(12) INTERNATIONAL APPLICATION P UBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(19) World Intellectual Property Organization
`International Bureau
`
`(43) International Publication Date
`22 March 2001 (22.03.2001)
`
`• I ~IIIIIIIIIIIIIIIIIIIUIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII
`
`(JO) lnternati.onal Publication Number
`WO 01119346 AI
`
`PCT
`
`(51) International Patent Classification 7:
`9/22, 9/24, 9/26, 9/28, 9/36
`
`A61K 9/14,
`
`(74) Agents: BRAINARD, Charles, R. et al.; Kenyon &
`Kenyon, One Broadway. New York, NY 10004 (US).
`
`(21) International Application Number: PCT/US00/25 172
`
`(22) International Filing Date:
`14 September 2000 (14.09.2000)
`
`(25) Filing Language:
`
`(26) Publication Language:
`
`English
`
`English
`
`(30) Priority Data:
`09/395,884
`
`14 September 1999 (14.09.1999) US
`
`(71) Applicant (for all designated States except US) : CUP(cid:173)
`LEY PHARMACEUTICAL, INC. [US/US]; Legal
`Department, 1090 Horsham Road, P.O. Box 1090, North
`Wales, PA 1.9454-1090 (US).
`
`= (72) Inventors; and
`
`;;;;;;;;;;;;;
`
`(75) Inventors/Applicants (for US only): HlRSCH, Jane, C.,
`_
`~ L (US/US]; 15 Peirce Road, Wellesley, MA 02181 (US).
`;;;;;;;;;;;;;
`_
`CHUNGI, Shubha [IN/US); 233 Wolomolopoag Streel,
`Sharon, MA 02067 (US).
`
`(81) Designated States (national) : AE, AG, AL, AM. AT, AU,
`AZ, BA, BB, BG, BR, BY, BZ, CA, CH, CN. CR. CU. CZ,
`DE, DK. DM. DZ. EE, ES, Fl. GB. GD, GE, GH, GM, HR.
`HU, ID, IL, IN, IS, JP, KE, KG, KP. KR, KZ, LC, LK, LR.
`LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, MZ,
`NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI. SK, SL, TJ, TM,
`TR, IT, TZ, UA, UG, US, UZ, VN, YU, ZA. ZW.
`
`(84) Designated States (regional): ARIPO patent (GH, GM,
`KE, LS, MW, MZ, SD, SL, SZ, TZ, UG, ZW), Eurasian
`patent (AM, AZ, BY, KG, KZ, MD, RU, TJ. TM), European
`patent (AT, BE, CH, CY, DE, DK, ES, Fl. FR, GB, GR, IE,
`IT, LU, MC, NL, PT, SE), OAPI patent (SF, BJ, CF, CG,
`Cl. CM, GA, GN, GW, ML, MR, NE, SN, TD, TG).
`
`Published:
`-
`With inJernational search report.
`
`For two·leuer codes and other abbreviations, refer to the "Guid(cid:173)
`ance Notes on Codes and Abbreviations" appearing at the begin(cid:173)
`ning of each regular issue of the PCT Gazette.
`
`;;;;;;;;;;;;;
`;;;;;;;;;;;;;
`
`\C)
`~
`~ --------------------------------------------------------------------
`0\ (54) Title: DELAYED RELEASE NABUMETONE FORMULATION
`~ ....._
`~ (57) Abstract: An enteric coated, delayed release nabumetone formulation is provided. The compo~ition comprises a drug-contain-
`ing core containing the active agent and an enteric polymer coating that provides the desired delayed release profile. A preferred
`0 enteric polymer L~ a copolymer of methacrylic acid and methyl methacrylate in which the ratio of free carboxyl to ester groups is
`:;, approximately 1:1. Methods for using the novel formulation are provided as well; a preferred use is in the treatment of conditions
`~ and disorders associated with inflammation.
`
`

`
`wo 01/19346
`
`PCT!US00/25172
`
`5
`
`10
`
`15
`
`DELAYED RELEASE NABUMETONE FORMULATION
`
`TECHNICAL FIELD
`
`This invention relates generally to pharmaceutical formulations for oral
`
`administration of a nonsteroidal anti-inflammatory drug (NSAID), and more particularly relates
`
`to a delayed release, enterically coated nabumetone formulation. The invention additionally
`
`relates to therapeutic methods wherein the novel formulation is administered to a patient to treat
`
`an NSAID-responsive condition, disease or disorder.
`
`BACKGROUND
`
`Nonsteroidal anti-inflammatory drugs such as diclofenac, ibuprofen, ketoprofen,
`
`naproxen, nabumetone and piroxicam are widely used to relieve mild to moderate pain, to reduce
`
`fever, and to treat inflammatory conditions. Nabumetone ( 4-(6'-methoxy-2'-naphthyl)butan-2-
`
`20
`
`one), for example, has been described in U.S. Patent No. 4,420,639 for use as an anti(cid:173)
`
`inflammatory agent for the treatment of rheumatic and arthritic conditions.
`
`25
`
`0
`
`NABUMETONE
`
`

`
`wo 01/19346
`
`PCT/US00/25172
`
`-2-
`
`In addition, U.S. Patent No. 5,695, 774 describes the use of nabumetone for the treatment and/or
`
`prevention of dementia, such as Alzheimer's disease.
`
`The NSAlDs are non-habit forming drugs and thereby offer a significant advantage
`
`over the use of traditional opioid- or steroid-based drugs. However, in some cases, systematic
`
`5
`
`admimstration of an NSAlD is not recommended. NSA1Ds can result in systemic toxicity in a
`
`host, and since the agent is administered systemically, its effects are also systemic. Thus, the
`
`chronic use ofNSAlDs or the administration of high doses ofNSAlDs has been associated with
`
`undesirable side effects such as bleeding, ulceration, and perforation. For example, chronic oral
`
`administration of aspirin can result in stomach upset and patient discomfort.
`
`10
`
`In view ofthe advantages ofNSAIDs, steps have been undertaken to minimize the
`
`adverse effects associated with the systemic administration of these drugs. In one approach to
`
`reduce the adverse effects ofNSAlDs, the agents are ingested with food or milk, or are taken in
`
`combination with antacids, histamine H2-receptor antagonists, omeprazole, or sucraflate. In
`
`another approach, NSAlDs have been administered locally, such as by injection or topical
`
`15
`
`administration, or have been co-administered with a prostaglandin.
`
`In yet another approach to reduce the undesirable gastrointestinal effects resulting
`
`from systemic administration ofNSAlDs, the agents have been enterically coated to give a
`
`delayed release formulation. In U.S. Patent Nos. 3,488,418, 3,341,416, and 3,155,590, aspirin is
`
`microencapsulated with ethylcellulose. After ingestion, the gastric fluids slowly diffuse through
`
`20
`
`the encapsulant walls, dissolve the aspirin, and the dissolved aspirin diffuses out through the
`
`encapsulant walls into the body. In U.S. Patent No. 3,906,086, aspirin is coated with a non(cid:173)
`
`aqueous solution of cellulose acetate phthalate. The cellulose acetate phthalate is substantially
`
`insoluble in the acidic media of the stomach and the tablet remains intact until it reaches the
`
`intestinal tract. Thus, as the cellulose acetate phthalate coating is dissolved by the alkaline
`
`25
`
`intestinal fluid, aspirin is released in the intestinal tract. U.S. Patent No. 4,966, 768 describes a
`
`sustained release tablet containing etodolac as the active agent and a mixture of
`
`hydroxypropylmethyl cellulose, ethyl cellulose, and dibasic sodium phosphate as a sustained
`
`release carrier.
`
`

`
`wo 01/19346
`
`PCT/US00/25172
`
`-3-
`
`Nabumetone, disclosed in U.S. Patent No. 4,061,779, is a nonacidic prodrug that is
`
`metabolized to an active nonsteroidal antiinflammatory moiety 6-methoxy-2-naphthylacetic acid
`
`(6-MNA). 6-MNA is a structural analog ofnaproxen, and like other NSAJDs, possesses
`
`analgesic, antipyretic and anti-inflammatory activity.
`
`5
`
`10
`
`COOH
`
`6-MNA
`
`See Pisko et al. (1987), "Nabumetone: a 'Nonacidic' Nonsteroidal Antiinflammatory Drug"
`
`Plzarmatherapeutica ~:90-98. The predominant gastrointestinal reactions associated with
`
`NSAJDs, as noted above, include abdominal pain and indigestion, nausea or vomiting; however,
`
`15
`
`the aforementioned publication and others suggest that with nabumetone, duodenal ulcer, gastric
`
`ulcer, and gastrointestinal bleeding occurs in less than 1% of patients taking the drug. (See, e.g.,
`
`S.L. Dahl (1993), "Nabumetone: a 'Nonacidic' Nonsteroidal Antiinflammatory Drug" Ann.
`
`Pharmacother. 2.1(4): 456-463, which presents a comparative safety study of patients with
`
`osteoarthritis or rheumatoid arthritis using nabumetone, diclofenac, naproxen, piroxicam, and
`
`20
`
`ibuprofen, and concluded that ulcers occurred in 0.03% ofnabumetone-treated patients, and in
`
`0.5% of patients using the other NSAJDs.) Thus, the current belief in the art is that nabumetone
`
`does not, in general, cause the gastrointestinal reactions usually associated with the
`
`administration ofNSAJDs, and is therefore safe in relatively high d oses and for long-term
`
`systemic administration. For this reason, controlled release nabumetone formulations, and
`
`25
`
`particularly delayed release, enterically coated nabumetone compositions, have not been
`
`manufactured or made available conunercially. However, applicants' own studies have shown
`
`that oral administration of an "immediate release" nabumetone formu lation results in the side
`
`effects associated with other NSAIDs in significantly more patients than previously believed,
`
`

`
`wo 01/19346
`
`PCT/US00/25172
`
`-4-
`
`primarily gastrointestinal reactions such as stomach upset, bleeding, ulceration, and perforation,
`
`and have now developed a novel formulation that avoids these side effects.
`
`SUMMARY OF THE INVENTION
`
`5
`
`Accordingly, it is a primary object of the invention to address the aforementioned need in
`
`the art and provide a delayed release formulation for the administration of nabumetone.
`
`It is another object of the invention to provide such a formulation comprising an
`
`enterically coated dosage form.
`
`It is yet another object of the invention to provide such a formulation wherein the active
`
`10
`
`agent is nabumetone.
`
`It is still another object of the invention to provide such a formulation which significantly
`
`reduces the side effects associated with immediate release nabumetone formulations, particularly
`
`gastrointestinal reactions such as stomach upset, bleeding, ulceration, and the like.
`
`It is an additional object of the invention to provide a method for treating a patient
`
`15
`
`suffering from a disorder or condition associated with inflammation, comprising orally
`
`administering to the patient a dosage form of the invention.
`
`It is a further object of the invention to provide such a method wherein the disorder or
`
`condition is a rheumatic or arthritic disease.
`
`In one aspect of the invention, then, a pharmaceutical formulation is provided comprising
`
`20
`
`a therapeutically effective amount of nabumetone. The formulation is an enterically coated,
`
`delayed release dosage form in which a core containing the therapeutically effective amount of
`
`nabumetone is coated with an enteric polymer effective to delay release ofthe active agent until
`
`the small intestine of the patient is reached. The drug-containing core of the formulation
`
`comprises:
`
`25
`
`approximately 60 wt.% to 90 wt.% nabumetone;
`
`approximately 5 wt.% to 15 wt.% sodium starch glycolate;
`
`approximately 0.1 wt.% to 2 wt.% surfactant;
`
`approximately 1 wt.% to 4 wt.% hydroxypropyl methylcellulose;
`
`approximately 2.5 wt.% to 7.5 wt.% polyethylene glycol; and
`
`

`
`wo 01/19346
`
`PCT /US00/25172
`
`-5-
`
`approximately 0.5 wt.% to 10 wt.% microcrystalline cellulose, with all of the
`
`aforementioned percentages representing the fractional portion of the core. The core is coated
`
`with an enteric coating comprised of a polymer of acrylic acid, methacrylic acid, an acrylic acid
`
`ester, a methacrylic acid ester, or a combination thereof, wherein the enteric coating represents
`
`5
`
`approximately 5 wt.% to 15 wt.% of the total dosage form.
`
`In another aspect of the invention, a method is provided for treating a patient with an
`
`NSAID-responsive disorder or condition, typically a disorder or condition associated with
`
`inflammation, e.g., a rheumatic or arthritic disease such as osteoarthritis, rheumatoid arthritis, or
`
`the like. The method involves orally administering the present delayed release formulation to the
`
`10
`
`patient within the context of a dosage regimen effective to treat the disorder or condition and/or
`
`alleviate the inflammation and pain associated therewith.
`
`DETAILED DESCRlPTION OF THE INVENTION
`
`In a first embodiment, the invention provides a pharmaceutical formulation comprising
`
`15
`
`(1) a therapeutically effective amount ofnabumetone as the active agent, and (2) a polymeric
`
`material that, following oral administration of the formulation to a patient, is effective to provide
`
`a desired delayed release profile, delaying release of the active agent until the small intestine of
`
`the patient is reached. The active agent is present in a core that is coated with a composition
`
`containing the polymeric material, i.e., is encapsulated within an "enteric coating," wherein the
`
`20
`
`polymeric material comprises an "enteric polymer."
`
`The term "delayed release" is used in its conventional sense to refer to a drug formulation
`
`in which there is a time delay between oral administration of the formulation and the release of
`
`the drug therefrom. "Delayed release" may or may not involve gradual release of drug over an
`
`extended period of time, and thus may or may not be "sustained release." The "delayed release"
`
`25
`
`formulations herein are enterically coated compositions.
`
`"Enteric coating" or "enterically coated" as used herein relates to the presence of
`
`polymeric materials in a drug formulation that result in an increase in the drug's resistance to
`
`disintegration in the stomach. Typically, the polymeric material is present as a coating
`
`

`
`wo 01/19346
`
`PCT/US00/25172
`
`-6-
`
`surrounding a drug-containing core, but the polymeric material may also be present in admixture
`
`with the drug itselfwithin a coated formulation.
`
`The nabumetone formulation of the invention is wherein a drug-containing core
`
`comprises:
`
`5
`
`approximately 60 wt.% to 90 wt.% nabumetone,
`
`approximately 5 wt.% to 15 wt.% sodium starch glycolate,
`
`approximately 0.1 wt.% to 2 wt.% surfactant,
`
`approximately I wt.% to 4 wt.% hydroxypropyl methylcellulose,
`
`approximately 2.5 wt.% to 7.5 wt.% polyethylene glycol, and
`
`approximately 0.5 wt.% to 10 wt.% microcrystalline cellulose, with all of the
`
`aforementioned percentages representing the fractional portion ofthe core; and wherein the core
`
`is coated with an enteric coating comprised of a polymer of acrylic acid, methacrylic acid, an
`
`acrylic acid ester, a methacrylic acid ester, or a combination thereof, wherein the enteric coating
`
`represents approximately 5 wt.% to 15 wt.% of the total dosage form.
`
`In a preferred enteric coated composition of the invention, the drug-containing
`
`core compnses:
`
`approximately 75 wt.% to 85 wt.% nabumetone,
`
`approximately 8 wt.% to 12 wt.% sodium starch glycolate,
`
`approximately 0.5 wt.% to 1.5 wt.% sodium Iaury! sulfate,
`
`approximately 1.5 wt.% to 2.5 wt.% hydroxypropyl methylcellulose,
`
`approximately 5 wt.% to 6 wt.% polyethylene glycol 8000, and
`
`10
`
`15
`
`20
`
`approximately 0.5 wt.% to 1.5 wt.% microcrystalline cellulose, wherein the above
`
`percentages represent the fractional portion of the core; and wherein the core is coated with an
`
`enteric coating comprised of a copolymer of methacrylic acid and methyl methacrylate, and
`
`25
`
`wherein the enteric coating represents approximately 5 wt.% to 15 wt.% of the total dosage form.
`
`The amount of nabumetone in the formulation is preferably a unit dosage, typically in the
`
`range of 250 mg to 1000 mg, preferably in the range of 500 mg to 1000 mg. More preferably, the
`
`formulations of the invention are tablets containing 500 mg, 750 mg or 1000 mg active agent,
`
`most preferably containing 500 mg or 750 mg active agent.
`
`

`
`wo 01/19346
`
`PCT /US00/25172
`
`-7-
`
`The drug-containing core of the formulation may also include pharmacologically
`
`acceptable "carriers" or "vehicles," i.e., carriers or vehicles that are nontoxic and do not interact
`
`with other components of the formulation in a deleterious manner. Other materials that may be
`
`present in the drug-containing core include, but are not limited to, diluents, disintegrants,
`
`5
`
`stabilizers, coloring agents, and the like.
`
`The enteric coating composition comprises a polymeric material that, following oral
`
`administration of the formulation to a patient, prevents release of the active agent until the small
`
`intestine of the patient is reached. Generally, this requires that the polymeric material--i.e., the
`
`enteric polymer--prevent drug release in the acidic environment of the stomach but dissolve
`
`I 0
`
`sufficiently in the small intestines to gradually release the active agent therein. The enteric
`
`polymers useful herein are formed from acrylic acid, methacrylic acid, methyl acrylate, ethyl
`
`acrylate, methyl methacrylate and/or ethyl methacrylate, with copolymers ofmethacrylic acid and
`
`methyl methacrylate preferred. Such copolymers are commercially available under the
`
`tradenames Eudragit L and Eudragit S, in which the ratio of free carboxyl to ester groups is
`
`15
`
`approximately 1:1 and 1 :2, respectively, and wherein each copolymer has a (weight average)
`
`molecular weight of approximately 135,000 Da. Most preferred for use in conjunction with the
`
`present invention is the commercially available copolymer known as Eudragit Ll 00-55, which
`
`comprises granules ofEudragit L that are soluble at an intestinal pH of5.5 and above. The
`
`amount of enteric coating material used is such that most, i.e., at least about 60%, preferably at
`
`20
`
`least about 75%, of the active agent is released within about two hours of drug administration. In
`
`order to achieve the aforementioned release profile, the amount of enteric coating used is on the
`
`order of 5 wt.% to 15 wt.% of the total dosage form.
`
`The enterically coated tablets of the invention may be manufactured using standard tablet
`
`processing procedures and equipment for making the drug-containing core, and conventional
`
`25
`
`coating procedures and equipment for encapsulating the core in an enteric coating. Such
`
`procedures are known to those skilled in the art and described in the pertinent texts, e.g., in
`
`Remington: The Science and Practice of Pharmacy, Nineteenth Ed. (Easton, PA: Mack
`
`Publishing Company, 1995). supra. A preferred method for forming the drug-containing core is
`
`by direct compression of a powdered, crystalline or granular drug-containing composition, alone
`
`

`
`wo 01/19346
`
`PCT /US00/25172
`
`-8-
`
`or in combination with diluents, binders, lubricants, disintegrants, colorants or the like. As an
`
`alternative to direct compression, the compressed core can be prepared using wet-granulation or
`
`dry-granulation processes. The tablet core may also be molded rather than compressed, starting
`
`with a moist material containing a suitable water-soluble lubricant; however, it is preferred that
`
`5
`
`the drug-containing core be manufactured using compression rather than molding. After the
`
`drug-containing core is prepared, the enteric coating composition is then applied using a coating
`
`pan, an airless spray technique, fluidized bed coating equipment, or the like.
`
`The novel formulations are to be administered orally to a mammalian individual within
`
`the context of a dosage regimen effective to treat an NSAID-responsive condition or disorder.
`
`10
`
`Typically the formulations are employed as anti-inflammatory and/or analgesic compositions,
`
`and may be used to treat individuals suffering from rheumatic or arthritic disorders, including, for
`
`example: rheumatoid arthritis (RA), degenerative joint disease (also known as DID and
`
`"osteoarthritis"); juvenile rheumatoid arthritis (JRA); psoriatic arthritis; gouty arthritis;
`
`ankylosing spondylitis; and lupus erythematoses such as systemic lupus erythematosus and
`
`15
`
`discoid lupus erythematosus. The term "treating" refers to reduction in severity and/or frequency
`
`of symptoms, elimination of symptoms and/or underlying cause, prevention of the occurrence of
`
`symptoms and/or their underlying cause, and improvement or remediaton of damage.
`
`Other potential uses for the formulation of the present invention include but are not
`
`limited to treating fever (via the anti-pyretic property ofNSAJDs) or myocardial infarction (MI),
`
`20
`
`transient ischemic attacks, and acute superficial thrombophlebitis (via inhibition of platelet
`
`aggregation). Further non-limiting uses for the present invention include either single or adjuvant
`
`therapy for ankylosing spondylitis, bursitis, cancer-related pain, dysmenorrhea, gout, headaches,
`
`muscular pain, tendonitis, and pain associated with medical procedures such as dental,
`
`gynecological, oral, orthopedic, post-partum and urological procedure.
`
`25
`
`The dosage regimen will generally although not necessarily involve drug administration
`
`once or twice daily. The amount of active compound administered will, of course, vary from
`
`subject to subject and depend on the particular disorder or condition, the severity of the
`
`symptoms, the subject's age, weight and general condition, and the judgment of the prescribing
`
`

`
`wo 01/19346
`
`PCT /US00/25172
`
`-9-
`
`physician. Generally, however, a daily dosage ofnabumetone using the present formulations will
`
`be in the range of approximately 250 mg/day to 1000 mg/day.
`
`It is to be understood that while the invention has been described in conjunction with the
`
`preferred specific embodiments thereof, that the description above as well as the examples which
`
`5
`
`follow are intended to illustrate and not limit the scope of the invention. Other aspects,
`
`advantages and modifications within the scope ofthe invention will be apparent to those skilled
`
`in the art to which the invention pertains.
`
`All patents, patent applications, journal articles and other reference cited herein are
`
`incorporated by reference in their entireties.
`
`10
`
`EXPERIMENTAL:
`
`The practice of the present invention will employ, unless otherwise indicated,
`
`conventional techniques of pharmaceutical formulation and the like, which are within the skill of
`
`the art. Such techniques are explained fully in the literature.
`
`15
`
`In the following example, efforts have been made to ensure accuracy with respect to
`
`numbers used (e.g., amounts, temperature, etc.) but some experimental error and deviation should
`
`be accounted for. Unless indicated otherwise, temperature is in degrees C and pressure is at or
`
`near atmospheric. All reagents were obtained commercially unless otherwise indicated.
`
`EXAMPLE 1
`
`PREPARATION OF 500 MG NABUMETONE TABLET
`
`An enteric coated nabumetone tablet was made by first preparing the nabumetone(cid:173)
`
`containing core, and then coating the core with an enteric coating. The nabumetone-containing
`
`core had the following components:
`
`20
`
`25
`
`

`
`wo 01/19346
`
`PCT /US00/25172
`
`-10-
`
`Component
`
`Function
`
`Amount in dosage form
`
`Nabumetone
`
`Sodium starch glycolate, NF
`
`5
`
`Sodium Iaury! sulfate, NF
`
`Active agent
`
`Disintegrant
`
`Surfactant
`
`Hydroxypropyl methylcellulose, USP, 3 CPS
`
`Binder
`
`Polyethylene glycol 8000, powdered, NF
`
`Lubricant
`
`Microcrystalline cellulose (Avice!®) PH 101, NF
`
`Filler
`
`500mg
`
`57.0 mg
`
`5.0mg
`
`12.0 mg
`
`32.7 mg
`
`6.7mg
`
`10
`
`The drug-containing core was prepared using a wet granulation technique, as follows. A
`
`granulating solution was first prepared by mixing the sodium lauryl sulfate, hydroxypropyl
`
`methylcellulose and water, ensuring thorough wetting of the solid particles and an even
`
`dispersion. Separately, the nabumetone and approximately 70 wt.% of the total sodium starch
`
`15
`
`glycolate were mixed and thoroughly blended. The granulating solution was then sprayed into
`
`the blend and granulation was conducted for about 15 minutes. The mixture was then dried and
`
`screened. Then, the remaining sodium starch glycolate, the polyethylene glycol and the
`
`microcrystalline cellulose were added to the dried nabumetone admixture, and blending was
`
`conducted for about 20 minutes. The final blend was compressed using a tablet press.
`
`20
`
`An enteric coating solution was then prepared by slowly adding 1200.0 g Eudragit Ll 00-
`
`55 to 2400.0 g water (USP) and mixing for approximately 10 to 15 minutes to ensure
`
`homogeneous wetting of the polymer powder. Then, 400.0 g IN sodium hydroxide was added,
`
`and mixing was continued for approximately 30 to 45 minutes. The mixture was then filtered
`
`through a No. 40 mesh stainless steel screen. The nabumetone cores (12 kg) were then coated
`
`25
`
`with the solution using a conventional (Accelacota ™) coating pan.
`
`

`
`wo 01/19346
`
`PCT/US00/25172
`
`EXAMPLE2
`
`PREPARATION OF 750 MG NABUMETONE TABLET
`
`The procedure of Example 1 was then used to prepare enteric-coated nabumetone tablets
`
`containing 750 mg active agent, wherein the drug-containing core had the following components:
`
`5
`
`Component
`
`Function
`
`Amount in dosage form
`
`Nabumetone
`
`Sodium starch glycolate, NF
`
`Sodium lauryl sulfate, NF
`
`Active agent
`
`Disintegrant
`
`Surfactant
`
`10
`
`Hydroxypropyl methylcellulose, USP, 3 CPS
`
`Binder
`
`Polyethylene glycol 8000, powdered, NF
`
`Lubricant
`
`Microcrystalline cellulose (Avice!®) PH 101, NF Filler
`
`750 mg
`
`85.5 mg
`
`7.5 mg
`
`18.0 mg
`
`49.0 mg
`
`10.0 mg
`
`15
`
`Preparation of the enteric coating solution was carried out as described in Example 1,
`
`using 1200.0 g Eudragit Ll 00-55, 2400.0 g water (USP), and 400.0 g IN sodium hydroxide. The
`
`nabumetone cores ( 12 kg), as in Example 1, were coated with the solution using a conventional
`
`coating pan.
`
`20
`
`EXAMPLE3
`
`TABLET EvALUATION
`
`DISSOLUTION AND DISINTEGRATION STUDIES
`
`(a) Disintegration Studies: The enteric efficiency of the enteric coated nabumetone tablets
`
`prepared in Examples 1 and 2 was evaluated using a modified USP test. Six of each strength of
`
`the enteric coated nabumetone tablets were examined in a modified disintegration tester for 1
`
`25
`
`hour, using simulated gastric fluid ("SGF"; pH 1.2) as the test medium at 3rC. Subsequently
`
`the disintegration time in simulated intestinal fluid ("SIF") was also evaluated. Results indicated
`
`an ability of both strengths to resist breakdown for the prescribed period, with a disintegration
`
`

`
`wo 01119346
`
`PCT IUS00/25172
`
`-12-
`
`time in the SIF solution of approximately 15 minutes, and a corresponding disintegration time of
`
`approximately 10 minutes for the uncoated cores.
`
`(b) Dissolution Studies: An evaluation of the release of each strength of the prepared
`
`nabumetone tablets in SGF over a two-hour period was carried out using a USP dissolution
`
`5
`
`apparatus (paddle method-75 rpm). After two hours, no nabumetone release, through the
`
`coatings, was detected. Dissolution was continued in 0.75% sodium lauryl sulfate in DI water
`
`and a comparison was made with uncoated tablets.
`
`Results are summarized in the following table:
`
`10
`
`Time
`
`Tablet Type
`
`% Nabumetone Released
`
`15 min.
`
`30 min.
`
`60 min.
`
`120 min.
`
`15
`
`180 min.
`
`Enteric
`
`Uncoated
`
`Enteric
`
`Uncoated
`
`Enteric
`
`Uncoated
`
`Enteric
`
`Uncoated
`
`Enteric
`
`Uncoated
`
`Mean± S.D.
`
`1.0 ± 0.0
`
`73 ± 1.5
`
`8.0± 5.6
`
`83 ± 2.9
`
`64 ± 8.8
`
`89 ± 0.2
`
`81 ± 4.7
`
`101±0.4
`
`94 ± 3.9
`
`102 ± 3.8
`
`

`
`wo 01119346
`
`PCT /US00/25172
`
`-13-
`
`EXAMPLE4
`
`COMPARATIVE TESTING WITH UNCOATED, IMMEDIATE RELEASE TABLETS
`
`The compositions prepared may be compared with immediate release nabumetone
`
`formulations with regard to therapeutic efficacy and gastrointestinal side effects, and will be
`
`5
`
`found to be far superior, insofar as the compositions of the invention are equally effective in
`
`treating NSAID-responsive conditions and disorders, while resulting in significantly reduced
`
`gastrointestinal side effects.
`
`At least 50 patients with rheumatoid arthritis or osteoarthritis are given 1500 mg
`
`nabumetone daily using 500 mg or 750 mg immediate release tablets, and, for purposes of
`
`10
`
`comparison, at least 50 patients with rheumatoid arthritis or osteoarthritis are given 1500 mg
`
`nabumetone daily using 500 mg or 750 mg enteric coated tablets as prepared in Example 1 or 2,
`
`for chronic treatment of the arthritic symptoms. After six weeks of treatment both groups are
`
`expected to report improved pain and inflammation management. The group receiving the
`
`enteric coated tablets, however, are expected to report statistically significant reduction in
`
`15
`
`gastrointestinal complaints.
`
`

`
`wo 01/19346
`
`PCT /US00/25172
`
`-14-
`
`CLAIMS
`
`5
`
`10
`
`15
`
`20
`
`1. A delayed release nabumetone formulation comprising:
`
`a drug-containing core that comprises
`
`approximately 75 wt.% to 85 wt.% nabumetone,
`
`approximately 8 wt.% to 12 wt.% sodium starch glycolate,
`
`approximately 0.5 wt.% to 1.5 wt.% sodium Iaury! sulfate,
`
`approximately 1.5 wt.% to 2.5 wt.% hydroxypropyl methylcellulose,
`
`approximately 5 wt.% to 6 wt.% polyethylene glycol 8000, and
`
`approximately 0.5 wt.% to 1.5 wt.% microcrystalline cellulose, wherein the
`
`above percentages represent the fractional portion of the core; and wherein the core is coated with
`
`an enteric coating comprised of a copolymer of methacrylic acid and methyl methacrylate in
`
`which the ratio of free carboxyl to ester groups is approximately 1: 1.
`
`2. The formulation of claim 1, comprising approximately 250 mg to 1000 mg
`
`nabumetone.
`
`3. The formulation of claim 2, comprising approximately 500 mg to 1000 mg
`
`nabumetone.
`
`4. The formulation of claim 3, comprising approximately 500 mg nabumetone.
`
`5. The formulation of claim 3, comprising approximately 750 mg nabumetone.
`
`25
`
`6. The formulation of claim 3, comprising approximately 1000 mg nabumetone.
`
`7. The formulation of claim 1, wherein the enteric coating represents approximately
`
`10 wt.% of the formulation.
`
`

`
`wo 01119346
`
`PCT IUS00/25172
`
`-15-
`
`8. The formulation of claim 1, wherein the copolymer has a weight average
`
`molecular weight of approximately 135,000 Da.
`
`9. A method for treating a patient afflicted with an NSAID-responsive condition or
`
`5
`
`disorder, comprising orally administering to the patient the pharmaceutical formulation of
`
`claim 1.
`
`10. The method of claim 9, wherein the NSAID-responsive condition or disorder is a
`
`disease associated with inflammation.
`
`10
`
`15
`
`pam.
`
`11. The method of claim I 0, wherein the disease is a rheumatic or arthritic disease.
`
`12. The method of claim 11, wherein the disease is rheumatoid arthritis.
`
`13. The method of claim 11, wherein the disease is osteoarthritis.
`
`14. The method of claim 9, wherein the NSAID-responsive condition or disorder is
`
`20
`
`15. A method for reducing the side effects associated with the oral administration of
`
`nabumetone, comprising administering the nabumetone in an enteric coated nabumetone
`
`formulation comprising: (a) a drug-containing core that comprises approximately.75 wt.% to 85
`
`wt.% nabumetone, approximately 8 wt.% to 12 wt.% sodium starch glycolate, approximately 0.5
`
`wt.% to 1.5 wt.% sodium lauryl sulfate, approximately 1.5 wt.% to 2.5 wt.% hydroxypropyl
`
`25
`
`methylcellulose, approximately 5 wt.% to 6 wt.% polyethylene glycol 8000, and approximately
`
`0.5 wt.% to 1.5 wt.% microcrystalline cellulose, wherein the above percentages represent the
`
`fractional portion of the core; and (b) an enteric coating surrounding the drug-containing core,
`
`comprised of a copolymer of methacrylic acid and methyl methacrylate in which the ratio of free
`
`carboxyl to ester groups is approximately 1:1.