KR20050016377A - Methods and dosage forms for controlled delivery of oxycodone - Google Patents

Abstract

Dosage forms and methods are disclosed for controlled release of oxycodone over an extended period of time. Sustained release dosage forms provide a therapeutically effective average steady state oxycodone concentration when administered once daily. This once daily dosing regimen results in one peak plasma oxycodone concentration for each 24 hours after administration, and the peak plasma oxycodone concentrations that occur after oxycodone administration are oxycodone in the immediate-release dosage form and other prior release extended release dosage forms. It is less than the peak plasma oxycodone concentration that occurs after administration.

Description

METHODS AND DOSAGE FORMS FOR CONTROLLED DELIVERY OF OXYCODONE}

The present invention relates to delivery modulating agents and methods, dosage forms and devices thereof, and in particular, the present invention relates to methods, dosage forms and devices for controlled delivery of oxycodone once daily for pain management.

Oxycodone is an analgesic whose main therapeutic effect is pain relief. Oxycodone is prescribed to adequately relieve severe pain such as surgery, cancer, trauma, gallbladder pain, kidney pain, myocardial infarction, and burn pain. Pharmaceutically acceptable oral dosage forms of oxycodone provided for analgesic treatment in a controlled manner over an extended time beyond their half-life are lacking in the pharmaceutical and medical industry.

The pharmacological and medical properties of opioid analgesics, including oxycodone, are described in Pharmaceutical Sciences , Remington, 17th Ed., Pp. 1099-1044 (1985); And The Pharmacological Basis of Therapeutics , Goodman and Rall, 8th Ed., Pp. 485-518 (1990). In general, the analgesic action of parenterally administered oxycodone is apparent in 15 minutes, whereas the onset of oral administration of oxycodone is somewhat slow with an analgesic effect in about 30 minutes. The half-life of the immediate-release oxycodone orally administered in human plasma is about 3.2 hours. ( Physicians' Desk Reference , Thompson Healthcare, 56th Ed., Pp. 2912-2918 (2002)).

Prior to the present invention, oxycodone was administered in conventional forms such as rate-controlled, rapid-release, rapid-release tablets, or by multiple-dose dosing intervals, usually by day-dose capsules. Oxycodone is also administered twice daily with a controlled release matrix system, Oxycontin ^R. However, Oxycontin ^R mode treatment initially shows high and low levels of oxycodone in the blood following administration. In addition, these peaks and troughs appear twice a day because they are twice daily regimens. The difference in concentration of the dose pattern is related to the presence or absence of the drug being administered, which is the main disadvantage of the prior dosage forms. Conventional dosage forms and their modes of operation, including dose peaks and curves, are described in Pharmaceutical Sciences , Remington, 18th Ed., Pp. 1676-1686 (1990), Mack Publishing Co .; The Pharmaceutical and Clinical Pharmacokinetics , 3rd Ed., Pp. 1-28 (1984), Lea and Febreger, Philadelphia; And US Pat. Nos. 3,598,122 and 3,598,123 to Zaffaroni.

Purdue Pharma currently markets Oxycontin ^R , an extended release oral dosage form of oxycodone, according to US Pat. No. 5,672,360. Oxycontin ^R is prescribed to be administered twice daily, while this patent contains an oxycodone which is described as achieving a maximum plasma concentration at 2 to 10 hours post-dose, which is greater than twice the plasma concentration at 24 hours post-dose. One-time oral sustained dosage forms are described. However, such a plasma concentration profile shows a delayed primary delivery rate similar to the immediate-release dosage form where once the concentration rises to a single peak concentration and then the concentration decreases consistently from the peak when the release rate of oxycodone from the dosage form decreases. It turns out that it is not too much.

The drawback of this plasma concentration profile is that it provides significant peak and lowest analgesic therapeutic effects throughout the day. The peak concentration of the immediate-release dosage form is higher than therapeutically necessary, and the lowest value is lower than the therapeutically beneficial treatment for the patient. This property causes side effects similar to immediate-release doses. That is, at the peak concentration it is calmed by the drug effect and becomes destructive pain when the concentration drops below the effective level during the 24-hour dosing regimen. Physicians' Desk Reference , Thompson Healthcare, 56th Ed., Pp. 2912-2918 (2002).

Other patents related to Oxycontin ^R include US Pat. No. 4,861,598; 4,970,075; 5,226,331; 5,508,042; 5,549,912; And 5,656,295. These patents disclose similar extended release dosage forms that deliver over 12 hours, but do not disclose once daily usage.

There is a wealth of description in the art for dosage forms for controlled release of a drug. Various dosage forms have been known for sustained release delivery of a particular drug with a short half-life, but because of the solubility, metabolic processes, absorption and other physical, chemical and physiological parameters that may be unique to the drug and mode of delivery, all drugs may be from these dosage forms. It may not be properly delivered.

Various dosage forms have been known for sustained release delivery of a particular drug with a short half-life, but because of the solubility, metabolic processes, absorption and other physical, chemical and physiological parameters that may be unique to the drug and mode of delivery, all drugs may be from these dosage forms. It may not be properly delivered.

In addition, side effects associated with oxycodone, such as sedation, tolerance, constipation, appear to be associated with high plasma concentrations, limiting the administration of a single daily, immediate-release dose.

Apparatus for delivering a pharmaceutical composition in the form of a slurry, suspension or solution from a small outlet orifice in the action of an expandable layer is described in US Pat. 5,190,765; 5,252,338; 5,620,705; 4,931,285; 5,006,346; 5,024,842; And 5,160,743. Exemplary devices include a drug layer surrounded by an expandable push layer and a semipermeable membrane. In certain cases, a subcoat is provided in the drug layer to extend the release of the pharmaceutical composition to the environment of use, or to form an annealed coating with the semipermeable membrane.

Devices for delivering a pharmaceutical composition dry from a large exit orifice in the action of an expandable layer are described in US Pat. Nos. 4,892,778, 4,915,949 and 4,940,465. These patents disclose a dispenser for delivering a formulation that is beneficial to the environment of use, including a semipermeable membrane containing an expandable layer of material that pushes the dry drug layer out of the wall formed by the walls. The outlet orifice in the device has a diameter substantially the same as the inner diameter of the partition formed by the wall.

Dosage forms that deliver a pharmaceutical composition to a dry environment may moderately release the drug over a long time, but exposure of the drug layer to the environment of use may cause agitation-dependent release of the drug, making some situations difficult to control. Thus, it may be advantageous to release the drug into a slurry or suspension, which can be metered by controlling the size of the exit orifice in the dosage form and the rate of expansion of the push layer, according to the present invention.

Effective dosages capable of long-term controlled release of the above-mentioned compounds for reducing the amount of active reagents, increasing the dosing intervals, and preferably once daily dosing regimens for the patient to be placed at any particular time. Methods, dosage forms, and devices are desired.

The present invention unexpectedly provides dosage forms containing oxycodone and therapeutic compositions containing oxycodone for continuous management of pain over 24 hours.

The present invention is directed to a novel release rate profile designed to provide an effective oxycodone regimen over a 24-hour period that can optionally but preferably utilize conventional tablet dosage forms overcoated for initial pain relief. This dosage form releases oxycodone for about 24 hours after administration using immediate-release drug overcoat delivery followed by continuous controlled drug delivery until the core stops drug release. Dosage forms of the invention are characterized by a T ₇₀ of about 10 to 20 hours, preferably 15 to 18 hours and more preferably about 17 hours. Dosage forms of the invention have a C _{max greater} than 6 hours, preferably greater than 12 hours, most preferably _greater than 15 hours, and less than 2 times C ₂₄ to produce an even plasma concentration profile over 24 hours after administration. It is characterized by. This property is remarkable in that the plasma concentration with and with the immediate-release coating does not reach a maximum plasma concentration until at least about 6 hours, preferably greater than 12 hours and most preferably about 15 hours after administration. be worth. This new property unexpectedly provides effective treatment while maintaining drug plasma levels low enough to reduce the side effects associated with high plasma concentration levels. This unique delivery property also provides 24-hour efficacy without high plasma concentrations and sub-plasma concentrations.

The present invention utilizes a semipermeable membrane surrounding a bilayer core containing a first drug layer comprising an oxycodone and an excipient and a second expandable layer called the push layer containing an osmotic agent but not containing an active ingredient. The orifice is perforated through the membrane on the drug layer end of the tablet to release the active reagent to the environment.

In the vortex aqueous environment of the gastrointestinal tract (GI), the drug coat dissolves rapidly. Water is then absorbed through the membrane at a controlled rate which is determined by the nature of the membrane and the osmotic pressure of the core component. This expands the push layer, hydrates the drug layer and forms a viscous but deformable mass. The push layer expands toward the drug layer, thereby pushing the drug layer through the orifice. The drug layer passes through the system through the orifice of the membrane at the same rate as water is absorbed into the core. The biologically inactive component of the tablet remains intact during GI passage and is removed as tablet shell along with the soluble core component.

The present invention is designed to be therapeutically effective, once daily, with fewer side effects than the extended immediate-release extended dosage form currently administered several times a day.

In one aspect, the invention encompasses sustained release dosage forms suitable for releasing an oxycodone compound at a uniform release rate over a long period of time.

In another aspect, the invention includes a method of treating a subject's symptoms responsive to administration of oxycodone, characterized by orally administering to the subject a dosage form suitable for releasing the compound at a uniform release rate over a long period of time. .

In another aspect, the invention provides a wall comprising: a wall defining or forming an outlet orifice and defining a partition wherein at least a portion of the wall is semipermeable; An inflatable layer in fluid communication with the semi-permeable portion of the wall and located within the septum away from the exit orifice; And a dosage form comprising a drug layer comprising an oxycodone compound located within the septum adjacent the exit orifice.

In another aspect, the present invention provides oxycodone in a steady state at a plasma concentration of about 5 to 10 ng / ml of the compound from a dose of 20 mg, provided that [C _max -C _min for 24 hours after dosage administration. ] / C _min , so that the quotient is 2 or less, and includes a method for treating symptoms responsive to administration of oxycodone.

The prior art did not recognize that oxycodone could be prepared in sustained release dosage forms or therapeutic compositions claimed herein that provide an effective analgesic effect over 24 hours. Prior art includes dosage forms that can be prepared including osmogels such as polyalkylene oxides and other ingredients such as osmagents that reduce peaks and knockdown with side effects or disruptive pain and No therapeutic composition was recognized.

The prior art did not produce apparent oxycodone formulated with polyalkylene oxides because of the complex mechanisms for controlling the release of oxycodone from polyalkylene oxides. For example, oxycodone can be incorporated into and fixed in polyalkylene oxides; The polyalkylene oxides can also expand unacceptably in the presence of aqueous solutions, including physiological fluids, to change the release rate of oxycodone from the polyalkylene oxide. Osmogels, such as polyalkylene oxides, can also have glass transition temperatures lower than human body temperature, preventing the use of oxycodone in such environments. In addition, the properties of oxycodone and polyalkylene oxides exemplify the crystallinity of oxycodone in polyalkylene oxide, the burst or retardation effect of oxycodone in polyalkylene oxide, and the oxycodone solubility in polyalkylene oxide hydrogels, all of which are illustrated Prove your progress.

The above description suggests that there is an urgent need for dosage and therapeutic compositions that overcome the disadvantages of conventional dosage and controlled release matrix forms, including tablets, capsules, elixirs, and suspending agents. Such conventional dosage forms and their plasma peak and curve concentrations do not provide optimal dose-modulating drug therapy over an extended period of time. Oxycodone delivered by the prior art is administered more than twice a day but does not provide self-regulating and sustained therapeutic effects. This prior art pattern of drug administration suggests that for certain treatments there is a need for dosage forms and therapeutic compositions capable of administering oxycodone in a rate controlled dose manner over an extended period of time without prior plasma concentration peaks, curves and multiple doses. . The present invention provides modes and modes of oral administration of oxycodone that are relatively easy to administer.

The drawings are not to scale and are shown to illustrate various embodiments of the invention.

1 shows an embodiment of a dosage form of the present invention showing a dosage form prior to subject administration.

FIG. 2 is a cutaway perspective view of the dosage form of FIG. 1 showing a dosage form of the present invention comprising an internally received pharmaceutically acceptable therapeutic oxycodone composition.

FIG. 3 is a cutaway perspective view of FIG. 1 showing a dosage form comprising a separate contact dissolution composition comprising internally an oxycodone composition and a means for pushing the pharmaceutical oxycodone composition out of the dosage form.

4 shows a dosage form provided by the present invention further comprising an immediate-release external overcoat of oxycodone in the dosage form.

FIG. 5 shows the mean plasma oxycodone concentration profile over 24 hours for a single 20 mg dose with 3 mg oxycodone overcoat and 17 mg oxycodone core.

FIG. 6 shows the mean plasma oxycodone concentration profile in a steady state over 24 hours for a single 20 mg dose with 3 mg oxycodone overcoat and 17 mg oxycodone core.

FIG. 7 shows the average release rate profile (release rate as a function of time) from a 20 mg oxycodone dosage form with 3 mg of oxycodone overcoat, 17 mg of oxycodone core and having the general characteristics shown in FIG. 4.

FIG. 8 shows cumulative release of oxycodone over time from a representative 20 mg oxycodone dosage form with 1 mg oxycodone overcoat, 19 mg oxycodone core and having the general characteristics shown in FIG. 4.

FIG. 9 shows the release profile (release rate as a function of time) of oxycodone percent hourly for a 20 mg dosage form with 1 mg oxycodone overcoat, 19 mg oxycodone core and having the general characteristics shown in FIG. 4.

FIG. 10 shows cumulative release of oxycodone over time from a representative 80 mg oxycodone dosage form with 4 mg oxycodone overcoat, 76 mg oxycodone core and having the general characteristics shown in FIG. 4.

FIG. 11 shows the release profile (release rate as a function of time) of oxycodone percent hourly for an 80 mg dosage form with 4 mg oxycodone overcoat, 76 mg oxycodone core and having the general characteristics shown in FIG. 4.

In the drawings and the description, like parts of relevant figures are represented by like numerals. The terms first appearing in the description of the specification and drawings, as well as in the embodiments thereof, are further depicted elsewhere in the description.

The invention is best understood with reference to the following definitions, figures and exemplary description provided herein.

Justice

By "dose" is an inactive ingredient optionally used to prepare and deliver the active agent, such as suspending agents, surfactants, disintegrants, binders, diluents, lubricants, stabilizers, antioxidants, osmotic agents, colorants, plasticizers, coatings, and the like. A pharmaceutical composition or device comprising an active agent, such as oxycodone or a pharmaceutically acceptable acid addition salt thereof, together with such pharmaceutically acceptable excipients.

"Active reagent", "drug" or "compound" means an agent, drug or compound having the properties of oxycodone or a pharmaceutically acceptable acid addition salt thereof.

"Pharmaceutically acceptable acid addition salt" or "pharmaceutically acceptable salt" as used herein interchangeably refers to a pharmacologically equivalent that the anion does not contribute significantly to the pharmacological activity or toxicity of the salt and is equivalent to the base of the oxycodone compound by itself. It means a salt having an effect. Examples of pharmaceutically acceptable acids useful for salt formation purposes include hydrochloric acid, hydrobromic acid, hydroiodic acid, citric acid, acetic acid, benzoic acid, mandelic acid, phosphoric acid, nitric acid, music acid, isethionic acid, palmitic acid, and the like. However, it is not limited only to these.

"Sustained release" means the continuous release of the active reagent to the environment for a long time.

When “exit”, “outlet orifice”, “delivery orifice” or “drug delivery orifice” and other similar expressions are used herein they are passages; Aperture; Orifices; And a member selected from the group consisting of bores. These representations also include orifices formed or formable from materials or polymers that corrode, dissolve or leach from the outer wall to form an outlet orifice.

Drug "Release Rate" means the amount of drug released from the dosage form per unit time, eg, milligrams of drug released per hour (mg / hr). The rate of drug release for a drug dosage form is typically determined by the rate of in vitro dissolution, ie the amount of drug released from the dosage form per unit time measured in a suitable fluid under appropriate conditions. The dissolution test used in the examples described herein is performed in a dosage form located on a metal coil sample holder attached to a USP Type VII bath indexer in a 37 ° C. constant temperature water bath. An aliquot of the release rate solution is injected into the chromatography system to quantify the amount of drug released during the test interval.

"Release Rate Assay" means a standardized assay for determining the release rate of a compound from a dosage form tested using a USP Type 7 interval release device. It is to be understood that equivalent grade reagents may be substituted for analysis according to generally accepted methods.

For the sake of clarity and convenience herein, the time of drug administration is, according to convention, 0 hours (t = 0 hours) and the time after administration is an appropriate time unit, for example t = 30 minutes or t = 20 hours and the like.

Unless otherwise specified, the drug release rate obtained at the designated time "after administration" as used herein refers to the in vitro drug release rate obtained at the specified time after performing the appropriate dissolution test. The time at which a specified percentage of drug is released in the dosage form may be a value of "T _x ", where "x" represents the percentage of drug released. For example, a baseline measurement commonly used to assess drug release from a dosage form is the time at which 70% of the drug in the dosage form is released. This measurement is called “T ₇₀ ” for the dosage form.

"Immediate-release dosage form" means a dosage form that releases the drug substantially completely within a short time after administration, generally within a few minutes to about 1 hour.

"Sustained release dosage form" means a dosage form that releases the drug substantially continuously for several hours. Sustained release dosage forms according to the invention exhibit a T ₇₀ value of at least about 10 to 20 hours, preferably 15 to 18 hours and more preferably about 17 hours or more. The dosage form continuously releases the drug for a sustained time of at least about 10 hours, preferably at least 12 hours, more preferably at least 16-20 hours.

Dosage forms according to the present invention have a uniform release rate of oxycodone for a long time within a sustained release time.

"Uniform release rate" as measured in a USP Type 7 interval release device, which varies from ± about 30% or less, preferably about 25% or less, most preferably 10% or less from the average hourly release rate before or after Mean hourly release rate from the core, wherein the cumulative release is about 25 to about 75%.

By "long time" is meant a continuous time of at least about 4 hours, preferably 6-8 hours or more, more preferably 10 hours or more. For example, the exemplary osmotic dosage forms described herein generally begin to release oxycodone at a uniform release rate within about 2 to about 6 hours after administration and the defined uniform release rate is from about 25% to at least about It lasts for up to 75% for a long time, and preferably at least about 85% of the drug is released from the dosage form. Thereafter, the release of the oxycodone lasts for several hours even if the release rate is generally slower than the uniform release rate.

"C" refers to the concentration of drug in the plasma of a subject and is generally expressed in mass per unit volume, typically nanograms per milliliter. For convenience, this concentration may be referred to herein as "plasma drug concentration" or "plasma concentration" intended to include the drug concentration measured in a suitable body fluid or tissue. At any time after drug administration, the plasma drug concentration is expressed as C _time , such as C _9h , C _24h, and the like.

By "normal state" is meant a state in which the amount of drug present in the subject's plasma does not change significantly over a long period of time. The drug accumulation pattern after sustained administration of the dosage form at a constant dose and at regular dosage intervals results in a "normal state" if the plasma concentration peak and the plasma concentration trough are essentially the same within each dosage interval. The steady state maximum (peak) plasma drug concentrations used herein are given as C _max , and the minimum (lowest) plasma drug concentration is given as C _min . The time to steady state peak plasma and trough drug concentration after drug administration are given by T _max and T _min , respectively.

Those skilled in the art recognize that the plasma drug concentration obtained in an individual subject will depend on the internal patient variability of many parameters that affect drug absorption, distribution, metabolism and excretion. For this reason, unless otherwise indicated, the mean values obtained from a group of subjects are given herein for the purpose of comparing plasma drug concentration data and analyzing the correlation between in vitro dosage rate of dissolution and plasma drug concentration in vivo.

The correlation between the dose of oxycodone and the peak plasma oxycodone concentration magnitude obtained after drug administration herein is used to demonstrate a significant difference between the dosage form and method of the present invention and the dosage form of the prior art. For example, as described in more detail below, unitless numbers are converted by calculating the ratio of mean C _max (ng / ml) to dose (mg) values, ie, C _max / dose. The difference in value at the converted ratios specifies a decrease in the peak plasma concentration size of oxycodone after administration of the sustained release oxycodone dosage form of the present invention relative to the peak plasma oxycodone concentration after administration of the conventional immediate-release oxycodone dosage form. Dosage administration according to the invention preferably provides a steady state C _max / dose ratio of less than about 30, more preferably less than about 25.

Surprisingly, sustained release oxycodone dosage forms may be provided that exhibit a T ₇₀ value of about 10 to 20 hours, preferably 15 to 18 hours and more preferably about 17 hours or more, releasing oxycodone at a uniform release rate for a long time. Turned out. Once daily administration of this dosage form provides a therapeutically effective average steady state plasma oxycodone concentration.

Exemplary sustained release oxycodone dosage forms, methods of making such dosage forms, and methods of using such dosage forms disclosed herein relate to osmotic dosage forms for oral administration. However, in addition to the osmotic systems disclosed herein, there are many other approaches to achieving sustained release of the drug from oral dosage forms known in the art. These different approaches include, for example, diffusion systems such as storage devices and matrix devices, encapsulation dissolution systems (including for example "small time pills") and dissolution systems such as matrix dissolution systems, diffusion / dissolution system combinations and Remington's Pharmaceutical Sciences, 1990 ed., Pp. Ion-exchange resin systems as described in 1682-1685. Oxycodone dosage forms that act in accordance with these approaches are encompassed by the scope of the present invention within a set in which the drug release profile and / or plasma oxycodone concentration characteristics cited in the claims describe the dosage form literally or equivalently.

Osmotic dosage forms generally utilize osmotic pressure to provide a driving force to absorb the fluid into a partition formed at least in part by a semipermeable wall that allows free diffusion of the fluid but not the drug or osmotic agent (s) that may be present. . A significant advantage with the osmotic system is that the operation is pH-independent, so that the dosage form continues to operate at an osmotic determined rate over an extended period of time, even if the dosage form is encountered through different gastrointestinal tracts where the pH value is significantly different. will be. A full description of these dosage forms is reviewed in Santus and Baker, "Osmotic drug delivery: patent review," Journal of Controlled Release 35 (1995) 1-21, which is incorporated herein by reference. In particular, the following US patents assigned to ALZA Corporation, each of which is incorporated herein by reference, relate to osmotic dosage forms: US Pat. 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.

1 is a perspective view of one embodiment of a sustained release osmotic dosage form according to the present invention. Dosage type 10 includes a wall 20 surrounded by an inner partition (not shown in FIG. 1). The inner partition contains a composition comprising oxycodone or a pharmaceutically acceptable acid addition salt thereof, as described in detail below. The wall 20 is provided with at least one drug delivery outlet 60 for connecting the inner partition to the use external environment. Thus, after oral ingestion of dosage form 10, body fluid is absorbed into wall 20 and oxycodone is released through outlet 60. One preferred geometric example of FIG. 1 is a standard tablet that is convex on both sides, but the geometry may include capsule caplets and other oral, buccal or sublingual dosage forms.

The present invention has been found to provide improved satisfaction and convenience as well as reduced side effects, increased tolerance, and improved efficiency that accompany the administration of oxycodone. It has also been found that additional signs are responsive to the dosage administration of the present invention.

FIG. 2 includes an oxycodone drug 31 with excipients selected to provide osmotic active ingredients for driving bodily fluids from the external environment through the wall 20 and forming oxycodone formulations deliverable upon body fluid absorption. 1 shows a cutaway view of an embodiment of the present invention having an inner partition 15 containing a single component layer, referred to as drug layer 30 in the circle. As described in more detail below, excipients may include suitable suspending agents, binders 33, lubricants 34 and osmotic actives, osmagents 35, also referred to herein as drug carriers 32. . In operation, after administration of the oral dosage form 10, as the osmotic active ingredient passes through the wall 20 and gastric juice is absorbed through the wall 20, an oxycodone preparation, ie a solution or suspension, is deliverable in the inner partition. . The deliverable oxycodone formulation is released through the outlet 60 as the body fluid enters the inner septum. The release of the drug causes the body fluids to be absorbed, thus inducing sustained release. In this way, oxycodone is released in a slow and sustained manner over an extended period of time.

3 shows a perspective view of FIG. 1 with another embodiment of the inner partition 15 having a two-layer structure. In this embodiment, the inner partition 15 contains a bilayer compression core having a first component drug layer 30 and a second component push layer 40. As detailed in FIG. 1, drug layer 30 contains oxycodone with selected excipients.

As described in more detail below, the second component, push layer 40, comprises the osmotic active component (s), but does not contain any active reagents. The components of the push layer 40 are typically one or more ossses having a relatively large molecular weight that swells as the body fluid is absorbed such that osmopolymers are not released through the osmagent 42 and the drug delivery orifice 60. And a polymer (41). Additional excipients such as binder 43, lubricant 44, antioxidant 45 and colorant 45 may also be included in push layer 40. The second component layer is also expandable herein as the osmopolymer (s) expands as body fluid is absorbed and pushes the deliverable agent of the first component drug layer to facilitate release of the liquid formulation from the dosage form. Also referred to as push layer.

In operation, as shown in FIG. 3, after oral ingestion of the dosage form 10, the osmotic active ingredient through the wall 20 causes the gastric fluid to be absorbed through the wall 20 such that the drug layer 30 is in the deliverable formulation. At the same time inflating the osmopolymer (s) in the push layer (40). As the body fluid enters the inner partition 15 and the push layer 40 expands, the deliverable drug layer 30 is released through the outlet 60. As the drug layer 30 is released, the body fluid is absorbed and the push layer expands to induce sustained release. In this way, oxycodone is released in a slow and sustained manner over an extended period of time.

The drug layer 30 described with reference to FIGS. 2 and 3 includes oxycodone with selected excipients. The push layer 40 described with reference to FIG. 3 contains the osmotic active ingredient (s) but no active reagents.

Drug layer 30 comprises a composition consisting of a pharmaceutically effective amount of oxycodone drug 31 or a pharmaceutically acceptable salt thereof and carrier 32. The drug oxycodone consists of 4,5-epoxy-14-hydroxy-3-methoxy-17-methylmorphinian-6-one with analgesic effect. Oxycodone is described in The Merck Index , 11th Ed., P. 1100 (1990). Oxycodone salts include oxycodone sulfate, oxycodone hydrochloride, oxycodone trifluoroacetate, oxycodone thiosemicarbazone hydrochloride, oxycodone pentafluoropropionate, oxycodone p-nitrophenylhydrazone, oxycodone o-methyloxine, oxycodone thiosemicarba Zone, oxycodone semicarbazone, oxycodone phenylhydroazone, oxycodone hydrazone, oxycodone hydrobromide, oxycodone mucate, oxycodone methyl bromide, oxycodone oleate, oxycodone n-oxide, oxycodone acetate, dibasic oxycodone phosphate, monobasic Oxycodone inorganic salt, oxycodone organic salt, oxycodone acetate trihydrate, oxycodone bis (heptafluorobutyrate), oxycodone bis (methylcarbamate), oxycodone (bispentafluoropropionate), Oxycodone bis (pyridine-3-carboxylate), oxycodone bis (trifluoroacetate), oxycodone bisartrate, oxycodone chlorohydrate and oxycodone sulfate pentahydrate.

Dosage forms and therapeutic compositions in preparation comprise 1 to 640 mg of oxycodone drug 31 or a pharmaceutically acceptable salt of oxycodone drug. Preferably the dosage form of the present invention comprises 20 to 160 mg of oxycodone drug 31.

Carrier 32 may comprise a hydrophilic polymer, indicated by horizontal lines in FIGS. 2 and 3. Hydrophilic polymers contribute hydrophilic polymer particles to the drug composition to regulate delivery of active reagents. Representative examples of such polymers include poly (alkylene oxide) having a number average molecular weight of 100,000 to 750,000, including poly (ethylene oxide), poly (methylenetilene oxide), poly (butylene oxide) and poly (hexylene oxide); And poly (carboxymethylcellulose) having a number average molecular weight of 40,000 to 400,000 represented by poly (alkali carboxymethylcellulose), poly (sodium carboxymethylcellulose), poly (potassium carboxymethylcellulose) and poly (lithium carboxymethylcellulose). The drug composition has a number average molecular weight of 9,200 to 125,000 hydroxypropylalkylcellulose represented by hydroxypropylethylcellulose, hydroxypropylmethylcellulose, hydroxypropylbutylcellulose and hydroxypropylpentylcellulose to improve the delivery properties of the dosage form. And poly (vinylpyrrolidone) having a number average molecular weight of 7,000 to 75,000 for improving the fluidity of the dosage form. Among these polymers, poly (ethylene oxide) having a number average molecular weight of 100,000 to 300,000 is preferred. Particular preference is given to carriers which corrode in the above environment, ie biocorrosive carriers.

Other carriers that may be impregnated with the drug layer 30 include carbohydrates that are used alone or in combination with other osmagents to exhibit sufficient osmotic activity. Such carbohydrates include monosaccharides, disaccharides and polysaccharides. Representative examples include maltodextrins (ie, glucose polymers provided by hydrolysis of corn starch) and sugars including lactose, glucose, raffinose, sucrose, mannitol, sorbitol, and the like. Preferred maltodextrins have a dextrose equivalent weight (DE) of 20 or less, preferably about 4 to about 20, and often 9 to 20. Maltodextrins having a DE of 9-12 have been found to be most useful.

The above-described carbohydrates, preferably maltodextrins, can be used in the drug layer 30 without the addition of osmagents, and from the dosage form, with a therapeutic effect over an extended time period of up to 24 hours with once daily administration. Oxycodone release can be obtained.

The drug layer 30 may further comprise a therapeutically acceptable vinyl polymer binder 33, indicated by the vertical lines in FIGS. 2 and 3. Vinyl polymers have an average molecular weight of 5,000 to 350,000, such as poly-n-vinylamide, poly-n-vinylacetamide, poly (vinylpyrrolidone) (also known as poly-n-vinylpyrrolidone), Consisting of poly-n-vinylcaprolactone, poly-n-vinyl-5-methyl-2-pyrrolidone, and vinyl acetate, vinyl alcohol, vinyl chloride, vinyl fluoride, vinyl butyrate, vinyl laurate and vinyl stearate A member selected from the group consisting of poly-n-vinylpyrrolidone copolymers with a member selected from the group is representative. Dosage form 10 and the therapeutic composition comprise 0.01 to 25 mg of a vinyl polymer provided as a binder or binder. Representative examples of other binders are acacia, starch and gelatin.

The drug layer 30 may further comprise a lubricant 34 indicated by the wavy lines in FIGS. 2 and 3. Lubricants are used to prevent die walls or punch faces from sticking during manufacture. Representative lubricants include magnesium stearate, sodium stearate, stearic acid, calcium stearate, magnesium oleate, oleic acid, potassium oleate, caprylic acid, sodium stearyl fumarate and magnesium palmitate. The amount of lubricating oil present in the therapeutic composition is 0.01 to 10 mg.

Drug layer 30 is typically formed by contact compression of the carrier and drug into one layer and the push composition into another layer.

Drug layer 30 is formed from a mixture containing oxycodone and a carrier that provides a slurry, solution, or suspension of a compound that can be dispersed by the action of a push layer when in contact with a physiological fluid in the environment of use. The drug layer can be formed from the particles by communication, which provides the size and drug size of the polymer used to prepare the drug layer, typically as a core containing the compound, in accordance with the modes and methods of the present invention. Means for providing the particles include granulation, spray drying, sieving, lyophilization, crushing, grinding, jet milling, microning and chopping to provide the desired micron particle size. This process includes micropulverizer mills, fluid energy grinding mills, grinding mills, rollers, roller mills, hammer mills, attritions and attritions. mills, chasers and ball mills, ball mills, vibrating ball mills, impact pulverizer mills, centrifugal pulverizers, coarse crushers It can be performed by a size reduction device such as a crusher and a fine crusher. Particle sizes include grizzly screens, flat screens, vibrating screens, revolving screens, shaking screens, oscillating screens and recipes. This can be confirmed by screening including a reciprocating screen. Processes and equipment for preparing drug and carrier particles are described in Pharmaceutical Sciences , Remington, 17th Ed., Pp. 1585-1594 (1985); Chemical Engineers Handbook , Perry, 6th Ed., Pp. 21-13 to 21-19 (1984); Journal of Pharmaceutical Sciences , Parrot, Vol. 61, no. 6, pp. 813-829 (1974); And Chemical Engineer , Hixon, pp. 94-103 (1990).

Drug layer 30 further comprises a surfactant and a disintegrant. Examples of surfactants include surfactants having an HLB value of about 10-25, such as polyethylene glycol 400 monostearate, polyoxyethylene-4-sorbitan monolaurate, polyoxyethylene-20-sorbitan monooleate, Polyoxyethylene-20-sorbitan monopalmitate, polyoxyethylene-20-monorarate, polyoxyethylene-40-stearate, sodium oleate and the like. Disintegrants may be selected from corn, clay, cellulose, argin and guar and crosslinked starch, cellulose and polymers. Representative disintegrating agents include corn starch, potato starch, croscarmellose, crospovidone, sodium starch glycolate, Veegum HV, methylcellulose, agar, bentonite, carboxymethylcellulose, arginine acid, guar gum and the like.

The active reagent is present in an amount of 0.1 to 640 mg, preferably 10 to 80 mg, more preferably 20 to 80 mg per dosage, depending on the required dosage level to be maintained over the period of delivery, ie the time between successive administrations of the dosage form. It may be provided to the drug layer. More typically, the dosage of compound in dosage form will provide the subject with a dose of the compound in the range of 10-160 mg, more generally 20-80 mg per day. In general, if the total dose required per day exceeds 160 mg, multiple units of the dosage form may be administered at the same time to provide the required amount of drug.

As a representative example of a compound having pain relief activity disclosed herein, immediate-release oxycodone is typically administered in two or three doses at a starting dose of about 10 mg per day. Effective dose ranges were generally determined to be 10 mg / day to 320 mg / day. If resistance to the starting dose is observed and additional clinical effects are needed, the dose is increased in increments of 5 mg / day to 80 mg / day.

Plasma concentrations in a subject can be determined by clinical analysis, which, at the same time as observation, determines the correlation between resistance and clinical effects and plasma concentrations of the drug. The plasma concentration is 0.1 to 100 ng / ml (nanogram / milliliter), more preferably 4 to 40 ng / ml.

The push layer 40 comprises a substitution composition of an arrangement of contact layers with the first component drug layer 30 shown in FIG. 3. Push layer 40 comprises an osmopolymer 41 that can absorb aqueous or physiological fluids and push the drug composition through the outlet means of the device. Polymers having suitable absorbency may be referred to herein as osmopolymers. Osmopolymers are expandable hydrophilic polymers that expand or expand in contact with water and physiological fluids, with a high, typically 2 to 50-fold increase in volume. Osmopolymers may be non-crosslinked or crosslinked, but preferred embodiments are at least slightly crosslinked to build a polymer network that is not too large or entangled to exit the dosage form. Thus, in a preferred embodiment, the expandable composition remains in dosage form for its operational lifetime.

The push layer 40 contains 20 to 375 mg of the osmopolymer 41 represented by " V " in FIG. Osmopolymer 41 in layer 40 has a higher molecular weight than osmopolymer 32 in drug layer 20.

Representative examples of body fluid-absorbing substituted polymers include poly (ethylene oxide) having a number average molecular weight of 500,000 to 3,500,000 and poly (alkylene oxide) having a number average molecular weight of 1 million to 15 million represented by poly (alkoxy carboxymethylcellulose). Selected from the group consisting of, wherein the alkali is sodium, potassium or lithium. Examples of additional polymers in the formulation of the push-substituted compositions include Carbopol ^R acid carboxypolymers, polyallyl sucrose and acrylic crosslinked polymers (also known as carboxypolymethylenes) and carboxyvinyl polymers having a molecular weight of 250,000-4,000,000; Cyanamer ^R polyacrylamide; Crosslinked water-expandable indenmaleic anhydride polymers; Good-rite ^R polyacrylic acid with a molecular weight of 80,000 to 200,000; Osmopolymers comprising polymers that form hydrogels, such as Aqua-Keepse ^R acrylate polymer polysaccharides composed of condensed glucose units such as diester cross-linked polygluran. Representative polymers that form hydrogels are described in US Pat. No. 3,865,108 to Hartop; US Patent No. 4,002,173 by Manning; US Patent No. 4,207,893 by Michaels; And in the prior art of Handbook of Common Polymers, Scott and Roff, Chemical Rubber Co., Cleveland, OH.

Push layer 40 comprises 0-75 mg, preferably 5-75 mg, osmogent effective compound, osmagent 42 (circled in FIG. 3). Osmotically effective compounds are also known as osmagents and osmotically effective solutes. Osmagents 42, which can be found in the drug and push layers of the dosage form, represent osmotic active ingredients through the wall 20. Suitable osmagents are sodium chloride, potassium chloride, lithium chloride, magnesium sulfate, magnesium chloride, potassium sulfate, sodium sulfate, lithium sulfate, phosphate phosphate, mannitol, urea, isocitol, magnesium succinate, tartaric acid, raffinose, sucrose, glucose , Lactose, sorbitol, inorganic salts, organic salts and carbohydrates.

Push layer 40 further comprises a therapeutically acceptable vinyl polymer 43, indicated by a triangle in FIG. 3. Vinyl polymers include poly-n-vinylamide, poly-n-vinylacetamide, poly (vinyl pyrrolidone) (also known as poly-n-vinylpyrrolidone), poly-n-vinylcaprolactone, poly- poly-n-vinyl with a member selected from the group consisting of n-vinyl-5-methyl-2-pyrrolidone and vinyl acetate, vinyl alcohol, vinyl chloride, vinyl fluoride, vinyl butyrate, vinyl laurate and vinyl stearate Viscosity-average molecular weights from 5,000 to 350,000 represented by a member selected from the group consisting of pyrrolidone copolymers. The push layer comprises 0.01 to 25 mg of vinyl polymer.

Push layer 40 may further comprise 0-5 mg of non-toxic colorant or dye 46, indicated by the wavy lines in FIG. The colorant is a food and drug administration colorant (FD & C), for example FD & C No. 1 blue dye, FD & C No. 4 red dye, red ferric oxide, yellow ferric oxide, titanium dioxide, carbon black and indigo.

The push layer 40 may further comprise a lubricant 44, shown in semicircle in FIG. 3. Representative lubricants include members selected from the group consisting of sodium stearate, potassium stearate, magnesium stearate, stearic acid, calcium stearate, sodium oleate, calcium palmitate, sodium laurate, sodium ricinoleate and potassium linoleate. Include. The concentration of lubricating oil is 0.01 to 10 mg.

Push layer 40 may further include an antioxidant 45, indicated by hatched in FIG. 3, to prevent oxidation of the components comprising inflatable formulation 40. Push layer 40 contains 0.00-5 mg of antioxidant. Representative antioxidants include ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, mixtures of 2 and 3 t-butyl-4-hydroxyanisole, butylated hydroxytoluene, sodium isoascorbate, dihydrogua With lactic acid, potassium sorbate, sodium bisulfate, sodium metabisulfate, sorbic acid, potassium ascorbate, vitamin, E, 4-chloro-2,6-di-t-butylphenol, alpha-tocopherol and propylgallate Contains members selected from the configured group.

4 depicts a preferred embodiment of the present invention comprising an overcoat 50 of drug 31 in the dosage form of FIG. 3. Dosage form 10 of FIG. 4 includes an overcoat 50 on the outer surface of the wall 20 of the dosage form 10. Overcoat 50 is a therapeutic composition comprising 0.5 to 75 mg of oxycodone 31 and 0.5 to 275 mg of a pharmaceutically acceptable carrier selected from the group consisting of alkylcelluloses, hydroxyalkylcelluloses and hydroxypropylalkylcelluloses. Overcoats are represented by methylcellulose, hydroxyethylcellulose, hydroxybutylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxypropylethylcellulose and hydroxypropylbutylcellulose. The overcoat 50 immediately exhibits a therapeutic effect by dissolving or dissolving the overcoat 50 in the presence of gastrointestinal fluid to enter the gastrointestinal tract with the delivery agent oxycodone drug 31 and immediately exhibit an oxycodone therapeutic effect.

Exemplary solvents suitable for preparing the dosage form components include aqueous or inert organic solvents that do not harm the materials used in the system. Solvents broadly include aqueous solvents, alcohols, ketones, esters, ethers, aliphatic hydrocarbons, halogenated solvents, cycloaliphatic, aromatic, heterocyclic solvents and mixtures thereof. Representative solvents are acetone, diacetone alcohol, methanol, ethanol, isopropyl alcohol, butyl alcohol, methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, methyl isobutyl ketone, methyl propyl ketone, n-hexane, n- Heptane, ethylene glycol monoethyl ether, ethylene glycol monoethyl acetate, methylenestyrene dichloride, ethylene dichloride, propylene dichloride, carbon tetrachloride nitroethane, nitropropane tatrachloroethane, ethyl ether, isopropyl ether, cyclohexane, cyclooctane , Aqueous solvents containing inorganic salts such as benzene, toluene, naphtha, 1,4-dioxane, tetrahydrofuran, diglyme, water, sodium chloride, calcium chloride, and the like, acetone and water, acetone and methanol, acetone and ethyl alcohol, Such as methylene chloride and methanol, and ethylene dichloride and methanol It includes a mixture of these.

The wall 20 is formed to penetrate through external body fluids such as water and menstrual fluid, and substantially does not penetrate oxycodone, osmagent, osmopolymer, and the like. It is semipermeable in itself. Optionally semipermeable compositions used to form walls are non-corrosive and they are substantially insoluble in menstrual fluid for the life of the dosage form.

Representative polymers forming the wall 20 include semipermeable homopolymers, semipermeable copolymers, and the like. Such materials include cellulose esters, cellulose ethers and cellulose ester-ethers. The cellulose polymer has an anhydrous glucose unit substitution degree (DS) of greater than 0 and 3 or less. Degree of substitution (DS) means the average number of hydroxyl groups originally present on anhydrous glucose units replaced by or substituted by a substitution group. Anhydroglucose units are in groups such as acyl, alkanoyl, alkenoyl, aroyl, alkyl, alkoxy, halogen, carboalkyl, alkylcarbamate, alkylcarbonate, alkylsulfonate, alkylsulfate, alkylsulfamate, semipermeable polymer forming groups, and the like. It may be partially or fully substituted, wherein the organic moiety contains 1 to 12, preferably 1 to 8 carbon atoms.

Semipermeable compositions typically comprise cellulose acylate, cellulose dicylate, cellulose triacylate, cellulose acetate, cellulose diacetate, cellulose triacetate, mono-, di- and tri-cellulose alklates, mono-, di-, and Members selected from the group consisting of tri-alkenylate, mono-, di- and tri-aroylate and the like. Exemplary polymers include cellulose acetate having a DS of 1.8 to 2.3 and an acetyl content of 32 to 39.9%; Cellulose diacetate with DS 1-2 and an acetyl content of 21-35%; Cellulose triacetate and the like having DS 2 to 3 and an acetyl content of 34 to 44.8%. More specific cellulose polymers include cellulose propionate having a DS 1.8 and propionyl content of 38.5%; Cellulose acetate propionate with an acetyl content of 1.5 to 7% and a propionyl 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%; Cellulose acetate butyrate having a DS 1.8, an acetyl content of 13 to 15% and a butyryl content of 34 to 39%; Cellulose acetate butyrate having an acetyl content of 2 to 29%, a butyryl content of 17 to 53%, and a hydroxyl content of 0.5 to 4.7%; Cellulose triacylates that are DS 2.6 to 3, such as cellulose trivalelate, cellulose trilamate, cellulose tripalmitate, cellulose trioctanoate and cellulose tripropionate; Cellulose diesters having a DS of 2.2 to 2.6, such as cellulose disuccinate, cellulose dipalmitate, cellulose dioctanoate, cellulose dicaprylate and the like; And mixed cellulose esters such as cellulose acetate valerate, cellulose acetate succinate, cellulose propionate succinate, cellulose acetate octanoate, cellulose valerate palmitate, cellulose acetate heptanoate, and the like. Semipermeable polymers are known from US Pat. No. 4,077,407 and described in Encyclopedia of Polymer Science and Technology , Vol. 3, pp. 325-354 (1964), Interscience Publishers Inc., New York, NY.

Additional semipermeable polymers for forming the outer wall 20 include cellulose acetaldehyde dimethyl acetate; Cellulose acetate ethyl carbamate; Cellulose acetate methyl carbamate; Cellulose dimethylaminoacetate; Semipermeable polyamides; Semipermeable polyurethanes; Semipermeable sulfonated polystyrene; US Patent No. 3,173,876; 3,276,586; 3,541,005; Crosslinked selective semipermeable polymers formed by coprecipitation of anions and cations as described in 3,541,006 and 3,546,142; Semipermeable polymers as described in US Pat. No. 3,133,132 to Loeb, et al .; Semipermeable polystyrene derivatives; Semipermeable poly (sodium styrenesulfonate); Semipermeable poly (vinylbenzyltrimethylammonium chloride); And semipermeable polymers exhibiting fluid permeability of 10 ⁻⁵ to 10 ⁻² (cc.mil/cm hr.atm) as converted for the atmosphere of hydraulic or osmotic pressure difference through the semipermeable wall. Such polymers in the art are described in US Pat. No. 3,845,770; 3,916,899 and 4,160,020; And Handbook of Common Polymers, Scott and Roff (1971) CRC Press, Cleveland, OH.

Wall 20 may also include a flux-regulator. Flux modifiers are compounds added to help regulate flux or fluid permeability through the wall 20. The flux-modulating agent may be a flux enhancer or a flux reducer. This agent may be preselected to increase or decrease the liquid flux. Agents that significantly increase the permeability to fluids such as water are often hydrophilic in nature, while agents that significantly reduce the permeability to fluids such as water are hydrophobic in nature. When impregnated into the wall the amount of intra-wall regulator is generally at least about 0.01 to 20% by weight. Flux modifiers may include polyhydric alcohols, polyalkylene glycols, polyalkylenediols, polyesters of alkylene glycols, and the like. Representative flux 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: polyalkylenediols such as poly (1,3-propanediol), poly (1,4-butanediol), poly (1 , 6-hexanediol); Aliphatic diols such as 1,3-butylene glycol, 1,4-pentamethylenestyrene glycol, 1,4-hexamethylenestyrene glycol, and the like; Alkylene triols such as glycerin, 1,2,3-butanetriol, 1,2,4-hexanetriol, 1,3,6-hexanetriol and the like; Esters such as ethylene glycol dipropionate, ethylene glycol butyrate, butylene glycol dipropionate, glycerol acetate esters and the like. Preferred flux enhancers for the present invention include difunctional block-copolymer polyoxyalkylene derivative groups of propylene glycol known as Pluronic (BASF). Representative flux reducers are phthalates substituted with alkyl or alkoxy, or both alkyl and alkoxy groups, for example diethyl phthalate, dimethoxyethyl phthalate, dimethyl phthalate, and [di (2-ethylhexyl) phthalate, aryl phthalate, eg Triphenyl phthalate, and butyl benzyl phthalate, polyvinyl acetate, triethyl straight, euuragit, insoluble salts such as calcium sulfate, barium sulfate, calcium phosphate, etc., insoluble oxides such as titanium oxide, powder Polymers in the form of granules, such as polystyrene, polymethylmethacrylate, polycarbonate, and polysulfone; Esters such as citric acid esters esterified with long-chain alkyl groups, inert and substantially water impermeable fillers, resins that are compatible with wall forming materials of the cellulose lineage, and the like.

Other materials may be included in the semipermeable wall material to impart flexibility and extensibility, to lessen the wall 20, and to impart burst strength. Suitable materials include phthalate plasticizers such as dibenzyl phthalate, dihexyl phthalate, butyl octyl phthalate, linear phthalates having 6 to 11 carbon atoms, diisononyl phthalate, diisodecyl phthalate and the like. Plasticizers include triacetin, dioctyl azelate, epoxidized talate, triisooctyl trimellitate, triisononyl trimellitate, sucrose asobutyrate, epoxidized soybean oil, and the like. When impregnated into the wall, the amount of plasticizer in the wall is about 0.01% to 20% by weight or more.

Fan coatings may conveniently be used to provide a full dosage form with the exception of the exit orifice. In a pan coating system, the wall-forming composition for the wall 20 is applied with a suitable wall composition onto a single or two-layer compression core comprising a drug layer for a single layer core or a push layer for a two layer core and a drug layer while tumbling the rotating pan. It is deposited by continuous spraying. Other techniques can be used for the compression core coating. Once coated, the walls are dried in a forced-air oven or temperature and humidity controlled oven to remove the solvent (s) used in the preparation from the dosage form. Drying conditions will typically be selected based on the equipment used, ambient conditions, solvents, coatings, coating thickness, and the like.

Other coating techniques can also be used. For example, the dosage form wall (s) can be formed by techniques using an air-suspension method. The method consists of floating and tumbling the compressed single or two-layer cores into the air and impermeable wall forming composition airflow until the walls are applied to the cores. Air-suspension methods are well suited for independently forming the walls of the dosage form. Air-suspension methods are described in US Pat. No. 2,799,241; J. Am. Pharm. Assoc ., Vol. 48, pp. 451-459 (1959); And Vol. 49, pp. 82-84 (1960). Dosage forms may also be coated with a Wurster ^R air-suspension coater using, for example, methylene dichloride methanol as cosolvent for the wall forming material. Aromatic ^R air-suspension coaters can be used using cosolvents.

Dosage forms according to the invention are prepared by standard techniques. For example, dosage forms can be made by wet granulation techniques. In wet granulation techniques, drugs and carriers are blended using an organic solvent, such as modified anhydrous ethanol, as the granulation fluid. The remaining ingredients are dissolved in the part of the granulation fluid as described above with the solvent, after which the solution prepared is slowly added to the drug blend by continuous mixing in the blender. The granulation fluid is added until a wet blend is obtained, after which the wet mass blend is forced into the oven tray through a predetermined screen. The blend is dried in a forced-air oven at 24-35 ° C. for 18-24 hours. The dried granules are sized. Magnesium stearate or other suitable lubricating oil is then added to the drug granules, the granules are introduced into the mill and then mixed on a mill for 10 minutes. The composition is compressed into a layer, for example on a Manesty ^R press or Korsch LCT press. In the case of a bilayer core, the drug-containing layer is compressed and, if wet blends of similarly prepared push layer compositions are included, they are compressed against the drug-containing layer. Interlayer compaction typically occurs under a force of about 50 to 100 Newtons. Final stage compression typically occurs under a force of at least 3,500 Newtons, often 3,500 to 5,000 Newtons. The single or double layer compression core is fed to a dry coater press, for example a Kilian ^R Dry Coater press, and subsequently coated with a wall material as described above.

One or more exit orifices are perforated at the drug layer end of the dosage form and coated with the dosage form with any water soluble overcoat that can be colored (eg Opadry color coating) or transparent (eg Opadry transparent) to provide the final dosage form. .

In another method of manufacture, the drug and other components, including the drug layer, are blended and compressed into a solid layer. The layer has a dimension corresponding to the internal dimension of the area that the layer occupies in the dosage form, which, when included, also has a size corresponding to the second push layer to make contact arrangement therewith. Drugs and other ingredients may also be blended with the solvent and mixed in a solid or semi-solid form by conventional methods, such as ballmilling, calendering, stirring or rollmilling, and then in a predetermined form. Can be compressed. Then, when included, the layer of osmopolymer composition is contacted in a manner similar to the drug layer. Lamination of the drug formulation and of the osmopolymer layer can be prepared by conventional two-layer compression techniques. The compression core can then be coated with a semipermeable wall material as described above.

Another method of preparation that can be used involves blending the powder components for each bed in a fluid bed granulator. After dry blending the powder components in the granulator, the granulating fluid, for example poly (vinylpyrrolidone) in water, is sprayed onto the powder. The coated powder is dried in a granulator. This process granulates all components present during the granulation fluid addition. After the granules are dried, lubricating oils such as stearic acid or magnesium stearate are mixed into the granules using a blender such as a V-blend or a tote blender. The granules are then compressed in the manner described above.

Each dosage form is provided with an outlet 60. The outlet 60 cooperates with the compressed core for uniform release of the drug from the dosage form. The outlet may be provided during dosage form manufacture or during drug delivery by dosage form in the use fluid environment.

The outlet 60 includes an orifice formed or formable from a material or polymer that erodes, dissolves or leaches from the outer wall to form the outlet orifice. Such materials or polymers include, for example, corrosive poly (glycol) acids or poly (acet) acids in semipermeable membranes; Gelatinous filaments; Water-removable poly (vinyl alcohol); Richable compounds, for example, fluid-removable pore-formers selected from the group consisting of inorganic or organic salts, oxides and carbohydrates.

The outlet or multiple outlets may leach a member selected from the group consisting of sorbitol, lactose, fructose, glucose, mannose, galactose, talos, sodium chloride, potassium chloride, sodium citrate and mannitol to provide a pore-outlet orifice with uniform emission dimensions Can be formed.

The outlet can take any form, for example round, triangular, square, oval, etc. to release a uniform dose from the dosage form.

One or more outlets in the dosage form may be configured at regular intervals or on one or more surfaces of the dosage form.

Drilling, including mechanical and laser drilling through a semipermeable membrane, can be used to form the exit orifice. Such outlets and outlet forming equipment are described in US Pat. No. 3,916,899 by Theeuwes and Higuchi and US Pat. No. 4,088,864 by Theeuwes et al., The contents of which are incorporated herein by reference. It is preferable to use a single outlet orifice herein.

The unique release rate profile of the present invention provides an effective oxycodone therapeutic effect over 24 hours. This dosage form releases oxycodone for 24 hours after dosing, which initiates immediate-release with drug overcoat and continuously delivers the drug in a controlled manner until the core stops drug release.

The release rate of the invention is characterized by a T ₇₀ of about 10 to 20 hours, preferably 15 to 18 hours and more preferably about 17 hours. Dosage forms of the invention are also characterized as having a C _max of _greater than 15 hours after administration and less than 2 times C ₂₄ to create an even plasma concentration profile over 24 hours. This property is remarkable in that it has an immediate-release coating and accompanying peak plasma concentrations, but does not reach maximum plasma concentrations until about 15 hours after administration. This new property unexpectedly provides effective treatment while maintaining drug plasma levels low enough to reduce the side effects associated with high plasma concentration levels. This delivery property also provides 24-hour efficacy without high plasma concentrations and sub-plasma concentrations.

According to the above information obtained empirically using conventional immediate-release dosage forms, oxycodone may be provided in the sustained release dosage form of the invention in an amount of preferably about 10 to 100 mg or less. In a preferred single drug layer embodiment of the daily dosage form according to the invention, the drug layer comprises oxycodone at a dose of 20 to 80 mg of oxycodone per dosage form.

Exemplary dosage forms have T ₇₀ values in excess of 14 hours and release oxycodone for consecutive hours in excess of 22 hours. Within about 2 hours after administration, each different dosage form releases the oxycodone from the core at a consistent, consistent release rate for at least about 22 hours. Such release in a preferred embodiment occurs subsequent to the release of the immediate-release coating.

In a bilayer embodiment of a once-daily dosage form according to the invention, the dosage form has a T ₇₀ value of about 15 to 18 hours and preferably about 17 hours, releasing oxycodone for a continuous time of at least about 24 hours. . Within about 2 hours after administration, oxycodone is released at a consistent, consistent release rate for a long time. According to this long, uniform release rate, drug release lasts for several hours until the dosage form disappears.

When the drug is released at a uniform release rate as determined by the sustained release rate assays disclosed herein, the dosage forms of the present invention slowly release the drug over a continuous time period that includes a long time. When administered to a subject, the dosage forms of the present invention provide plasma drug concentrations in the subject in a less variable state over a longer period than that obtained with an immediate-release dosage form. When the dosage form of the present invention is administered in a once-daily manner, the dosage form of the present invention provides a therapeutically effective average steady-state plasma oxycodone concentration, while taking existing extended release dosage forms and immediate-release oxycodone doses. It is less than the steady state peak plasma oxycodone concentration that occurs after administration of the form and provides a steady state peak plasma oxycodone concentration that occurs later time after dose administration.

The present invention includes methods for treating disease states and symptoms responsive to the treatment of oxycodone by oral administration of a sustained release dosage form of oxycodone to a subject. The method is carried out in a dosage form prepared to release the compound at a uniform release rate of from about 1% / hr to about 6% / hr over at least about 20 hours, preferably 22 hours or more.

It is preferable to treat the pain by performing the above method by orally administering the oxycodone dosage form to the subject once a day. Other disease states and symptoms that can be clinically judged or manifest as signs of pain can be treated with the oxycodone dosage forms and methods of the present invention. In addition, other disease states and symptoms that may or may not appear with pain, but may respond to oxycodone treatment, may also be treated with the dosage forms and methods of the present invention.

Preferred methods for preparing the dosage forms of the invention are described generally in the Examples below. All percentages are by weight unless otherwise specified.

Description of Embodiments of the Invention

The following examples are intended to illustrate the invention, and as these examples and other equivalents thereof will be apparent to those skilled in the art in light of the description, drawings and claims of the invention, it is intended to limit the scope of the invention in any way. It should not be interpreted.

Example 1

Biconvex Oxycodone-Hydrochloride Bilayer 20 mg System

Modified, designed and shaped dosage forms as an osmotic drug delivery device were prepared as follows: Oxycodone hydrochloride, USP, 1933 g, 7803 g polyethylene oxide with an average molecular weight of 200,000, an average molecular weight of 40,000 and identified as K29-32. 200 g of polyvinylpyrrolidone was added to a fluid bed granulator ball. A binder solution was then prepared by dissolving 500 g of the same polyvinylpyrrolidone in 4500 g of water. The dry material is a granulated fluidized bed sprayed with 2000 g of binder solution. The wet granules were then dried to an acceptable level of moisture content in the granulator and sized by passing through a 7-mesh screen. The granules were then transferred to a blender, mixed with 2 g of butyltoluene butylated with antioxidant and lubricated with 25 g of magnesium stearate.

Next, the push composition was prepared as follows: First, a binder solution was prepared. 15.6 g of polyvinylpyrrolidone identified as K29-32 with an average molecular weight of 40,000 was dissolved in 104.4 kg of water. 24 kg sodium chloride and 1.2 kg ferric oxide were then sized using Quadro Comil with a 21-mesh screen. Subsequently, 88.44 kg of the sifted material and polyethylene oxide (molecular weight about 2,000,000) were added to the fluid bed granulator ball. The dry material was fluidized and 46.2 kg of the binder solution was sprayed onto the powder from three nozzles while mixing. The granules were dried to an acceptable moisture level in the fluid bed chamber. The coated granules were sized using a Fluid Air Mill with 7-mesh screen. The granules were transferred to a tote tumbler, mixed with 15 g of butylated hydroxytoluene and lubricated with 294 g of magnesium stearate.

Next, the oxycodone hydrochloride drug composition and push composition were compressed into a bilayer tablet. First, 113 mg of the oxycodone hydrochloride composition was added to the die cavity and pre-compressed, then 103 mg of the push composition was added and the layers compressed into a standardized round concave bilayer arrangement of 5/16 "in diameter.

The bilayer arrangement was coated with semipermeable walls. The wall-forming composition consists of 99% cellulose acetate with an acetyl content of 39.8% and 1% polyethylene glycol with a viscosity-average molecular weight of 3.350. The wall-forming composition was dissolved in an acetone: water (95: 5 wt: wt) cosolvent to make a 5% solid solution. The wall-forming composition was sprayed over and around the bilayer arrangement in a pan coater until 39 mg of film was applied to each tablet.

Next, a 40 mil (1 mm) exit passage was perforated with a laser in the semipermeable membrane to connect the drug layer with the outside of the dosing system. The residual solvent was removed by drying at 45 ° C. and 45% humidity for 48 hours. After drilling, the osmotic system was dried at 45 ° C. for 4 hours to remove excess moisture.

The perforated drying system was then coated with an immediate-release drug overcoat. Drug overcoat is an 8% solid aqueous solution containing oxycodone HCl, USP, 157.5 g and 850 g of hydroxypropyl methylcellulose with an average molecular weight of 11,200. The drug overcoat solution was sprayed onto the dried coating core until a coating weight of about 8 mg per system was obtained.

The drug-overcoated system is then color overcoated. Color overcoat is a 12% solid suspension of Opadry in water. The color overcoat suspension was sprayed onto the drug overcoated system until a coating weight of about 8 mg per system was obtained.

The color-overcoated system was then transparent coated. The clear coating is 5% solid solution of Opadry underwater. The clear coat solution was sprayed onto the color coated cores until a coating weight of about 3 mg per system was obtained.

The clear coated system was then coated with about 1 g of carnauba wax in such a way that the wax dispersed on the system when tumbling in a pan coater.

The dosage form produced by this preparation was delivered as an immediate-release from overcoat consisting of oxycodone HCl, USP 15% and hydroxypropyl methylcellulose, followed by delivery of 1 mg of oxycodone hydrochloride USP, followed by oxycodone hydrochloride, USP 17.7%, It is designed to control release 78.03% polyethylene oxide with a molecular weight of 200,000, 4% polyvinylpyrrolidone with a molecular weight of 40,000, 0.02% of butylated hydroxytoluene and 0.25% of magnesium stearate. The push composition consists of 73.7% polyethylene oxide with a molecular weight of 7,000,000, 20% sodium chloride, 5% polyvinylpyrrolidone with an average molecular weight of 40,000, 1% ferric oxide, 0.05% butylated hydroxytoluene and 0.25% magnesium stearate. The semipermeable wall is composed of 99% by weight cellulose acetate with 39.8% acetyl content and 1% polyethylene glycol. The dosage form includes one 40 mil (1 mm) passageway in the center of the drug side. Final dosage forms include color overcoat, clear overcoat and wax coat and have an average release rate (4.66% / hr) of oxycodone hydrochloride, USP 0.93 mg per hour.

Example 2

Biconvex Oxycodone Hydrochloride Bilayer 80 mg System

Modified, designed and shaped dosage forms as osmotic drug delivery devices were prepared as follows: Oxycodone hydrochloride, USP, 32.28 kg, 63.73 kg polyethylene oxide with an average molecular weight of 200,000 was added to the fluid bed granulator ball. A binder solution was then prepared by dissolving 5.45 kg g of polyvinylpyrrolidone identified as K29-32 with an average molecular weight of 40,000 in 40 g of water. The dry material is a granulated fluidized bed sprayed with 33.3 kg of binder solution. The wet granules were then dried to an acceptable level of moisture content in the granulator and sized by passing through a 7-mesh screen. The granules were then transferred to a blender, mixed with 0.02 kg of butyltoluene butylated with antioxidant, and lubricated with 0.25 kg of magnesium stearate.

Next, a push composition was prepared as follows: First, a binder solution was prepared by dissolving 15.6 g of polyvinylpyrrolidone, identified as K29-32, with an average molecular weight of 40,000 in 104.4 kg of water. 24 kg sodium chloride and 1.2 kg ferric oxide were then sized using Quadro Comil with a 21-mesh screen. 88.44 kg of the sized material and polyethylene oxide (molecular weight about 2,000,000) were added to the fluid bed granulator ball. The dry material was fluidized and 46.2 kg of the binder solution was sprayed onto the powder from three nozzles while mixing. The granules were dried to an acceptable moisture level in the fluid bed chamber. The coated granules were sized using a Fluid Air Mill with 7-mesh screen. The granules were transferred to a tote tumbler, mixed with 15 g of butylated hydroxytoluene and lubricated with 294 g of magnesium stearate.

Next, the oxycodone hydrochloride drug composition and push composition were compressed into a bilayer tablet. First, 250 mg of the oxycodone hydrochloride composition was added to the die cavity to pre-compress, then 192 mg of the push composition was added and the layers compressed into a standardized round concave bilayer arrangement of 13/32 "(1.03 cm) in diameter.

The bilayer arrangement was coated with semipermeable walls. The wall forming composition consists of 99% cellulose acetate with an acetyl content of 39.8% and 1% polyethylene glycol with a viscosity-average molecular weight of 3.350. The wall-forming composition was dissolved in acetone: water (95: 5 wt: wt) cosolvent to make 5.5% solid solution. The wall-forming composition was sprayed over and around the bilayer arrangement in a pan coater until 40 mg of film was applied to each tablet.

Next, a 40 mil (1 mm) exit passage was perforated with a laser in the semipermeable membrane to connect the drug layer with the outside of the dosing system. The residual solvent was removed by drying at 45 ° C. and 45% humidity for 48 hours. After drilling, the osmotic system was dried at 45 ° C. for 4 hours to remove excess moisture.

The perforated drying system was then coated with an immediate-release drug overcoat. Drug overcoat is a 13% solid aqueous solution containing oxycodone HCl, USP, 1.08 kg and 6.1 kg hydroxypropyl methylcellulose with an average viscosity of 3 centipoise. The drug overcoat solution was sprayed onto the dried coating core until a coating weight of about 31 mg per system was obtained.

The drug-overcoated system is then color overcoated. Color overcoat is a 12% solid suspension of Opadry in water. The color overcoat suspension was sprayed onto the drug overcoated system until a coating weight of about 36 mg per system was obtained.

The color-overcoated system was then transparent coated. The clear coating is 5% solid solution of Opadry underwater. The clear coat solution was sprayed onto the color coated cores until a coating weight of about 7 mg per system was obtained.

The clear coated system was then coated with about 100 ppm carnauba wax in such a way that the wax dispersed on the system when tumbling in a pan coater.

The dosage form produced by this preparation was delivered as an immediate release from overcoat consisting of 15% oxycodone HCl USP and 85% hydroxypropyl methylcellulose, followed by delivery of 4 mg oxycodone hydrochloride USP 32%, oxycodone hydrochloride USP 32%, molecular weight 200,000 Designed to release 63.73% polyethylene oxide, 4% polyvinylpyrrolidone having a molecular weight of 40,000, 0.02% butylated hydroxytoluene and 0.25% magnesium stearate. The push composition consists of 73.7% polyethylene oxide with a molecular weight of 7,000,000, 20% sodium chloride, 5% polyvinylpyrrolidone with an average molecular weight of 40,000, 1% ferric oxide, 0.05% butylated hydroxytoluene and 0.25% magnesium stearate. The semipermeable wall is composed of 99% by weight cellulose acetate with 39.8% acetyl content and 1% polyethylene glycol. The dosage form includes one 40 mil (1 mm) passageway in the center of the drug side. Final dosage forms include color overcoat, clear overcoat and wax coat and have an average release rate (5.52% / hr) of 4.42 mg of oxycodone hydrochloride per hour.

Example 3

Capsule-type Oxycodone Hydrochloride Tablets 23.1 mg System

Modified, designed and shaped dosage forms as an osmotic drug delivery device were prepared as follows: 23.1 g of oxycodone hydrochloride, 166.5 g of polyethylene oxide with an average molecular weight of 200,000, polyvinyl having an average molecular weight of 40,000 and identified as K29-32. 10.0 g of pyrrolidone was added to a KitchenAid planetary mixing bowl. Next, the dry material was mixed for 30 seconds.

Then 80 ml of denatured anhydrous alcohol was slowly added to the blended material with continuous mixing for approximately 2 minutes. The freshly prepared wet) granules were then dried at room temperature for approximately 18 hours and passed through a 16-mesh screen. The granules were then transferred to a suitable container for mixing and lubricated with 1.0 g of stearic acid followed by 0.5 g of magnesium stearate.

Next, the push composition was prepared as follows: First, a binder solution was prepared. 5.2 kg of poly (vinylpyrrolidone) identified as K-29-32 with an average molecular weight of 40,000 was dissolved in 34.8 kg of water.

22,400 g of sodium chloride were sized using Quadro Comil with a 21-mesh screen.

Next, 1,120 g of ferric oxide was passed through a 40-mesh screen. Subsequently, 82,5400 g of all sifted material, pharmaceutically acceptable poly (ethylene oxide) having a molecular weight of 7,000,000 was added to the Glatt Fluid Bed Granulator ball. The granulation process was initiated to attach the balls to the granulator and to granulate. The dry powder was then air suspended and mixed. The binder solution was then sprayed onto the powder from three nozzles. During the process, the granulation conditions were monitored as follows: 700 g / min spray rate of the total solution; Inlet temperature of 45 ° C .; And process air flow 2000 m 3 / hour.

While spraying the binder solution, the filter bag was shaken every 30 minutes for 10 seconds to release any possible powder precipitation. At the end of the solution spray, the dry process continued for 43,080 g of coated granulated particles. The machine was stopped and the coating powder removed from the granulator.

The coated granules were sized using a Fluid Air mill with a 7-mesh screen. The granules were transferred to Tote Tumbler, mixed with 56 g of butylated hydroxytoluene and lubricated with 280 g of magnesium stearate.

The oxycodone hydrochloride drug component and push composition were then compressed into bilayer tablets on a Carver tablet. First, 164.3 mg of the oxycodone hydrochloride component was pre-compressed by addition to the die cavity, then 109.5 mg of the push composition was added, and the layers were placed in a concave vertical layer arrangement of diameter 13/64 "(0.516 cm) under pressure of approximately 500 kilograms. Compressed.

The bilayer arrangement was coated with a subcoat layer. The wall-forming component comprises 70% of hydroxypropyl cellulose having an average molecular weight of 60,000 and 30% of poly (vinylpyrrolidone) having an average molecular weight of 40,000 and identified as K29-32. The wall-forming component was dissolved in ethanol to make 6% solid solution. The wall-forming component was sprayed over or around the bilayer in a 12 "Vector HiCoater.

The subcoated arrays were coated with semipermeable walls. The wall-forming component consists of 99% cellulose acetate with an acetyl content of 39.8% and 1% polyethylene glycol with a viscosity-average molecular weight of 3.350. The wall-forming component was dissolved in acetone: water (95: 5 wt: wt) cosolvent to make 5% solid solution. The wall-forming component was sprayed over or around the bilayer in a 12 "Vector HiCoater.

Next, one 35 mil (0.889 mm) outlet passage was mechanically drilled into the semipermeable membrane to connect the drug layer to the outside of the dosing system. The residual solvent was removed by drying at 45 ° C. and 45% humidity for 66 hours. The osmotic system was then dried at 45 ° C. for 4 hours to remove excess moisture. The dosage forms produced by this preparation were 11.5% oxycodone hydrochloride USP, 82.78% poly (ethylene oxide) with a molecular weight of 200,000, 4.97% poly (vinylpyrrolidone) with a molecular weight of 40,000, 0.5% stearic acid and 0.25% magnesium stearate. To provide. The push composition is 73.7% poly (ethylene oxide) with a molecular weight of 7,000,000, 20% sodium chloride, 5% poly (vinylpyrrolidone) with an average molecular weight of 40,000 and identified as K29-32, ferric oxide 1%, butylated hydroxytoluene 0.05% and 0.25% stearic acid. The semipermeable wall consists of 99% by weight cellulose acetate with 39.8% acetyl content and 1% polyethylene glycol with a viscosity-average molecular weight of 3350. The dosage form includes one 35 mil (0.899 mm) passageway and its oxycodone hydrochloride average release rate was 0.77 mg / hr.

Example 4

Oxycodone Hydrochloride 23.1 g Two-Layer System

Modified, designed and shaped dosage forms as an osmotic drug delivery device were prepared as follows: 23.1 g of oxycodone hydrochloride, 156.5 g of poly (ethylene oxide) having a molecular weight of 200,000, a poly having an average molecular weight of 40,000 and identified as K29-32. 10.0 g of (vinylpyrrolidone) and 10.0 g of sodium chloride were added to the KitchenAid planetary mixing bowl. Next, the dry material was mixed for 30 seconds. 80 ml of denatured anhydrous alcohol was then slowly added to the blended material with continuous mixing for approximately 2 minutes. Next, the freshly prepared wet granules were dried at room temperature for approximately 18 hours and passed through a 16-mesh screen. The granules were then transferred to a suitable container for mixing and lubricated with 1.0 g of stearic acid followed by 0.5 g of magnesium stearate.

Next, the push composition was prepared as follows: First, a binder solution was prepared. 3.4 kg of hydroxypropylmethylcellulose having an average molecular weight of 11,200 were dissolved in 30.6 kg of water.

27,000 g of sodium chloride were sized using Quadro Comil with a 21-mesh screen.

Next, 900 g of ferric oxide was passed through a 40-mesh screen. Subsequently, all sifted material, 57,300 g of pharmaceutically acceptable poly (ethylene oxide) with a molecular weight of 2,000,000 and 1,800 g of hydroxypropylmethylcellulose with an average molecular weight of 11,200 were added to the Glatt Fluid Bed Granulator ball. The granulation process was initiated to attach the balls to the granulator and to granulate. The dry powder was then air suspended and mixed. The binder solution was then sprayed onto the powder from three nozzles. During the process, the granulation conditions were monitored as follows: 700 g / min spray rate of the total solution; Inlet temperature of 45 ° C .; And process air flow 3000 m 3 / hour.

While spraying the binder solution, the filter bag was shaken every 10 minutes for 10 seconds to release any possible powder precipitation. At the end of the solution spray, the dry process continued for 27,000 g of coated granulated particles. The machine was stopped and the coating powder removed from the granulator.

The coated granules were sized using a Fluid Air mill with a 7-mesh screen. The granules were transferred to Tote Tumbler, mixed with 72 g of butylated hydroxytoluene and lubricated with 225 g of magnesium stearate.

The oxycodone hydrochloride drug component and push composition were then compressed into bilayer tablets on a Carver tablet. First, 113 mg of the oxycodone hydrochloride component is pre-compressed by addition to the die cavity, then 87 mg of the push composition is added, and the layers are placed in a concave vertical layer arrangement of diameter 5/16 "(0.794 cm) under pressure of approximately 500 kilograms. Compressed.

The bilayer arrangement was coated with semipermeable walls. The wall-forming component consists of 99% cellulose acetate with an acetyl content of 39.8% and 1% polyethylene glycol with a viscosity-average molecular weight of 3.350. The wall-forming component was dissolved in acetone: water (95: 5 wt: wt) cosolvent to make 5% solid solution. The wall-forming component was sprayed over or around the bilayer in a 12 "Vector HiCoater.

Next, one 20 mil (0.508 mm) outlet passage was mechanically drilled into the semipermeable membrane to connect the drug layer to the outside of the dosing system. The residual solvent was removed by drying at 45 ° C. and 45% humidity for 48 hours. The osmotic system was then dried at 45 ° C. for 4 hours to remove excess moisture. The dosage forms produced by this preparation are 18.7% oxycodone hydrochloride USP 18.7%, poly (ethylene oxide) 75.55% molecular weight 200,000, 4.96% poly (vinylpyrrolidone) molecular weight 40,000, 0.5% stearic acid and 0.25% magnesium stearate To provide. Push composition consists of 63.67% poly (ethylene oxide) 63.67% molecular weight, 30% sodium chloride, 5% hydroxypropylmethylcellulose with an average molecular weight of 11,200, ferric oxide 1%, butylated hydroxytoluene 0.08% and stearic acid 0.25% do. The semipermeable wall consists of 99% by weight cellulose acetate with 39.8% acetyl content and 1% polyethylene glycol with a viscosity-average molecular weight of 3350. The dosage form includes one 20 mil (0.508 mm) passageway and its oxycodone hydrochloride average release rate was 1.1 mg / hr.

Example 5

Oxycodone Hydrochloride Monolayer Elementary Osmotic Pump System

The system represents an osmotic core containing a drug, surrounded by a semipermeable membrane with a delivery orifice. When this system is exposed to water, the core osmoticly absorbs water at a controlled rate determined by the osmotic pressure of the core components and by the membrane permeability. Because the internal volume is constant, the system delivers an amount of saturated solution equal to the volume of solvent absorbed.

The following shows a prototype system formulation:

Oxycodone HCl 68 mg Monolayer Elementary Osmotic Pump System

core:

Oxycodone HCl 18.9%

Mannitol, NF 73.1

Povidone, USP, Ph Eur (K29-32) 1.0%

Crospovidone 3.0%

HPMC, 2910, USP, 5 cps 3.0%

Magnesium Stearate, NF 1.0%

Total core weight 378 mg

Semipermeable membrane

Cellulose acetate, NF, 320 90%

Polyethylene Glycol 3350, NF, LEO 10%

Solvent: 88% acetone, 12% water

The coating solution contains 5% solids.

Modified, designed and shaped dosage forms as an osmotic drug delivery device were prepared as follows: 37.8 g of oxycodone hydrochloride, 146.2 g of mannitol, poly (vinylpyrrolidone) 2.0 with an average molecular weight of 40,000 and identified as K29-32. 6.0 g and hydroxypropyl methylcellulose (HPMC) 2910 were added to the KitchenAid Planetary Mixing Bowl.

Next, the dry material was mixed for 30 seconds. Then 70 ml of denatured anhydrous alcohol was slowly added to the blended material with continuous mixing for approximately 1 minute. The freshly prepared wet granules were then dried at room temperature for approximately 18 hours and passed through a 12-mesh screen. The granules were then transferred to a suitable container and mixed with 6.0 g crospovidone and blended for 1 minute. The granules were then lubricated with 2.0 g magnesium stearate for 30 seconds.

The oxycodone HCl drug component was compressed into monolayer tablets on a Carver tablet. First, 378 mg of oxycodone hydrochloride composition was added to the die cavity and then compressed into a monolayer arrangement of 3/8 "diameter (0.375 cm) under pressure of Y 2a metric ton.

The compressed arrangement was coated with semipermeable walls. The wall-forming composition comprises 90% cellulose acetate with 32.0% acetyl content and 10% polyethylene glycol with a viscosity-average molecular weight of 3.350. The wall-forming component was dissolved in acetone: water (88:12 wt: wt) cosolvent to make 5% solid solution. Wall-forming components were sprayed over or around the bilayer arrangement in a 12 "Vector HiCoater.

Next, two 10 mil (0.25 mm) outlet passages (one on each side of the tablet) were mechanically drilled into the semipermeable membrane to connect the drug layer to the outside of the dosing system. The residual solvent was removed by drying at 45 ° C. and 45% humidity for 48 hours.

The osmotic system was then dried at 45 ° C. for 4 hours to remove excess moisture.

Example 6

Oxycodone Hydrochloride 73.6 mg Double Layer System

Modified, designed and shaped dosage forms as an osmotic drug delivery device were prepared as follows: 73.6 g of oxycodone hydrochloride, 121.4 g of high viscosity poly (ethylene oxide) with an average molecular weight of 200,000 and an average molecular weight of 40,000 and identified as K29-32. 4.0 g of the prepared poly (vinylpyrrolidone) was added to the KitchenAid planetary mixing bowl. Next, the dry material was mixed for 30 seconds. Then 70 ml of denatured anhydrous alcohol was slowly added to the blended material with continuous mixing for approximately 3 minutes. Next, the newly prepared wet granules were dried at room temperature for approximately 18 hours and passed through a 12-mesh screen. The granules were then transferred to a suitable container for mixing and lubricated with 1.0 g of magnesium stearate.

The push composition was prepared as follows: First, a binder solution was prepared. 5.2 g of poly (vinylpyrrolidone) identified as K29-32 with an average molecular weight of 40,000 were dissolved in 34.8 kg of water.

22,400 g of sodium chloride were sized using Quadro Comil with a 21-mesh screen. Next, 1120 g of ferric oxide was passed through a 21-mesh screen. Subsequently, 82,540 g of all sifted material, pharmaceutically acceptable poly (ethylene oxide) having a molecular weight of 7,000,000 were added to the Glatt Fluid Bed Granulator ball. The granulation process was initiated to attach the balls to the granulator and to granulate. The dry powder was then air suspended and mixed. The binder solution was then sprayed onto the powder from three nozzles. During the process, the granulation conditions were monitored as follows: 700 g / min spray rate of the total solution; Inlet temperature of 45 ° C .; And process air flow 2000 m 3 / hour.

While spraying the binder solution, the filter bag was shaken every 30 seconds for 10 seconds to release any possible powder precipitation. At the end of the solution spray, the dry process continued for 43,080 g of coated granulated particles. The machine was stopped and the coating powder removed from the granulator. The coated granules were sized using a Fluid Air mill with a 7-mesh screen. The granules were transferred to Tote Tumbler, mixed with 56 g of butylated hydroxytoluene and lubricated with 285 g of magnesium stearate.

The oxycodone HCl drug component and push composition were compressed into bilayer tablets on a Carver tablet. First, 194 mg of the oxycodone hydrochloride component was pre-compressed by addition to the die cavity, then 149 mg of push composition was added and the layers were compressed into a monolayer arrangement of 3/8 "diameter (0.375 cm) under pressure of Y 2a metric ton. .

The bilayer arrangement was coated with a subcoat layer. The wall forming composition comprises 70% hydroxypropyl cellulose with an average molecular weight of 60,000 and 30% poly (vinylpyrrolidone) identified with K29-32 with an average molecular weight of 40,000. 6% solid solution is prepared by dissolving the wall-forming composition in ethanol. The wall-forming composition was sprayed onto and around the bilayer of the 12 "Vector HiCoater.

The subcoated arrays were coated with semipermeable walls. The wall forming composition comprises 99% cellulose acetate with an acetyl content of 39.8% and 1% polyethylene glycol with a viscosity-average molecular weight of 3.350. The wall-forming composition was dissolved in an acetone: water (95: 5 wt: wt) cosolvent to prepare a 5% solid solution. The wall-forming composition was sprayed onto and around the bilayer arrangement of 12 "Vector HiCoater.

Next, a 25 mil (0.64 mm) passage was mechanically drilled into the semipermeable wall to connect the drug layer with the exterior of the dosing system. Residual solvent was removed by drying at 45 ° C. and 45% humidity for 48 hours. The osmotic system was then dried at 45 ° C. for 4 hours to remove excess moisture.

The dosage form produced by this preparation provides 36.8% oxycodone hydroclyde USP, 60.7% poly (ethylene oxide) having a molecular weight of 200,000, 4.0% poly (vinylpyrrolidone) having a molecular weight of 40,000, and 0.5% magnesium stearate. . The push composition is 73.7% poly (ethylene oxide) with a molecular weight of 7,000,000, 20% sodium chloride, 5% poly (vinylpyrrolidone) with an average molecular weight of 40,000, 1% ferric oxide, 0.05% butylated hydroxytoluene, and magnesium stearate Contains 0.25%. The semipermeable wall comprises 99% by weight cellulose acetate with an acetyl content of 39.8% and 1% polyethylene glycol with a viscosity-average molecular weight of 3,350.

The dosage form includes one passage of 25 mils (0.64 mm) with an average release rate of oxycodone hydrochloride of 5 mg / hr.

Example 7

Biconvex Oxycodone Hydrochloride 9.5 mg Bilayer System

Dosage forms designed, designed and shaped with an osmotic drug delivery device were prepared as follows:

8.2 g of oxycodone hydrochloride, 72.55 g of poly (ethylene oxide) having a molecular weight of about 200,000, 4 g of poly (vinylpyrrolidone) identified as K29-32 having an average molecular weight of 40,000, and 15 g of sodium chloride were placed in a kitchen aid planetary mixing bowl. . The dry material was mixed for 30 seconds. Thereafter, 70 ml of anhydrous denatured alcohol was slowly added to the mixture while continuing to mix for about 3 minutes. Freshly prepared wet granules were dried at room temperature for about 18 hours and then passed through a 12 mesh sieve. The granules were then transferred to a suitable container for mixing and lubricated with 0.25 g of magnesium stearate.

Push compositions were prepared as follows:

Binder solution was prepared. 5.2 kg of poly (vinylpyrrolidone) identified as K2932 with an average molecular weight of 40,000 was dissolved in 34.8 kg of water.

Next, 22,400 g of sodium chloride were sized using Quadro Comil with a 21-mesh sieve. 1120 g of ferric oxide were passed through a 21-mesh sieve. All filtered material was then placed in a Glatt Fluid Bed Granulator ball with 82,540 g of pharmaceutically acceptable poly (ethylene oxide) having a molecular weight of 7,000,000. The dry powder was air suspended and mixed for about 2 minutes in the granulation chamber. The binder solution is then sprayed onto the powder from three nozzles. The granulation conditions were monitored during the process as follows: total solution spray rate 700 g / min; Inlet temperature of 45 ° C .; And process air flow 2000 m 3 / hr.

While spraying the binder solution, the filter bag was shaken for 10 seconds every 30 seconds to release possible powder precipitation. At the end of solution spray, 43,080 g of coated granulated particles were dried to a loss of about 1.5% of moisture content when dried at 75 ° C. in a granulation chamber. The machine was turned off and the coated granules were removed from the granulator. The size of the coated granules was sized using a Fluid Air mill with a 7 mesh sieve. The granules were transferred to Tote Tumbler, mixed with 56 g of butylated hydroxytoluene and lubricated with 280 g of stearic acid.

Oxycodone HCl drug composition and push composition were compressed into bilayer tablets on the Carver Tablet Press. Initially, 122 mg of the oxycodone hydrochloride composition was placed in a die cavity and pre-compressed, followed by 94 mg of the push composition to compress the layers into a two-layer arrangement of 5/16 "(0.312 cm) diameter under a pressure head of approximately Y 2a metric tons. It was.

The bilayer arrangement was coated with a semipermeable membrane. The film forming composition is 99% of cellulose acetate having an acetyl content of 39.8% and 1% of polyethylene glycol having a viscosity-average molecular weight of 3.350. The dry material was dissolved in an acetone: water (95: 5 wt: wt) cosolvent to prepare a 5% solid solution. The film-forming composition was sprayed on and around the bilayer arrangement in a 24 "Vector HiCoatet.

Next, one 40 mil (1.01 mm) exit passage was mechanically drilled into the semipermeable wall to connect the drug layer with the exterior of the dosing system. Residual solvent was removed by drying at 45 ° C. and 45% humidity for 48 hours. The osmotic system was then dried at 45 ° C. for 4 hours to remove excess moisture.

The dosage form produced by this process provides 8.2% oxycodone hydroclyde USP, 72.55% poly (ethylene oxide) having a molecular weight of 200,000, 4.0% poly (vinylpyrrolidone) having a molecular weight of 40,000, and 0.25% magnesium stearate. . The push composition is 73.7% poly (ethylene oxide) with a molecular weight of 7,000,000, 20% sodium chloride, 5% poly (vinylpyrrolidone) with an average molecular weight of 40,000, 1% ferric oxide, 0.05% butylated hydroxytoluene, and magnesium stearate Contains 0.25%. The semipermeable wall comprises 99% by weight cellulose acetate with an acetyl content of 39.8% and 1% polyethylene glycol with a viscosity-average molecular weight of 3350.

The dosage form comprises one 40 mil (1.01 mm) passageway with 35 mg of membrane and delivers 9.5 mg of oxycodone hydrochloride at an average release rate of 0.5 mg / hr in a 7th order profile of 71.6%.

Description for using the present invention

The invention also relates to a method of administering 1 to 500 mg of oxycodone to a patient in need of analgesic action. This method comprises a poly (vinyl) having from 1 to 500 mg of oxycodone, a poly (alkylene oxide) having a molecular weight of 50,000 to 750,000, 20 to 375 mg of a molecular weight of 5,000 to 350,000, selected from the group consisting of oxycodone base or oxycodone salt administered to a patient from a therapeutic composition. Pyrrolidone) from 0.01 to 25 mg, and from 0.01 to 10 mg of lubricant once orally, wherein the composition provides oxycodone therapy over a long period of time.

The present invention also relates to a method for orally administering 1 to 500 mg of oxycodone to a patient who is allowed to orally 1 to 500 mg of oxycodone, wherein the oxycodone is permeable to aqueous-physiological fluids and contains a semipermeable wall that prevents the passage of oxycodone. Is administered from. The semipermeable wall surrounds an interior space or partition including the oxycodone drug composition and the push composition. The oxycodone drug composition comprises 1 to 500 mg of oxycodone, 20 to 375 mg of poly (alkylene oxide) having a molecular weight of 50,000 to 750,000, 0.01 to 25 mg of poly (vinylpyrrolidone) having a molecular weight of 5,000 to 350,000, and 0 to 10 mg of lubricant. Include. The push composition is a hydrogel polymer such as 20 to 375 mg of poly (alkylene oxide) having a molecular weight of 1,000,000 to 10,000,000, 0 to 75 mg of osmagent, 0 to 75 mg of hydroxyalkylcellulose, 0.01 to 5.5 mg of colorant, lubricant 0.01 to 10 mg, and 0 to 10 mg of antioxidant; At the outlet means of the semipermeable wall, fluid is absorbed through the semipermeable wall and introduced into the dosage form so that the oxycodone composition can be dispensed and the push composition can be expanded to push the oxycodone composition through the outlet to deliver oxycodone from the dosage form. With the combinatorial action of the forms, oxycodone is delivered over a sustained period of time at a controlled rate at a therapeutically effective dose.

Figure 5 shows the mean plasma oxycodone concentration profile for oxycodone treatment on day 1. Osmotic extended-release dosage form results are shown in solid lines with black circles. This dosage form is administered once daily and contains 20 mg of oxycodone.

6 shows mean plasma oxycodone concentrations following oxycodone treatment at steady state on days 4 and 5. In FIG. 6, the solid line with black circles defines the plasma profile for the osmotic dosage form of the present administration administered once daily, the dosage form consisting of 20 mg of oxycodone.

The present invention provides a method of administering oxycodone to a patient, and a method of generating plasma concentrations of oxycodone. The methods of the present invention allow the patient to orally accept a dosage form administered at controlled rates over a continuous time of up to 24 hours of oxycodone for the intended treatment. The method also includes orally administering to the patient a therapeutic dose of oxycodone from a single dosage form administering oxycodone over 24 hours. The method further comprises administering oxycodone to produce a first oxycodone concentration in the plasma, a second elevated oxycodone concentration in the plasma, and a third continuous oxycodone concentration.

Although the embodiments disclosed herein are included, modifications and variations are possible in accordance with the disclosed principles without departing from the invention.

Claims (21)

(a) (i) an osmotic agent and (ii) oxycodone and / or pharmaceutically acceptable acid addition salts (compounds) thereof A core comprising a; (b) a semipermeable membrane surrounding the core; And (c) an outlet orifice in communication with the core to release the compound to the environment through the semipermeable membrane, During the time the average hourly release rate from the core is ΔT _uniform (this starts from the time when the cumulative release of the compound from the core reaches about 25% and ends at the time when the cumulative release of the compound from the core reaches 75%). Or a sustained release oral dosage form for once-daily controlled delivery of oxycodone, which releases the compound at a uniform release rate over an extended period of time such that it varies from ± mean 30% or less from the subsequent hourly mean release rate. The dosage form of claim 1, wherein the hourly mean release rate from the core can vary from ± about 25% or less from the hourly mean release rate before or after DELTA T _uniformity . The dosage form of claim 1, wherein the average hourly release rate from the core can vary from ± about 10% or less from the average hourly release rate before or after DELTA T _uniformity . The dosage form of claim 1, wherein the ΔT _uniformity is at least about 4 hours. The dosage form of claim 1, wherein the ΔT _uniformity is at least about 6 hours. The dosage form of claim 1, wherein the ΔT _uniformity is at least about 10 hours. The dosage form of claim 1, wherein the T ₇₀ value is at least about 10 hours. The dosage form of claim 1, wherein the T ₇₀ value is at least about 15 hours. The dosage form of claim 1, wherein the T ₇₀ value is at least about 17 hours. The dosage form of claim 1, wherein the core comprises polyalkylene oxide. The method of claim 1 wherein the core is (i) a first drug layer comprising a compound and (ii) A dosage form comprising a second expandable layer comprising an osmotic agent but no compound. The dosage form of claim 1 further comprising an immediate-release coating containing the compound. A method of treating a subject's symptoms responsive to administration of oxycodone, characterized in that the dosage form of claim 1 or 12 is administered orally to the subject. 14. The steady-state mean plasma concentration profile of claim 13, wherein the administration of the reference dosage form once daily comprises a maximum value C _max at which the maximum value C _max appears at a time greater than 6 hours after dosing, beginning with administration of the dosage form. How to give. The method of claim 14, wherein C _max appears at a time _greater than 12 hours after administration. The method of claim 14, wherein C _max appears at a time _greater than 15 hours after administration. The method of claim 13, wherein the administration of the reference dosage form once daily provides a steady state mean plasma concentration profile having a maximum value C _max that satisfies the following equation for 24 hours beginning with administration of the dosage form: C _max / D <30 Where C _max is measured in nanograms / milliliter, D is the amount of compound in the dosage form measured in milligrams. 18. The method of claim 17, wherein C _max / D <25. 14. The mean plasma at steady state according to claim 13, wherein the administration of the reference dosage form once a day has a maximum value C _max and a 24-hour value C ₂₄ satisfying the following equation for 24 hours starting with administration of the dosage form. To provide a concentration profile: C _max / 2, C ₂₄ 14. The mean plasma concentration profile of a steady state according to claim 13, wherein the administration of the reference dosage form once a day has a minimum and maximum value C _min and C _max satisfying the following equation for 24 hours starting with administration of the dosage form. How to provide: (C _max -C _min ) / C _min ≤2 The method according to claim 13, wherein the administration of the once-daily reference dosage form has a concentration value of about 5 to about 10 ng / ml when the dosage form contains 20 mg of the compound for 24 hours starting with administration of the dosage form. Providing a mean plasma concentration profile at steady state.