US00898O319B2

(12) United States Patent (10) Patent No.: US 8,980,319 B2 Park et al. (45) Date of Patent: *Mar. 17, 2015

(54) METHODS OF PRODUCING STABILIZED A613 L/445 (2006.01) SOLID DOSAGE PHARMACEUTICAL A613 L/47 (2006.01) COMPOSITIONS CONTAINING A6II 45/06 (2006.01) MORPHINANS A63/67 (2006.01) (52) U.S. Cl. (71) Applicant: Mallinckrodt LLC, Hazelwood, MO CPC ...... A6 IK3I/485 (2013.01); A61 K9/1652 (US) (2013.01); A61 K9/2031 (2013.01); A61 K 9/2081 (2013.01); A61 K9/2086 (2013.01); (72) Inventors: Jae Han Park, Olivette, MO (US); A6IK9/2095 (2013.01); A61 K9/5042 Tiffani Eisenhauer, Columbia, IL (US); (2013.01); A61 K3I/4355 (2013.01); A61 K Spainty,S.Isna Gupta, F11llsborough, 31/4375A6 (2013.01); IK3I/445 gets (2013.01); it' A6 (2013.01); IK3I/47 Stephen Overholt, Middlesex, NJ (US) (2013.01); A61K 45/06 (2013.01); A61 K 9/2013 (2013.01); A61 K9/209 (2013.01); (73) Assignee: Mallinckrodt LLC, Hazelwood, MO A6 IK3I/167 (2013.01) (US) USPC ...... 424/472: 424/465; 424/468; 424/490; c - r - 514/282; 514/289 (*) Notice: Subject to any disclaimer, the term of this (58) Field of Classification Search patent is extended or adjusted under 35 N U.S.C. 154(b)b) by 0 daysyS. Seeone application file for complete search history. This patent is Subject to a terminal dis claimer. (56) References Cited (21) Appl. No.: 14/092.375 U.S. PATENT DOCUMENTS (22) Filed: Nov. 27, 2013 2008, 0026052 A1 ck 1/2008 Schoenhard ...... 424/456 (65) Prior Publication Data FOREIGN PATENT DOCUMENTS US 2014/0086987 A1 Mar. 27, 2014 WO WO 2008O15221 A2 * 2, 2008 OTHER PUBLICATIONS Related U.S. Application Data Michael J. Akers. Excipient Drug Interactions in Parenteral For (63) Continuation of application No. 13/166,770, filed O mulations. Journal of Pharmaceutical Sciences, vol. 91, No. 11, Nov. Jun. 22, 2011, now Pat. No. 8,597,681, which is a 2002, pp. 2283-2300.* continuation-in-part of application No. 12/973.962, filed on Dec. 21, 2010. * cited by examiner (60) typal application No. 61/284,651, filed on Dec. Primary Examiner — Frederick Krass s Assistant Examiner — Michael P Cohen (51) Int. Cl. (74) Attorney, Agent, or Firm — Mayer Brown LLP A6 IK3I/485 (2006.01) A6 IK9/20 (2006.01) (57) ABSTRACT A6 IK 9/22 (2006.01) Methods for producing stabilized solid dosage form pharma A6 IK9/24 (2006.01) ceutical compositions are provided. In particular, methods for A 6LX 9/50 (2006.01) preparing protected granules containing morphinans, and A6 IK 9/16 (2006.01) Solid dosage form pharmaceutical compositions produced A6 IK3I/4355 (2006.01) using the morphinan-protected granules are provided. A6 IK3I/4375 (2006.01) A6 IK3I/439 (2006.01) 30 Claims, No Drawings US 8,980,319 B2 1. 2 METHODS OF PRODUCING STABILIZED carrier in order to achieve a desired release profile after SOLID DOSAGE PHARMACEUTICAL administration of the compound. Polymer carriers such as a COMPOSITIONS CONTAINING polyethylene oxide (PEO) polymer may be incorporated into MORPHINANS a pharmaceutical composition to impart an extended release profile to the composition. PEO polymers are produced by a CROSS-REFERENCE TO RELATED process of radical polymerization process followed by oxida APPLICATIONS tive degradation of the polymer to achieve the desired molecular weight. The resulting PEO polymer carriers may This application is a continuation of U.S. application Ser. retain residual peroxides and other oxidative species from the No. 13/166,770 filed on Jun. 22, 2011, which is a continua 10 production process that may cause the oxidation of the API tion-in-part of U.S. application Ser. No. 12/973.962, filed molecules in any pharmaceutical composition that incorpo Dec. 21, 2010, which claims priority to U.S. Provisional rates PEO polymers. Typically, other excipients such as anti Application No. 61/284,651 filed on Dec. 22, 2009, each of oxidants or pH-lowering excipients may be incorporated into which is hereby incorporated by reference in its entirety. the API composition to minimize the degradation of the API 15 in the presence of incompatible carriers such as PEO poly FIELD OF THE INVENTION mers in the pharmaceutical composition. However, in a solid dosage form composition, this approach is less effective than The present invention relates to methods of producing sta in other dosage forms such as solutions or Suspensions. bilized solid dosage forms of morphinan pharmaceutical Morphinans, a widespread class of APIs, are compositions. In particular, the present invention relates to particularly Vulnerable to oxidative degradation, especially in methods of preparing morphinan-protected granules that may compositions that incorporate PEO polymer carriers or other be incorporated into Solid dosage forms of morphinan phar pharmaceutical carriers that contain residual peroxides or maceutical compositions. other oxidative species. Because the physiological effects of morphinans are notoriously sensitive to Small changes in BACKGROUND OF THE INVENTION 25 chemical structure, the formation of degradants may intro duce undesirable properties to a pharmaceutical composition Minimizing the degradation of active pharmaceutical in which a morphinan is vulnerable to degradation. For solid ingredients (APIs) in pharmaceutical compositions is an dosage forms of morphinan compositions, the introduction of ongoing challenge in research and development. Degradation additional antioxidant excipients or pH-lowering excipients may occur from the physical or chemical instability of the API 30 to prevent the degradation of the morphinan, particularly with incompatible pharmaceutical carriers in a pharmaceuti when formulated in a solid dosage form, has been relatively cal composition, or by reactions of the API with headspace ineffective to date. oxygen or residual water in a composition. A need exists in the art for a method of protecting an API Oxidation is a common mechanism of API degradation in from degradation in a solid dose form of a pharmaceutical pharmaceutical compositions. The process of oxidative deg 35 composition. In particular, a need exists for a method of radation may occur via various mechanisms such as autooxi stabilizing morphinan APIs, which are especially vulnerable dation, nucleophilic addition, electrophilic addition, or elec to oxidative degradation, in Solid dosage forms of pharma tron transfer. Regardless of the mechanism, degradant ceutical compositions. compounds formed by the degradation of an API in a phar maceutical composition may impart potentially harmful 40 SUMMARY OF THE INVENTION properties to the composition. If degradants are present in a pharmaceutical composition Briefly, therefore, one aspect of the disclosure provides a above the levels prescribed by ICH Guidelines Q3A and Q3B, method for the preparation of a solid dosage form pharma the degradants must undergo a qualification procedure as part ceutical composition comprising a morphinanand at least one of the approval process required before the use and sale of the 45 other active pharmaceutical ingredient. The method com composition is allowed. Qualification of impurities typically prises three steps. In the first step, a mixture comprising the involves costly studies using multiple animal models, and morphinan and at least one excipient is granulated in a man introduces considerable risk into the development process. If ner Such that the amount of morphinan exposed on the Surface degradants of a pharmaceutical composition are found to be of the granule is Substantially reduced thereby forming a carcinogenic or teratogenic, the composition will not gain 50 morphinan-protected granule. The second step comprises FDA approval, diminishing the opportunity for commercial granulating a mixture comprising the morphinan-protected ization of the API. granule, the active pharmaceutical agent, and at least one As a result, the process of selecting functional carriers for excipient to form a granulated mixture. In the third step, the a pharmaceutical composition is particularly challenging. A granulated mixture is blended with a release-controlling functional pharmaceutical carrier is typically selected prima 55 polymer comprising a polyethylene oxide polymer to form rily to impart desired performance characteristics to the com the Solid dosage form pharmaceutical composition compris position Such as an extended release profile. In addition, it is ing a Sustained release layer. desirable to select functional carriers that are chemically In another aspect of the disclosure, a method for the prepa compatible with the API in the composition. In certain com ration of a Solid dosage form pharmaceutical composition positions, it may be necessary to incorporate functional car 60 comprising oxycodone and acetaminophen is provided. The riers that may be incompatible with the API in order to method comprises three steps. In the first step, a mixture achieve a desired performance of the API in the body. In this comprising the oxycodone and at least one excipient is granu situation, identifying an effective means to prevent the deg lated in a manner Such that the amount of oxycodone exposed radation of the API is an essential part of the development of on the surface of the granule is substantially reduced thereby a successful therapeutic composition. 65 forming an oxycodone-protected granule. In the next step, a For example, the formulation of a solid dosage form of an mixture comprising the oxycodone-protected granule, the API may incorporate a release-modifying pharmaceutical acetaminophen, and at least one excipient is granulated to US 8,980,319 B2 3 4 form a granulated mixture. The third step comprises blending excipient, wherein the granule contains less than about 0.5% the granulated mixture with a release-controlling polymer w/w of the total mass of hydrocodone of a degradant selected comprising a polyethylene oxide polymer is granulated to from hydrocodone n-oxide and hydrocodone aldol dimer form the Solid dosage form pharmaceutical composition com after being stored for 6 months at 40° C. and 75% relative prising a Sustained release layer. humidity. An additional aspect of the disclosure provides a method Yet another aspect provides a solid dosage pharmaceutical for the preparation of a bilayer tablet comprising a Sustained composition comprising a plurality of oxycodone-protected release layer and an immediate release layer. The method granules and acetaminophen, the composition prepared by a comprises four steps. In a first step, a mixture comprising process comprising (a) granulating a mixture comprising the oxycodone or hydrocodone and at least one excipient is 10 oxycodone and at least one excipientina manner Such that the granulated in a manner Such that the amount of oxycodone or amount of oxycodone exposed on the Surface of the granule is hydrocodone exposed on the Surface of granule is Substan substantially reduced thereby forming the plurality of oxyc tially reduced thereby forming a morphinan-protected gran odone-protected granules; (b) granulating a mixture compris ule. In the next step, a mixture comprising the morphinan ing the plurality of oxycodone-protected granules, the protected granule, the acetaminophen, and at least one 15 acetaminophen, and at least one excipient to form a granu excipient is granulated to form a granulated mixture. In the lated mixture; and (c) blending the granulated mixture with a third step, the granulated mixture is blended with a release release-controlling polymer comprising a polyethylene oxide controlling polymer comprising a polyethylene oxide poly polymer to form the solid dosage form the pharmaceutical mer to form a Sustained release layer. In the final step, a composition comprising a Sustained release layer. mixture comprising the morphinan-protected granule from Other features and iterations of the invention are described the first step is granulated with the acetaminophen and at least in more detail below. one excipient to form the immediate release layer. A further aspect of the disclosure encompasses a granule DETAILED DESCRIPTION that is Substantially resistant to oxidative degradation of oxy codone. The granule comprises an interior region Substan 25 The invention provides methods of preparing morphinan tially comprising oxycodone that is surrounded by an exterior protected granules by combining a morphinan with at least region Substantially comprising at least one excipient. More one excipient to form a mixture, and granulating the mixture. over, the granule contains less than about 0.5% w/w of the The resulting morphinan-protected granules have a physical total mass of oxycodone of a degradant selected from 10-hy structure that minimizes the amount of morphinan that is droxy oxycodone, di-hydroxy oxycodone, and oxycodone 30 exposed on the Surface of the granule. The morphinan-pro n-oxide after being stored for 6 months at 40° C. and 75% tected granules may stabilize the morphinan against various relative humidity. mechanisms of degradation such as oxidation by substan Another aspect of the disclosure provides a granule Sub tially decreasing the amount of morphinan exposed on the stantially resistant to oxidative degradation of hydrocodone. Surface of the granule thereby reducing the degree of contact The granule comprises an interior region Substantially com 35 between the morphinan and the oxidative species in the envi prising hydrocodone that is surrounded by an exterior region ronment Surrounding the granules, including but not limited Substantially comprising at least one excipient, wherein the to carriers and residual water in the composition, and atmo granule contains less than about 0.5% w/w of the total mass of spheric oxygen and moisture. hydrocodone of a degradant selected from hydrocodone-n- In addition, if chemically protective excipients including oxide and hydrocodone aldol dimer after being stored for 6 40 but not limited to antioxidants and pH-adjusting agents are months at 40°C. and 75% relative humidity. included in the excipient mixture forming the morphinan Yet another aspect of the disclosure provides a granule protected granule, the morphinan contained within the gran Substantially resistant to oxidative degradation of a morphi ule is further protected against degradation. Any oxidative nan, the granule prepared by a process comprising granulat species contained in the environment Surrounding the mor ing a mixture comprising the morphinan and at least one 45 phinan-protected granules may react with the chemically pro excipient in a manner Such that the amount of morphinan tective excipients situated the granules before they can reach exposed on the Surface of the granule is Substantially reduced the morphinan. thereby forming the morphinan-protected granule. The morphinan-protected granules may be prepared using An additional aspect of the disclosure encompasses a phar any device known in the art, including but not limited to a maceutical composition comprising a plurality of oxyc 50 high-shear wet granulator. The particular device used for odone-containing granules Substantially resistant to oxidative granulation may affect the physical properties of the resulting degradation of oxycodone and at least one pharmaceutically granules, including but not limited to granule size, granule acceptable carrier. The plurality of granules comprise an inte density, and granule porosity, all of which may influence the rior region Substantially comprising oxycodone that is Sur protective properties of the granule against degradation of the rounded by an exterior region Substantially comprising at 55 morphinan. Regardless of the granulation method used to least one excipient, wherein the granule contains less than form the granules, the distribution of morphinan and excipi about 0.5% w/w of the total mass of oxycodone of a degradant ents within the granules is influenced by at least several fac selected from 10-hydroxy oxycodone, di-hydroxy oxyc tors including but not limited to the size of the morphinan odone, and oxycodone n-oxide after being stored for 6 particles relative to the excipient particles in the mixture prior months at 40°C. and 75% relative humidity. 60 to granulation, the chemical properties of the morphinan and Another aspect of the disclosure provides a pharmaceutical excipients including but not limited to hydrophobicity and composition comprising a plurality of hydrocodone-contain ionic charge, and the presence of excipients dissolved in the ing granules Substantially resistant to oxidative degradation granulation Solution used to prepare the granules. of hydrocodone and at least one pharmaceutically acceptable The morphinan-protected granules prepared by the meth carrier. The plurality of granules comprise an interior region 65 ods of the invention may be incorporated into a solid dose Substantially comprising hydrocodone that is Surrounded by form of a pharmaceutical composition, including but not lim an exterior region Substantially comprising at least one ited to tablet and capsule formulations. In addition to protec US 8,980,319 B2 5 6 tion against degradation, the inclusion of the morphinan in the chemically interacting with degradative compounds Sur form of granules imparts several other advantageous aspects rounding or within the granule. For example, the effective to the resulting composition. Because the morphinan in the ness of the excipients at protecting the morphinans in the granules is protected, the choice of carrier may be selected to granule may be enhanced if at least one of the excipients satisfy constraints other than compatibility with the morphi includes but is not limited to an antioxidant, a chelating agent, nan. Carriers in the composition may instead be selected or a pH-adjusting agent. Various embodiments of the excipi based on factors including but not limited to the cost of the ents included in the granule are described in detail below. carrier, the desirable modified-release properties imparted by The density and porosity of the exterior regions of the a particular carrier. Further, variation in the characteristics of granules may influence the effectiveness of the exterior the morphinan-protected granules including granule size, 10 regions at protecting the morphinans in the granules from excipients included in the granules, and the physical structure degradation. Exterior regions having higher densities and of the granules may be used to control the release profile or lower porosities may be more resistant to penetration by other pharmacokinetic characteristics of pharmaceutical degradative compounds from outside the granule. The densi compositions. ties and porosities of the exterior regions of the granules may Detailed descriptions of various embodiments of the mor 15 be influenced by at least several factors including but not phinan protected granules, methods of preparing the morphi limited to the particular morphinan and excipients included in nan protected granules, and solid dosage forms of pharma the granule and the device used to prepare the granule. For ceutical compositions that include the morphinan-protected example, a granule prepared using a high-shear wet granula granules are described in detail below. tor may have a higher density and lower porosity compared to a granule with a similar composition prepared using a fluid (I) Morphinan-Protected Granules bed granulator. The doo of the granules in various embodiments may be The granules prepared by the methods of the invention selected based on the intended use of the granules, in particu stabilize the morphinan contained within the granules by lar the particular solid dosage form in which the granules are Substantially reducing the amount of morphinan exposed on 25 to be incorporated. The particular do of the granule may be the Surface of the granule. In this regard, significantly less of influenced by a variety of factors including but not limited to the morphinan is in contact with any oxidative species in the the composition of the granule and the granulation device environment outside of the granule, and may additionally used to prepare the granules. The do of the granules may be provide chemical protection of the morphinan against degra larger for granule compositions having a higher proportion of dation by Surrounding the morphinan with chemically pro 30 excipients including but not limited to binders and fillers tective excipients including but not limited to antioxidants relative to other types of excipients. that are contained within the morphinan-protected granule. In various embodiments, the granules may have an average The physical structure of the morphinan-protected granule do of less than about 2000 um. In other embodiments, the may influence the protective efficacy of the granule against granules may have an average doo of less than about 1800 um, degradation of the morphinan, and further influences the Suit 35 less than about 1500 um, less than about 1000 um, less than ability of the granules for inclusion in various solid dose about 900 um, less than about 800 um, less than about 700 um, forms of pharmaceutical compositions, including but not lim less than about 600 um, less than about 500 um, less than ited to tablets and capsules. about 400 um, less than about 300 um, less than about 200 um, (a) Granule Structure less than about 150 um, and less than about 100 um. In one The physical structure of the granule includes the morphi 40 exemplary embodiment in which the granules are to be incor nan dispersed within the excipient mixture and granulated in porated in a Solid dosage form including but not limited to a a manner Such that the amount of morphinan exposed on the capsule, the granules may be less than about 1000 um in surface of the granule is substantially reduced. The particular average doo. In another exemplary embodiment in which the physical structure of any embodiment of a morphinan-pro granules are to be incorporated in a solid dosage form includ tected granule is influenced by at least several factors related 45 ing but not limited to a tablet, the granules may be less than to the method of preparing the granules and the particular about 800 um in average doo. In yet another embodiment, the morphinan and excipients included in the granule. The influ granules may range from about 150 um to about 200 um in ence of these factors on the physical structure of the granules average doo. is described in detail below. In general, the physical structure of the granules may vary 50 (II) Granule Composition from an essentially random spatial distribution of the morphi nan and excipients throughout the granules to a highly The composition of the granules prepared using the meth ordered distribution in which essentially all of the morphinan ods of the invention include a morphinan and at least one is contained within a sharply delineated interior region that is excipient. The particular composition of the granules may Surrounded by an exterior region that contains essentially all 55 influence a variety of properties of the granules including but of the excipients. In an embodiment, the amount of morphi not limited to the physical structure of the granules, the sta nan that is exposed at the Surface of the granules is less than bility of the morphinan contained within the granule, and the about 100% of the total weight of the morphinan in the gran Suitability of the granules for incorporation into a particular ules. In other embodiments, the amount of morphinan that is dry dosage form of a pharmaceutical composition. exposed at the surface of the granules is less than about 95%, 60 One aspect of the composition that may influence the less than about 90%, less than about 80%, less than about physical structure of the granules is the do of the morphinan 70%, less than about 60%, less than about 50%, less than particles relative to the doo of the excipient particles in the about 40%, less than about 30%, less than about 20%, less mixture that used to form the granules. As used herein, do than about 10%, and less than about 5% of the total weight of represents the particle diameter at which 90% of the indi morphinan in the granule. 65 vidual particles of a compound are smaller than the specified Excipients contained within the granule may provide addi diameter. Without being bound to any particular theory, when tional protection against degradation of the morphinan by a granulation device including but not limited to a low-shear US 8,980,319 B2 7 8 wet granulator, a high-shear wet granulator, or a fluid bed tives, semi-synthetic derivatives, and synthetic opium granulator is used to granulate the mixture of the morphinan derivatives. Non-limiting examples of Suitable morphinans and at least one excipient, the compounds having a smaller for various embodiments of the granules include adlumine, do relative to the other compounds in the mixture tend to , , benzylmorphine, , bicu aggregate near the interior regions of the granules, and the culine, bicucine, , buprenorphine, butorphanol, compounds having larger doo tend to aggregate near the exte , capaurine, , , codamine, rior regions of the granules, regardless of whether the com , , coreximine, corlumine, corybulbine, pound is a morphinan or an excipient. corycavamine, cory cavine, , corydine, corytu As a practitioner skilled in the art may appreciate, for berine, cularine, cotamine, , , granule compositions in which the morphinan accounts for an 10 cycloartenone, cyclolaudenol, dehydroreticuline, desomor extremely low proportion of the total mass of the granule, the phine, dextropropoxyphene, dextrorphanol, diacetylmor size of the morphinan particles relative to the excipient par phine, , , dipropanoylmor ticles may not exert the same influence on the physical struc ture of the resulting granules as described previously. By way phine, epiporphyroXine, ethylmorphine, eupaverine, of a non-limiting example, if a granule is prepared using a fagarine, fentanyl, , homochelidonoine, hydroc mixture containing about 5% morphinan and about 95% 15 odone, hydrocotamine, hydromorphone, hydroxythebaine, excipients by weight, and the do of the morphinan is larger isoboldine, isocorybulbine, isocorydine, isocorypalmine, than the do of the excipients, the relative scarcity of the , laudanidine, laudanine, , levorpha morphinan particles may result in a granule in which the nol, , , methadone, , nal individual morphinan particles are surrounded by excipient buphine, nalmefene, naloxone, naltrexamine, C.-naltrexol. particles, and the morphinan particles may be located in both B-maltrexol, naltrexone, naphthaphenanthridine, narceline, the interior region and the exterior region of the granule. narceinone, narcotoline, narcotine, neopine, nicomorphine, In one embodiment, the doo of the morphinan is Smaller norlaudanosoline, norsanguinarine, , opium, oripa than the doo of the excipients. In another embodiment, the doo vine, oxycodone, oxymorphone, oxysanguinarine, palau of the morphinan is less than about 80% of the do of the dine, , papaveraldine, papaverrubine, perparin, excipients. In yet other embodiments, the do of the morphi 25 pethidine, , phtalide-isoquinoline, porphyroX nan is less than about 75%, less than about 70%, less than ine, , pseudocodeine, , , about 65%, less than about 60%, less than about 55%, or less , sinoacutine, , , som than about 50% of the do of the excipients. niferine, , tapentadol, tetrahydroprotoberberine, The doo values of the morphinan and the excipients may , , and Xanthaline. In an exemplary embodi also be influenced by the capabilities of the particular device ment, the morphinan included in the granules may be selected used to prepare the granules. Without being bound to any 30 from oxycodone, Oxymorphone, hydrocodone, hydromor particular theory, when a granulation device including but not phone, nalbuphine, naloxone, buprenorphine, and naltrexone. limited to a low-shear wet granulator, a high-shear wet granu In another exemplary embodiment, the morphinan in the lator, or a fluid bed granulator is used to granulate the mixture granules is oxycodone or hydrocodone. of the morphinan and at least one excipient, if the doo of a Any of the morphinans included in the embodiments of the particular compound falls below a threshold do the particles 35 granules may have a (-) or (+) orientation with respect to the of that compound tend to aggregate before they are granu rotation of polarized light, depending upon whether the start lated, resulting in granules that have a non-homogenous dis ing Substrate has (-) or (+) optical activity, and are referred to tribution of the compound from granule to granule. herein as (-)-morphinans and (+)-morphinans respectively. In other embodiments, other properties of the morphinan More specifically, each chiral center may independently have and excipients may influence the physical structure of the 40 an R oran S configuration. granule including but not limited to the hydrophobicity and As an illustrative example, an embodiment of the granules ionic charge of the morphinan relative to the one or more may include a morphinan compound possessing a fused car excipients. As a non-limiting illustrative example, if the mor bon ring structure. The ring atoms of the morphinan com phinan is hydrophobic relative to the excipients and if a polar pound may be numbered as diagrammed in Formula (I) granulation fluid is used in the granulation process, hydro below. Morphinan compounds have asymmetric centers and phobic repulsive forces may tend to situate the morphinan 45 the core morphinan compound may have at least four chiral within the interior region of the granules. carbons including but not limited to C-5, C-13, C-14, and C-9. In one embodiment, the composition of the granules In various embodiments, the configuration of the chiral car includes one morphinan compound. In other embodiments, bons C-5, C-13, C-14, and C-9 may be RRRR, RRSR, RRRS, the composition of the granules may further include one or RRSS, RSRR, RSSR, RSRS, RSSS, SRRR, SRSR, SRRS, more additional morphinan compounds within each granule. 50 Any number of different morphinans may be included in the SRSS, SSRR, SSSR, SSRS, or SSSS, provided that the C-15 composition of the granules, so long as all morphinans that and the C-16 carbons are both oriented either on the alpha are included in the granule are physically and chemically face or the beta face of the morphinan molecule. compatible. An acid, as defined herein, refers to the acid and any phar 55 maceutically acceptable salt of the acid. (I) (a) Morphinans The compositions of various embodiments of the granules include a morphinan. In one embodiment, the morphinan may be included in the granules in an amount of up to about 90% of the total weight of the granules. In other embodiments, the 60 morphinan may be included in the granules in an amount ranging up to about 80%, up to about 70%, up to about 60%, up to about 50%, up to about 40%, up to about 30%, up to about 20%, up to about 10%, up to about 1%, and up to about 0.5% of the total weight of the granules. 65 The morphinan included in various embodiments of the granules may be selected from opium, natural opium deriva US 8,980,319 B2 9 10 In various embodiments of the granules, the morphinan (iii) Antioxidants may be provided in any solid form including but not limited to Antioxidants are excipients included in various embodi a finely divided Solid, a crystal, a particle, a powder, or any ments of the granules to prevent the oxidation of the morphi other finely divided solid form known in the art. Any finely nan in the granules. Suitable antioxidants include, but are not divided solid form of the morphinan may be used so long as 5 limited to anoXomer, N-acetylcysteine, benzyl isothiocyan the doo of the morphinan particles are Smaller than the doo of ate, m-aminobenzoic acid, o-aminobenzoic acid, p-ami the one or more excipients as described above. nobenzoic acid (PABA), butylated hydroxyanisole (BHA), (b) Excipients butylated hydroxytoluene (BHT), caffeic acid, canthaxantin, Various embodiments of the granules include one or more alpha-carotene, beta-carotene, beta-caraotene, beta-apo excipients in addition to the morphinan. In general, the one or 10 carotenoic acid, carnosol, , catechins, chlorogenic acid, citric acid and its salts, extract, coffee bean extract, more excipients are selected to impart at least one or more p-coumaric acid, 3,4-dihydroxybenzoic acid, N,N'-diphenyl desired physical or chemical properties to the granules, p-phenylenediamine (DPPD), dilauryl thiodipropionate, dis including but not limited to adhesion of the particles of the tearyl thiodipropionate, 2,6-di-tert-butylphenol, edetic acid, morphinan and excipient compounds in the mixture to facili 15 ellagic acid, erythorbic acid, Sodium erythorbate, esculetin, tate the formation of granules, formation of physical barriers esculin, 6-ethoxy-1,2-dihydro-2,2,4-trimethylduinoline, around the morphinans in the granules, and chemical inhibi ethyl maltol, ethylenediaminetetraacetic acid (EDTA) and tion of various mechanisms of degradation of the morphinans EDTA salts, eucalyptus extract, , ferulic acid, fla including but not limited to oxidation. Non-limiting examples vonoids (e.g., catechin, epicatechin, epigallocatechin (EGC), of the one or more excipients include binders, fillers, antioxi flavones (e.g., apigenin, chrysin, luteolin), flavonols (e.g., dants, pH-adjusting agents, chelating agents, and antimicro datiscetin, myricetin, daemfero), flavanones, fraxetin, bial agents. fumaric acid, gallic acid, gentian extract, gluconic acid, gly In one embodiment, the one or more excipients may be cine, gum guaiacum, hesperetin, alpha-hydroxybenzyl phos introduced into the mixture to be granulated in a solid form phinic acid, hydroxycinammic acid, hydroxyglutaric acid, including but not limited to a crystal, a particle, a powder, or 25 hydroquinone, N-hydroxysuccinic acid, hydroxytryrosol, any other finely divided solid form known in the art. In hydroxyurea, rice bran extract, lactic acid and its salts, leci another embodiment, the one or more excipients may be thin, lecithin citrate; R-alpha-lipoic acid, lutein, lycopene, dissolved or Suspended in a solvent and sprayed onto the malic acid, maltol, 5-methoxy tryptamine, monoglyceride mixture in a granulation device as a binder fluid during granu citrate; monoisopropyl citrate; morin, beta-naphthoflavone, lation. 30 nordihydroguaiaretic acid (NDGA), oxalic acid, palmityl cit (i) Binders rate, phenothiazine, phosphatidylcholine, phosphoric acid, In general, binders are excipients included in various phosphates, phytic acid, phytylubichromel, pimento extract, embodiments of the granule to impart structural integrity to polyphosphates, quercetin, trans-resveratrol, the granules by binding together the particles making up each extract, rosmarinic acid, sage extract, Sesamol, silymarin, 35 Sinapic acid, Succinic acid, Stearyl citrate, Syringic acid, tar granule. Non-limiting examples of binders suitable for the taric acid, , tocopherols (i.e., alpha-, beta-, gamma formulations of various embodiments include starches, and delta-tocopherol), tocotrienols (i.e., alpha-, beta-, pregelatinized starches, gelatin, polyvinylpyrrolidone, cellu gamma- and delta-tocotrienols), tyrosol, Vanilic acid, 2,6-di lose, methylcellulose, sodium carboxymethylcellulose, eth tert-butyl-4-hydroxymethylphenol (i.e., Ionox 100), 2,4- ylcellulose, polyacrylamides, polyvinyloxoazolidone, poly 40 (tris-3',5'-bi-tert-butyl-4'-hydroxybenzyl)-mesitylene (i.e., vinylalcohols, C12-C18 fatty acid alcohols, polyethylene Ionox330), 2,4,5-trihydroxybutyrophenone, ubiquinone, ter glycol, polyols, Saccharides, oligosaccharides, polypeptides, tiary butyl hydroquinone (TBHQ), thiodipropionic acid, tri oligopeptides, and combinations thereof. The polypeptides hydroxy butyrophenone, tryptamine, tyramine, uric acid, may be any arrangement of amino acids ranging from about Vitamin Kand derivates, vitamin Q10, wheat germ oil, Zeax 100 to about 300,000 Daltons. 45 anthin, or combinations thereof. In one embodiment, the binder may be introduced into the In another embodiment, an antioxidant agent may be Sub mixture to be granulated in a solid form including but not jected to a particle size reduction process including but not limited to a crystal, a particle, a powder, or any other finely limited to grinding, milling, Sonication, or hammer milling in divided solid form known in the art. In another embodiment, order to reduce the do of the antioxidant agent to a value less the binder may be dissolved or suspended in a solvent and 50 than the do of the morphinan (or other API included in the sprayed onto the mixture in a granulation device as a binder formulation) prior to granulation. In this embodiment, the fluid during granulation. reduced doo of the antioxidant agent may result in a distribu (ii) Fillers tion of antioxidant agent that is clustered around the morphi Fillers may be included in various embodiments of the nan particles, rather than near the outer Surface of the granule. granule composition as an excipient to increase the bulk Vol 55 A granule having this physical structure may provide compa ume of the granules and to impart suitable compressibility rable protection of the morphinan in the granules against characteristics to the granules for Subsequent inclusion in degradation as compared to granules in which the antioxidant Solid dosage forms of pharmaceutical compositions includ agent is situated on the outside of the granule using a signifi ing but not limited to tablets. Non-limiting examples of fillers cantly lower amount of the antioxidant agent. include carbohydrates, inorganic compounds, and polyvi 60 In an exemplary embodiment, the granule composition nylpyrrolidone. Other non-limiting examples of fillers includes at least one antioxidant including but not limited to include dibasic Sulfate, tribasic calcium Sulfate, citric acid and Na-EDTA. starch, calcium carbonate, magnesium carbonate, microcrys (iv) pH-Adjusting Agents talline cellulose, dibasic calcium phosphate, tribasic calcium In various embodiments of the granule composition, a pH phosphate, magnesium carbonate, magnesium oxide, cal 65 adjusting agent may be included as an excipient to raise or cium silicate, talc, modified Starches, lactose, , man lower the pH of the granule in order to prevent the oxidation nitol, and sorbitol. of the morphinan in the granules. For example, a pH-adjust US 8,980,319 B2 11 12 ing agent including but not limited to citric acid may be excess of 0.05% of the total API mass must be reported. The incorporated into the composition granule in order to lower ICH guidelines apply throughout the effective shelflife of the the pH of the granule. In this example, a lower pH prevents the pharmaceutical composition. oxidation of the granule by various oxidative compounds Although no standardized method of assessing API stabil associated with release-modifying polymer incorporated into ity exists at present, drug developers typically subject poten a sold dosage form, including but not limited to peroxides. tial pharmaceutical compounds to periods of storage at accel In another embodiment, a pH-adjusting agent may be Sub erated degradation conditions, typically defined as a jected to a particle size reduction process including but not temperature of about 40°C. and a relative humidity of about limited to grinding, milling, Sonication, or hammer milling in 75%. The period of storage time at the accelerated degrada order to reduce the doo of the pH-adjusting agent to a value 10 tion conditions may vary from about 1 day to about 6 months, but is typically about 6 months. In an embodiment, the for less than the do of the morphinan prior to granulation. In this mation of any one degradant in the composition may be embodiment, the reduced do of the pH-adjusting agent may limited to less than about 0.5%, less than about 0.4%, less result in a distribution of pH-adjusting agent that is clustered than about 0.3%, less than about 0.2%, less than about 0.1%, around the morphinan particles, rather than near the outer 15 less than 0.05%, less than 0.04%, less than 0.03%, less than Surface of the granule. Non-limiting examples of pH-adjust 0.02%, or less than 0.01% of the total mass of the morphinan ing agents include citric acid, acetic acid, tartaric acid, malic after about two months of storage at a temperature of about acid, fumaric acid, lactic acid, phosphoric acid, Sorbic acid, 40° C. and a relative humidity of about 75%. In another benzoic acid, Sodium carbonate and Sodium bicarbonate. embodiment, the formation of any one degradant in the com (V) Chelating Agents position may be limited to less than about 0.5%, less than In various embodiments of the granule composition, a about 0.4%, less than about 0.3%, less than about 0.2%, less chelating agent may be included as an excipient to immobi than about 0.1%, less than 0.05%, less than 0.04%, less than lize oxidative species including but not limited to metal ions 0.03%, less than 0.02%, or less than 0.01% of the total mass in order to inhibit the oxidative degradation of the morphinan of the morphinan after about six months of storage at a tem by these oxidative species. Non-limiting examples of chelat 25 perature of about 40°C. and a relative humidity of about 75%. ing agents include lysine, methionine, glycine, gluconate, In yet another embodiment, the formation of any one polysaccharides, glutamate, aspartate, and Na2EDTA. degradant in the composition may be limited to less than (vi) Antimicrobial Agents about 0.5%, less than about 0.4%, less than about 0.3%, less In various embodiments of the granule composition, an than about 0.2%, less than about 0.1%, less than 0.05%, less antimicrobial agent may be included as an excipient to mini 30 than 0.04%, less than 0.03%, less than 0.02%, or less than mize the degradation of the morphinan by microbial agents 0.01% of the total mass of the morphinan after about four including but not limited to bacteria and fungi. Non-limiting weeks of storage at accelerated stability conditions at a tem perature of about 40°C. and a relative humidity of about 75%. examples of antimicrobials include parabens, chlorobutanol, In an exemplary embodiment, for a pharmaceutical com phenol, calcium propionate, Sodium nitrate, Sodium nitrite, 35 position incorporating oxycodone as the morphinan and at NaEDTA and sulfites including but not limited to sulfur least one excipient in the form of granules, the granules con dioxide, Sodium bisulfite, and potassium hydrogen Sulfite. tain less than about 0.5% w/w of the total mass of oxycodone of a degradant selected from 10-hydroxy oxycodone, di-hy (III) Granule Stability droxy oxycodone, and oxycodone n-oxide after being stored 40 for 6 months at 40°C. and 75% relative humidity. In another In various embodiments of the granule composition, the exemplary embodiment, for a pharmaceutical composition morphinan in the granule is substantially resistant to degra incorporating oxycodone and at least one excipient in the dation due to interactions of the morphinan with degradative form of granules, the granules contain less than about 0.5% compounds or conditions present in the environment or in the w/w of the total mass of oxycodone of each of one or more carriers Surrounding the granules in a solid dosage form of a 45 degradants selected from 10-hydroxy oxycodone, di-hydroxy pharmaceutical composition. In one embodiment, the mor oxycodone, and oxycodone n-oxide after being Stored for 6 phinan in the granules is Substantially resistant to the forma months at 40°C. and 75% relative humidity. tion of degradants resulting from a chemical change in the In another exemplary embodiment, for a pharmaceutical morphinan brought about during the production and/or stor composition incorporating hydrocodone as the morphinan age of the pharmaceutical composition containing the mor 50 and at least one excipient in the form of granules, the granules phinan by the effect of factors including but not limited to contain less than about 0.5% w/w of the total mass of hydro light, temperature, pH, water, or reaction with an excipient or codone of a degradant selected from hydrocodone n-oxide carrier included in the pharmaceutical composition. The par and hydrocodone aldol dimer after being stored for 6 months ticular degradants formed in a pharmaceutical composition at 40° C. and 75% relative humidity. In another exemplary depend on the particular morphinan and the at least one 55 embodiment, for a pharmaceutical composition incorporat excipient within the granule, as well as the particular carriers ing hydrocodone and at least one excipient in the form of included in the pharmaceutical composition along with the granules, the granules containless than about 0.5% w/w of the granules. total mass of hydrocodone of each of one or more degradants Statutory requirements, including but not limited to ICH selected from hydrocodone n-oxide and hydrocodone aldol Guidelines Q3A and Q3B identify maximum allowable 60 dimer after being stored for 6 months at 40° C. and 75% amounts of degradants above which the degradants must be relative humidity reported and Subjected to the qualification process described above. According to ICH Guideline Q3B, the amount of any (IV) Method of Preparing Granules individual degradant must be reported if the amount of degradant exceeds 0.10% of the total API weight for maxi 65 In various embodiments, the granules may be prepared by mum daily doses of 1000 mg of API or below. For APIs combining the morphinan with at least one excipient to form having average daily doses of above 1000 mg. degradants in a mixture and granulating the mixture in a manner Such that US 8,980,319 B2 13 14 the amount of morphinan exposed on the Surface of the gran include uncoated tablets, coated tablets, mini-tablets, orally ules is minimized (thereby forming a morphinan-protected disintegrating tablets, and bilayer tablets. Non-limiting granule). embodiments of capsules include hard capsules and multi Suitable morphinans for the granule embodiments are layer capsules. Depending on the selection of particular for described in detail in Section (IIa) above, and suitable excipi mulation, the Solid dosage pharmaceutical composition may ents are described in Section (IIb) above. The mixture may be have release characteristics including but not limited to rapid formed using any suitable method known in the art including release, Sustained release, extended release, slow release, but not limited to stirring, shaking, vibrating, and blending. In time release, and combinations thereof. an embodiment, the morphinan and dry excipients may be In an exemplary embodiment, Solid dosage form pharma charged into a granulation device and mixed prior to the 10 ceutical compositions are made via a two step process. First, addition of the granulation fluid. the morphinan-protected granule is formed. The morphinan Any suitable granulation device known in the art may be protected granule is then mixed with excipients and other used to prepare the granules. As previously discussed, the active pharmaceutical ingredients, which are then granulated particular granulation device selected for the preparation of to form the solid dosage form pharmaceutical composition. the granules may influence the physical properties of the 15 The Solid dosage form pharmaceutical composition may resulting granules. Non-limiting examples of Suitable devices include additional APIs. In an exemplary embodiment, the for the preparation of the granules include a low-shear wet Solid dosage form pharmaceutical composition comprises a granulator, a high-shear wet granulator, a fluid-bed granula morphinan and acetaminophen. In additional embodiments, tor, a roller compactor, a vertical granulator, an oscillating the Solid dosage form pharmaceutical composition may com granulator, a gelatinizer, a pelletizer, and a spheronizer. The prise Sustained release (SR) and immediate release layers granulation device may be selected in order to prepare gran (IR). Typically, the SR and IR layers both include the mor ules having the desired granule physical characteristics phinan and acetaminophen. In each of the foregoing embodi described in Section (II) above. ments, the SR layer typically comprises a release-controlling In an exemplary embodiment, a high-shear wet granulator polymer comprising a polyethylene oxide polymer. is used to prepare the granules. The high-shear wet granulator 25 (a) Compositions of Solid Dosage Forms may be capable of preparing granules having properties that Various embodiments of the solid dosage pharmaceutical enhance the protective effect of the granule, including but not compositions incorporating the morphinan-protected gran limited to higher granule densities and lower granule porosi ules may include one or more pharmaceutically acceptable ties relative to granules prepared by other devices. Further, carriers in addition to the granules. Pharmaceutically accept the high-shear wet granulator is capable of preparing granules 30 able carriers suitable for embodiments of the solid dosage with a do that is larger than other granulation devices, result pharmaceutical compositions may include but are not limited ing in granules suitable for inclusion in a wider variety of to binders, fillers, lubricants, diluents, non-effervescent dis Solid dosage forms of morphinan compositions. integrants, effervescent disintegrants, flavor-modifying In the same exemplary embodiment, the morphinan and the agents, Sweeteners, dispersants, coloring agents, mask excipients in dry form of the composition are introduced into 35 ing agents, release-controlling polymers and combinations the wet high shear granulator in order to form the mixture. thereof After the morphinan and the dry excipients are essentially (i) Binders homogeneously distributed within the granulator, a granula Non-limiting examples of binders suitable for the formu tion fluid is sprayed into the granulator. In various embodi lations of various embodiments include starches, pregelati ments, the granulation fluid may be any volatile, non-toxic 40 nized starches, gelatin, polyvinylpyrrolidone, cellulose, granulation fluid known in the art. Non-limiting examples of hydroxypropyl methylcellulose, hydroxypropyl cellulose, Suitable granulation fluids include water, ethanol, isopro methylcellulose, sodium carboxymethylcellulose, ethylcel panol, and combinations thereof. In other embodiments, one lulose, polyacrylamides, polyvinyloxoazolidone, polyvinyla or more of the excipients may be mixed with the granulation lcohols, C12-C18 fatty acid alcohols, polyethylene glycol, fluid prior to spraying the granulation fluid into the granula 45 polyols, Saccharides, oligosaccharides, polypeptides, oli tor. In an exemplary embodiment, a binder including but not gopeptides, and combinations thereof. The polypeptide may limited to pregelatinized starch may be dissolved into the be any arrangement of amino acids ranging from about 100 to granulation fluid including but not limited to water to form a about 300,000 Daltons. granulation Solution, and the granulation solution may be (ii) Fillers sprayed into the granulator in order to prepare the granules. 50 Non-limiting examples of fillers include carbohydrates, In an additional embodiment, the wet granules prepared in inorganic compounds, and polyvinylpyrrolidone. Other non the high shear wet granulator may be dried using a drying limiting examples of fillers include dibasic calcium sulfate, device, resulting in dried granules having a water content of tribasic calcium sulfate, starch, calcium carbonate, magne less than about 5%, less than about 4%, less than about 3%, or sium carbonate, microcrystalline cellulose, dibasic calcium less than about 2% of the total weight of the granules. Any 55 phosphate, tribasic calcium phosphate, magnesium carbon suitable drying device known in the art may be used to dry the ate, magnesium oxide, calcium silicate, talc, modified wet granules, including but not limited to an oven, a vacuum starches, lactose, Sucrose, mannitol, and Sorbitol. oven, and a rotary drum dryer. (iii) Lubricants Non-limiting examples of lubricants include magnesium (V) Solid Dosage Forms Incorporating Granules 60 Stearate, calcium Stearate, Zinc Stearate, hydrogenated veg etable oils, sterotex, polyoxyethylene monostearate, talc, The morphinan-protected granules prepared by various polyethylene glycol, Sodium benzoate, sodium lauryl Sulfate, embodiments may be incorporated into various Solid dosage magnesium lauryl Sulfate, and light mineral oil. pharmaceutical compositions. Non-limiting examples of (iv) Diluents Solid dosage pharmaceutical compositions incorporating 65 Diluents suitable for use include but are not limited to embodiments of the morphinan granules include granules, pharmaceutically acceptable saccharides such as Sucrose, tablets, and capsules. Non-limiting embodiments of tablets dextrose, lactose, microcrystalline cellulose, , Xyli US 8,980,319 B2 15 16 tol, and Sorbitol; polyhydric alcohols; Starches; pre-manufac as mixtures of HPMC and stearic acid, cyclodextrins, and tured direct compression diluents; and mixtures of any of the mixtures of these materials. In other embodiments, additional foregoing. taste-masking agents contemplated are those described in (v) Non-Effervescent and Effervescent Disintegrants U.S. Pat. Nos. 4,851,226, 5,075,114, and 5,876,759, each of Non-limiting examples of non-effervescent disintegrants which is hereby incorporated by reference in its entirety. include starches Such as corn Starch, potato starch, pregelati (xi) Release-Controlling Polymers nized and modified Starches thereof, Sweeteners, clays. Such Release-controlling polymers may be included in the vari as bentonite, micro-crystalline cellulose, alginates, sodium ous embodiments of the Solid dosage pharmaceutical compo Starch glycolate, gums such as agar, guar, locust bean, karaya, sitions incorporating the granules. In one embodiment, the pecitin, and tragacanth. Suitable effervescent disintegrants 10 release-controlling polymers may be used as a tablet coating. include but are not limited to sodium bicarbonate in combi In other embodiments, including but not limited to bilayer nation with citric acid, and sodium bicarbonate in combina tablets, a release-controlling polymer may be mixed with the tion with tartaric acid. granules and other excipients prior to the formation of a tablet (vi) Flavor-Modifying Agents by a known process including but not limited to compression Suitable flavor-modifying agents include but are not lim 15 in a tablet mold. Suitable release-controlling polymers ited to synthetic flavor oils and flavoring aromatics and/or include but are not limited to hydrophilic polymers and natural oils, extracts from plants, leaves, flowers, fruits, and hydrophobic polymers. combinations thereof. Other non-limiting examples of flavor Suitable hydrophilic polymers include, but are not limited modifying agents include oils, oil of wintergreen, to, cellulose acetate, cellulose diacetate, cellulose triacetate, peppermint oils, clover oil, hay oil, anise oil, eucalyptus, cellulose ethers, hydroxyethyl cellulose, hydroxypropyl cel , citrus oils such as lemon oil, orange oil, grape and lulose, hydroxypropyl methylcellulose, microcrystalline cel grapefruit oil, fruit essences including apple, peach, pear, lulose, nitrocellulose, crosslinked Starch, agar, casein, chitin, Strawberry, raspberry, cherry, plum, pineapple, and apricot. collagen, gelatin, maltose, mannitol, maltodextrin, pectin, (vii) Sweeteners pullulan, Sorbitol, Xylitol, polysaccharides, ammonia algi Non-limiting examples of Sweeteners include 25 nate, sodium alginate, calcium alginate, potassium alginate, (corn Syrup), dextrose, invert Sugar, fructose, and mixtures propylene glycol alginate, alginate Sodium carmellose, cal thereof (when not used as a carrier); saccharin and its various cium carmellose, carrageenan, fucoidan, furcellaran, ara salts such as the sodium salt; dipeptide Sweeteners such as bicyum, carrageensgum, ghaftigum, guargum, karayagum, aspartame; dihydrochalcone compounds, glycyrrhizin; Ste locustbeangum, okragum, tragacanthgum, Scleroglucangum, via rebaudiana (); chloro derivatives of sucrose 30 Xanthangum, hypnea, laminaran, acrylic polymers, acrylate Such as Sucralose; Sugar alcohols such as Sorbitol, mannitol, polymers, carboxyvinyl polymers, copolymers of maleic sylitol, hydrogenated starch hydrolysates and the synthetic anhydride and styrene, copolymers of maleic anhydride and sweetener 3,6-dihydro-6-methyl-1,2,3-oxathiazin-4-one-2, ethylene, copolymers of maleic anhydride propylene or 2-dioxide, particularly the potassium salt (acesulfame-K), copolymers of maleic anhydride isobutylene), crosslinked and sodium and calcium salts thereof 35 polyvinyl alcohol and poly N-vinyl-2-pyrrolidone, diesters of (viii) Dispersants polyglucan, polyacrylamides, polyacrylic acid, polyamides, Dispersants may include but are not limited to starch, alg polyethylene glycols, polyethylene oxides, poly(hydroxy inic acid, polyvinylpyrrolidones, guar gum, kaolin, bentonite, alkyl methacrylate), polyvinyl acetate, polyvinyl alcohol, purified wood cellulose, Sodium starch glycolate, isoamor polyvinyl chloride, polystyrenes, polyvinylpyrrolidone, phous silicate, and microcrystalline cellulose as high HLB 40 anionic and cationic hydrogels, and combinations thereof. emulsifier Surfactants. Non-limiting examples of suitable hydrophobic polymers (ix) Coloring Agents include cellulose acetate butyrate, cellulose acetate ethylcar Suitable coloring agents include but are not limited to food, bamate, cellulose acetate heptanoate, cellulose acetate meth drug and cosmetic colors (FD&C), drug and cosmetic colors ylcarbamate, cellulose acetate octanoate, cellulose acetate (D&C), or external drug and cosmetic colors (Ext. D&C). 45 phthalate, cellulose acetate propionate, cellulose acetate Suc These colors or dyes, along with their corresponding lakes, cinate, cellulose acetate trimaletate, cellulose acetaldehyde and certain natural and derived colorants may be suitable for dimethyl acetate, cellulose butyrate, cellulose dimethylami use in various embodiments. noacetate, cellulose disuccinate, cellulose dipalmitate, cellu (X) Taste-Masking Agents lose dicaprylate, cellulose propionate, cellulose propionate Taste-masking agents include but are not limited to cellu 50 Succinate, cellulose trioctanoate, cellulose tripropionate, cel lose hydroxypropyl ethers (HPC) such as Klucel(R), Nisswo lulose trimellitate, cellulose tripalmitate, cellulose trivalerate, HPC and PrimaFlo HP22; low-substituted hydroxypropyl cellulose Valerate palmitate, carboxymethyl cellulose, cal ethers (L-HPC); cellulose hydroxypropyl methyl ethers cium carboxymethyl cellulose, Sodium carboxymethyl cellu (HPMC) such as Seppifilm-LC, Pharmacoat(R), Metolose SR, lose, ethyl cellulose, ethylhydroxy ethylcellulose, hydroxy Opadry YS, PrimaFlo, MP3295A, Benecel MP824, and 55 propyl methylcellulose phthalate, methyl cellulose, methyl Benecel MP843; methylcellulose polymers such as Metho ethyl cellulose, propyl cellulose, sodium carboxymethyl cel(R) and Metolose(R); Ethylcelluloses (EC) and mixtures starch, polyvinyl acetate phthalate, polyvinyl alcohol phtha thereof such as E461, Ethocel(R), AqualonR)-EC, Surelease: late, methacrylic acid copolymers, methacrylic acid ester Polyvinyl alcohol (PVA) such as Opadry AMB; hydroxyeth copolymers, methyl methacrylate copolymers, ethoxyethyl ylcelluloses such as Natrosol(R); carboxymethylcelluloses and 60 methacrylates, cyanoethyl methacrylate, aminoalkyl meth salts of carboxymethylcelluloses (CMC) such as Aualon(R)- acrylate copolymer, poly(acrylate), poly(methacrylate), poly CMC; polyvinyl alcohol and polyethylene glycol co-poly (methyl methacrylate), poly(ethylacrylate), poly(ethyl meth mers such as Kollicoat IRR); monoglycerides (Myverol), trig acrylate), poly(methacrylic acid anhydride), glycidyl lycerides (KLX), polyethylene glycols, modified food starch, methacrylate copolymers, ammonio methacrylate copoly acrylic polymers and mixtures of acrylic polymers with cel 65 mers, lecithins, aluminum monostearate, cetylalcohol, lulose ethers such as EudragitR) EPO, Eudragit(R) RD100, and hydrogenated beef tallow, hydrogenated castor oil, hydroge EudragitR) E 100; cellulose acetate phthalate; sepifilms such nated vegetable oil, 12-hydroxyStearyl alcohol, glyceryl US 8,980,319 B2 17 18 monopalmitate, glyceryl dipalmitate, glyceryl monostearate, profile to the hard capsule composition. In yet other embodi glyceryl distearate, glyceryl tristearate, myristyl alcohol, ments, a fraction of the morphinan-protected granules may be Stearic acid, Stearyl alcohol, polyethyleneglycols, Zein, shel coated with a release-controlling polymerand combined with lac, bee’s wax, carnauba wax, glyceryl behenate, Japan wax, the remaining uncoated morphinan-protected granules prior paraffin, spermaceti, synthetic waxes, and combinations to loading the granules into the hard capsule. thereof. (b) Methods of Producing Solid Dosage Forms (VI) Exemplary Embodiments The solid dosage pharmaceutical compositions may be produced using any Suitable method known in the art. The Exemplary embodiments of a granule and a solid dose particular production method selected may depend on the 10 pharmaceutical composition are described below. desired type of solid dosage form and the desired release (a) Oxycodone-Protected Granule profile. An exemplary embodiment of a granule includes oxyc (i) Production of Tablet Compositions odone, microcrystalline cellulose, pregelatinized starch, The pharmaceutical compositions in the form of a tablet NaEDTA, and citric acid. The overall composition of the may be produced using any suitable method known in the art 15 exemplary oxycodone-protected granule embodiment is including but not limited to direct compression, wet granula listed in Table 10 below. In this embodiment, the granules tion, dry granulation, and combinations thereof. In one may beformed using the wet granulation method described in embodiment, the morphinan-protected granules may be com Example 5 below. In this embodiment, the oxycodone gran bined with the one or more carriers and granulated into tablet ules have a granule doo ranging from about 100 um to about granules using any of the known granulation devices 400 um, and contain less than about 2% water by weight. described previously. In this same embodiment, the tablet (b) Bilayer Oxycodone/APAP Tablet granules formed from the combination of the morphinan An exemplary embodiment of a Solid dose pharmaceutical protected granules and the one or more carriers may be composition may be a bilayer tablet that includes the oxyc optionally blended with one or more additional carriers odone-protected granules described above. The exemplary including but not limited to lubricants, and the resulting tablet 25 bilayer tablet may be formed using the method described in blend may be compressed into a tablet form. In another Example 2 below. The two layers of the bilayer tablet in this embodiment, one or more carriers incorporated into the tablet embodiment include an immediate release (IR) layer and a granules may include a release-controlling polymer to impart sustained release (SR) layer. The overall compositions of the a modified release profile to the resulting tablet. IR layer and the sustained release layer of the exemplary In yet another embodiment, a bilayer tablet may beformed 30 bilayer tablet embodiment are listed in Table 1 below. The by producing a first tablet blend and a second tablet blend stability of the oxycodone in the exemplary bilayer tablet using a tablet granulation and blending process similar to composition that incorporates oxycodone in a granular form those previously described. In this embodiment, the first tab is significantly better than a similar bilayer tablet composition let blend may include a disintegrant in order to imparta rapid that incorporates oxycodone in an unprotected powder form, release profile to the resulting tablet produced using the first 35 as described in Example 2 below. tablet blend. The second tablet blend of this embodiment may include a release-controlling polymer to impart a modified TABLE 1 release profile to the resulting tablet produced using the sec ond tablet blend. The first tablet blend and the second tablet Composition of Exemplary Oxycodone Bilayer Tablet Composition blend may be loaded into a tableting device including but not 40 limited to a bilayer tablet press, and pressed into a bilayer Dry Wt. (90 total tablet in which the first layer may have a rapid release profile Compound IR Layer SR Layer and the second layer may have a modified release profile. Protected oxycodone 2.99% 2.62% In yet another embodiment, the morphinan-protected gran granules ules may be coated with a release-controlling polymer prior 45 APAP 77.739% 22.73% to incorporating the morphinan-protected granules into a MCC 4.82% 26.81% Hydroxypropyl cellulose 7.719, 1.34% solid tablet form in order to impart a modified release profile Cross carmellose sodium 6.00% to the resulting tablet. In an additional embodiment, the solid Silicon dioxide O.S.0% O.S9/o tablet form may be coated with a release-controlling polymer Magnesium stearate O.25% 1.0% to impart a modified release profile. Other combinations of 50 Polyethylene oxide 45.0% the embodiments described above may be used to produce polymer additional embodiments having a desired release profile or other desired performance characteristic including but not (c) Hydrocodone-Protected Granule limited to masked taste, acceptable tongue-feel and mouth An exemplary embodiment of a granule includes hydroc feel, and enhanced stability. 55 odone, microcrystalline cellulose, pregelatinized starch, (ii) Production of Capsule Compositions NaEDTA, and citric acid. The overall composition of the The pharmaceutical compositions in the form of a capsule exemplary hydrocodone-protected granule embodiment is may be produced using any suitable method known in the art listed in Table 13 below. In this embodiment, the granules including but not limited to direct loading into two-piece may beformed using the wet granulation method described in telescoping hard capsules. Non-limiting examples of suitable 60 Example 6 below. In this embodiment, the hydrocodone gran hard capsules include hard starch capsules, hard gelatin cap ules have a granule do ranging from about 100 um to about Sules, and hard cellulose capsules. In one embodiment, the 400 um after milling, and contain less than about 5% water by capsule form of the pharmaceutical compositions may be weight. produced by loading the morphinan-protected granules in to (d) Bilayer Hydrocodone/APAP Tablet the hard capsule and sealing the capsule. In other embodi 65 An exemplary embodiment of a Solid dose pharmaceutical ments, the morphinan-protected granules may be coated with composition may be a bilayer tablet that includes the hydro a release-controlling polymer to impart a modified release codone-protected granules described above. The exemplary US 8,980,319 B2 19 20 bilayer tablet may be formed using the method described in ules used to form the IR and SR Layers of a bilayer tablet, Example 2 below. The two layers of the bilayer tablet in this respectively. Both the IR granules and the SR granules were embodiment include an immediate release (IR) layer and a formed using separate fluid bed granulation processes. In sustained release (SR) layer. The overall compositions of the each process, the previously-formed protected oxycodone IR layer and the sustained release layer of the exemplary granules, powdered acetaminophen (APAP), and various bilayer tablet embodiment are listed in Table 2 below. The excipients including disintegrants, binders, and fillers were stability of the hydrocodone in the exemplary bilayer tablet charged into the fluid bed granulation device and sprayed composition that incorporates hydrocodone in a granular with a granulation fluid, resulting in the formation of IR form is significantly better than a similar bilayer tablet com granules in one batch and SR granules in a second batch. The position that incorporates hydrocodone in an unprotected 10 composition of the resulting IR and SR granules are Summa powder form. rized in Table 4:

TABLE 2 TABLE 4 Composition of Exemplary Hydrocodone Bilayer Tablet Composition 15 Composition of IR and SR Granules Dry Wt. (% total Dry Wt. (90 total wt. Compound IR Layer SR Layer Compound IR Layer SR Layer Protected hydrocodone granules 2.99% 2.62% Protected oxycodone 16.1% 14.2% APAP 77.739% 22.73% granules MCC 4.82% 26.81% APAP 67.8% 81.2% Hydroxypropyl cellulose 7.719, 1.34% MCC S.0% Cross carmellose sodium 6.00% Hydroxypropyl cellulose 8.1% 4.5% Silicon dioxide O.S.0% O.S90 Cross carmellose sodium 3.0% Magnesium stearate O.25% 1.0% Polyethylene oxide polymer 45.0% 25 The IR granules were blended with lubricant excipients in preparation for the tablet pressing process. Similarly, the SR EXAMPLES particles were blended with various excipients including 30 lubricants, and polyethylene oxide polymer, and a filler in The following examples demonstrate various aspects of the preparation for the tablet pressing process. The compositions invention. of the IR blend and the SR blend are summarized in Table 5: Example 1 TABLE 5 35 Incorporation of Protected Oxycodone Granules into Composition of IR and SR Blends Bilayer Tablet Composition Dry Wt. (% total wt. To demonstrate the feasibility of forming protected mor Compound IRBlend SR Blend phinan granules and incorporating the protected morphinan 40 IR granules 99.25% granules into a solid dosage form, the following experiment SR granules S2.30% was conducted. Silicon dioxide O.S.0% O.S.0% Magnesium stearate O.25% O.10% Powdered oxycodone HCl, microcrystalline cellulose MCC 1.20% (MCC), and citric acid powder (an antioxidant) were mixed Polyethylene oxide 45.00% together and charged into a high-shear granulator. An aque 45 polymer ous solution containing pregelatinized starch (PGS) and Na2EDTA (an antioxidant) was sprayed into the high-speed The IR blend and the SR blend were loaded into a bilayer granulator, resulting in the formation of wet granules. The tablet press and formed into bilayer tablets having about 29% wet granules were then dried until less than about 2% water of the IR blend and about 71% the SR blend by weight. remained in the granules. The dried granules had particle 50 The results of this experiment demonstrated that protected sizes ranging from about 100-300 Lum. The composition of the morphinan granules could be formed using a process of high protected oxycodone granules is Summarized in Table 3: shear wet granulation and incorporated into a solid oral thera peutic composition. TABLE 3 55 Example 2 Composition of Protected Oxycodone Granules Dry Weight Oxidative Stability Assessment of Bilayer Tablet Compound (% tot. wt.) Composition Oxycodone HCI 30.0% MCC 63.6% 60 To assess the effect of incorporating a morphinan in the PGS 4.0% form of protected granules into a solid dosage therapeutic Na2EDTA O.4% composition on the oxidative stability of the composition, the Citric acid 2.0% following experiment was conducted. Unprotected bilayer tablets were formed using a process The oxycodone-protected granules were divided into two 65 similar to that described in Example 1, except that powdered groups to be incorporated into batches of immediate release oxycodone HCl, rather than protected oxycodone granules, (IR) granules and into batches of sustained release (SR) gran were incorporated into the IR and SR granules formed using US 8,980,319 B2 21 22 the fluid bed granulation device. Protected bilayer tablets TABLE 7 formed using protected oxycodone granules as described in Example 1 were also obtained. The unprotected bilayer tab Composition of IR and SR Granules lets were similar in composition to the protected bilayer tab lets, except that the unprotected bilayer tablets lacked anti Granule Composition (% ww. oxidant excipients and oxycodone-protected granules, Compound 1 2 3 5 6 although the overall oxycodone contents of the two formula Oxycodone 30 30 30 30 30 tions of bilayer tablet were comparable. MCC 65 64.95 62.2 64.95 62.2 A batch of protected bilayer tablets and a batch of unpro HPC 5 4.6 4.6 tected tablets were placed into an environmental chamber and 10 BHA O.OS O.OS EDTA 0.4 0.4 0.4 0.4 exposed to accelerated Stability conditions. In particular, all Ascorbic Acid 2.8 2.8 bilayer tablets were kept in the environmental chamber at a PGS 4.6 4.6 temperature of 55° C. and a relative humidity of 80% for a period of six days. For the remainder of the first month and for the duration of a second month, the bilayer tablets were 15 For granule compositions 1, 2, and 3 the HPC and EDTA exposed to a temperature of 40°C. and a relative humidity of were dissolved in a granulation Solution and applied to a dry 75%. mixture of the remaining ingredients. For granule composi After six days, one month, and two months in the environ tions 5 and 6, the PGS and EDTA were dissolved in a granu mental chamber, samples of the protected and unprotected lations solution and applied to a dry mixture of the remaining formulations were removed from the chamber and submitted ingredients. to mass spectrographic analysis to determine the presence of The resulting granules were stored at accelerated Stability three oxidative degradants of oxycodone: dihydroxy oxyc conditions for a period of 4 weeks at 40°C. and 75% relative odone, oxycodone n-oxide, and 10-hydroxy oxycodone. The humidity. Samples of the granules were taken just before results of these analyses are summarized in Table 6 below: storage and after one, two, and four weeks of storage at TABLE 6 Oxidative Stability of Unprotected vs. Protected Formulations of Bilayer Tablets Amount of Degradant Formed (90 weight of Oxycodone Degradation Di-hydroxy 10-hydroxy Oxycodone Conditions Oxycodone Oxycodone n-oxide

Time Temp. Relative Not Not Not (days) (C.) Humidity (%) Protected Protected Protected Protected Protected Protected 6 55 8O O.20 O.OO O.04 O.OO O.12 O.O3 30 40 75 O.OS O.O1 O.O1 O.OO O.12 O.O1 60 40 75 O.11 O.O2 O.O3 O.OO O.21 O.O3

The protected formulation of the bilayer tablets that incor- 40 accelerated stability conditions and subjected to mass spec porated the oxycodone-protected granules had significantly trographic analysis as described in Example 2 to determine lower levels of all degradants after exposure to all environ the presence of oxidative degradants of oxycodone. The mental conditions. No 10-hydroxy oxycodone was measured results of the analyses of the samples taken after four weeks of at any environmental condition for the protected formulation storage are summarized in Table 8 below: of the bilayer tablet. 45 The results of this experiment demonstrated that the for TABLE 8 mation of oxidative degradants of oxycodone was signifi cantly inhibited by the incorporation of the oxycodone in the Oxidative Stability of Granule Formulations form of protected granules. In particular, the bilayer tablets Impurity After 4Weeks at formed using the protected oxycodone granules were signifi 50 Accelerated Degradation cantly more stable than similar bilayer tablets formed using Conditions unprotected oxycodone powder. % wt of oxycodone Composition 6-a-Oxycodol Noroxy Example 3 55 1 O.11 O.O1 2 O.11 O.O2 3 O.33 O.13 Effect of Granule Composition on Oxidative 5 O.11 O.OO Stability 6 O.29 O.14

60 To assess the effect of various granule compositions on the The impurities for granule compositions 1, 2, and 5 were all oxidative stability of the morphinan encapsulated in the gran of comparable low amounts, indicating that the granulation of ules, the following experiment was conducted. the oxycodone resulted in a protective effect from oxidative Granules containing oxycodone and various combinations degradation. This protective effect was achieved eveningran of excipients were formed using methods similar to those 65 ule composition 1, which did not include any antioxidant described in Example 1. The specific compositions of the excipients. However, granule compositions 3 and 6, which granules are Summarized in Table 7: contained ascorbic acid, resulted in much higher levels of US 8,980,319 B2 23 24 oxidative impurities after 4 weeks of storage at accelerated codone and excipients in a loose powderform, independent of stability conditions, indicating that the ascorbic acid may the particular composition of excipients in the formulation. produce oxidative products that result in the long-term deg radation of the oxycodone. Example 5 The results of this experiment demonstrated the protective 5 effect of granulation against the oxidative degradation of Incorporation of Protected Oxycodone Granules into oxycodone, so long as ascorbic acid was not included in the Bilayer Tablet Composition granule composition. To demonstrate the feasibility of forming protected mor Example 4 10 phinan granules and incorporating the protected morphinan granules into a solid dosage form, the following experiment Effect of Granulation Composition on Oxidative was conducted to prepare a 7.5 mg oxycodone/325 mg Stability of Solid Dose Oxycodone/APAP acetaminophen tablet. Formulations Powdered oxycodone HCl, microcrystalline cellulose 15 (MCC), pregelatinized starch (PGS), Na-EDTA (an antioxi To assess the effect of encapsulation on the oxidative sta dant), and citric acid powder (an antioxidant) were charged bility of the morphinan invarious solid dose formulations, the into a high-shear granulator and mixed together. An aqueous following experiment was conducted. Solution containing pregelatinized starch (PGS) was sprayed Solid dose tablets were formed using the methods into the high-speed granulator, resulting in the formation of described in Example 2. The solid dose tablets contained the wet granules. The wet granules were then dried until less than oxycodone either in the protected granular form described in about 5% water remained in the granules. The dried granules Example 3, or as the same ingredients in a powdered form had particle sizes ranging from about 100-300 um after mill rather than as granules. In both cases, the oxycodone and ing. The composition of the oxycodone-protected granules is excipients were combined with APAP and polyethylene oxide 25 summarized in Table 10: (PEO) polymer. Each tablet contained 10% of the oxycodone granule compositions described in Example 3, in either TABLE 10 granulated or powdered form, 46.8% APAP, and 43.2% PEO polymer on a weight basis. Composition of Protected Oxycodone Granules The protected and unprotected tablet formulations were 30 Dry Weight stored at accelerated stability conditions for a period of 4 Compound (% tot. wt.) weeks at 40° C. and 75% relative humidity. Samples of the Oxycodone HCI 30.0% tablets were taken just before storage and after one, two, and MCC 63.6% four weeks of storage at accelerated Stability conditions and PGS 4.0% 35 Na-EDTA O.4% Subjected to mass spectrographic analysis as described in Citric acid 2.0% Example 2 to determine the presence of oxidative degradants of oxycodone. The results of these analysis of the samples taken after four weeks of storage are summarized in Table 9 The oxycodone-protected granules were divided into two below: groups to be incorporated into batches of immediate release 40 (IR) granules and into batches of sustained release (SR) gran ules used to form the IR and SR Layers of a bilayer tablet, TABLE 9 respectively. Both the IR granules and the SR granules were formed using separate fluid bed granulation processes. In Effect of Granulation On Oxidative Stability of Tablet Formulations each process, the previously-formed oxycodone-protected Impurity After 4Weeks at Accelerated Degradation 45 granules, powdered acetaminophen (APAP), and various Composition Conditions excipients including disintegrants, binders, and fillers were Combined % wt of Oxycodone charged into the fluid bed granulation device and sprayed with APAP 6-a-Oxycodol Noroxy with a granulation fluid, resulting in the formation of IR granules in one batch and SR granules in a second batch. The and PEO Protected Protected 50 Polymer granules Unprotected Granules Unprotected composition of the resulting IR and SR granules are Summa rized in Table 11: O.20 .74 27 O.22 S1 28 O.60 1.25% 14: TABLE 11 O.17 49 18 55 Composition of IR and SR Granules * measured at two weeks after storage Dry Wt. (96 total wt. All of the protected tablet formulations, in which the oxy IR codone was granulated using methods similar to those Compound Granules SR Granules described in Example 1 formed significantly lower levels of 60 Protected oxycodone 3.10% 9.79% impurities after storage for 4 weeks at accelerated Stability granules conditions compared to tablets containing non-granulated APAP 80.65% 84.81% oxycodone and the same excipients MCC S.0% Hydroxypropyl cellulose 8.0% S.0% The results of this experiment demonstrated that granulat Cross carmellose sodium 3.0% ing the oxycodone and excipients prior to incorporating the 65 Silicon Dioxide O.25% O.4% granules in a tableting process resulted in tablets with Supe rior stability compared to tablets formed using the same oxy US 8,980,319 B2 25 26 The IR granules were blended with lubricant excipients in (SR) granules used to form the IR and SR Layers of a bilayer preparation for the tablet pressing process. Similarly, the SR tablet, respectively. Both the IR granules and the SR granules particles were blended with various excipients including were formed using separate fluid bed granulation processes. lubricants, and polyethylene oxide polymer, and a filler in In each process, the previously-formed protected hydroc preparation for the tablet pressing process. The compositions 5 odone granules, powdered acetaminophen (APAP), and vari of the IR blend and the SR blend are summarized in Table 12: ous excipients including disintegrants, binders, and fillers were charged into the fluid bed granulation device and TABLE 12 sprayed with a granulation fluid, resulting in the formation of IR granules in one batch and SR granules in a second batch. Composition of IR and SR Blends 10 The composition of the resulting IR and SR granules are summarized in Table 14: Dry Wt. (96 total wt. Compound IRBlend SR Blend TABLE 1.4 IR granules 96.38% Composition of IR and SR Granules SR granules 26.80% 15 Croscarmellose Sodium 3.11% Dry Wt. (96 total wt. Silicon dioxide O.26% O.39% Magnesium stearate O.25% 1.0% IR MCC 26.81% Compound Granules SR Granules Polyethylene oxide 45.00% polymer Protected hydrocodone 3.10% 9.79% granules APAP 80.65% 84.81% The IR blend and the SR blend were loaded into a bilayer MCC S.0% Hydroxypropyl cellulose 8.0% S.0% tablet press and formed into bilayer tablets having about 23% Cross carmellose sodium 3.0% of the IR blend and about 77% the SR blend by weight. 25 Silicon Dioxide O.25% O.4% The results of this experiment demonstrated that protected morphinan granules could be formed using a process of high The IR granules were blended with lubricant excipients in shear wet granulation and incorporated into a solid oral thera preparation for the tablet pressing process. Similarly, the SR peutic composition. particles were blended with various excipients including 30 lubricants, and polyethylene oxide polymer, and a filler in Example 6 preparation for the tablet pressing process. The compositions Incorporation of Protected Hydrocodone Granules of the IR blend and the SR blend are summarized in Table 15: into Bilayer Tablet Composition TABLE 1.5 35 To demonstrate the feasibility of forming protected mor Composition of IR and SR Blends phinan granules and incorporating the protected morphinan granules into a solid dosage form, the following experiment Dry Wt. (90 total wt. was conducted to prepare a 7.5 mg hydrocodone/325 mg Compound IRBlend SR Blend acetaminophen tablet. 40 Powdered hydrocodone bitartrate, microcrystalline cellu IR granules 96.38% SR granules 26.80% lose (MCC), pregelatinized starch (PGS) and citric acid pow Croscarmellose Sodium 3.11% der (an antioxidant) were mixed together and charged into a Silicon dioxide O.26% O.39% high-shear granulator. An aqueous solution containing prege Magnesium stearate O.25% 1.0% 45 MCC 26.81% latinized starch (PGS) and NaEDTA (an antioxidant) was Polyethylene oxide 45.00% sprayed into the high-speed granulator, resulting in the for polymer mation of wet granules. The wet granules were then dried until less than about 5% water remained in the granules. The dried granules had particle sizes ranging from about 100-300 The IR blend and the SR blend were loaded into a bilayer um after milling. The composition of the protected hydroc 50 tablet press and formed into bilayer tablets having about 23% odone granules is Summarized in Table 13: of the IR blend and about 77% the SR blend by weight. The results of this experiment demonstrated that protected TABLE 13 morphinan granules could be formed using a process of high shear wet granulation and incorporated into a solid oral thera Composition of Protected Hydrocodone Granules 55 peutic composition. Dry Weight Having described the invention in detail, it will be apparent Compound (% tot. wt.) that modifications and variations are possible. Those of skill in the art should, in light of the present disclosure, appreciate Hydrocodone 30.0% that many changes could be made in the specific embodi bitartrate MCC 63.6% 60 ments that are disclosed and still obtain alike or similar result PGS 4.0% without departing from the spirit and scope of the invention, Na2EDTA O.4% therefore all matter set forth is to be interpreted as illustrative Citric acid 2.0% and not in a limiting sense. What is claimed is: The hydrocodone-protected granules were divided into 65 1. A solid dosage pharmaceutical composition comprising: two groups to be incorporated into batches of immediate (a) a plurality of granules containing a pharmaceutically release (IR) granules and into batches of Sustained release acceptable salt of oxycodone, wherein the granules are US 8,980,319 B2 27 28 Substantially resistant to oxidative degradation of the lulose propionate Succinate, cellulose trioctanoate, cellulose pharmaceutically acceptable salt of oxycodone; and tripropionate, cellulose trimellitate, cellulose tripalmitate, (b) an additional active ingredient, cellulose trivalerate, cellulose Valerate palmitate, carboxym wherein the granules comprise an interior region Substan ethyl cellulose, calcium carboxymethyl cellulose, sodium tially comprising the pharmaceutically acceptable salt of oxy carboxymethyl cellulose, ethyl cellulose, ethylhydroxy eth codone and an exterior region Substantially comprising at ylcellulose, hydroxy propyl methylcellulose phthalate, least one excipient; methyl cellulose, methyl ethyl cellulose, propyl cellulose, wherein the granule contains less than about 0.5% w/w of the Sodium carboxymethyl starch, polyvinyl acetate phthalate, total mass of the pharmaceutically acceptable salt of oxyc polyvinyl alcohol phthalate, methacrylic acid copolymers, odone of each of any one or more of a degradant selected from 10 methacrylic acid ester copolymers, methyl methacrylate 10-hydroxy oxycodone, di-hydroxy oxycodone, and oxyc copolymers, ethoxyethyl methacrylates, cyanoethyl meth odone N-oxide after being stored for 6 months at 40° C. and acrylate, aminoalkyl methacrylate copolymer, poly(acry 75% relative humidity. late), poly(methacrylate), poly(methyl methacrylate), poly 2. A solid dosage pharmaceutical composition of claim 1, (ethylacrylate), poly(ethyl methacrylate), poly(methacrylic wherein the additional active ingredient is acetaminophen. 15 acid anhydride), glycidyl methacrylate copolymers, ammo 3. A solid dosage pharmaceutical composition of claim 1, nio methacrylate copolymers, lecithins, aluminum wherein the at least one excipient is chosen from the group monostearate, cetylalcohol, hydrogenated beef tallow, hydro consisting of a binder, a filler, an antioxidant, a chelating genated castor oil, hydrogenated vegetable oil, 12-hydroxys agent, and combinations thereof. tearyl alcohol, glyceryl monopalmitate, glyceryl dipalmitate, 4. A solid dosage pharmaceutical composition of claim 1, glyceryl monostearate, glyceryl distearate, glyceryl tristear further comprising at least one additional excipient selected ate, myristyl alcohol, Stearic acid, Stearyl alcohol, polyethyl from the group consisting of pH adjusting agents, antimicro eneglycols, Zein, shellac, bee's wax, carnauba wax, glyceryl bial agents, and combinations thereof. behenate, Japan wax, paraffin, Spermaceti, Synthetic waxes, 5. A solid dosage pharmaceutical composition of claim 1, and combinations thereof. wherein the composition further comprises microcrystalline 25 10. A solid dosage pharmaceutical composition of claim 1, cellulose, pregelatinized Starch, Na-EDTA, and citric acid. wherein the composition is a bilayer tablet. 6. A solid dosage pharmaceutical composition of claim 1, 11. A solid dosage pharmaceutical composition compris wherein the composition further comprises a hydrophilic 1ng: polymer. (a) an immediate release layer, and 7. A solid dosage pharmaceutical composition of claim 6. 30 (b) a Sustained release layer, wherein the hydrophilic polymer is selected from the group wherein both the immediate release layer and the sustained consisting of cellulose acetate, cellulose diacetate, cellulose release layer comprise a plurality of granules containing a triacetate, cellulose ethers, hydroxyethyl cellulose, hydrox pharmaceutically acceptable salt of oxycodone, ypropyl cellulose, hydroxypropyl methylcellulose, microc wherein the granules containing the pharmaceutically accept rystalline cellulose, nitrocellulose, crosslinked starch, agar, 35 able salt of oxycodone comprise an interior region Substan casein, chitin, collagen, gelatin, maltose, mannitol, maltodex tially comprising the pharmaceutically acceptable salt of oxy trin, pectin, pullulan, Sorbitol. Xylitol, polysaccharides, codone and an exterior region Substantially comprising at ammonia alginate, Sodium alginate, calcium alginate, potas least one excipient, sium alginate, propylene glycol alginate, alginate sodium wherein the granule contains less than about 0.5% w/w of the carmellose, calcium carmellose, carrageenan, fucoidan, fur 40 total mass of the pharmaceutically acceptable salt of oxyc cellaran, arabicgum, carrageensgum, ghaftigum, guargum, odone of each of any one or more of a degradant selected from karayagum, locust beangum, okragum, tragacanthgum, 10-hydroxy oxycodone, di-hydroxy oxycodone, and oxyc Scleroglucangum, Xanthangum, hypnea, laminaran, acrylic odone n-oxide after being stored for 6 months at 40° C. and polymers, acrylate polymers, carboxyvinyl polymers, 75% relative humidity. copolymers of maleic anhydride and styrene, copolymers of 45 12. A solid dosage pharmaceutical composition of claim maleic anhydride and ethylene, copolymers of maleic anhy 11, wherein the at least one excipient is chosen from the group dride propylene or copolymers of maleic anhydride isobuty consisting of a binder, a filler, an antioxidant, a chelating lene, crosslinked polyvinyl alcohol and poly N-Vinyl-2-pyr agent, and combinations thereof. rolidone, diesters of polyglucan, polyacrylamides, 13. A solid dosage pharmaceutical composition of claim polyacrylic acid, polyamides, polyethylene glycols, polyeth 50 11, further comprising at least one additional excipient ylene oxides, poly(hydroxyalkyl methacrylate), polyvinyl selected from the group consisting of pH adjusting agents, acetate, polyvinyl alcohol, polyvinyl chloride, polystyrenes, antimicrobial agents, and combinations thereof. polyvinylpyrrolidone, anionic and cationic hydrogels, and 14. A solid dosage pharmaceutical composition of claim combinations thereof. 11, wherein the at least one excipient is chosen from the group 8. A solid dosage pharmaceutical composition of claim 1, 55 consisting of microcrystalline cellulose, pregelatinized wherein the composition further comprises a hydrophobic starch, NaEDTA, and citric acid. polymer. 15. A solid dosage pharmaceutical composition of claim 9. A solid dosage pharmaceutical composition of claim 8. 11, wherein the composition further comprises a hydrophilic wherein the hydrophobic polymer is selected from the group polymer. consisting of cellulose acetate butyrate, cellulose acetate eth 60 16. A solid dosage pharmaceutical composition of claim ylcarbamate, cellulose acetate heptanoate, cellulose acetate 15, wherein the hydrophilic polymer is polyethylene oxide. methylcarbamate, cellulose acetate octanoate, cellulose 17. A solid dosage pharmaceutical composition of claim acetate phthalate, cellulose acetate propionate, cellulose 11, wherein the composition further comprises an additional acetate Succinate, cellulose acetate trimaletate, cellulose active ingredient. acetaldehyde dimethyl acetate, cellulose butyrate, cellulose 65 18. A solid dosage pharmaceutical composition of claim dimethylaminoacetate, cellulose disuccinate, cellulose 17, wherein the additional active ingredient is acetami dipalmitate, cellulose dicaprylate, cellulose propionate, cel nophen. US 8,980,319 B2 29 30 19. A solid dosage pharmaceutical composition compris 25. A solid dosage pharmaceutical composition of claim 1ng: 19, wherein the composition further comprises a hydrophobic (a) a plurality of granules containing a pharmaceutically polymer. acceptable salt of hydrocodone, wherein the granules 26. A solid dosage pharmaceutical composition of claim are Substantially resistant to oxidative degradation of hydrocodone; and 5 19, wherein the composition is a bilayer tablet. (b) an additional active ingredient, 27. A solid dosage pharmaceutical composition compris wherein the granules containing the pharmaceutically accept ing: able salt of hydrocodone comprise an interior region Substan (a) an immediate release layer, and tially comprising the pharmaceutically acceptable salt of 10 (b) a Sustained release layer, hydrocodone and an exterior region Substantially comprising wherein both the immediate release layer and the sustained at least one excipient; release layer comprise a plurality of granules containing a wherein the granule contains less than about 0.5% w/w of the pharmaceutically acceptable salt of hydrocodone, total mass of the pharmaceutically acceptable salt of hydro wherein the granules containing the pharmaceutically accept codone of each of any one or more of a degradant selected able salt of hydrocodone comprise an interior region Substan from hydrocodone-N-oxide and hydrocodone aldol dimer 15 tially comprising the pharmaceutically acceptable salt of after being stored for 6 months at 40° C. and 75% relative humidity. hydrocodone and an exterior region Substantially comprising 20. A solid dosage pharmaceutical composition of claim at least one excipient, 19, wherein the additional active ingredient is acetami wherein the granule contains less than about 0.5% w/w of the nophen. total mass of the pharmaceutically acceptable salt of hydro 21. A solid dosage pharmaceutical composition of claim codone of each of any one or more of a degradant selected 19, wherein the at least one excipient is chosen from the group from hydrocodone-n-oxide and hydrocodone aldol dimer consisting of a binder, a filler, an antioxidant, a chelating after being stored for 6 months at 40° C. and 75% relative agent, and combinations thereof. humidity. 22. A solid dosage pharmaceutical composition of claim 25 28. A solid dosage pharmaceutical composition of claim 19, further comprising at least one additional excipient 27, wherein the at least one excipient is chosen from the group selected from the group consisting of pH adjusting agents, consisting of a binder, a filler, an antioxidant, a chelating antimicrobial agents, and combinations thereof. agent, and combinations thereof. 23. A solid dosage pharmaceutical composition of claim 29. A solid dosage pharmaceutical composition of claim 19, wherein the composition further comprises microcrystal 30 27, wherein the composition further comprises an additional line cellulose, pregelatinized starch, Na-EDTA, and citric active ingredient. acid. 30. A solid dosage pharmaceutical composition of claim 24. A solid dosage pharmaceutical composition of claim 29, wherein the additional active ingredient is acetami 19, wherein the composition further comprises a hydrophilic nophen. polymer.