$098738 CONTROLLED RELEASE OXYCODONE COMPOSITIONS
~ACR(3ROUND OF THE INVENTION
Surveys of daily dosages of opioid analgesics required to control pain suggest that an approximately eight-fold range in daily dosages is required to control pain in approximately 90% of patients. This extraordin-ary wide range in the appropriate dosage makes the titra-tion process particularly time consuming and resource consuming, as well as leaving the patient without acceptable pain control for an unacceptably long duration.
In the management of pain with opioid analgesics, it has been commonly observed and reported that there is considerable inter-individual variation in the response to a given dose of a given drug, and, therefore, consid-erable variability among patients in the dosage of opioid analgesic required to control pain without unacceptable side effects. This necessitates considerable effort on the part of clinicians in establishing the appropriate dose in an individual patient through the time consuming process of titration, which requires careful assessment of both therapeutic and side effects and dosage adjust-ments over a period of days and sometimes longer. before the appropriate dosage is determined. The American Pain Society's 3rd Edition of Principles of Analgesic Use in the Treatment of Acute Pain and Cancer Pain, by Mitchell B. Max, M.D., et al., published in l992, explains that one should "be aware that the optimal analgesic dose varies widely among patients. Studies have shown that in a11 age groups, there is enormous variability in doses of opioids required to provide relief, even among opioid naive patients~with identical surgical lesions.... This great variability underscores the need to write analgesic orders that include provision for supplementary doses, and to use intravenous boluses and infusions.to provide rapid relief of severe pain.... Give each analgesic an adequate trial by dose titration...before switching to another drug."
An opioid analgesic treatment which acceptably controls pain over a substantially narrower daily dosage range would, therefore, substantially improve the efficiency and quality of pain management.
It has previously been known in the art that con-trolled release compositions of opioid analgesics such as morphine, hydromorphone or salts thereof could be pre-pared in a suitable matrix. For example, U.S. Patent No.
4,990,341 (Goldie), also assigned to the assignee of the present invention, describes hydromorphone compositions wherein the dissolution rate in vitro of the dosage form, when measured by the USP Paddle Method at 100 rpm in 900 ml aqueous buffer (pH between 1.6 and 7.2) at 37' C, is between 12.5 and 42.5% (by wt) hydromorphone released after 1 hour, between 25 and 55% (by wt) released after 2 hours, between 45 and 75% (by wt) released after 4 hours and between 55 and 85% (by wt) released after 6 hours.
SOMMARY OF THE INVENTION
The present invention provides a method for substantially improving the efficiency and quality of pain management.
The present invention, in another aspect, provides an opioid analgesic formulation which substantially improves the efficiency and quality of pain management.
Another aspect of the present invention can provide a method and formulations) which substantially reduce the approximately eight-fold range in daily dosages required to control pain in approximately 90~ of patients.
B

The present invention can also provide a method and formulations) which substantially reduce the variability in daily dosages and formulation requirements necessary to control pain in substantially a11 patients.
In yet another aspect the present invention provides a method for substantially reducing the time and resources need to titrate patients requiring pain relief on opioid analgesics.
The present invention can also provide controlled release opioid formulations which have substantially less inter-individual variation with regard to the dose of opioid analgesic required to control pain without unacceptable side effects.
The above aspects and others are attained by virtue of the present invention, which is related to a solid controlled release oral dosage form, the dosage form comprising from about 10 to about 40 mg of oxycodone or a salt thereof in a matrix wherein the dissolution rate in vitro of the dosage for~a, when measured by the USP Paddle Method at 1O0 rpm in 900 ml aqueous buffer (pH between 1.6 and 7.2) at 37'C is between 12.5 and 42.5% (by wt) oxycodone released after 1 hour, between 25 and 56% (by wt) oxycodone released after 2 hours, between 45 and 75%
(by wt) oxycodone released after 4 hours and between 55 and 85% (by wt) oxycodone released after 6 hours, the in vitro release rate being substantially independent of pH, such that the peak plasma level of oxycodone obtained in vivo occurs between 2 and 4.5 hours after administration of the dosage form.
USP Paddle Method is the Paddle Method described, e.g., in U.S. Pharmacopoeia XXII (1990).
In the present specification, "substantially independent of pH" means that the difference, at any given time, between the amount of oxycodone released at, e.g., pH 1.6, and the amount released at any other pH, e.g., pH 7.2 (when measured in vitro using the USP Paddle Method at 100 rpm in 900 ml aqueous buffer), is 10% (by weight) or less. The amounts released being, in a11 cases, a mean of at least three experiments.
The present invention is further related to a method for substantially reducing the range in daily dosages re-quired to control pain in approximately 90% of patients, comprising administering an oral solid controlled release dosage formulation comprising from about 10 to about 40 mg of oxycodone or a salt thereof, said formulation pro-viding a mean maximum plasma concentration of oxycodone from about 6 to about 60 ng/ml from a mean of about 2 to about 4.5 hours after administration, and a mean minimum plasma concentration from about 3 to about 30 ng/ml from a mean of about 10 to about 14 hours after repeated "ql2h" (i.e., every 12 hour) administration through steady-state conditions.
The present invention is further related to a method for substantially reducing the range in daily dosages required to control pain in substantially a11 patients, comprising administering an oral solid controlled release dosage formulation comprising up to about 160 mg of oxycodone or a salt thereof, said formulation providing a mean maximum plasma concentration of oxycodone up to about 240 ng/ml from a mean of up to about 2 to about 4.5 hours after administration, and a mean minimum plasma concentration up to about 120 ng/ml from a mean of about 10 to about 14 hours after repeated "ql2h" (i.e., every 12 hour) administration through steady-state conditions.
The present invention is further related to con-trolled release oxycodone formulations comprising from about 10 to about 40 mg oxycodone or a salt thereof, said formulations providing a mean maximum plasma concentra-tion of oxycodone from about 6 to about 60 ng/ml from a SUBSTITUTE SHEET

mean of about 2 to about 4.5 hours after administration, and a mean minimum plasma concentration from about 3 to ,about 30 ng/ml from about 10 to about 14 hours after repeated ql2h administration through steady-state 5 conditions.
The present invention is further related to con-trolled release oxycodone formulations comprising up to about 160 mg oxycodone or a salt thereof, said fonaula-tions providing a mean maximum plasma concentration of l0 oxycodone up to about 240 ng/ml from a mean of about 2 to about 4.5 hours after administration, and a mean minimum plasma concentration up to about 120 ng/ml from about 10 to about 14 hours after repeated ql2h administration through steady-state conditions.

The following drawings are illustrative of embodi-ments of the invention and are not meant to limit the scope of the invention as encompassed by the claims.
Figures 1-4 are graphs showing the time-effect curves for pain intensity differences and pain relief for Example 17;
Figure 5 is a graph showing the mean plasma oxy-codone concentration for a 10 mg controlled release oxycodone formulation prepared in accordance with the present invention and a study reference standard.
DETAILED DESCRIPTION
It has now been surprisingly discovered that the presently claimed controlled release oxycodone formula-tions acceptably control pain over a substantially narrower, approximately four-fold (l0 to 40 mg every 12 hours - around-the-clock dosing) in approximately 90% of patients. This is in sharp contrast to the approximately SUBSTITUTE SHEET

6 ~ ~ ~ ~ ~ ~ ~ '~ PCT/US92/10146 eight-fold range required for approximately 90% of patients for opioid analgesics in general.
The use of from about 10 mg to about 40 mg of 12-hourly doses of controlled-release oxycodone to control pain in approximately 90% of patients relative to a wider dosage range of other mu-agonist analgesics, indicated for moderate to severe pain, is an example of the unique characteristics of the present invention. It should also be appreciated that the remaining 10% of patients would also be successfully managed with 12-hourly controlled-release oxycodone over a relatively narrower dosage range than with the use of other similar analgesics. Substan-tially all of those remaining 10% of patients not managed with controlled release oxycodone, 10 mg to 40 mg every 12 hours, would be managed using dosages of greater than 40 mg every 12 hours through 160 mg every 12 hours util-izing any one of a number or multiples of formulation strengths such as 10, 20, 40, 80 and 160 mg unit dosages or combinations thereof. In contrast, the use of other similar analgesics such as morphine would require a wider range of dosages to manage the remaining 10% of patients.
For example, daily dosages of oral morphine equivalents in the range of 1 gram to more than 20 grams have been observed. Similarly, wide dosage ranges of oral hydro-morphone would also be required.
Morphine, which is considered to be the prototypic opioid analgesic, has been formulated into a 12 hour controlled-release formulations (i.e., MS Contin~
tablets, commercially available from Purdue Pharma, L.P.). Despite the fact that bath controlled-release oxycodone and controlled release morphine administered every 12 hours around-the-clock possess qualitatively comparable clinical pharmacokinetic characteristics, the oxycodone formulations of the presently claimed invention can be used over approximately 1/2 the dosage range as SUBSTITUTE SHEET

20987 3 ~

compared to commercially available controlled release morphine formulations (such as MS Continue) to control 90%
of patients with significant pain.
Repeated dose studies with the controlled release oxycodone formulations administered every 12 hours in comparison with immediate release oral oxycodone admin-istered every 6 hours at the same total daily dose result in comparable extent of absorption, as well as comparable maximum and minimum concentrations. The time of maximum concentration occurs at approximately 2 - 4.5 hours after oral administration with the controlled-release product as compared to approximately 1 hour with the immediate release product. Similar repeated dose studies with MS
Continue tablets as compared to immediate release morphine provide for comparable relative results as with the controlled release oxycodone formulations of the present invention.
There exists no substantial deviation from paral-lelism of the dose-response curves for oxycodone either in the forms of the controlled release oxycodone fonau-lations of the present invention, immediate release oral oxycodone or parenteral oxycodone in comparison with oral and parenteral opioids with which oxycodone has been compared in terms of dose-response studies and relative analgesic potency assays. Beaver, et al., "Analgesic Studies of Codeine and Oxycodone in Patients with Cancer.
II. Comparisons of Intramuscular Oxycodone with Intra-muscular Morphine and.Codeine", J. Pharmacol.. and Exp.
Ther., Vol. 207, No. l, pp. 10l-l08, 1978 reported comparable dose-response slopes for parenteral oxycodone as compared to parenteral morphine and comparable dose-response slopes for oral as compared to parenteral oxycodone.
A review of dose-response studies and relative analgesic assays of mu-agonist opioid analgesics, which include oxycodone, morphine, hydromorphone, levorphanol, A0987 3 8 , methadone, meperidine, heroin, a11 indicate no signifi-cant deviation from parallelism in their dose response relationships. This is so well established that it has become an underlining principal providing for establish-ing relative analgesic potency factors and dose ratios which are commonly utilized when converting patients from one mu-agonist analgesic to another regardless of the dosage of the former. Unless the dose-response curves are parallel, conversion factors would not be valid across the wide range of dosages involved when substituting one drug for another.
The clinical significance provided by the controlled release oxycodone formulations of the present invention at a dosage range from about 10 to about 40 mg every 12 hours for acceptable pain management in approximately 90%
of patients with moderate to severe pain, as compared to other opioid analgesics requiring approximately twice the dosage range provides for the most efficient and humane method of managing pain requiring repeated dosing. The expertise and time of physicians and nurses, as well as the duration of unacceptable pain patients must endure during the opioid analgesic titration process is substan-tially reduced through the efficiency of the controlled release oxycodone formulations of the present invention.
It is further clinically significant that a dose of about 80 mg controlled release oxycodone administered every 12 hours will provide acceptable pain relief management in, e.g., approximately 95% of patients with moderate to severe pain, and that about 160 mg controlled release oxycodone administered every 12 hours will pro-vide acceptable pain relief management in, e.g., approxi-mately a11 patients with moderate to severe pain.
In order to obtain a controlled release drug dosage form having at least a 12 hour therapeutic effect, it is usual in the pharmaceutical art to produce a formulation SUBSTITUTE SHEET

WO 93/1076s PCT/L1S92/10146 that gives a peak plasma level of the drug between about 4-8 hours after administration (in a single dose study).
The present inventors have surprisingly found that, in the case of oxycodone, a peak plasma level at between 2 -4.5 hours after administration gives at least 12 hours pain relief and, most surprisingly, that the pain relief obtained with such a formulation is greater than that achieved with formulations giving peak plasma levels (of oxycodone) in the normal period of up to 2 hours after administration.
A further advantage of the present composition, which releases oxycodone at a rate that is substantially independent of pH, is that it avoids dose dumping upon oral administration. In other words, the oxycodone is released evenly throughout the gastrointestinal tract.
The present oral dosage form may be presented as, for example, granules, spheroids or pellets in a capsule or in any other suitable solid form. Preferably, how-ever, the oral dosage form is a tablet.
The present oral dosage form preferably contains between 1 and 500 mg, most especially between 10 and 160 mg, of oxycodone hydrochloride. Alternatively, the dosage form may contain molar equivalent amounts of other oxycodone salts or of the oxycodone base.
The present matrix may be any matrix that affords in vitro dissolution rates of oxycodone within the narrow ranges required and that releases the oxycodone in a pH
independent manner. Preferably the matrix is a controll-ed release matrix, although normal release matrices having a coating that controls the release of the drug may be used. Suitable materials for inclusion in a controlled release matrix are (a) Hydrophilic polymers, such as gums, cellulose ethers, acrylic resins and protein derived materials. Of these polymers, the cellulose ethers, especially hydroxy-SUBSTITUTE SHEET

PCT/L)S92/ 10146 WO 93/1076~
alkylcelluloses and carboxyalkylcelluloses, are pre-ferred. The oral dosage form may contain between 1% and 80% (by weight) of at least one hydrophilic or hydrophobic polymer.
5 (b) Digestible, long chain (C8-C50, especially C12 C40) substituted or unsubstituted hydrocarbons, such as fatty acids, fatty alcohols, glyceryl esters of fatty acids, mineral and vegetable oils and waxes. Hydrocar-bons having a melting point of between 25° and 90°C are 10 preferred. Of these long chain hydrocarbon materials, fatty (aliphatic) alcohols are preferred. The oral dosage form may contain up to 60% (by weight) of at least one digestible, long chain hydrocarbon.
(c) Polyalkylene glycols. The oral dosage form may contain up to 60% (by weight) of at least one polyalkyl-ene glycol.
One particular suitable matrix comprises at least one water soluble hydroxyalkyl cellulose, at least one C12-C36, preferably C14-C22' aliphatic alcohol and, optionally, at least one polyalkylene glycol.
The at least one hydroxyalkyl cellulose is prefer-ably a hydroxy (C1 to C6) alkyl cellulose, such as hydroxypropylcellulose, hydroxypropylmethylcellulose and, especially, hydroxyethyl cellulose. The amount of the at least one hydroxyalkyl cellulose in the present oral dosage form will be determined, inter alia, by the precise rate of oxycodone release required. Preferably however, the oral dosage form contains between 5% and 25%, especially between 6.25% and 15% (by wt) of the at least one hydroxyalkyl cellulose.
The at least one aliphatic alcohol may be, for example, lauryl alcohol, myristyl alcohol or stearyl alcohol. In particularly preferred embodiments of the present oral dosage form, however, the at least one aliphatic alcohol is cetyl alcohol or cetostearyl SUBSTITUTE SHEET

WO 93/1076~ PCT/L.!S92/10146 2098738 '~

alcohol. The amount of the at least one aliphatic alcohol in the present oral dosage form will be determined, as above, by the precise rate of oxycodone release required. It will also depend on whether at least one polyalkylene glycol is present in or absent from the oral dosage form. In the absence of at least one polyalkylene glycol, the oral dosage form preferably contains between 20% and 50% (by wt) of the at least one aliphatic alcohol. When at least one polyalkylene glycol is present in the oral dosage form, then the combined weight of the at least one aliphatic alcohol and the at least one polyalkylene glycol preferably constitutes between 20% and 50% (by wt) of the total dosage.
In one preferred embodiment, the controlled release composition comprises from about 5 to about 25% acrylic resin and from about 8 to about 40% by weight aliphatic alcohol by weight of the total dosage form. A particu-larly preferred acrylic resin comprises Eudragit~ RS PM, commercially available from Rohm Pharma.
In the present preferred dosage form, the ratio of, e.g., the at least one hydroxyalkyl cellulose or acrylic resin to the at least one aliphatic alcohol/polyalkylene glycol determines, to a considerable extent, the release rate of the oxycodone from the formulation. A ratio of the at least one hydroxyalkyl cellulose to the at least one aliphatic alcohol/polyalkylene glycol of between 1:2 and 1:4 is preferred, with a ratio of between 1:3 and 1:4 being particularly preferred.
The at least one polyalkylene glycol may be, for example, polypropylene glycol or, which is preferred, polyethylene glycol. The number average molecular weight of the at least one polyalkylene glycol is preferred between 1000 and 15000 especially between 1500 and 12000.
Another suitable controlled release matrix would comprise an alkylcellulose (especially ethyl cellulose), SUBSTITUTE SHEET

WO 93/1076 ~ ~ ~ ~ ~ ~ ~ ~ PCT/L'S92/10146 a C~Z to C36 aliphatic alcohol and, optionally, a poly-alkylene glycol.
In addition to the above ingredients, a controlled release matrix may also contain suitable quantities of other materials, e.g. diluents, lubricants, binders, granulating aids, colorants, flavorants and glidants that are conventional in the pharmaceutical art.
As an alternative to a controlled release matrix, the present matrix may be a normal release matrix having a coat that controls the release of the drug. In par-ticularly preferred embodiments of this aspect of the invention, the present dosage form comprises film coated spheroids containing active ingredient and a non-water soluble spheronising agent. The term spheroid is known in the pharmaceutical art and means a spherical granule having a diameter of between 0.5 mm and 2.5 mm especially between 0.5 mm and 2 mm.
The spheronising agent may be any pharmaceutically acceptable material that, together with the active in-gredient, can be spheronised to form spheroids. Micro-crystalline cellulose is preferred.
A suitable microcrystalline cellulose is, for example, the material sold as Avicel PH 101 (Trade Mark, FMC Corporation). According to a preferred aspect of the present invention, the film coated spheroids contain between 70% and 99% (by wt), especially between 80% and 95% (by wt), of the spheronising agent, especially microcrystalline cellulose.
In addition to the active ingredient and spheron-ising agent, the spheroids may also contain a binder.
Suitable binders, such as low viscosity, water soluble polymers, will be well known to those skilled in the pharmaceutical art. However, water soluble hydroxy lower alkyl cellulose, such as hydroxy propyl cellulose, are preferred. Additionally (or alternatively) the spheroids SUBSTITUTE SHEET

WO 93/1076 PCT/I!S92/10146 2098738:~~s may contain a water insoluble polymer, especially an acrylic polymer, an acrylic copolymer, such as a methacrylic acid-ethyl acrylate copolymer, or ethyl cellulose.
The spheroids are preferably film coated with a material that permits release of the oxycodone (or salt) at a controlled rate in an aqueous medium. The film coat is chosen so as to achieve, in combination with the other ingredients, the in-vitro release rate outlined above (between 12.5% and 42.5% (by wt) release after 1 hour, etc.).
The film coat will generally include a water insoluble material such as (a) a wax, either alone or in admixture with a fatty alcohol, (b) shellac or zein, (c) a water insoluble cellulose, especially ethyl cellulose, (d) a polymethacrylate, especially Eudragit~.
Preferably, the film coat comprises a mixture of the water insoluble material and a water soluble material.
The ratio of water insoluble to water soluble material is determined by, amongst other factors, the release rate required and the solubility characteristics of the materials selected.
The water soluble material may be, for example, polyvinylpyrrolidone or, which is preferred, a water soluble cellulose, especially hydroxypropylmethyl cellulose.
Suitable combinations of water insoluble and water soluble materials for the film coat include shellac and polyvinylpyrrolidone or, which is preferred, ethyl cellulose and hydroxypropylmethyl cellulose.
In order to facilitate the preparation of a solid, controlled release, oral dosage form according to this SUBSTITUTE SHEET

WO 93/1076 ~ ~ ~ ~ ~ , PCT/US92/10146 invention there is provided, in a further aspect of the present invention, a process for the preparation of a solid, controlled release, oral dosage form according to the present invention comprising incorporating hydro-morphone or a salt thereof in a controlled release matrix. Incorporation in the matrix may be effected, for example, by (a) forming granules comprising at least one water soluble hydroxyalkyl cellulose and oxycodone or a oxycodone salt, (b) mixing the hydroxyalkyl cellulose containing granules with at least one C -C aliphatic alcohol, and (c) optionally, compressing and shaping the granules. Preferably, the granules are formed by wet granulating the hydroxyalkyl cellulose/oxycodone with water. In a particularly preferred embodiment of this process, the amount of water added during the wet granulation step is preferably between 1.5 and 5 times, especially between 1.75 and 3.5 times, the dry weight of the oxycodone.
The present solid, controlled release, oral dosage form may also be prepared, in the form of film coated spheroids, by (a) blending a mixture comprising oxycodone or a oxycodone salt and a non-water soluble spheronising agent, (b) extruding the blended mixture to give an extrudate, (c) spheronising the extrudate until spheroids are formed, and (d) coating the spheroids with a film coat.
The present solid, controlled release, oral dosage form and processes for its preparation will now be described by way of example only.
SUBSTITUTE SHEET

2098738 a DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The following examples illustrate various aspects of the present invention. They are not meant to be con strued to limit the claims in any manner whatsoever.

Controlled Release Oxycodone HC1 30 ma Tablets - Aqueous Manufacture The required quantities of oxycodone hydrochloride, 10 spray-dried lactose, and Eudragit~ RS PM are transferred into an appropriate-size mixer, and mixed for approxi-mately 5 minutes. While the powders are mixing, the mixture is granulated with enough water to produce a moist granular mass. The granules are then dried in a 15 fluid bed dryer at 60°C, and then passed through an 8-mesh screen. Thereafter, the granules are redried and pushed through a 12-mesh screen. The required quantity of stearyl alcohol is melted at approximately 60-70°C, and while the granules are mixing, the melted stearyl alcohol is added. The warm granules are returned to the mixer.
The coated granules are removed from the mixer and allowed to cool. The granules are then passed through a 12-mesh screen. The granulate is then lubricated by mixing the required quantity of talc and magnesium stearate in a suitable blender. Tablets are compressed to 375 mg in weight on a suitable tableting machine. The formula for the tablets of Example 1 is set forth in Table 1 below:

Formula of Oxycodone HC1 30-ma Tablets Component mg/Tablet % fbv wt) Oxycodone Hydrochloride 30.o 8 Lactose (spray-dried) 213.75 57 Eudragit~ RS PM 45.0 . 12 SUBSTITUTE SHEET

WO 93/1076 2 0 9 8 7 3_ V .gin PCT/US92/10146 Purified Water q.s* --Stearyl Alcohol 75.0 20 Talc 7.5 2 Magnesium Stearate 3.75 1 Total: 375.0 100 *Used in manufacture and remains in final product as residual quantity only.
The tablets of Example 1 are then tested for dis-solution via the USP Basket Method, 37°C, 100 RPM, first hour 700 ml gastric fluid at pH 1.2, then changed to 900 ml at 7.5. The results are set forth in Table 2 below:

Dissolution of Oxycodone 30 mg Controlled Release Tablets Time % Oxycodone Dissolved 1 33.1 2 43.5 4 58.2 8 73.2 12 81.8 18 85.8 24 89.2 Controlled Oxycodone HCl 10 mg Release Tablets - Organic Manufacture The required quantities of oxycodone hydrochloride and spray dried lactose are transferred into an appro-priate sized mixer and mix for approximately 6 minutes.
Approximately 40 percent of the required Eudragit~ RS PM
powder is dispersed in Ethanol. While the powders are mixing, the powders are granulated with the dispersion and the mixing continued until a moist granular mass is formed. Additional ethanol is added if needed to reach granulation end point. The granulation is transferred to a fluid bed dryer and dried at 30°C; and then passed SUBSTITUTE SHEET

WO 93/10?6~ PCT/US92/10146 2 0 987 ~8.;

through a 12-mesh screen. The remaining Eudragit~ RS PM
is dispersed in a solvent of 90 parts ethanol and 10 parts purified water; and sprayed onto the granules in the fluid bed granulator/dryer at 30°C. Next, the granu-late is passed through a 12-mesh screen. The required quantity of stearyl alcohol is melted at approximately 60-70°C. The warm granules are returned to the mixer.
While mixing, the melted stearyl alcohol is added. The coated granules are removed from the mixer and allowed to cool. Thereafter, they are passed through a 12-mesh screen.
Next, the granulate is lubricated by mixing the required quantities of talc and magnesium stearate in a suitable blender. The granulate is then compressed to 125 mg tablets on a suitable tableting machine.
The formula for the tablets of Example 2 (10 mg con trolled release oxycodone) is set forth in Table 3 below:
Table 3 Formula of Oxycodone HC1 10 ma Controlled Release Tablets Percent Component MgjTablet Sby wt) Oxycodone hydrochloride 10.00 8 Lactose (spray-dried) 71.25 57 Eudragit~ RS PM 15.00 12 Ethanol q.s.* -Purified Water q.s.* --Stearyl Alcohol 25.00 20 Talc 2.50 2 Magnesium stearate 1.25 1 Total: 125.00 mg 100 *Used only in the manufacture and remains in final product as residual quantity only.
The tablets of Example 2 are then tested for dis-solution via USP Basket Method at 37°C, 100 RPM, first SUBSTITUTE SHEET

'098738 : 18 hour 700 ml simulated gastric (pH 1.2) then changed to 900 ml at pH 7.5.
The results are set forth in Table 4 below:
Table 4 Dissolution of Oxycodone 10 mg Controlled Release Tablets Hour $ Dissolved 1 35.9 2 47.7 4 58.5 8 6?.7 12 74.5 18 76.9 24 81.2 EgAMPLEB 3 - 4 Coatrollad Releaso Oxyaodone 10 and 20 me Tablets (Acu~ous Manufacture) Eudragit~ RS 30D and Triacetin~ are combined while passing though a 60 mesh screen, and mixed under low shear for approximately 5 minutes or until a uniform dispersion is observed.
Next, suitable quantities of Oxycodone HC1, lactose, and povidone are placed into a fluid bed granulator/dryer (FBD) bowl, and the suspension sprayed onto the powder in the fluid bed. After spraying, the granulation is passed through a #12 screen if necessary to reduce lumps. The dry granulation is placed in a mixer.
In the meantime, the required amount of stearyl alcohol is melted at a temperature of approximately 70°C.
The melted stearyl alcohol is incorporated into the granulation while mixing. The waxed granulation is transferred to a fluid bed granulator/dryer or trays and allowed to cool to room temperature or below. The cooled granulation is then passed through a #12 screen. There-SUBSTITUTE SHEET

WO 93/1076 PCf/US92/10146 after, the waxed granulation is placed in a mixer/blender and lubricated with the required amounts of talc and magnesium stearate for approximately 3 minutes, and then the granulate is compressed into 125 mg tablets on a suitable tableting machine.
The formula for the tablets of Example 3 is set forth in Table 5 below:
Table 5 Formula of Controlled Release mq Tablets Oxycodone 10 Component Mg~Tablet %(by wt) Oxycodone Hydrochloride 10.0 8.0 Lactose (spray dried) 69.25 55.4 Povidone 5.0 4.0 Eudragit~ RS 30D (solids) 10.0* 8.0 Triacetin~ 2.0 1.6 Stearyl Alcohol 25.0 20.0 Talc 2.5 2.0 Magnesium Stearate 1.25 1.0 Total: 125.0 100.0 *Approximately 33.33 mg Eudragit~ RS 30D Aqueous dispersion is equivalent to 10 mg of Eudragit~
RS 30D dry substance.

The tablets of Example 3 are then testedfor dis-solution via the USP Basket Method at 37C, 00 RPM, first hour 700 ml simulated gastric fluid pH 1.2, then at changed to 900 ml at pH 7.5. The results are set forth in Table 6 below:

Table 6 Dissolution of Oxycodone l0 mg Controlled Release Tablets Hour % Oxycodone Dissolved 1 38.0 2 47.5 4 62.0 8 79.8 SUBSTITUTE SHEET

2098738e 20 12 91.1 18 94.9 24 98.7 The formula for the tablets of Example 4 is set forth in Table 7 below:
Table 7 Formula of Controlled Release Oxycodone 20 mg' Tablets Component Mg,/Tablet Oxycodone Hydrochloride 20.0 Lactose (spray dried) 59.25 Povidone 5.0 Eudragit~ RS 30D (solids) 10.0*
Triacetin~ 2.0 Stearyl Alcohol 25.0 Talc 2.5 Magnesium Stearate 1.25 Total: 125.0 The tablets of Example 4 are then tested for dissolution via the USP Basket Method at 37°C, 100 RPM, first hour 700 ml simulated gastric fluid at pH 1.2, then changed to 900 ml at pH 7.5. The results are set forth in Table 8 below:
Table 8 Dissolution of Oxvcodone 20 ma Controlled Release Tablets Hour % Oxycodone Dissolved SUBSTITUTE SHEET

WO 93/1076 PCT/C.'S92/10146 In Example 5, 30 mg controlled release oxycodone hydrochloride tablets are prepared according to the process set forth in Example 1.
In Example 6, 10 mg controlled release oxycodone hydrochloride tablets are prepared according to the process set forth in Example 2.
Thereafter, dissolution studies of the tablets of Examples 5 and 6 are conducted at different pH levels, namely, pH 1.3, 4.56, 6.88 and 7.5.
The results are provided in Tables 9 and 10 below:
Table - Example 5 Percentage Oxycodone 30 mq Tablets Time Dissolved Over pH 1 2 4 8 12 18 24 1.3 29.5 43.7 61.8 78.9 91.0 97.0 97.1 4.56 34.4 49.1 66.4 82.0 95.6 99.4 101.1 6.88 33.8 47.1 64.4 81.9 92.8 100.5 105.0 7.5 27.0 38.6 53.5 70.0 81.8 89.7 96.6 Table - Example Percentage HC1 - 0 mg Oxycodone l Tablets Over Dissolved Time pH 1 2 4 8 12 18 24 1.3 25.9 41.5 58.5 73.5 85.3 90.7 94.2 4.56 37.8 44.2 59.4 78.6 88.2 91.2 93.7 6.88 34.7 45.2 60.0 75.5 81.4 90.3 93.9 7.5 33.2 40.1 51.5 66.3 75.2 81.7 86.8 In Examples 7-12, 4 mg and 10 mg oxycodone HC1 tablets were prepared according to the formulations and methods set forth in the assignee's U.S. Patent No.
4,990,341.
SUBSTITUTE SHEET

In Example 7, oxycodone hydrochloride (10.00 gm) was wet granulated with lactose monohydrate (417.5 gm) and hydroxyethyl cellulose (100.00 gm), and the granules were sieved through a 12 mesh screen. The granules were then dried in a fluid bed dryer at 50° C and sieved through a 16 mesh screen.
Molten cetostearyl alcohol (300.0 gm) was added to the warmed oxycodone containing granules, and the whole was mixed thoroughly. The mixture was allowed to cool in the air, regranulated and sieved through a 16 mesh screen.
Purified Talc (15.0 gm) and magnesium stearate (7.5 gm) were then added and mixed with the granules. The granules were then compressed into tablets.
Example 8 is prepared in the same manner as Example 7; however, the formulation includes 10 mg oxycodone HC1/tablet. The formulas for Examples 7 and 8 are set forth in Tables 11 and 12, respectively.
Table 11 Formulation of Example 7 Inctredient mg~/tablet ct/batch Oxycodone hydrochloride 4.0 10.0 Lactose monohydrate 167.0 417.5 Hydroxyethylcellulose 40.o 100.0 Cetostearyl alcohol 120.0 300.0 Purified talc 6.0 15.0 Magnesium stearate 3.0 7.5 Table 12 Formulation of Example 8 Ingredient mg~/tablet g/batch Oxycodone hydrochloride 10.0 25.0 Lactose monohydrate 167.0 417.5 Hydroxyethylcellulose 40.0 100.0 SUBSTITUTE SHEET

Cetostearyl alcohol 120.0 300.0 Talc 6.0 15.0 Magnesium stearate 3.0 7.5 In Example 9, 4 mg oxycodone HC1 controlled release tablets are prepared according to the excipient formula cited in Example 2 of U.S. Patent No. 4,990,341. The method of manufacture is the same as set forth in Examp-les 7 and 8 above. Example l0 is prepared according to Example 9, except that 10 mg oxycodone HC1 is included per tablet. The formulas for Examples 9 and 10 are set forth in Tables 13 and 14, respectively.
Table 13 Formulation of Example 9 Ingredient mq/tablet ct/batch Oxycodone hydrochloride 4.0 10.0 Anhydrous Lactose 167.0 417.5 Hydroxyethylcellulose 30.0 75.0 Cetostearyl alcohol 90.0 225.0 Talc 6.0 15.0 Magnesium stearate 3.0 7.5 Table 14 Formulation of Example 14 Ingredient mQ/tablet ct/batch Oxycodone hydrochloride 10.0 25.0 Hydrous lactose 167.0 417.5 Hydroxyethylcellulose 30.0 75.0 Cetostearyl alcohol 90.0 225.0 Talc 6.0 15.0 Magnesium stearate 3.0 7.5 In Example 11, oxycodone 4 mg controlled release tablets are prepared with the same excipient formula cited in Example 3 of U.S. patent No..4,990,341.
SUBSTITUTE SHEET

2098738 ' 24 Oxycodone hydrochloride (32.0 gm) was wet granulated with lactose monohydrate (240.0 gm) hydroxyethyl cellu-lose (80.0 gm) and methacrylic acid copolymer (240.0 gm, Eudragit~ L-100-55), and the granules were sieved through a 12 mesh screen. The granules were then dried in a Fluid Bed Dryer at 50° C and passed through a 16 mesh screen.
The warmed oxycodone containing granules was added molten cetostearyl alcohol (240.0 gm), and the whole was mixed thoroughly. The mixture was allowed to cool in the air, regranulated and sieved through a 16 mesh screen.
The granules were then compressed into tablets.
Example 12 is prepared in identical fashion to Example~ll, except that 10 mg oxycodone HC1 is included per tablet. The formulations for Examples 11 and 12 are set forth in Tables 15 and 16, respectively.
Table 15 Formulation of Example 11 Inqredient mg,/tablet q/batch Oxycodone hydrochloride 4.0 32.0 Lactose monohydrate 30.0 240.5 Hydroxyethylcellulose 10.0 80.0 Methacrylic acid copolymer 30.0 240.0 Cetostearyl alcohol 30.0 240.0 Table 16 Formulation of Example 12 Ingredient mg/tablet a/batch Oxycodone hydrochloride 10.0 80.0 Lactose monohydrate 30.0 240.5 Hydroxyethylcellulose 10.0 80.0 Methacrylic acid copolymer 30.0 240.0 Cetostearyl alcohol 30.0 240.0 SUBSTITUTE SHEET

2~98~ 3g Next, dissolution studies were conducted on the tablets of Examples 7-12 using the USP basket method as described in the U.S. Pharmacopoeia XXII (1990). The speed was 100 rpm, the medium was simulated gastric fluid 5 for the first hour followed by simulated intestinal fluid thereafter, at a temperature of 37° C. Results are given in Table 17.

Time $ Oxycodone Dissolved ~hrs) Ex. 7 Ex. 8 Ex. 9 Ex. 10 Ex. 11 Ex. 12 1 23.3 25.5 28.1 29.3 31.3 40.9 2 35.6 37.5 41.5 43.2 44.9 55.6 15 4 52.9 56.4 61.2 63.6 62.1 74.2 8 75.3 79.2 83.7 88.0 82.0 93.9 12 90.7 94.5 95.2 100.0 91.4 100.0 2o clinical studies In Examples 13-16, randomized crossover bioavail-ability studies were conducted employing the formulation of Examples 2 (organic manufacture) and 3 (aqueous manufacture).
25 In Example 13, a single dose fast/fed study was conducted on 24 subjects with oxycodone tablets prepared according to Example 3.
In Example 14, a steady-state study was conducted on 23 subjects after 12 hours with oxycodone tablets pre-pared according to Example 2, and compared to a 5 mg oxycodone immediate-release solution.
In Example 15, a single dose study was conducted on 22 subjects using oxycodone tablets prepared according to Example 3, and compared to a 20 mg oxycodone immediate release solution.
SUBSTITUTE SHEET

In Example 16, a 12 subject single-dose study was conducted using 3 x 10 mg oxycodone tablets prepared according to Example 3, and compared to a 30 mg oxycodone immediate release solution.
The results of Examples 13-16 are set forth in Table 18.
Table 18 AUC Cmax Tmax Example Dosacre ng/mlLhr n ml hr 13 10 mg CR Fast 63 6.1 3.8 10 mg CR Fed 68 7.1 3.6 14 5 mg IR q6h 121 17 1.2 10 mg CR ql2h 130 17 3.2 20 mg IR 188 40 1.4 15 2 x 10 mg CR 197 18 2.6 16 30 mg IR 306 53 1.2 3 x 10 mg CR 350 35 2.6 30 mg CR 352 36 2.9 IR denotes immediate-rel ease oxycodone solution.

CR denotes controlled-re lease tablets CLINICAL STUDIES
In Example 17, a single dose, double blind, random-ized study determined the relative analgesic efficacy, the acceptability, and relative duration of action of an oral administration of controlled release oxycodone 10, 20 and 30 mg prepared according to the present invention (CR OXY) compared to immediate release oxycodone 15 mg (IR OXY), immediate release oxycodone 10 mg in combina-tion with acetaminophen 650 mg (IR OXY/APAP) and placebo in 180 patients with moderate or severe pain following abdominal or gynecological surgery. Patients rated their pain intensity and pain relief hourly for up to 12 hours postdosing. Treatments were compared using standard SUBSTITUTE SHEET

scales for pain intensity and relief, and onset and duration of pain relief.
A11 active treatments were significantly superior to placebo for many of the hourly measures, and for sum pain intensity differences (SPID) and total pain relief (TOTPAR). A dose response was seen among the 3 dose levels of CR OXY for pain relief and peak pain intensity difference (PID), with CR OXY 20mg and 30 mg being significantly better than the 10 mg dose. IR OXY was significantly superior to CR OXY 10 mg at hr 1 and 2. IR
OXY/APAP was significantly superior to the 3 doses of CR
OXY at hr 1, and to CR OXY 10 mg at hrs 2 through 5.
Onset time was significantly shorter for the IR OXY and IR OXY/APAP treatment groups in comparison to the 3 CR
OXY treatments. The distribution functions for duration of relief revealed significantly longer duration of relief for the three CR OXY doses than for IR OXY and IR
OXY/APAP. No serious adverse experiences were reported.
The results are more particularly reported in Table 19 below.

PATIENT DISPOSITION
TREATMENT GROUP
IR OXY -----CR OXY------l5mq PLACEBO l Omq 2 Omcr 3 Omq 2 PERC~ TOTAL
Enrolled and Randomized to Study Treatment 31 31 30 30 30 30 182 Entered the Study Treat-ment Phase 31 31 30 30 30 30 182 Completed the Study 31 30 30 30 30 30 181 SUBSTITUTE SHEET

WO 93/1076 PCT/l.'S92/10146 ~098~'38 ~;~ 28 Discontinued from the Study 0 1 0 0 0 0 1 Excluded from Efficacy Analysis -Vomited prior to 1 hr post dose 0 -1. _. 0 0 0 0 1 -Inadvertently received rescue during study 1 0 0 0 0 0 1 Analysis Population:
-Evaluable for Safety and Efficacy 30 30 30 30 30 30 180 -Evaluable for Safety 31 31 30 30 30 30 182 * 2 tablets of Percocet~
The time-effect curves for pain intensity, pain intensity differences and pain relief are shown in Figures 1-4. CR OXY l0 mg had significantly (p < .05) lower pain intensity scores than the placebo-treated patients at hours 3-11 and lower pain scores than IR OXY
15 mg and Percocet~ at hour 10. CR OXY 20 mg has sig-nificantly (p < .05) lower pain intensity scores compared to placebo at hours 2 - 11 and significantly (p < .05) lower pain scores than CR OXY 10 mg, IR OXY 15 mg and Percocet at hours 9-11. CR OXY 30 mg had significantly (p < .05) lower pain scores than placebo at hours 2-11 and lower pain scores than CR OXY 10 mg at hours 2, 3, and 5 and lower scores than Percocet~ at hour 10.
For hourly pain relief scores categorical and visual analog scales (CAT and VAS), CR OXY 10 mg had signifi-cantly (p < .05) higher pain relief scores than placebo at hours 3-11 and higher relief scores than IR OXY and Percocet~ at hour 10 (and Percocet~ at hour 11). CR OXY
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WO 93/l076~ PCT/US92/10146 r_ 20987 38 20 mg had significantly (p < .05) higher relief scores than placebo at hours 2-12 and higher relief scores than Percocet~ at hours 9-12. In addition, CR OXY had sig-nificantly (p < .05) higher pain relief than IR OXY at hours 10-12. CR OXY 30 mg had significantly (p < .05) higher pain relief scores than placebo at hours 2-12 and higher scores than Percocet~ at hours 9-12 and IR OXY 15 mg at hour 10.
Each treatment group was significantly (p < .05) better than placebo with respect to the sum of the pain intensity differences (SPID) and total pain relief (TOTPAR).
Duration of pain relief as measured by the patient stopwatch method showed that CR OXY 10 mg, 20 mg and 30 mg had significantly (p < .05) longer duration of action compared to IR OXY 15 mg and 2 tablets Percocet~. In addition, the three controlled-release formulations had significantly (p < .05) longer times to remedication compared to Percocet~.
Before remedication, a total of 104 (57%) of patients reported 120 adverse experiences. The most common were somnolence, fever, dizziness and headache.
Based upon the results of this study it is concluded that the controlled release oxycodone formulations of the present invention relieve moderate to severe post operative pain, e.g., due to abdominal or gynecological surgery in women. There is a dose response noted in which placebo < l0 mg < 20 mg < 30 mg CR OXY following a single dose. Onset of action occurred in one hour with peak effects noted from 2 to 5 hours and a duration of effect from 10 to 12 hours. In the chronic pain situa-tion steady state dosing may prolong this effect. Side effects are expected and easily managed. Headache may be related to dose. Dizziness and somnolence were reported.
SUBSTITUTE SHEET

WO 93/1076 PCf/US92/10146 IR OXY 15 mg has an intermediate peak effect compared to controlled release oxycodone. Its duration of action is shorter (6-8 hours). Percocet~ is quite effective in terms of onset, peak effect and safety. The duration of action is 6-8 hours.
In summary, CR OXY was clearly an effective oral analgesic, with a slower onset but a longer duration of effect than either IR OXY or IR OXY/APAP.

CLINICAL BTUDIEB
In Example 18, a steady state crossover trial was conducted in 21 normal male subjects comparing a. CR OXY 10 mg administered every 12 hours (ql2h); and b. Roxicodone~ oral solution 5 mg (ROX) administered every 6 hours (q6h), Treatment (b) was the study reference standard. The average age was 34 years, height 176 cm and weight 75 kg.
No unusual features were noted about the group.
Figure 5 shows the mean plasma oxycodone concen-trations for the two formulations over the 12 hour dosing interval. The results are summarized in Table 18 in terms of mean values, ratios of mean values and 90%
confidence intervals.
As inspection of Table 18 reveals, with one excep-tion, no significant differences were detected between the two formulations. The single exception is the mean tax for CR OXY of 3.18 hours which, as expected for a controlled release formulation, significantly exceeded the ROX mean of 1.38 hours. Mean AUC-based bioavail-ability, (ROX = 100%) was 104.4% with 90% confidence limits of 90.9 to 117.9%. Thus, the FDA specification of +20% is met so that the study results support an assertion of equal oxycodone availability.
SUBSTITUTE SHEET

.~ 2098738 SUNIHIARY OF PHARMACOKINETIC PARAMETERS FOR OXYCODONE
FOLLOWING A SINGLE DOSE OF CR OXY (lOmg ql2H) AND ROXICODONE~ ORAL SOLUTION (5mct a6h) OXY/
ROXICODONE ROXI
PARAMETER CR OXY SOLUTION (%) 90% CI~
l0 C
(ng/mL) ~x 97.08 85.59-ARITH.MEAN(SD) 15.11(4.69) 15.57(4.4l) 108.50 GEOMETRIC MEAN 14.43 15.01 95.14 Cm~~ (ng/mL) ARITH.MEAN(SD) 6.24(2.64) 6.47(3.07) 96.41 80.15-112.74 GEOMETRIC MEAN 5.62 5.83 96.48 tax ( hrS ) ARITH.MEAN 160.71-(SD) 3.18(2.21J 1.38(0.71)* 230.17 298.71 AUC(0-12 hrs) ARITH. 90.92-MEAN(SD) 103.50(40.03) 99.10(35.04) 104.44 117.94 GEOMETRIC

MEAN 97.06 93.97 103.29 %Swing ARITH.MEAN 62.06-(SD) 176.36(139.0) 179.0(124.25) 98.53 134.92 %Fluctuation ARITH. 76.81-MEAN(SD~ 108.69(38.77) 117.75 (52.47) 92.22 107.57 End Point ARITH. 117.77-MEANISD) -1.86(2.78) -1.8612.19) 99.97 22.23 90% Confidence Interval --Significant Difference p < o.05 CLINICAL BTUDIEB
In Example 19, twenty-four normal, healthy male sub-jects were enrolled in a randomized single-dose two-way crossover study to compare the plasma oxycodone concen-trations obtained after dosing with two controlled-release oxycodone 10 mg tablets versus 20 mg (20 ml of 5 mg/5 ml) of immediate release (IR) oxycodone hydro-chloride solution. Twenty-three subjects completed the study and were eligible for analysis.
SUBSTITUTE SHEET

WO 93/1076~ PCT/L1S92/10146 Plasma oxycodone concentrations were determined by a high performance liquid chromatographic procedure. Arith-metic Mean C~x, tax, AUC, and half-lives calculated from individual plasma oxycodone concentration-versus-time data are set forth in Table 21:

Reference Test Pharmaco- Product Product 90%
kinetic IR Oxycodone CR Oxycodone Confidence l0 Parameter 20 mg 2 x 10 mg F, (%) Interval Cmex (ng/ml) 41.60 l8.62 44.75 32.5-57.0 (hours) 1.30 2.62 200.83 169.8-232.6 AUC

(0-36) 194.35 199.62 102.71 89.5-115.9 (mg x hr/ml) AUC (0-~) 194.38 208.93 107.49 92.9-121.9 (ng x hr/ml) ~
e m) t s .98* 249.15 219.0-( h~
~
3.21 7 278.8 (~~hr )) 0.35 0.92* 264.17 216.0-310.7 F, % - oral bioavailability (CR oxycodone 2 x 10 mg/IR oxycodone 20 mg) *Statistically significant (p = 0.0001) FOr C~x, tax, t,h ~e~~m) dnd t,~ Webs) there were statistically significant differences between the CR OXY
and IR OXY. There were no statistically significant differences between the two treatments in the extent of absorption [AUC (0,36), AUC (0,~). The 90% confidence SUBSTITUTE SHEET

2098~3~

interval for CR OXY relative to IR OXY relative was 89.5%
- 115.9% for AUC (0,36) and 92.9% - 121.9% for AUC (O,ao).
Based on the 90% confidence interval analysis, the controlled-release oxycodone tablets were equivalent in extent of absorption (AUC 0,36) to the immediate-release oxycodone solution. The controlled-release oxycodone absorption was slower by approximately 1.3 hours. No statistically significant differences were noted between the two treatments with reference to adverse experiences, none of which were considered clinically unusual for opiates for this type of study.
The above studies demonstrate a significant dose-response relationship utilizing the controlled release oxycodone formulations of the present invention at dosages of 10, 20 and 30 mg which does not deviate from parallelism with dose-response slopes for MS Contin in similarly designed well-controlled analgesic efficacy studies of MS Contin reported by Kaiko R.S., Van Wagoner D., Brown J., et al., "Controlled-Release Oral Morphine (MS Contina Tablets, MSC) in Postoperative Pain.", Pain Suppl., 5:S149 1990, who compared 30, 60, 90, and 120 mg of MS Contin as compared with~l0 mg of intramuscular morphine and placebo and Bloomfield, et al., "Analgesic Efficacy and Potency of Two Oral Controlled-Release Mor-phine Preparations", Clinical Pharmacology & Therapeutics, Vol. 53, No. 4, l993, who compared 30 and 90 mg of MS Contin as compared to 30 and 90 mg of another controlled-release oral morphine preparation, Oramorph SR 30 mg tablets.
The examples provided above are not meant to be 'exclusive. Many other variations of the present invention would be obvious to those skilled in the art, and are contemplated to be within the scope of the appended claims.