximately 72 hours, the pump infusion vehicle or oxycodone were stopped and the catheters were removed from the animals in groups 1 and 2, and the ALZET® pumps were removed from the animals in groups 3 and 4. Flow six to eight hours after the completion of the infusion, each subgroup of groups 1-4 was administered with 0., 0.25, 0.5, 0.75, 1 or 3 mg / kg oxycodone by subcutaneous injection (SC), respectively. Animals were tested for antinociception (tail whip latency) approximately 15 minutes after injection. For the biphasic and SZO dosing regimens, the dose of oxycodone during the 72-hour (3-day) test period was on average about 10 mg / kg »d, that is, a total of about 30 mg / kg was administered duranfe the trial period.

The results of these experiments are shown in tables 12A and 12B, and in figures 17A and 17B, where figure 17A shows all the data of tables 12A and 12B, while figure 17B shows the damages of day +3 for Tail whiplash test doses of 0.25, 0.25, 0.5, 0.75, 1.0 mg / kg. The numbers of the curve in Figures 17A and 17B correspond to the following. curve 154a: SZO - - Day -1 / saline group; curve 154b: SZO - - Day + 3 / saline group; curve 156a: SZO - - Day -1 / oxycodone group; curve 156b: SZO - - Day + 3 / oxycodone group; curve 158a: biphasic - - Day -1 / group of saline solution; curve 158b: biphasic - - Day + 3 / saline group; curve 160a: biphasic - - Day -1 / oxycodone group; curve 160b: biphasic - - Day + 3 / oxycodone group. As can be seen more clearly in Figure 17B, the groups that were trapped with oxycodone for 3 days (curves 156b and 160b) had generally lower MPE values for the tail whiplash test dose than the groups that were treated with saline. for 3 days (curves 154b and 158b), ie, the animals treated with oxycodone became tolerant to oxycodone so that the same dose of whiplash test generally had a minor analgesic effect and thus produced less latency before The whiplash of the tail occurred.

The examination of the dose-effect curves suggests that not all curves were modeled in the same way by the same equation. Also, the curves representing day +3 did not increase monotonically, and all of the effects of the day +3 in the test dose of 1 mg / kg are below 50% of% MPE, thus making the estimation of ED50 difficult or with high uncertainty even with the much greater effect observed in 3 mg / kg. Due to these modeling difficulties, an alternative approach was taken to obtain a statistical measurement of tolerance. The study design had each rat receiving the same oxycodone test dose on day -1 and day +3, except animals that received 1.5 mg / kg on day -1, received 3.0 mg / kg on day + 3. Intuitively, the difference between the effect of the same test on day +3 and day -1 should be a direct measure of tolerance. The data collected from rats tested for the responses at 0, 0.25, 0.5, 0.75 and 1 mg / kg in this way were used to perform the statistical analysis. For these rats, the design of the target study followed a (2) x (2) x (5) format, that is: (2) SZO dosing regimen against the biphasic dosing regimen (2) Oxycodone treatment versus solution treatment saline (5) 0 mg / kg against 0.25 mg / kg against 0.5 mg / kg against 0.75 mg / kg against 1.0 mg / kg tail whiplash test. The total number of races included in the analysis of the format (2) x (2) x (5) was 158. The data (difference between day +3 and day -1) were analyzed by means of the analysis of the variation method ( ANOVA). The model of total variation consisted of three primary factors, its interaction of first order qualifies and its interaction of second order qualifies, mainly: dosing regimen, treatment of 3 days, dosage of tail whiplash test, dosing regimen x 3 days, dosing regimen x tail whiplash test dose, 3-day trailing dose x tail test dose, and dosing regimen x 3-day interval x taiga trial dose. The ANOVA analysis was performed with SAS software. None of the four interaction terms or the dosing regimen term in the ANOVA model were statistically significant (with a critical value at 0.05). There was a statistically significant effect on the 3-day interval (p = 0.0039) and the tail-gleam test dose (p <0.0001). Therefore, the ANOVA analysis concluded that the difference was statistically different between rats treated with oxycodone for 3 days against those rats treated with saline., and different among rats tested in different doses of tail whiplash test, but not statistically significantly different among rats brought with the SZO dosing regimen conira the biphasic dosing regimen. Due to the lack of significant interaction terms in the total ANOVA model, the data were also analyzed using a reduced ANOVA model that only contains the primary design factors: dosing regimen, 3-day interval, whiplash test dosing of tail. This analysis also revealed the same conclusions as the analysis with the full ANOVA model. The difference was significantly different between oxycodone and rats brought with saline (p = 0.0035) and between the rats tested with different doses of oxycodone (p <; 0.0001). However, tolerance was again statistically different between rats treated with the SZO dosing regimen against the biphasic dosing regimen. The estimated average tolerance difference was -10.7% MPE between oxycodone and rats irradiated with saline and -3.2% MPE between the SZO dosing regimen and the biphasic dosing regimen. The difference -10.7% MPE was essentially different from a value of 0.05, but the value -3.2% MPE was not. The lack of a significant difference between the rationed rations with a SZO dosing regimen, with a biphasic dosing regimen, will be in direct agreement with the concerns expressed in the literature that the substantial order of dosage from zero will be more likely to lead to tolerance. that the biphasic dosage (see Benziger et al. 1997 and Kaiko 1997 which was discussed earlier). Based on this literature, one can expect that rationed strains with the SZO dosing regimen may present more tolerance at a significantly more important level than those brought with the biphasic dosing regimen, but no such important difference was found. From the above, it can be seen that the invention provides suitable dosage forms to provide once-daily dosing of oxycodone and / or one or more of its pharmaceutically acceptable salts for relief of moderate to severe pain in patients requiring an opioid for more days. . Potential benefits for once-a-day dosing of current IR and CR oxycodone formulations include improved convenience, improved quality, a simpler dosing regimen, and more pain relief consisting of fewer adverse events over a 24-hour period. . Although the specific embodiments of the invention have been described and illustrated, it should be understood that a variety of modifications that do not depart from the scope and spirit of the invention will be apparent to those skilled in the art from the foregoing description.

REFERENCES Citations of several of the documents mentioned above are set forth below. The contents of these documents, as well as those mentioned in this specification, are incorporated herein by reference. Benzinger et al., "A Pharmacokinetic / Pharmacodynamic Sfudy of Conirolled-Release Oxycodone," Journal of Pain and Symp- tom Management, 1997, 13: 75-82. Cleary J., Mikus G, Somogyi A, Bochner F. The Influence of Pharmacogenetics on Opioid Analgesia: Sludies wifh Codeine and Oxycodone in the Sprague-Dawley / dark Agouti Raí Model. J. Pharmacol Exp Ther 1994; 271: 1528-1534. D'Armour FE, Smiíh DL. A Meyhod for Determining Loss of Pain Sensation. J. Pharmacol Exp Ther 1941; 72: 74-79. DURECT Corporation, 2003. ALZET Osmotic Pump Model 2ML1, Instruction and Specification Sheet. Duííaroy A, Yobum BC. The Effecl of Intrinsic Efficacy on Opioid Tolerance. Anesihesiology 1995; 82; 1226-1236. Ekblom M. Hammarlund-Udenaes M, Paalzow L. Modeling of Tolerance development and rebound Effecí During Differení Infravenous Administrations of Morphine to Rats. J. Pharmacol Exp. Ther 1993; 266 (1): 244-252.

Gardmark M, Ekblom, M, Bouw R, Hammarlund-Udenaes M. Quantification of the Effects Delay and Acute Tolerance Development to Morphine in the Raí. J. Pharmacol Exp. Therap 1993; 267 (5): 1061-1067. Kaiko RF. Pharmacokinetics and Pharmacodynamics of Conírolled Relaise Opioids 1997 Acia Anaesíhíol Scand 1997; 41: 166-174. Nielsen CK, Ross FB, Smith MT. Incomplete, Asymmetric, and Route-Dependenf Cross-Tolerance between Oxycodone and Morphine in the Dark Agouti Raí. J. Pharmacol Exp Ther 2000; 295 (1): 91-99. Ouellet DM-C, GM Pollack. A Pharmacokinetic-Prarmacodynamic Model of Tolerance I Morphine Analgesia During Infusion ¡n Rats. J. Pharmacokinetics Biopharmaceutics. nineteen ninety five; 23 (6): 531-549. Ouelleí DM-C, Pollack GM. Pharmacodynamics and Tolerance Development During Multiple Intravenous Bolus Morphine Administration in Raís. J. Pharmacol Exp The 1997; 281 (2): 713-720. Van, F. and P. E. Rolan. The use of the cold pain test to measure analgesia from intravenous morphine. Br J. Clin Pharmacol. nineteen ninety six; 42: 663-4. STANPUMP User's Manual 1998 hydr: //anesihesia.sianford.edu/pkpd/Targei%20Conírol%20Drug%20Deliverv/S TANPUMP / Forms / Alltems.hím (August 2004) National Research Council. Guide for the Care and Use of Laboratory Animáis. Washington DC: National Academy Press 1996.

TABLE 1 TABLE 2 TABLE 3 TABLE 4 TABLE 5 TABLE 5 (CONTINUED) ncluyendo 5% of surplus of the system in nucleus TABLE 6 Mean (DE) ratio of AUC for each quartile to AUC for the total stable state profile (0-24 hr) TABLE 7 Concentrations in single-dose plasma for 40 mq of dosage form of SZO-24 (oxycodone HCl) TABLE 8 Mean parameters of Oxycodone PK after a single dose a This calculation used Cmax and Tmax during the first dosing interval (0 to 12 hours).

TABLE 9 Mean parameters (OD) of Oxycodone PK after multiple doses TABLE 10 Mean (DE) ratio of AUC for each quartile to AUC for the total stable state profile (0-24 hours) TABLE 11 a Doses calculated in terms of the hydrochloride salt. b 0.9% saline solution.

TABLE 12A Dosing of SZO 1 mean ± SD; n = 8 23.0 mg / kg for day +3.

TABLE 12B Biphasic dosing mean ± SD; n = 8, except when indicated. 23. 0 mg / kg for day +3. 3n = 7

Claims (106)

1. NOVELTY OF THE INVENTION CLAIMS 1. A controlled release oxycodone formulation for oral administration once a day for human patients comprising a D dose of: (i) oxycodone, (ii) one or more pharmaceutically acceptable acid addition salts of oxycodone, or (iii) a combination of oxycodone and one or more pharmaceuically acceptable acidic addition salts of oxycodone, said formulation provides (a) a maximum average concentration of single dose in plasma Cmax and (b) a mean area, single dose, under a concentration curve in plasma-time for 0-48 hours AUC0-48 satisfying the ratios: 3.5 x 10"4 liter" 1 < Cmax / D < 6.8 x 10"4 liter" 1, and 7.6 x 10"3 hour / liter <AUC 0-48 / D <16.7 x 10" 3 hour / liter, wherein said formulation provides pain relief for approximately 24 hours or more after administering the patient.
2. 2. The formulation according to claim 1, further characterized because Cma? and AUC0- s are determined by using plasma samples from individuals who have been administered one or more opioid antagonists.
3. 3. The formulation according to claim 1, further characterized in that Cmax and AUC0-8 are determined by using plasma samples from individuals who have been administered naltrexone.
4. 4. The formulation according to claim 1, further characterized in that Cmax and AUC0. 8 are determined using plasma samples from individuals who have not been given an opioid aniiagonism.
5. 5. The formulation according to claim 1, further characterized in that Cmax and AUC0-48 are determined using plasma samples from individuals who have not been administered naltrexone.
6. 6. The formulation according to claim 1, 2 or 4, further characterized in that said formulation provides a time for maximum concentration, single dose, in plasma Tmax which satisfies the ratio: Tmax 17 hours.
7. 7. The formulation according to claim 6, further characterized in that Tmax satisfies the relation: Tmax > 18 hours 8. The formulation according to claim 6, further characterized in that Tmax satisfies the ratio: Tmax > 19 hours 9.- The formulation according to claim 1, 2 or 4, further characterized in that said formulation provides a time for maximum average concentration, single dose, in Tmax plasma, and D, Cmax, and Tmax satisfy the relation: Cmax / (Tmax »D) < 3 x 10"4 (liter * hour)" 1. 10. - The formulation according to claim 9, further characterized in that D, Cmax, and Tmax satisfy the ratio: 2 x 10"5 (one hour") "1 < Cmax / (Tmax «D) < 6 x 10"5 (one hour • hour)" 1. 11. The formulation according to claim 1, 2 or 4, characterized in that said formulation provides average areas, single dose, under a concentration curve in plasma-time for 0-12 hours AUC0-12 and for 12- 24 hours AUC12.2 that satisfies the relationship: AUC12.24 / AUC0-i2 > 1 -0. 12. The formulation according to claim 11, further characterized in that AUC0-12 and AUC? 2.24 satisfy the ratio AUC12-13. The formulation according to claim 11, further characterized by AUC0-? 2 and AUC? 2.24. satisfy the relationship: AUC12.24 AUCo-? 2 > 1.7. 14. The formulation according to claim 11, further characterized in that AUC0-12 and AUC 2-24 satisfy the ratio: AUC-, 2-24 / AUC0-12 > 2.0. 15. The formulation according to claim 1, 2 or 4, further characterized in that: (a) the dose comprises a first component for immediate release and a second component for sustained release; and (b) the weight ratio W of the first component to the sum of the first and second components is less than approximately 0.25. 16. - The formulation according to claim 15, further characterized in that D is approximately 20 mg and W is approximately 0.05. 17. A controlled release oxycodone formulation for oral administration once a day to human patients comprising a D dose of: (i) oxycodone; (ii) one or more pharmaceutically acceptable acid addition salts of oxycodone, or (ii) a combination of oxycodone and one or more pharmaceutically acceptable acid addition salts of oxycodone, wherein: (a) the formulation provides a concentration profile average, single dose, in plasma that increases substantially monotonously during 24 hours or more; (b) the formulation provides a mean, single-dose area, under a plasma-time concentration curve for 0-48 hours AUCo-48 that satisfies the ratio: 7.6 x 10"3 hours / liter <AUCo -« / D < 16J x 10"3 hours / hour; and (c) the formulation provides pain relief lasting approximately 24 hours or more after administration to the patient. 18. The formulation according to claim 17, further characterized in that AUCo-48 and the single-dose mean concentration profile in plasma are determined using samples of plasma from individuals who have been administered one or more opioid antagonists. 19. The formulation according to claim 17, further characterized in that AUC0-48 and the single-dose mean concentration profile in plasma are determined using plasma samples from individuals who have been administered naltrexone. 20. The formulation according to claim 17, further characterized in that AUCo-48 and the average single-dose concentration profile in plasma are determined using plasma samples from individuals who have not been administered an opioid aniiagonism. 21. The formulation according to claim 17, further characterized in that AUC0-48 and the average single dose concentration profile in plasma are determined using plasma samples from individuals who have not been administered nalirexone. 22. The formulation according to claim 17, 18 or 20, further characterized in that the single-dose mean concentration profile, in plasma comprises a first elevation phase and a second phase, wherein the slope of the first phase of elevation is greater than the magnitude of the slope of the second phase. 23. The formulation according to claim 22, further characterized in that the transition between the first lifting phase and the second phase occurs between 12 and 16 hours. 24. The formulation according to claim 23, further characterized in that the first lifting phase comprises a first subphase and a second subphase, wherein the first subphase rises faster than the second subphase. 25. The formulation according to claim 24, further characterized in that the transition between the first subphase and the second subphase occurs between 1 to 3 hours. 26. - The formulation according to claim 17, 18 or 20, also characterized in that: (a) the dose comprises a first component for immediate release and a second component for sustained release; and (b) the weight ratio W of the first component to the sum of the first and second components is less than approximately 0.25. 27. The formulation according to claim 26, further characterized because D is approximately 20 mg and W is approximately 0.05. 28. A controlled release oxycodone formulation for oral administration once a day to human patients comprising a D dose of: (i) oxycodone, (ii) one or more pharmaceutically acceptable oxycodone addition salts, or (iii) ) a combination of oxycodone and one or more pharmaceutically acceptable acid addition salts of oxycodone, said formulation provides (a) a mean, single-dose, 12-hour concentration in C-2 plasma and (b) an average area of single dose, under a plasma concentration-time curve for 0-48 hours AUCo-48 satisfying Relations: 2.7 x 10"4 liter" 1 < C12 / D < 5.7 x 10"4 liter" 1, and 7.6 x 10"3 hour / liter < AUC D < 16.7 x 10" 3 hour / liter, wherein said formulation provides pain relief during approximately 24 hours or more after administering the patient. 29. - The formulation according to claim 28, characterized in that C? 2 and AUC0-48 are determined using plasma samples from individuals who have been administered one or more opioid antagonists. 30.- The formulation according to claim 28, further characterized in that C-? 2 and AUCo-48 are determined by using plasma samples of individuals who have been administered nalirexone. 31. The formulation according to claim 28, further characterized in that C12 and AUC0-8 are determined by using plasma samples from individuals who have not been administered an opioid aniiagonism. 32. The formulation according to claim 28, further characterized in that C? 2 and AUCo-s are determined using plasma samples from individuals who have not been administered naltrexone. 33.- The formulation according to claim 28, 29, or 31 further characterized in that: (a) the dose comprises a first component for immediate release and a second component for sosfenide release; and (b) the weight ratio W of the first component to the sum of the first and second components is less than 0.25. 34.- The formulation according to claim 33, further characterized in that D is approximately 20 mg and W is approximately 0.05. 35. - A oxycodone formulation for controlled release for oral administration once a day to human patients comprising a D dose of: (i) Oxycodone, (ii) one or more pharmaceutically acceptable acid addition salts of oxycodone, or (iii) a combination of oxycodone and one or more pharmaceutically acceptable acid addition salts of oxycodone, said formulation provides average areas , of stable state under a plasma-time concentration curve for 0-6 hours AUCo-6, 6-12 hours AUC6- 12 12-18 hours AUC12-18, 18-24 hours AUC18-24, and 0-24 hours AUC0-24 satisfying the relationships: AUC6.12 / AUC0-24 > 0.18, AUC12-18 AUC0-24 > 0.18, and AUC18-24 / AUC0-24 > 0.18, wherein said formulation provides pain relief lasting approximately 24 hours or more after administration to the patient. 36.- The formulation according to claim 35, further characterized in that AUC0-6, AUC6-12, AUC12-18, AUC? 8.24 and AUC0.24 are determined using plasma samples of individuals who are has administered one or more opioid aniiagonias. 37. - The formulation according to claim 35, characterized in that AUC0-6, AUC6-? 2, AUC? 2.18, AUC18-24 and AUC0-24 are determined by using plasma samples of individuals who have been administered nalirexone. 38. - The formulation according to claim 35, also characterized because AUC0-6, AUC6-12, AUC? 2-? 8, AUC-? 8-24 and AUC0-24 are determined using plasma samples from individuals who have not been administered an opioid antagonism. 39.- The formulation according to claim 35, further characterized because AUC0-6, AUC6-? 2, AUC12.
8. 8, AUC? 8.24 and AUC0.24 are determined by using samples of plasma from individuals who have not been administered nalirexone. 40. - The formulation according to claim 35, 36, or 38, also characterized because AUC0-6, AUC6-12, AUC12-18, AUC18-24 and AUCo-24 satisfy the relationships: AUC6-i2 / AUC0-24 > 0.20, AUC12-i8 / AUC0-24 > 0.20, and AUC18-24 / AUC0-24 > 0.20 41. - The formulation according to claim 35, 36 or 38, also characterized by the magnitude of the difference between any pair of AUC0-6 / AUCo-24, AUC6-? 2 / AUCo-24, AUC12.18 / AUC0-24, and AUC18.24 / AUC0-24, is less than or equal to 0.05. 42. - The formulation according to claim 41, further characterized in that the magnitude of the difference between each of: AUCo-e / AUCo-24 and AUC6-12 / AUC0-24, AUC6-12 / AUC0-24 and AUCi2-18 / AUC0-24, AUC? 2-? 8 / AUC0-24 and AUC18-24 / AUC0-24 and AUC? 8.24 AUCo-24 and AUCo-e / AUCo-24 5 is less than or equal to 0.03. 43.- The formulation according to claim 35, 36 or 38, characterized also because the magnitude of the difference between each one from: AUCoVAUCo-24 and AUC6-? 2 / AUC0-24, AUC6-i2 / AUC0-24 and AUC12-i8 / AUC0-24, ° AUCI2-I8 / AUC0-24 and AUC18-24 AUC0-24 and AUC18-24 / AUC0-24 and AUC0-6 / AUC0-24 is less than or equal to 0.03. 44.- The formulation according to claim 35, 36 or 38, further characterized in that: (a) the dose comprises a first component for immediate release and a second component for sustained release; and (b) the weight ratio W of the first component to the sum of the first and second components is less than about 0.25. 45.- The formulation according to claim 44, characterized further because D is approximately 20 mg and W is approximately 0.05. 46.- A controlled release oxycodone formulation for oral administration once a day to human patients comprising a D dose of: (i) oxycodone, (ii) one or more pharmaceutically acceptable acid addition salts of oxycodone, or (iii) a combination of oxycodone and one or more acid salts of pharmaceutically acceptable oxycodone addition, said formulation has an in vitro release profile in which: (a) 0-20% of the dose is released in 0-2 hours; (b) 30-65% of the dose is released in 0-12 hours; and (c) 80-100% of the dose is released in 0-24 hours; wherein the release profile is determined using a USP type IV bath indexer in a water bath of 37 ° C where said formulation provides pain relief lasting approximately 24 hours or more after administration to the patient. 47.- The formulation according to claim 46, further characterized in that 33-63% of the dose is released in 0-12 hours. 48. The formulation according to claim 46, further characterized in that: (a) the dose comprises a first component for immediate release and a second component for sosfenide release; and (b) the weight ratio W of the first component to the sum of the first and second components is less than approximately 0.25. 49.- The formulation according to claim 48, further characterized in that D is approximately 20 mg and W is approximately 0.05. 50.- A formulation of oxycodone for controlled release for oral administration once a day to human patients comprising a D dose of: (i) oxycodone, (ii) one or more pharmaceutically acceptable acid addition salts of oxycodone, or (iii) ) a combination of oxycodone and one or more acid pharmaceutically acceptable oxycodone addition salts, wherein: (a) the dose comprises a first component for immediate release and a second component for sustained release; and (b) the weight ratio W of the first component to the sum of the first and second components is less than about 0.25. 51.- The formulation according to claim 50, further characterized in that W is less than about 0.10. 52. The formulation according to claim 50, further characterized in that W is less than or equal to about 0.05. 53. The formulation according to claim 50, further characterized in that D is approximately 20 mg and W is approximately 0.05. 54.- The use of a D dose of: (i) oxycodone, (ii) one or more pharmaceutically acceptable acid addition salts of oxycodone, or (iii) a combination of oxycodone and one or more pharmaceutically acceptable oxycodone addition salts. In order to prepare a controlled release dosage form for pain treatment in humans, said dosage form provides (a) a maximum mean plasma concentration, a single dose Cmax and (b) a single dose, average area, under a Concentration curve in plasma-time lasts 0-48 hours AUC0-48 which satisfies the relations: 3.5 x 10"4 liíro" 1 < Cmax / D < 6.8 x 10"4 liter" 1, and 7.6 x 10"3 hr / liter <AUC0-48 / D <16.7 x 10" 3 hour / lire, where the dosage form provides pain relief for approximately 24 hours or more and wherein said dosage form is administrable on a once-a-day basis. 55. The use as claimed in claim 54, wherein Cmax and AUCo-48 are determined by using plasma samples from individuals who have been administered one or more opioid aniiagonias. 56. The use as claimed in claim 54, wherein Cmax and AUCo-48 are determined by using plasma samples of individuals who have been administered naltrexone. 57. The use as claimed in claim 54, wherein Cmax and AUC0-48 are determined using plasma samples from individuals who have been administered an opioid aniiagonism. 58. The use as claimed in claim 54, wherein Cmax and AUCo-48 are determined using samples of plasma from individuals who have not been administered naltrexone. 59. The use as claimed in claim 54, 55 or 57, wherein the dosage form provides a time for maximum average concentration, single dose, in plasma Tmax that satisfies the relationship: Tmax > 17 hours. 60.- The use as claimed in claim 59, where Tmax satisfies the relationship: Tmax >; 18 hours. 61.- The use as claimed in claim 59, where Tmax satisfies the relation: Tmax > 19 hours 62. - The use as claimed in claim 54, 55 or 57, wherein the dosage form provides a time for maximum average concentration, single dose, in plasma Tmax and D, Cmax, and Tmax satisfy the ratio: Cmax / (Tmax * D) < 3 x 10"4 (liter" hour) "1, 63.- The use as claimed in claim 62, wherein D, Cmax, and Tmax satisfy the ratio: 2 x 10" 5 (liter »hour) "1 < Cmax / (Tmax »D) < 6 x 10"5 (liter» hour) "1. 64.- The use as claimed in claim 54, 55 or 57, also characterized because the dosage form provides average areas of single dose, under a concentration curve in plasma-fime for 0-12 hours AUC0-12 and for 12-24 hours AUC12-24 satisfying the ratio: AUC12-24 / AUC0-12 > 1.0. 65.- The use as claimed in claim 64, wherein AUC0-12 and AUC12-24 satisfy the relation: AUC? 2-2 / AUC0-? 2 > 1.5. 66.- The use as claimed in claim 64, wherein AUC0-? 2 and AUC? 2-24 satisfy the relationship: AUC? 2-247AUC0-i2 > 1 -7. 67.- The use as claimed in claim 64, wherein AUC0-12 and AUC12-24 satisfy the relation: AUC12-24 / AUC0-12 > 2.0. 68.- The use as claimed in claim 54, 55 or 57, wherein: (a) the dose comprises a first component for immediate release and a second component for sustained release; and (b) the weight ratio W of the first component to the sum of the first and second components is less than about 0.25. 69. - The use as claimed in claim 68, wherein D is approximately 20 mg and W is approximately 0.05. 70.- The use of a D dose of: (i) oxycodone, (ii) one or more pharmaceutically acceptable acid addition salts of oxycodone, or (ii) a combination of oxycodone and one or more acid addition salts of oxycodone pharmaceutically acceptable, to prepare a controlled release dosage form for pain in humans, wherein: (a) the dosage form provides a single-dose, medium-concentration plasma profile, which substantially increases in a mono-ionic fashion for 24 hours. hours; (b) the dosage form provides a mean, single dose area, under a plasma-fime concentration curve for 0-48 hours AUCo-48 satisfying the ratio: 7.6 x 10"3 hour / liter <AUC0. 48 / D < 16.7 x 10"3 hour / lif; and (c) the dosage form provides pain relief for approximately 24 hours and is administrable on a once-a-day basis. 71. The use as claimed in claim 70, wherein AUC0.48 and the profile of average concentration, single dose, in plasma, are determined using plasma samples of individuals who have been administered one or more opioid aniagonysias. 72. Use as claimed in claim 70, wherein AUC0-48 and the single dose, plasma concentration profile are determined by using plasma samples of individuals who have been administered nalfrexone. 73. - The use as claimed in claim 70, wherein AUC0-48 and the profile of average concentration, single dose, in plasma, are determined using plasma samples of individuals who have not been administered an opioid antagonism . 74.- The use as claimed in claim 70, wherein AUCo-48 and the profile of average concentration, single dose, in plasma, are determined by using plasma samples from individuals who have not been administered nalirexone. . 75.- The use as claimed in claim 70, 71, or 73, wherein the profile of average concentration, single dose, in plasma, comprises a first phase of elevation and a second phase, wherein the slope The first phase of elevation is greater than the magnitude of the slope of the second phase. 76.- The use as claimed in claim 75, wherein the transition between the first lifting phase and the second phase occurs between 12 and 16 hours. 77.- The use as claimed in claim 76, wherein the first lifting phase comprises a first subphase and a second subphase, wherein the first subphase rises faster than the second subphase. 78.- The use as claimed in claim 77, wherein the transition between the first subphase and the second subphase occurs between 1 and 3 hours. 79. - The use as claimed in claim 70, 71, or 73, wherein: (a) the dose comprises a first component for immediate release and a second component for sustained release; and (b) the weight ratio W of the first component to the sum of the first and second components is less than approximately 0.25. 80.- The use as claimed in claim 79, wherein D is approximately 20 mg and W is approximately 0.05. 81.- The use of a D dose of: (i) oxycodone, (ii) one or more pharmaceutically acceptable acid addition salts of oxycodone, or (ni) a combination of oxycodone and one or more pharmaceutically acceptable oxycodone addition salts. In order to prepare a conjoined release dosage form for pain relief in humans, said dosage form provides (a) a mean, single dose, 12 hour concentration in C12 plasma and (b) a single dose, average area , under a concentration curve in plasma-time lasts 0-48 hours AUC0-48 that satisfies the relations: 2.7 x 10"4 liíro" 1 < C12 / D < 5.7 x 10"4 liter" 1, and 7.6 x 10"3 hr / liter <AUC0-48 / D <16.7 x 10" 3 hour / lire, wherein said dosage form provides pain relief for approximately 24 hours. hours or more, and wherein said dosage form is administrable on a once-a-day basis. 82. - The use as claimed in claim 81, wherein C12 and AUC0-48 are determined by using plasma samples of individuals who have been administered one or more opioid antipsychotics. 83. The use as claimed in claim 81, wherein C12 and AU MS are determined using plasma samples from individuals who have been administered naltrexone. 84. The use as claimed in claim 81, wherein C? 2 and AUCo-48 are determined using plasma samples to which an opioid ani-anonymity has not been administered. 85. The use as claimed in claim 81, wherein C12 and AUCo-48 are determined using samples of plasma from individuals who have not been administered naltrexone. 86.- Use as claimed in claim 81, 82, or 84, wherein: (a) the dose comprises a first component for immediate release and a second component for sustained release; and (b) the weight ratio W of the first component to the sum of the first and second components is less than about 0.25. 87. The use as claimed in claim 86, wherein D is approximately 20 mg and W is approximately 0.05. 88.- The use of a D dose of: (i) oxycodone, (ii) one or more pharmaceutically acceptable acid addition salts of oxycodone, or (ii) a combination of oxycodone and one or more acid addition salts of oxycodone pharmaceutically acceptable, to prepare a controlled release dosage form to relieve pain in humans, said dosage form provides average areas, stable state, under a plasma concentration-time curve for 0-6 hours AUC0-6, 6- 12 hours AUC6. 12, 12-18 hours AUC12-18, 18-24 hours AUC? 8.24, and 0-24 hours AUC0-24 satisfying the relationships: AUC0-6, / AUCo-24 > 0.18, AUC6-? 2, / AUC0-24 > 0.18, AUC 2-? 8 / AUC0-24 > 0.18, and AUC? 8_24 / AUCo-24 > 0.18, wherein said dosage form provides pain relief for approximately 24 hours or more and is administrable on a once-a-day basis. 89.- The use as claimed in claim 88, wherein AUC0-6, AUC6-12, AUC? 2-? 8, AUC? 8. 4, and AUC0-24 are determined by using plasma samples from individuals who have been administered one or more opioid ani-anagonists. 90. The use as claimed in claim 88, wherein AUC0-6, AUC6-12, AUC? 2-? S, AUC18-24 and AUC0-24 are determined by using plasma samples of individuals to whom they are assigned. he has given them naltrexone. 91.- The use as claimed in claim 88, wherein AUC0-6, AUC6-? 2l AUC? 2-? 8, AUC? 8.24 and AUC0.24 are determined by using plasma samples from individuals who have not been administered an opioid antagonist. 92. The use as claimed in claim 88, wherein AUC0-6, AUC6-12, AUC12-18, AUC18-24 and AUC0-24 are determined using plasma samples of plasma individuals who are not he has given them naltrexone. 93.- The use as claimed in claim 88, 89 or 91, wherein AUC0-6, AUC6-12, AUC? 2_? 8, AUC18-24 and AUC0-24 satisfy the relations: AUC0.6, / AUCo-24 >; 0.20, AUC6-12. AUC0-24 > 0.20, AUC-12-18 / AUCo-24 > 0.20, and AUC? 8-24 AUC0-24 > 0.20 94. Use as claimed in claim 88, 89 or 91, where the magnitude of the difference between any two of AUC0. 6 / AUCo-24, AUC6-i2 / AUC0-24, AUC? 2-? 8 / AUC0-24, and AUC? 8-2 / AUCo.24 is less than or equal to 0.05. 95.- The use as claimed in claim 94, wherein the magnitude of the difference between each of: AUCo-6 / AUCo-24 and AUC6-? 2 / AUCo-24, AUC6-12 / AUCo- 24 and AUC12-I8 / AUCo-24, AUC12-18 / AUCo-24 and AUCis AUCo-24, and AUC18-24 / AUCo-24 and AUCo-6 / AUC0-24, is less than or equal to 0.03. 96.- The use as claimed in claim 88, 89, or 91, where the magnitude of the difference includes each of: AUCo-e / AUCo-24 and AUC6.?2/ AUC0-24, AUC6 -12 / AUCo-24 and AUC12-18 / AUC0-24, AUC12-18 / AUC0-24y AUCis AUCo-24, and AUC18-24 / AUCo-24 and AUCo-d / AUCo-24, is less than or equal to 0.03 . 97. The use as claimed in claim 88, 89, or 91, wherein: (a) the dose comprises a first component for immediate release and a second component for sustained release; and (b) the weight ratio W of the first component to the sum of the first and second components is less than about 0.25. 98.- The use as claimed in claim 97, wherein D is approximately 20 mg and W is approximately 0.05. 99.- The use of a D dose of: (i) oxycodone, (ii) one or more pharmaceutically acceptable acid addition salts of oxycodone, or (iii) a combination of oxycodone or one or more pharmaceutically acceptable oxycodone addition salts. acceptable for preparing a controlled release dosage form for pain in humans, wherein said dosage form provides pain relief for approximately 24 hours or more after administration to the patient and has an in vitro release profile in which: (a) 0-20% of the dose is released in 0-2 hours; (b) 30-65% of the dose is released in 0-12 hours; and (c) 80-100% of the dose is released in 0-24 hours; wherein the release profile is determined using a USP type IV bath indexer in a femur water bath at 37 ° C and wherein said dosage form is administrable on a once a day basis. 100.- The use as claimed in claim 99 wherein 33-63% of the dose is released in 0-12 hours. 101. The use as claimed in claim 99, wherein: (a) the dose comprises a first component for immediate release and a second component for sustained release; and (b) the weight ratio W of the first component to the sum of the first and second components is less than about 0.25. 102.- The use as claimed in claim 101, wherein D is approximately 20 mg and W is approximately 0.5. 103. The use of a D dose of: (i) oxycodone, (ii) one or more pharmaceutically acceptable acid addition salts of oxycodone, or (iii) a combination of oxycodone and one or more pharmaceutically acceptable oxycodone addition salts. acceptable for preparing a controlled release dosage form for bringing pain in humans, wherein: (a) the dose comprises a first component for immediate release and a second component for sustained release; (b) the weight ratio W of the first component to the sum of the first and second components is less than about 0.25; and (c) the dosage form provides pain relief for approximately 24 hours or more and is administrable on a once-a-day basis. 104.- The use as claimed in claim 103 wherein W is less than about 0.10. 105.- The use as claimed in claim 103, wherein W is less than or equal to approximately 0.05. 106. The use as claimed in claim 103, wherein D is approximately 20 mg and W is approximately 0.05.