ZA200504215B - Controlled-release compositions - Google Patents

Description

CONTROLLED-RELEASE COMPOSITIONS

FIELD OF THE INVENTION ) [DOOR] - This invention relates to a solid dosage formaulation in which an active ingreadiient is released over a sustained period. ‘

BACKGROUND OF THE INVENTION . -

[00022]. . An important factor influencing the rate of abssorption of an active agent admimistered as a tablet or other solid dosage formulation, and thus the efficacy and safety of the formulation, is the rate of dissolution of the dosage form in the body fluids of a human or animal. :

[00033] The ability of components of the formulatior fo influence the rate of release of the active agent(s) thus constitutes the basis for the so-called controlled-release, extended-release, sustained-release or prolonged-action pharmaceutical preparations that are designed to produce slow, uniform release and abso rption of the active agent over a period of hours, «lays, weeks, or months. © 156 Advantages of controlled-release formulations include a mreduction in the required frequeency of administration of the drug as compared to irmmediate-release dosage formss, often resulting in improved patient compliance; m=aintenance of a relatively stable concentration of the drug in the body leading to a sumstained therapeutic effect over a set period of time; and decreased incidence and iratensity of undesired side effects of the active agent resuiting from a reduction of the high plasma conceentrations that often occur after administration of inmediate-release dosage formss. . .

[00024] Many materials have been proposed and desveloped as matrices for : controlled release of active- agents, l.e. drugs, pro-drugys, etc. These include polymeric materials such as polyvinyl chloride, polyethylene amides, ethyl cellulose, silico ne and poly (hydroxymethyl methacrylate). See, for e=xample, U.S. Patent No. 3,087,860 to Endicott et al.; U.S. Patent No. 2,987,445 to L_evesque et al.; Salomon et aP., Pharm. Acta Helv., 55, 174-182 (1980); Korsmeyyer, Diffusion Controlied

Systeams: Hydrogels, Chap. 2, pp 15-37 in Polymers for Controlled Drug Delivery,

Ed Tarcha, CRC Press, Boca Raton, Fla. USA (1991); amd Buri et al, Pharm. Acta’

Helv. 55, 189-197 (1980). Co

[0005] High amylose starch has also been ussed for controlied-release purposes, and, in particular, recent advances have beer made using cross-linked high amylose starch. For example, U.S. Patent No. 5,456,921 (Mateescu et al), which issued October 10, 1995, U.S. Patent No. 5,616,343 (Cartilier et &L), which issuead April 1, 1997, U.S. Patent No. 6,284,273 (Lenamerts et al), which issued

September 4, 2001, U.S. Patent No. 6,419,957 (Lenaertss et al), which issued July 16, 22002, and U.S. Patent No. 6,607,748 (Lenaerts et al.)), which issued August 19, 2003: describe solid controlled release oral pharmaceutical dosage units in the form of talblets comprising a dry powder of a pharmaceutical product and a dry powder of cross-linked high amylose starch in which the cross-limked high amylose starch incluedes a mixture of about 10-60% by weight of amylopectin and about 40-80% _ amyl«ose. : :

[00065] Further examples of controlled-release mate rials include Kollidon™ SR marlceted by BASF (Germany), this material being a pimysical mixture of polyvinyl acetate (PVA) and polyvinylpyrrolidone (povidone), reporte=dly made up of about 80%

PVA and 19% povidone, and approximately 0.8% sodiuma dodecylsulfate and about 0.2% silica as stabilizer. BASF Technical Information «July 2001) discloses that

Kollidon™ SR can be used in the preparation of sustairsed release matrix dosage formss including tablets, pellets and granules, and that different technologies such as direct compression, roller compaction, wet granulatiorm and extrusion may be . emplsoyed in the manufacture of pharmaceutical formulati ons. A number of patent : publieations provide further information on PVA-povidon e mixtures: U.S. Patent Publiscation No. 2001/0038852 (Kolter et al) published November 8, 2001; U.S.

Paterit Publication No. 2002/0012701 (Kolter et al.) publisi—ed January 31, 2002, and

U.S. Patent Publication No. 2003/0021846 (Koiter et al.) published January 30, 2003.

[0007] Extended and controlled release formulationss relating to tramadol have been suggested, examples being described in: U.S. Patent Publication No. 20030143270, (Deboeck et al.) published July 31, 2003; LJ.S. Patent No. 6,254,887 (Mille r et al.) issued July 3, 2001; U.S. Patent Publication NO. 2001/0036477 (Miller at al) p ublished November 1, 2001; U.S. Patent No. 6,326,027 (Miller et al.) issued

December 4, 2001, WO 03/080031 (CILAG AG et al) published October 2, 2003.

Articles have been published in which compa rative data between “once-daily” tramadol formulations and immediate release trarmadol formulations are presented:

Adler et al., “A Comparison of Once-Daily Tramacdol with Normal Release Tramadol in the Treatment of Pain in Osteoarthritis,” The Journal of Rheumatology (2002) 29(10): 2195-2199; and Bodalia et al, “A Comparison of the Pharmacokinetics, : Clinical Efficacy, and Tolerability of Once-Daily Tramadol Tablets with Normal

Release Tramadol Capsules,” Jounal of Pain a nd Symptom Management (2003) . 25(2): 142-149. . 10008] | Citation or identification of any reference in this specification is not intended to be construed as an admission that such reference is available as prior art to the present invention.

SUMMARY OF THE INVENTION : } {0009} The present invention relates to a solid dosage formulation that provides for controlled-release of a pharmacological agent. In one embodiment, the . formulation includes a core having a pharmacological agent dispersed in a first controlied-release matrix comprising cross-linked high amylose starch, from which matrix release of the agent is relatively slow. Th ere is a coat formed over the core and the coat includes the agent dispersed in a second controlled-release matrix from which release of the agent is relatively fast.

[0010] in the context of this invention, “rela tively fast” means at least twice as fast when the initial rate of release of an agent Is measured under the same conditions separately for each matrix material. T © make such a measurement, one makes a formulation having the agent of the core and the agent of the coat differentially labeled from each other. In the case of tramadol, for example, the tramadol of the core could be labeled with '*N and the tramadol of the coat could be labeled with °C. There are many ways known fo a skilled person for differentially labeling such a compound so that its diffusion farom the formulation can be traced without significantly affecting its rate of diffusion. A skilled person could estimate such relative rates to a reasonable approximation , provided the rates are sufficiently different from each other, from the biphasic behavior observed for release of the

V0 2004/038428 PCT/CA2003/001637 agent from a single formulation, e.g., from the reates at 1=0, and t=12 hr of Figure 2.

Typically, the measurement would be made under the conditions set forth in connection with Figure 2. : {0011} In another broad embodiment, the invention is a solid dosage f omulation having a core with a pharmacological agent in a first controlled-release rnatrix. There is a coat formed over the core having the pharmacological agent in a second controlled-release matrix. The second controlled-release matrix is a physical rnixture of polyvinyl acetate and polyvinyipyrrolicione, and release of the agent from tthe matrix of the core is relatively slow with respeect to release of the agent from the rratrix of the coat. Relatively slow means no m-ore than half as fast when the initial wate of release of an agent is measured under the same conditions separately for «cach matrix material, the measurement being determined as described above in econnsction with the determination of relatively fasst. - oo - 0012] The agent in the core and coat may, in either embodiment, be the same sor different. In a preferred embodiment, the forrmulation includes a single agent that iis tramadol. y

T0013) in a preferred aspect of the inveantion, the coat and core comprise relative amounts of the agent such that release of the agent from the formulation is. foiphasic. : foo14] Preferably, the agent is soluble in vwater, and the first matrix is relatively hydrophilic relative to the second matrix. oo {oa15] Many agents are capable of formi ng ionic salts, and this Is often the preferred form of the agent for incorporation Ento a formulation of the invention.

Preferred agents contain at least one amino group, and these are conveniently incorporated in the form of, for example a hydrocFloride salt. . joo16] Preferably, the rate of release of the agent from the coat is at least -twice the rate of release of the agent from the core. Other relative rates are possible: “the rate of release of the agent from the coat cean be at least three times the rate of release of the agent from the core; the rate of reBease of the agent from the coat can be up to fifteen times the rate of release of trae agent from the core; the rate of release of the agent from the coat can be Lp to twelve times the rate of release of the agent from the core; the rate of release of the agent from the coat can be up to ten times the rate of release of the agent fron the core; the rate -of release of the agent from the coat can be up to eight times the rate of release of the agent from the core; the rate of release of the agent from the coat can be up to six times the rate of release of the agent from the core; or the rate of release of the agent from the coat can be about four times the rate of release of the agent from the core. In other embodiments, biphasic release behavior i s observed, and the rate of release of the agent from the coat Is between three and nine times the rate of release of the agent from the core, more preferably the rate of release of the agent from the coat is between four and eight times the rate of release of the agent from the core, more preferably the rate of release of the agerat from the coat is between five and seven times the rate of release of the agent from the core. oo .

[0017] In ceriain embodiments, between 10% and 30% per hour of the agent is released between 0 and 2 hours when tessted in vitro using a USP Type | apparatus in 50 mM phosphate, pH 6.8, and stirring between 50 and 150 rpm. oo [0018] In certain embodiments, beetween 10% and 40% of the agent is released from the formulation between 0 and about 2 hours of measurement, between about 30% and 60% of the agent: is released from the formulation between 2 and about 7 hours of the measurement, b-etween about 50% and 80% of the agent is released from the formulation between 7 and about 12 hours of measurement, and between about 80% and 100% of the agent is released from the formulation after about 20 hours of measurement.

[0019] A preferred active agent of Thoth the core and the coat Is an analgesic, specifically, the active can be tramadol. :

[0020] An agent of the formulation «of the invention is preferred to be soluble in water at least to the extent of 1 g/L, or rmore than 10 g/L, or more than 100 g/L, or more than 500 g/L, or more than 1000 g/L, or more than 2000 gL.

[0021] In certain embodiments, the formulation of the invention is generated to have the ratio of the core to the coat w/w) between about 1 and about 0.1, or * between about 0.9 and about 0.2, or between about 0.8 and about 0.2, or between about 0.7 and about 0.2, or betweren about 0.5 and about 0.2, or between about 0.4 and about 0.2, or about 0.35. In this context, it is the total weight of the core and the total weight of the coat that would koe considered when determining the weight ratio.

[0022] In certain embodiments, the ratio of the agent in core to the agent in the coat (w/w) is between about 0.1 and about 10, or between about 0.1 and about 8, or between about 0.2 and about 7, or between about 0.3 and about 6, or between about 0.4 and about 5, or between aboust 0.5 and about 4, or between about 0.6 and about 3, or between about 0.6 and about 2, or between about 0.6 and about 1.5, or between about 0.6 and about 1.3, or between about 0.7 and about 1, or between about 0.7 and about 0.9 or about 0.8.

[0023] In particular embodirnents of the invention, a formulation is one in which the core is between about 10% and about 90% by weight agent, or between about 20% and about 80% by weight agent, or between about 30% and about 70% by weight agent, ‘or between about 40% and about 60% by welght agent, or about 50% 186 by weight agent. . . oo [0024] In particular embodirnents, a formulation of the invention is one in which the coat is between about 5% and about 90% by weight agent, or between about 5% and about 80% by weight agent, or between about 10% and about 70% by weight agent, or between about 10% and about 60% by weight agent, or between about 15% and about 50% by weight agent, or between about 15% and about 45% by weight agent, or between about “15% and about 40% by weight agent, or between about 20% and about 35% by wesight agent, or between about 20% and about 30% by weight agent. N

[0025] According to certain aspects of the invention, the formulation is such that the ratio of the matrix of the coat to the agent of the coat (w/w) is between about 0.1 and about 10, or between about 0.2 and about 9, or between about 0.2 and about 8, or between about 0.3 and about 7, or between about 0.4 and about 6, or between about 0.5 and about 5, or betweer about 0.6 and about 4, or between about 0.7 and about 4 or between about 1 and about 4, or between about 1 and about 3 and about 1.5 and about 2.5. a

[0026] According to certain aspects, the formulation is such that the ratio of the matrix of the core to the agent of the «ore (w/w) is between about 0.1 and about 10, or.between about 0.2 and about 9, ox between about 0.3 and about 7, or between about 0.4 and about 6, or between abeout 0.5 and about 5, or between about 0.5 and about 4, or between about 0.5 and albout 3, or between about 0.6 and about 3, or between about 0.7 and about 2 or bretween about 0.8 and about 1.5, or between about 0.9 and about 1.5, or between aabout 0.9 and about 1.3, or about 1, or is about 0.55.

[0027] Preferably, the agent i= a single agent soluble in water at room temperature (about 21°C) to the extent of at least 0.5 gm per mL.

[0028] In certain aspects, each agent of the formulation contains an acid group, a base group or both an acidl group and a basse group, and each agent is present in the form of a salt of such group. Preferably, the agent contains an ionizable group and said group is at least 90% ionized in gastric juices (0.1M HCI).

[0029] Agents of a formulation eof the invention can be any one or more of the oo following: isonicotinic acid hydrazide, sodium salicylate, ~ pseudoephedrine hydrochloride, pseudoephedrine sulfate, acetaminophen or diclofenac sodium, verapamil, glipizide, nifedipine, fellodipine, betahistine, albuterol, acrivastine, omeprazole, misoprostol, tramadol, oxybutynin, trimebutine, ciprofloxacin, and salts thereof. In addition, the pharmaceutical agent can be an antifungal agent, such as ketoconazole, or an analgesic agent such as acetylsalicylic acid, acetaminophen, paracetamol, ibuprofen, ketoprofen, indomethacin, diflunisal, naproxen, ketorolac, diclofenac, tolmetin, sulindac, pohenacetin, piroxicam, mefamanic acid, dextromethorphan, other non-steroida 1 anti-inflammatory drugs including salicylates, pharmaceutically acceptable salts theresof or mixtures thereof.

J0030} Preferably, a formulation of the invention is prepared by compression.

Typically, the core is formed, by compression, and then the coat is prepared by being compressed onto the pre-formed core.

[0031] In a preferred aspect, thes coat is made up of an admixture of polyvinyl acetate, polyvinylpyrrolidone. The rati o of polyvinyl acetate and polyvinylpyrrolidone in the coat (w/w) is usually between about 6:4 and 9:1, or 7:3 and 9:2, or it Bs about 8:2. : ’ :

[0032] ° The coat often includes a binding agent, a preferred bindingy agent being xanthan gums.

[0033] The “formulation can. be a tablet, and a preferred cross-linkesd high amylose starch is a chemically-modified, cross-linked high amylose starch prepared by a method comprising: (a) cross-linking high amylose starch, followed by (b) chemically modifying the cross-linked high amylose starch, followed by (c) gelatinization, a.nd : (d) drying to obtain a powder of said controlled release excipient; : wherein said cross-linked high amylose starch is characterized in that upon solubilization in 90% DMSO at 80°C. for about three days and gel perrmeation : chromatography, the height of the peak corresponding to amylose in said cross- linked high amylose starch Is at least 30% of that of the peak corresponding to : amylose in said high amylose starch prior to (a). _

[0034] Another process for obtaining a cross-linked high amylose starch for formulations of this invention includes: (a) cross-linking high amylose starch thereby forming a reaction medium containing a reaction product co nsisting of a cross-linked high amylose starch slurry; : (b) subjecting sald cross-linked high amylose starch slurry from step (a) to clmemical modification at a temperature of about 10 to about 90°C. for about 1 to ab out 72 hours; (c) neutralizing said reaction medium obtained in step (b) with an acid, washing the slurry formed and o ptionally dewatering or to form a starch cake or a dry powder; (d) diluting said slu sty or re-slurrifying said starch cake or said dry powder froran step (c) with water to fom a slurry at a concentration of about 2% to about 40% w/w,

‘adjusting pH to a desired valu e between about 3 and about 12, and gelatinizing said slurry at a temperature of atoout 80 to 180°C. for about 1 second to about 120 minutes; and (e) drying the thermally treated product obtained in step (d) to obtain said controlled release excipient consisting mainly of chemically modified and cross-linked high amylose starch in form of a powder.

[0035] Another process for manufacturing, in an aqueous medium, a controlled release excipient consisting primarily of cross-linked high amylose starch is one including (a) subjecting high amylose starch to chemical modification at a temperature of about 10 to about 90°C. for about 1 to about 72 hours thereby forming a reaction medium. containing a chemically modified high amylose slurry; : : " (b) cross-linking said chemically modified high amylose starch in said slurry obtained in step (a); Co . 15 (c) neutralizing said slurry obtained in step (b) with an acid, washing the slurry formed and optionally dewatering to fasrm a starch cake or drying to form dry powder; (d) diluting said slurry, or re-st urrifying said starch cake or said dry powder from step (c) with water to form a slurry at a concentration of about 2% to about 40% ww, adjusting pH to a desired valume between about 3 and about 12, and gelatinizing said slurry at a temperature of alibout 80 to 180°C. for about 1 second to about 120 minutes; and (e) drying the thermally treate«d product obtained in step (d) to obtain said controlled release excipient consisting wmainly of chemically modified and cross-linked high "amylose starch in form of a powder. :

[0036] Another process for obtaining a cross-linked high amylose starch for this invention includes: (a) cross-linking high amylose starch, followed by (b) chemically modifying the creoss-linked high amylose starch, followed by q

* (c) gelatinization, and : (d) drying to obteain a powder of sald controlled release excipient; Co wherein said cross-linked high amylose starch is characterized in that upon solubilization in 90% DMSO at 80°C. for about three days and geel permeation chromatography, the height of the peak corresponding to amylose #in said cross- linked high amylose starch is at least 90% of that of the peak corresponding to amylose in said high amylose starch prior to (a). : : [0037] Arother process for obtaining a cross-linked high amyleose starch for this invention includes: : (a) cross-linkings high amylose starch, followed by (b) chemically modifying the cross-linked high amylose starch, followed by " (c) gelatinizatior, and (d) drying to ob&ain a powder of said controlled release excipient; wherein said creoss-linked high amylose starch is characterized in that leess than about 20% of the amylose present in said high amylose starch prior to (aD is chemically cross-linked to amylopectin. } [0038] Amother process for obtaining a cross-linked high amyl ose starch for this invention imecludes: (a) cross-linking high amylose starch, followed by . (b) chemically rnodifying the cross-linked high amylose starch, followed by - (c) gelatinizatio-n, and oo (d) drying to ob-tain a powder of said controlled release excipient; wherein said cross-linked high amylose starch is characterized in that upon solubilization im 90% DMSO at 80°C. for about three days and ggel permeation chromatographay, less than about 20% of the amylose present prior to (a) is chemically cross-linked to and eluted with amylopectin. 10 _

[0039] Another process for obtaining a cross-linked high amylose starch for this invention inclucies: : (8) cross-linking high amylose starch, followed by oo (b) chemically modifying the cross-linked high amylose starch, followed by (c) gelatinization, aand (d) drying to obtairm a powder of said controlled release excipient; wherein said cross-linked high amylose starch is characterized in that upon solubilization in 90% DMSO at 80°C. for about three days and gel permeation chromatography, t he height of the peak corresponding to amylose is highe=r than that of the peak corresgoonding to amylopectin-containing entities.

[0040] Another process for obtaining a cross-linked high amylose starch for this invention Incluades: (a) cross-linking high amylose starch, followed by (b) chemically mosdiifying the cross-linked high amylose starch, followed by (c) gelatinization, sand - (d) drying to obtaimn a powder of said controlled release excipient; wherein said cros=s-linked high amylose starch is characterized in that less than about - 20% of the amyleose present in sald high amylose starch prior to (a) Is chemically cross-linked to amylopectin. | CC

[0041] Ano-ther process for obtaining a cross-linked high amylose starch for this invention includes: . (a) cross-linking haigh amylose starch, followed by (b) chemically modifying the cross-linked high amylose starch, followed by (c) gelatinization, and

. (d) dryimg to obtain a powder of said controlled release excipiert, whereira said cross-linked high amylose starch is characterized in ‘that upon solubllization in 90% DMSO at 80°C. for about three day"s and gel permeation chromatography, less than about 20% of the amylose peresent prior to (a) is chemically cross-linked to and eluted with amylopectin.

[0042] Another process for obtaining a cross-linked h igh amylose starch for this invention includes: (a) cross-linking high amylose starch, followed by : (b) che=mically modifying the cross-linked high amylose starch, followed by (c) gelatinization, and : (d) drying to obtain a powder of said controlled release excipie nt; : wherelin said cross-linked high amylose starch is characterized in that upon solubilization in 90% DMSO at 80°C. for about three daws and gel permeation oo chromatography, the height of the peak corresponding to amylose is higher than that 16 of the peak corresponding to amylopectin-containing entities. Co

[0043] Of course, a product having the structure «of a. cross-linked high amylose starch obtained by one of these processes, even theough the manufacturing processs is not identical one of these is also within the scope off this invention.

[0044] The core of a formulation of this invention often includes a lubricant which is optionally hydrogenated vegetable oil. Ce [00453 In a preferred aspect, a formulation of the invention is a tablet formuBated for oral administration.

[0046] In one pariicular embodiment, the invention is a solid dosage formulation that includes: a core having a pharmacological agent dispersed in aa first controlled-release matrix from which release of the agent is relatively slow; and

: a coat formed over the core and comprising said agent dispersed in a second controllesd-release matrix, the second controlied-release matrixc comprising a physical mixture «of polyvinyl acetate and polyvinyipyrrolidone and frorn which release of the agent is relatively fast.

In another embodiment, the invention provides a solid dossage formulation that includes: . : a core comprising a pharmacological agent disperse«d in a first controlled- release matrix comprising cross-linked high amylose starch, from which matrix release of the agent is relatively slow; and au coat formed over the core and comprising a pharmacological agent in a second controlled-release matrix, the second controlled-relea-se matrix comprising a physical mixture of polyvinyl acetate and polyvinyipyrrolidone, and wherein: reelease of the agent from the matrix of the core is rela-tively slow with respect to relea=se of the agent from the matrix of the coat. . 15 [0047] Another aspect of the invention is a solid dosage formulation that “includes: a core comprising a pharmacological agent in a first controlled-release matrix; and - a coat formed over the core and comprising a pharrmacological agent in a. second controlled-release matrix, the second controlied-relea_se matrix comprising a physicaal mixture of polyvinyl acetate and polyvinylpyrrolidone, &and wherein: release of the agent from the matrix of the core is rela_tively slow with respect . to release of the agent from the matrix of the coat.

[0048] in another aspect, the invention includes a solid dosage formulation comprising a pharmacological agent for release thereof over an extended period of time, thme formulation comprising: & core comprising agent in a first controlled-releasse release matrix, the controll ed-release matrix comprising cross-linked high amylose starch; and a coat formed over the core and comprising the agent in a second controlled- release matrix, the second controlled-release matrix comprising a physical mixture of polyvinyl acetate and polyvinylpyrrolidone, and wheresin: : the agent is present in the core sufficient to obtain release into an aqueous environment, e.g. gastric juices, of no more than 50% of the agent from the formulation within one quarter of the period. oo

[0049] In such a formulation, the period can be between about 12 and about 24 hours, and between about 30% and about 70% of the agent is in the core. The agent in the first matrix and the agent in the second matrix is preferably soluble in water at least to the extent of 1 g/L, or more than 10 g/L, or more than 100 gi, or more than 500 g/L, or more than 1000 g/L, or more than 2000 g/l. The agent can be an analgesic. : . [0050] A particular embodiment of the invesntion includes a solid dosage formulation for use for a period of every four hourss, or every six hours, every eight hours, every twelve hours, or every twenty-four hourss, the formulation comprising: a compressed core comprising a pharmacological agent including an amino group, the agent being present as a pharmacolog3cally acceptable salt and being dispersed in a first controlied-release matrix comprising cross-linked high amylose starch; and a coat formed by compression over the core and comprising the agent in a second coritrolled-release matrix, the second controslled-release matrix comprising a physical mixture of polyvinyl acetate and polyvinylpyrrolidone, and wherein: release of the agent from the formulation over the period includes a first phase with the average rate of release over the first 5% of" the period being between three and eight times the rate of release of the agent half way through the period.

[0051] In a particular aspect of this particulzar embodiment, the ratio of the agent in core to the agent in the coat (w/w) is between 0.2 and about 7, the core is between 20% and 80% by weight agent, the coat is between 15% and 50% by weight agent, and the ratio of the matrix of the coat to the aggent of the coat (w/w) is between

0.3 amd 7. Further, the preferred agent is tramadol, ard preferably the coat includes a bincling agent. - - [0052:) - in another aspect, the invention is =a controlled released tablet ) comp rising: a compressed .core comprising cross-linked high amylose starch having tramandol, or a salt thereof, embedded therein; and a coat formed over the core by compressior, and comprising a physical mixtu re of polyvinyl acetate, polyvinylpyrrolidone, a binder, tramadol; and wherein: the ratio of the core/coat (w/w) is between about 0.2 and 0.6; the ratio of the tramadol in the core to the tramadol in the coat is between about 0.7 and about 1; ’ the ratio of polyvinyl acetate/polyvinylpyrrolidne (w/w) is between about 6:4 - and 9:1; and Co : the rate of release of tramadol from the coat matrix is at least twice the rate of release of tramadol from the core when measured by & USP Type | apparatus in 50 mM phosphate, pH 6.8, and between 50 and 150 rpm.

[0053] The invention includes a method of manufacturing a controlled-release medication, the method comprising: (i) blending a pharmacological agent and a first matrix material comprising a cross—linked high amylose starch; : (ii) forming the resultant blend of step (i) Into a core; (ii) blending a pharmacological. agent and a second. matrix material comprising a relatiwely fast release material with respect to the first matrix material; (iv) forming the resultant blend of step (ili) as a coat osnto the exterior of the core.

[00547] A method of manufacturing a controlled-re=lease medication of invention’ can imclude:; :

(@) blending a pharmacological agent and a Hirst matrix material; Co (i) forming the resultant blend of step (i) inte a core; A (il) blending a pharmacological agent and = second matrix material; the second matrix material comprising a physical rmixture of polyvinyl acetate and polyvinylpyrrolidone and being a relatively fast release material with respect to the first matrix material; (iv) forming the resultant blend of step (iii) ass a coat onto the exterior ofthe core.

[0055] Step (ii) preferably comprises compressing the resultant blend of step (i). Step (iil) can comprise compressing the= resultant blend of step (ili) onto the exterior of the core. The agent in the core amd the coat is preferably tramadol, the total amount of tramadol in the medication iss effective as a daily dosage, and the medication comprises a formulation, as appropriate as defined within this "specification. : ’ :

[0056] The invention includes an oral tramadol pharmaceutical composition suitable for once daily administration comprising an effective amount of tramadol or a pharmaceutically acceptable salt thereof prosviding after a single administration in . vivo, a median time to tramadol peak plasmaa concentration (Tmax) between 2 and 8 hours and a mean peak tramadol plasma corcentrations (Cmax) which are less than three times the mean plasma concentration obtained 24 hours after administration (Cam) of a single dose of such composition.

[0057] Such a composition can be such that said mean peak tramadol plasma concentrations (Cmex) are less than two ti mes the mean plasma concentration obtained 24 hours after administration (C24) Of a single dose of such composition.

[0058] in another embodiment, the invention is an oral tramadol pharmaceutical composition suitable for successive administration, once daily, comprising .an effective amount of tramadol or a pharmaceutically acceptable salt thereof providing in vivo a steady state in which, during a given 24 hour period, a tramadol maximum mean plasma concentratzion (Cmax) of between 2 and 3 times a tramadol minimum mean plasma concentration (Crp) is obtained. According to a particular aspect, the mean Cmax is No great-er than 350 ng/ml. Tthe mean plasma concentration of tramadol is preferably less than 80 percent of Cmax for at least 18 hours of a said 24 hour period. : oe

[0059] = The invention includes a solid dosage formulation comprising: a core comprising a pharmacological agent dispersed in a first controlled- release matrix comprising cross-linked high amylose starch; and : a coat formed over the core and comprising said agent dispersed in a-second controlled-release matrix, different from the first such that release of the agent from the formulation Is biphasic.

[0060] According to another aspect, the invention is a solid dosage formulation comprising: a core comprising a pharmacological agent dispersed in a first controlied- release matrix; and a coat formed over the core and comprising said agent dispersed in a second controlled-release matrix comprising a physical mixture of polyvinyl acetate and polyvinylpyrrolidone such that release of t he agent from the formulation is biphasic.

[0061] According to yet another aspect, the invention is a solid dosage formulation comprising: a core comprising a pharmacological agent dispersed in a controlled-release matrix comprising a cross-linked high amylose starch; and a coat formed over the core and comprising & pharmacological agent in a second controlled-release matrix comprising a physical mixture of polyvinyl acetate and polyvinylpyrrolidone.

[0062] In another embodiment, the invention is a solid dosage formulation comprising: } ‘ a core comprising about 50 mg, or about 75 mg or about 100 mg or about 125 mg or about 150 mg or about 175 mg or about 200 mg or about 225 mg or about 250 mg or about 275 mg or about 300 mg or about 325 mg or about 350 mg or about 375 mg or about 400 mg tramadol dispersed ik a controlled-release matrix comprising a8 cross-linked high amylose starch; and oo a coat formed.over the core and comprising a pharmacological agent ina second controlled-release matrix comprisi ng a physical mixture of polyvinyl acetate and polyvinylpyrrolidone.

[0063] The torm “comprising” as useed herein is used in its. open-ended sense, unless the context would dictate otherwisse. That is, a formulation comprising first and second matrices and an agent, for example, could thus also include other ingredients, such as a lubricant.

[0064] Formulations of the above-described formulations provide advantageous characteristics in vivo, as s et out further below. Another aspect of the invention is thus a once daily oral pharmaceutical composition for controlled release ~ of tramadol or a salt thereof, in which the composition, upon initial administration of one dose, provides an onset of analgesic effect within 2 hours, which analgesic effect continues for at least 24 hours after adminmistration. ) [0065] Another aspect of the invesntion is a once daily oral pharmaceutical composition for controlled release of tramadol or a salt thereof, wherein the composition, upon initial administration of one dose, provides a mean plasma concentration of at least 100 ng/mL withir 2 hours of administration and continues to provide a mean plasma concentration of &t least 100 ng/mL for at least 22 hours after administration.

[0066] Another aspect of the invention is a once daily oral pharmaceutical composition for controlled release of tramadol or a salt thereof, wherein the composition, upon initial administration of one dose, provides a mean plasma concentration of at least 100 ng/mL withir 2 hours of administration and continues to . provide a mean plasma concentration of et least 100 ng/ml for at least 23 hours after administration. :

[0067] In another aspect, the inveantion is a once daily oral pharmaceutical composition for controlled release of tramadol or a salt thereof, wherein the composition, upon Initial administration of one dose, provides a mean plasma concentration of at least 100 ng/mL within 2 hours of administration and continues to provide a mean plasma conc entration of at least 100 ng/mL for at least 24 hours after administration. : [oo68] "A once daily oral pharmaceutical composition of the invention, in a preferred aspect, includes ab»out 200 mg of tramadol of a salt thereof.

[0069] in yet another aspect, the invention is a once daily oral pharmaceutical composition for controlled re lease of tramadol or a salt thereof comprising 100 mg of tramadol or a salt thereof, wherein the composition, upon initial administration of one= dose, provides a mean plas ma concentration of at least 50 ng/mL within 2 hours of administration and continues to provide a mean plasma concentration of at least 50 ng/mL for at least 22 hours after administration.

[0070] | According to another aspect, the invention provides a once daily oral pharmaceutical compositiora for controlled release of tramadol or a salt thereo¥ comprising 100 mg of tramadol or a salt thereof, wherein the composition, upon initial administration of one dose, provides a mean plasma concentration of at least 508 ng/mL within 2 hours of administration and continues to provide a mean plasmaa concentration of at least 50 ng/mL for at least 23 hours after administration.

[0071] Another aspect of the invention is a once daily oral phamaceuticall composition for controlled release of tramadol ora salt thereof comprising 300 mg of tramadol or a salt thereof, wherein the composition, upon initial administration of one» dose, provides a mean plasma concentration of at least 150 ng/mL within 2 hours of - administration and continues to provide a mean plasma concentration of at least 1508 ng/mL for at least 22 hours after administration.

[0072] . Another aspect of the invention is a once daily oral pharmaceutical composition for controlled release of tramadol or a sait thereof comprising 300 mg of° tramadol or a salt thereof, wherein the composition, upon initial administration of one» doss, provides a mean plasma concentration of at least 150 ng/mL within 2 hours of administration and continues to provide a mean plasma concentration of at least 150m ng/mL for at least 23 hours after administration.

[0073] Another aspect of the invention is a once daily oral pharmaceutical composition for controlled release of tramadol or a salt thereof comprising 300 mg of tramadol or a salt thereof, wherein thes composition, upon initial administration of one dose, provides a mean plasma concesntration of at least 150 ng/mL within 2 hours of administration and continues to provicie a mean plasma concentration of at least 150 ng/mL for at least 24 hours after admimnistration.

[0074] In another aspect of the A once dally oral pharmaceutical composition for controlled release of tramadol or & salt thereof comprising 200 mg of tramadol or a salt thereof, wherein upon initial adrninistration of 400 mg, the composition provides a mean plasma concentration of at least 200 ng/mL for at least 22 hours after administration.

[0075] Another aspect of the invention is a once daily oral pharmaceutical composition for controlled release of dramadol or a salt thereof comprising 200 mg of " tramadol or a salt thereof, wherein upon initial administration of -400 mg, the composition provides a mean plasmae concentration of at least 190 ng/mL for at least 23 hours after administration. : '

[0076] Another aspect of the invention is a once daily oral pharmaceutical composition for controlled release of Iramadol or a salt thereof comprising 200 mg of tramadol or a salt thereof, whereimn upon initial administration of 400 mg, the composition provides a mean plasma. concentration of at least 180 ng/mL for at least 24 hours after administration. .

[0077] The Invention also provides a once daily oral pharmaceutical : composition wherein the mean maxi mum plasma concentration (Cmax) i$ less than 100 ng/mL.

[0078] Further, a once dally oral pharmaceutical composition of the invention can provide a mean maximum plasma concentration (Cmax) Is less than 300 ng/mL, or a mean maximum plasma concentration (Cmax) is less than 200. ng/mL.

[0079] A once daily oral pharrmnaceutical composition of the invention can be such that the mean maximum plasma concentration (Cmax) is less than 2.2 times the mean plasma concentration obtained 24 hours after administration (Caan). -

Jo080] The orice daily oral pharmaceutical composition can be suech that the mean maximum plasma concentration (Cmax) is less than 300 ng/mL.

[0081] : The m ean maximum plasma concentration (Cmax) Can be less than two times the mean plassma concentration obtained 24 hours after administratiosn (Caan).

[0082] The maean maximum plasma concentration (Cmax) can be le=ss than 2.3 times the mean plassma concentration obtained 24 hours after administratican (Cas).

[0083] The osnce daily oral pharmaceutical composition of the invention can provide a’ median tisne to the mean maximum plasma concentration (tmex) of between 2 and 10 hours, or between 3 and 6 hours, or between 5 and 6 hours.

[0084] The invention also provides a once daily oral pharmaceutical composition for cortrolled release of tramadol or a salt thereof comprising 200 mg of tramadol or a salt thereof, wherein the composition, upon initial administration of one dose, provides an O-desmethyitramadol mean plasma concentration of at least 24 ng/mL within 2 hours of administration and continues to provi<de an -O- 16 desmethyltramadol mean plasma concentration of at least 25 ng/mL for at least 24 hours after adminis tration.

[0085] According to another embodiment, the invention provides ea once daily oral pharmaceutical composition for controlled release of tramadol or a salt thereof comprising 100 mg of tramadol or a salt thereof, wherein the composition,. upon initial administration of one dose, provides an O-desmethyltramadol me=an plasma concentration of at least 11 ng/mL within 2 hours of administration and continues to provide an O-desmethyitramadol mean plasma concentration of at least 1 2 ng/mL for at least 24 hours affter administration. . [oos6] Accowding to another embodiment, the invention provides & once daily oral pharmaceutical composition for controlled release of tramadol or a salt thereof comprising 300 mgy of tramadol or a salt thereof, wherein the composition, upon Initial administration of one dose, provides an O-desmethyiramadol me-an plasma concentration of att least 32 ng/mL within 2 hours of administration and continues to provide an O-desnmethyltramadol mean plasma concentration of at least 3-2 ng/mL. for atleast 24 hours after administration. :

[0087] In another embodiment, the invention is a once daily oral pharmaceutical composition for controlled release of tramadol or a salt thereof” comprising 200 mg of tramadol or a salt thereof, wherein upon initial administration of 400 mg, the composition provides an O-desmethyltramadol mean plasmas concentration of at least 50 ng/mL within 2 hours of administration and continues tos provide an O-desmethyltramadol mean plasma concentration of at least 50 ng/mL for” at least 24 hours after administration.

[0088] One object of the present invention is to provide flexible dosing options for patients with different analgesic requirements with a once daily formulation.

[0089] One embodliment of the present invention is to provide a once daily formulation which upon initial ingestion of a dose of 100 mg would provide the desired early onset of action but achieve mean tramadol plasma concentrations of a-t least 45 ng/mL between 2 and 24 hours. =

[0090] A further enbodiment of the present invention is to provide a once daily formulation which upon initial ingestion of a dose of 200 mg would provide the desired early onset of action but achieve mean tramadol plasma concentrations of a_t - least 100 ng/mL between 2 and 24 hours.

[0091] A further ermbodiment of the present invention is to provide a once dailwy/ formulation which upon initial ingestion of a dose of 300 mg would provide thes desired early onset of action but achieve mean tramadol plasma concentrations of a_t least 150 ng/mL between 2 and 24 hours. oo

[0092] A further ermbodiment of the present invention is to provide a once daitwy formulation which upon initial ingestion of a dose of 400 mg would provide the desired early onset of action but achieve mean tramadol plasma concentrations of a:t least 180 ng/mL betweem 2 and 24 hours. Co

[0093] A further ernbodiment of the present invention is to provide a once dailwy formulation which upon Initial ingestion of a dose would provide a C'max to dose ratio of from about 0.90 to about 1.0.

[0094] A further ernbodiment of the present invention is to provide a once dailwy formulation which upon Snitial ingestion of a dose would provide a tramadol plasma concentration which. rises steadily until peak tramadol concentrations are attained at a Trax Of about 4 hosurs to about 6 hours. Preferably, the Tmax occurs at about 5.hours to about 6.5 hours.

[0095] A furtbher embodiment of the present invention is to provide a_ once daily formulation which tapon initial ingestion of a dose would provide a tramaiol plasma concentration which, after Tmax, declines in a slow but steady manner, reflecting continuing absorption in addition to elimination processes. Preferably, the decline in the tramadol plasma concentration after Tmex Occurs in a log-linear fashion with a : mean apparent termminal elimination half-life of between about 5.5 hours and about 6.5 hours. :

[00986] A further embodiment of the present invention is to provide ea once daily formulation which wupon Initial ingestion of a dose would provide a tramaedol plasma concentration whicsh, after Tmax, declines in a slow but steady mannew, reflecting continuing absorption in addition to elimination processes, and which absorption continues for at leaast 20 hours after Tmax. oo oo [0097] A further embodiment of the present invention is to provide & once daily formulation which upon initial ingestion of a dose provides a tramaedol plasma concentration which, after Tmax, declines in a log-linear fashion with aun apparent. terminal eliminatiosn rate constant (Az) of about 0.12 h? for the trama-dol plasma concentration.

[0098] A further embodiment of the present invention is to provide & once daily formulation which upon initial ingestion of a dose would provide a mear residence time (MRT) of tramadol ranging from about 15 hours and about 18 hours.

[0099] A further embodiment of the present invention is to provide & once daily formulation which upon initial ingestion of a dose would provide a half vat.ue duration (HVD) of tramadol which ranges from about 22.5 hours to about 25.4 hourss.

[00100] A further embodiment of the present invention is to provide & once daily formulation which upon initial ingestion of a dose would provide 8 C'max to AUCo-. ratio of from abourt 0.04 h™ to about 0.06 h™. Preferably, the Cmax to AUCo... ratio is from about 0.04 h™ to about 0.05 h'. The ratio Cna/AUCo-. is used for evaluating the rate of drug absorption. Co [001 01)" A further embodiment of the p resent invention is to provide a once dally . "formulation which upon initial Ingestion of a dose would provide a mean AUCo.24 With respect to the tramadol plasma concentration which increases proportionally with dose over the range of dosage strengths- of 100 mg to 300 mg of the controlled : release composition. :

[00102] A further embodiment of the present invention is to provide a once daily formulation which upon Initial ingestion of a dose of 100 mg would provide a mean

AUCoTmex of from about 610 ng-h/mL to about 630 ng/mL.

[00103] A further embodiment of the goresent invention is to provide a once daily formulation which upon initial ingestion of a dose of 200 mg would provide a mean ~ AUCo.1max Of from about 910 ng-h/mL to ab-out 820 ng-h/mL. - [00104] A further embodiment of the present invention is to provide a once daily formulation which upon initial ingestion of a dose of 300 mg would provide a mean ©" AUCq.max of from about 1570 ng-h/mL to a:bout 1590 ng-r/mL. So

[00105] A further embodiment of the present invention is to provide a onge daily formulation which upon initial ingestion of a dose provides a mean ratio of

AUC.24/AUC-. of tramadol plasma concentration which ranges between about 70% and about 85%. Preferably, the mean ratio of AUC;24/AUCo- of tramadol plasma concentration ranges between about 74% and about 80%. Asa result, about. 15% to about 30% of the administered dose is sll circulating in the plasma 24 hours post- dose, depending on the dose administered. ‘

[00106] A further embodiment of the- present invention is to provide a once daily {formulation which upon initial ingestion of a dose would provide a ratio of the C'max to the dose released to the blood plasma ir the first 24 hours (that is, AUCo-24/AUCo-.. muitiplied by the dose) of from about 1.140 to about 1.35. Preferably the ratio is from about 1.15 to about 1.31. 24 Lo

[o0107] A further embodiment of the present invention Is to provide a once daily formulation which upon initial ingestion of a dose, would provide a ratio of the C'max [Timex to the dose administered of from about 0.10 to about 0.20. Preferably the ratio is from about 0.12 to about 0.19

[00108] A further embodiment of the present invention Is to provide a once daily formulation which upon initial ingestion of a dose would provide a slope in ng/mi-hr following the peak blood plasma concentration level, which does not exceed a factor of about 0.035 of the total dose administered in mg. Preferably, the factor is about : 0.03.

[00109] A further embodiment of the present invention is to provide a once daily formulation which upon initial ingestion of a dose would provide a ratio of the C'mex calculated with respect to the blood plasma concentration of O-desmethyitramadol, to =~ the dose of tramadol from about 0.19 to about 0.22. Preferably the ratio is from about 0.20 to 0.21. oo

[00110] A further embodirment of the present invention is to provide a once daily formulation which upon Initial ingestion of a dose would provide an o- desmethyitramadol plasma co ncentration which rises steadily until peak tramadol concentrations are attained at ea Tmax Of about 8 hours to about 16 hours. ) .

[00111] A further embodirment of the present invention is to provide a once daily formulation which upon initial ingestion of a dose would provide .an O- desmethyitramadol plasma comcentration which, after Tmax, declines in a slow but steady manner, reflecting continuing tramadol absorption and subsequent metabolite formation in addition to elimiration processes. Preferably, the deciine in the O- desmethyltramadol plasma corcentration occurs in a log-linear fashion with a mean apparent terminal elimination half-life of between about 6.7 hours and about 8.1 hours. oo

[00112] A further embodizment of the present invention is to provide a once daily formulation which upon initial ingestion of a dose would provide, after Tmax, the formation of metabolite for at least 18 hours.

[00113] A further embodiment of th © present invention Is to provide-a once dally formulation which upon initial ingestion of a dose would, after Tmax, provide a decline in the O-desmethyltramadol plasma concentration .in a log-linear fashion with an apparent terminal elimination rate constant (AJ) for O-desmethyitramadol concentration of about 0.1 h™. :

[00114] A further object of the inv-ention is to provide a once daily formulation which upon initial ingestion of 100 mg, 200 mg and 300 mg strengths provides a half value duration (HVD) of O-desmethyitwramado! plasma concentration which ranges from 25.6 to 28.1 hours. .

[00115] A further embodiment of tlhe present invention is to provide a once daily formulation which upon Initial ingestion of a dose would provide a half value duration (HVD) of O-desmethyitramadol which ranges from about 25.6 hours to about 28.1 hours. :

[00116] A further embodiment of the present invention is to provide a once daily formulation which upon initial ingestior of a dose would provide 8 C'max 10 AUC0- oo ratio calculated with respect to the Or-desmethyltramadol plasma concentration, of about 0.04 h™'. The ratio C'max’AUCo— is used for evaluating the rate of metabolite formation. 5

[00117] A further embodiment of ®he present invention is to provide a once daily formulation which upon initial ingestion of a dose would provide a mean AUCp24 calculated with respect to the O-dessmethyltramadol plasma concentration, which increases proportionally with dose ove=r the range of dosage strengths of 100mg to 300 mg of the controlled release compaoosition.

[00118] A further embodiment of the present invention is to provide a once daily~ formulation which upon initial ingestiom of a dose of 100 mg would provide a mean

AUCo1max With respect to the O-desmmethyitramadol plasma concentration of from about 175 ng-h/mL to about 180 ng-h/nnL. :

[00118] A further embodiment of the present invention is to provide a once daily~ formulation which upon initial ingestion of a dose of 200 mg would provide a meama

AUCo1mex With respect to the O-desmethyitramadol plasma concentration of from about 530 ng-h/mL_ to about 5650 ng/mL. : So

[00120] A further embodiment of the present invention is to provide a onece daily formulation which upon initial ingestion of a dose of 300 mg would provide @& mean

AUCormax With re spect to the O-desmethyltramadol plasma concentration of from about 580 ng-h/mL. to about 590 ng-h/mL.

[00121] A further embodiment of the present invention is to provide a ormce daily formulation which upon initial. ingestion of a dose provides a mean ratio of

AUGo24/AUCo.. of O-desmethyitramadol plasma concentration which ranges between about 65% and about 80%. Preferably, the mean ratio of AUCo.24/A-UCo-. Of

O-desmethyltram adol plasma concentration ranges between. about 68% amd about 76%. As a result, about 25% to about 32% of the active metabolite is still ci reulating in the plasma 24 hours post-dose. B

[00122] A further embodiment of the present invention is to provide a omce daily formulation which upon initial ingestion of a dose would provide a ratio of ®he Cmax calculated with respect to the O-desmethyltramadol plasma concentration, to the O- desmethyltramado! blood plasma concentration in the first 24 hours (AUCq-=4/AUCo- multiplied by the dose of tramadol) of from about 0.0025 to about 0.0035. Preferably the ratio is from about 0.0027 to about 0.0031. :

[00123] Thee present invention may be understood more fully by refererace to the following detailed description and illustrative examples which are intended to exemplify non-lirniting embodiments of the invention.

DESCRIPTION OF THE DRAWINGS

: [00124] Various features and advantages of the present invention wild become clear from the more detalled description given below with references to the accompanying clrawings, in which: :

[00125] Fi gure 1: Flow diagram showing manufacturing process for talblets.

[00126] Fi gure 2: Dissolution profiles (% released) of formulations A_oBandC over 24 hours: In vitro performance of formulations A, B and C: under USSP Type 1

Conditions; sodium phosphate buffer, 50 mM, pH 6.8, 100 rpm. 6 tables were tested per time point. - oo

[00127] Figure 3(a): Mean tramadol plasma concentrations (ng/ml) for 48 hours following administration of 2 x 200 mg doses of composition (formulation B) (A)and 1 x 200 mg Topalgic® LP BID gi2h (A). Plasma concemnrations were determined using an kHPLC/UV assay. CL

[00128] Figure 3(b): Mean O-desmethyltramadol plasma «concentrations (ng/ml) for 48 hours following a single administration of 1 x 200 mg dose of the composition (formulation B) (®), 2 x 200 mg dose of the composition (aA), 1 x 100 mg

Topalgic® LP BID gi 2h (O), and 1 x 200 mg Topalgic® LP BID qi2h (A).

[00129] Figure 4(a): Plasma tramadol concentrations (ng/ml) of 27 subjects for 48 hours following a single administration of either 100 mg (#), 200 rmg (O), or 300 mg (A) strength trarnadol formulations (A, B, and C, respectively).

[00130] Figure- 4b): Plasma O-desmethyl tramadol concentrations (ng/ml) of 27 subjects for 48 hwours following a single administration of either 1080 mg (®), 200

Co mg (0), and 300 mgr (A) strength tramadol formulations (A,B,and C, respectively).

[00131] Figures 5: Mean steady-state plasma tramadol (®) and O-desmethyl - tramadol (O) concertrations (ng/ml) of 26 subjects dosed with the 200 mg tramadol, formulation B, and Steady-state plasma tramadol (A) and O-desmethy/l tramadol (LD) concentrations of 26 subjects dosed with Topalgic LP 100 mg BID.

DETAILED DESCRIPTION OF THE INVENTION :

CORE : :

[00132] The core of a tablet of the invention includes at least one active ingredient and a matrix, these components associated in such a'way that release of the pharmaceutical ingredient from the matrix is controlled. In a specific embodiment, the nmatrix of the core is a cross-linked high amylose starch known under the name Contramid®, and described most recently in U_S. Patent No.

6,607,74-8 (Lenaerts et al), which issued August 19, 2003. A preferred formulation in the context of this invention is provided in the specification of US. Patent No. 6,607,748. : © [00133] Preferably, the core is formed by admixing the ingredie nts (in granular or powd er form) and then compressing the mixture to form the core over which the coat is subsequently formed. The weight of the core can be any pesrcentage of the weight of the total composition between 10% and 80%. The preferred percentage dependss, upon other things, the total dosage of the pharmaceutic-al agent. Ina particular embodiment described further below, a tablet contains 100 mg tramadol hydrochloride and the core is about 26% of the total weight of the talblet. In another embodimment, a tablet contains 200 mg tramadol hydrochloride and -the core makes up about 33% of the total weight of the tablet. In yet another emboediment, a tablet containss 300 mg tramadol hydrochloride, and the core contributes 33% to the total - weight «of the tablet.

Active Agent in the Core : Ce oo [00134] An active pharmaceutical ingredient is present in thhe core of the composition of the present invention. A suitable pharmaceutical imigredient of the presenk invention is any such ingredient that is desired to be delivered: in a. sustain ed-release dosage form. A comprehensive list of suitable pharmaceutical agents can be found in The Merck Index, 42" Ed. Preferably, the pharmaceutical ingredient is, but not limited to, isonicotinic acid hydrazide, so dium salicylate, pseudoephedrine hydrochloride, pseudoephedrine sulfate, ace=taminophen or dicloferac sodium, verapamil, glipizide, nifedipine, felodipine, betahmistine, albuterol, acrivasstine, omeprazole, misoprostol, tramadol®, oxybutynim, trimebutine, ciprofloxacin, and salts thereof. In addition, the pharmaceutical agent can be an : antifun gal agent, such as ketoconazole, or an analgesic agent such as acetylsalicylic acid, acetaminophen, paracetamol, ibuprofen, ketoprofen, indomethacin, diflunisal, naproxen, ketorolac, diclofenac, toimetin, sulindac, phenacetin, piroxicam, mefarmanic acid, dextromethorphan, other non-steroidal anti-inflaammatory drugs including salicylates, pharmaceutically acceptable salts thereof or rmixtures thereof.

Pro-drugs are part of the invention.

100135] The solubility of the pharmaceutical agent ir aqueous solution can be a wide variety of values. The aqueous solubility of the pharmaceutical agent can be less tham 10° g/L, more than 10° g/L, more than 10° g/L, more than 10" gL, more than 1 g/L, more than 10 g/L, more than 100 g/L, more than 500 g/L, more than 8 1000 g/E_, or more than 2000 g/L. Preferably, the solu bility is more than 100 g/L.

More preferably, the solubility is more than 500 g/L. Most preferably, the solubility is more than 1000 gL. [001363 The pharmaceutical agent can meet a variety of dosage requirement.

For exaample, the dosage requirement of the pharmaceutical agent can be less than 1 mg/dos age unit, more than 1 mg/dosage unit, more than 10 mg/dosage unit, more than 100 mg/dosage unit, more than 200 mg/dosage unit, more than 300 mg/dosage unit, 'm ore than 400 mg/dosage unit, more than 500 mg/dosage unit, or more than 1000 nmg/dosage unit. Preferably, the pharmaceutical agent” is more than : 50 mg/«dosage unit. More preferably, the pharmaceutical agent is 100 mg/dosage : 16 unit, oe more, e.g. 150 mg/dosage unit, or 200 mg/dosage unit, or 250 mg/dosage unit, or 300 mg/dosage unit, or more. Co

[001377] Particular embodiments include a «ore containing tramadol hydrochloride in which the core. contains between about 10% and 90% of the total tramadlol present in the tablet, e.g. about 45 mg of a 10-0 mg strength tablet (45% of the tablet total), or about 90 of a 200 mg strength tablet (45% of the tablet total), or about ~151 mg of a 300 mg strength tablet (50% of the tablet total).

Matrix of the Core ol

[001388] The release from the formulation of an actlive pharmaceutical ingredient located in the core is slower than the release of an active pharmaceutical ingredient located in the matrix of the coat. A preferred matrix of the core Is cross-linked high amylosse starch, known under the name Contramid® and described in U.S. Patent No. 6,607,748. In particular embodiments, the matrix makes up between about 10% and about 90% by weight of the core le., the ratio of the matrix of the core to the active ingredient of the core (w/w) is between about 0.1 and alwout 10, or between about 0.2 and about 9, or between about 0.2 and about 8, or between about 0.3 and about 7, or between about 0.4 and about 6, or between about 0.5 ard about 5, or between about

WYO 2004/038428 PCT/CA2003/001637 0.6 and about 4, or between about 0.7 and about 4 or betwee n about 1 and about 4, or between about 1 and about 3 and about 1.5 and about 2.5. In one particular embodiment, the core totals about 90 mg, of which about 44 mg is Contramid®, and 45 mg is tramadol hydrochloride. In this case, Contramid® trmus makes up about 49 weight percent of the core.} :

Optional Components .

[00139] The core composition of the present invention ranay optionally include a pharmaceutically acceptable carrier or vehicle. Such carriers or vehicles are known to .those skilled In the art and are found, for exanmple, In Remingtons's

Pharmaceutical Sciences, 14™ Ed. (1970). Examples of suach carriers or vehicles include lactose, starch, dicalicium phosphate, calcium suifat-e, kaolin, mannitol and powdered sugar. Additionally, when required, suitable binders, lubricants, and disintegrating agents can be included. If desired, dyes, ass well as sweetening or flavoring agents can be included.

[00140] The core composition of the present invention may optionally include . accessory Ingredients including, but not limited to dispesrsing agents such as microcrystalline cellulose, starch, cross-linked starch, cross-linked poly(vinyl pyrrolidone), and sodium carboxymethyl! cellulose; flavoring &gents; coloring agents; binders; preservatives; surfactants and the like. i

[00141] The core can, optionally, also include one or more suitable binders known to one of ordinary skilled In the art.

[00142] “Suitable forms of microcrystalline cellulose, for -example, MCC-PH101,

MCC-102, MCC-105, etc. a. [00143] | Suitable lubricants, such as those known to the skilled person, may also be included. For example, magnesium stearate, vegetable oll, talc, sodium-stearyl fumarate, calcium stearate, stearic acid, etc. }

[00144] Suitable glidants, known in the art, may also bes included. Examples of such glidants include, but are not limited to talc, colloidal silicon dioxide, etc.

Proportion

-[00145]) The active agent is present at lewels ranging from about 1 to about 90 Wt.% of the total weight of the core, preferably from about 10 to about 70 wt.% of the total composition of the core, more preferably from about 20 to about 80 wt.% of the total composition of the core, and probably rreost often between about: 30 to about 50wt.% of the total composition of the core.

[00146] Of course, the total amount of all components is 100 wt.%, and those of ordinary skill in the art can vary the amounts within the stated ranges to achieve useful compositions.

COAT i.

[00147] The coat of the dosage form includes a physical mixture of polyvinyl acetate and polyvinylpyrrolidone and the actives pharmaceutical ingredient(s) of the coat The coat can also include a cross-linked high amylose: starch, e.g.

Contramid®, and other optional components. Ins a preferred embodiment, the coat is formed by dry compression. The weight of the coat can be any percentage of the weight of the total composition between about 1 0% and about 90%, but is preferably } in the higher part of this range. The coat thus usually makes up between about 20% Co to about 90%, (w/w) of a tablet of the invention, or about 25% to about 90%, or about 30% to about 85%, or about 35 % to about 85%, or about 40% to about 85%, or. about 45% to about 85%, or ‘about 45% to about 80%, or about 50% to about 90% or 2» about 50% to about 85 %, or about 55% to about 90%, or about 55% to about 85%, or about 55% to about 80%, or about 60% to ab out 90%, or about 60% to about 85%, or about 60% to about 80%, or about 60% to ab out 75%, or about 65% to about 90%, or about 65% to about 85%, or about 65% to ab out 80%, or about 65% to about 75%, or about 65% or about 70% or about 75%.

The coat often includes an optional binding agent.

Polyvinyl Acetate and Polyvinylpyrrolidone of the Coat

[00148] The weight percentage of the polyvinyl acetate/polyvinylpyrrolidone mixture in the coat can be anywhere within a wide range of values. Depending on the solubility in water of the active ingredient in the coat, the amount of the polyvinyl acetate/polyvinylpyrrolidone mixture in the coat can be adjusted. United States

Patent Publication No.. 2001/0038852 describes weays in which such adjustments can be made.. For example, for active ingredients that are soluble to extremely soluble In water, polyvinyl acetate/polyvinylpyrrolidone mixture can be about 20 to about . 80 WL% of the coat, preferably about 30 to abowut 65 wi.%, or about 40 to about 55wi%. In a particular embodiment described below, Kollidon™ SR makes up : about 45% by weight of a coat that is about 31% by weight tramadol! hydrochloride and about 23% xanthan gum. For active ingred ients that are sparingly soluble to slightly soluble in water, the amount of polyvinyl aacetate/polyvinylpyrrolidone mixture is often lower, as described in United States Patent Publication No. 2001/0038852.

[00149] The weight ratio of polyvinyl acetate to polyvinylpyrrolidone in the polyvinyl acstate/polyvinylpyrrolidone mixture can be a wide range of values.

Preferably, such ratio is between about 6:4 and ©:1; more likely between about 7:3 and 6:1, even more preferably about 8:2. : [00150]} The molecular weight of the polyvinyl acetate component in the polyvinyl acetate/polyvinyipyrrolidone mixture ce&an be a wide range of values.

Preferably, the average molecular weight of the polyvinyl acetate is about 100 to : about 10,000,000; or about 1,000 to about 1,0030,000; or about 10,000 to about 1,000,000; or about 100,000 to about 1,000,000; ow about 450,000.

[00151] The molecular weight of the polywinyipyrrolidone component. in the polyvinyl acetate/polyvinylpyrrolidone mixture can be a wide range of values. The average molecular weight of the polyvinylpyrrolidome can be from about 100 to about 10,000,000; or about 1,000 to about 1,000,000; ow about 5,000 to about 500,000; or about 10,000 to about 100,000; or about 50,000.

[00152] The polyvinyl acetate and polyvinylpyyrrolidone mixture can be prepared by a variety of processes including simply mixing F2owders of polyvinylpyrrolidone and polyvinyl acetate. In a preferred embodiment, sucsh mixture is spray dried powder of a colloidal dispersion of polyvinyl- acetate zand polyvinyipyrrolidone solution.

Optionally, sodium lauryl sulfate is used as a stabilizer in order to prevent agglomeration during spray drying process and/or colloidal silica is used to improve the flow properties of the polyvinyl acetate/polyvirylpyrrolidone mixture. Optionally, -

polyvinyl acetate and polyvinylpyrrolidone can be formed in a random or a block copolymer. A Co.

Optional Components : I

[00153] Suitable binding agents For the present invention include, but are not limited to, plant extracts, gums, synthetic or natural polysaccharides, polypeptides, alginates, synthetic polymers, or a mixture thereof. Co ) {o0154) Suitable plant extracts to be used as gelling agents include, but are not . limited to, agar, ispaghula, psyllium, cycionia, ceratonia or a mixture thereof. -

[00155] Suitable gums to be used as gelling agents include, but are not limited to, xanthan gum, guar gum, acacia gusm, ghatti gum, karaya gum, tragacanth gum or a mixture thereof. CL © [00156] Sultable synthetics or natural hydrophilic polysaccharides to be used as gelling agents include, but are not limited to, hydroxyalkylcelluloses, cellulose ethers, cellulose esters, nitrocelluloses, dextrin, agar, carrageenan, pectin, furcellaran, starch or starch derivatives, cross-linked high amylose starch, or a mixture thereof.

[00157] Suitable polypeptides to be used as gelling agents include, but-are not limited to, gelatin, collagen, polygeline ©r a mixture thereof. Co

[00158] Suitable alginates to be used as gelling agents include, but are not limited to, alginic acid, propylene glycol alginate, sodium alginate or a mixture thereof.

[00158] Suitable synthetic polymers to be used as gelling agents include, but are not limited to, carboxyvinyl polymer, polyvinyl alcohol, polyvinyl pyrrolidone, polyethelene oxide, polyethylene glycols, copolymers of ethylene oxide and propylene oxide and their copolymers or a mixture thereof.

[00160] - In a preferred embodimemt, the gelling agent is a gum such as xanthan gum, guar gum, acacia gum, ghatti gum, karaya gum, tragacanth gum or a mixture thereof, PEO 7,000,000 and HPMC K1Q0 M. [o0161] In a most preferred embo diment, the gelling agent is xanthan gum.

Active agent of the Coat

[00162] A suitable active pharmaceutical ingredient of the present invention is any active agent that it Is desired to be delfvered in a sustained-release dosage form. )

A comprehensive list of suitable pharmaceutical agents can be found in The Merck

Index, 12" Ed. Preferably, the pharmaceutical agent Is, but not limited to, isonicotinic acid hydrazide, sodium salicylate, pseudoephedrine hydrochloride, pseudoephedrine sulfate, acetaminophen or diclofenac ssodium, verapamil, glipizide, nifedipine, felodipine, betahistine, albuterol, acrivastine, omeprazole, misoprostol, tramadol®, oxybutynin, trimebutine, ciprofloxacin, and salts thereof. In addition, the phammaceutical agent can be an antifurmgal agent, such as ketoconazole, or an analgesic agent such as acetylsalicylic aci«d, acetaminophen, paracetamol, ibuprofen, ketoprofen, Indomethacin, diflunisal, nexproxen, ketorolac, diclofenac, tolmetin, sulindac, phenacetin, piroxicam, mefsamanic acid, dextromethorphan, other non-steroidal anti-inflammatory drugs including salicylates, pharmaceutically . acceptable salts thereof or mixtures therecsf. (00163) The solubility of the pharmaceutical agent In aqueous solution can be a : wide variety of values. The aqueous sol ubility of the pharmaceutical agent can be ‘less than 102 g/L, more than 10° g/L, more than 102 g/L, more than 10” g/L, more than 1 g/L, more than 10 g/L, more tham 100 g/L, more than 500 g/L, more than 1000 g/L, or more than 2000 g/L. Preferably, the solubility is more than 100 g/L.

More preferably, the solubility is more tharm 500 gl. or even 1000 g/L.

[00164] The pharmaceutical agent can meet a variety of dosage requirements.

For example, the dosage requirement of <the pharmaceutical agent can be less than 1 mg/dosage unit, more than 1 mg/dosagee unit, more than 10 mg/dosage unit, more than 100 mg/dosage unit, more than 200 ang/dosage unit, more than 300 mg/dosage : unit, more than 400 mg/dosage unit, mowe than 500 mg/dosage unit, or more than 1000 mg/dosage unit. Preferably, th-e pharmaceutical agent is more than 50 mg/dosage unit. More preferably, the pharmaceutical agent is more than 100 mg/dosage unit. Most preferably, the pharmaceutical agent is more than 200 mg/dosage unit.

[c0165] The coat can be between about 5% and about 90% by weight active } pharmaceutical ingredient, or betvweéen about 5% and about 80% by weight api, or between about 10% and about 702% by weight api, or between about 10% and about 60% by weight api, or between abeut 15% and about 50% by weight ap; of between about 15% and about 45% by wei-ght api, or between about 15% and about 40% by weight api, or between about 20% and about 35% by weight api, or between about 20% and about 30% by weight api. - [00166} In particular embodiments, described further below, the weight of tramadol from a 100 mg tramadol tablet is about 21% by weight of the coat. The weight of tramadol from a 200 m g tablet is about 31 % by weight of the coat. The weight of tramadol from a 300 mg tablet is about 30% by weight of the coat.

ROUTES OF ADMINISTRATION oo ~ [00167] The tablet composition of the present invention can be administered through, but not limited to, a number of routes such as oral, sublingual, and rectal. 156 The preferred route of administration of the compositions of the present invention is oral. a

[00168] Compositions of the present invention that are suitable. for oral administration may be presented as discrete units such as tablets or granules.

Preferably, the compositions of the present invention are presented in a tablet form.

Such tablets may be conventionallly formed by compression or molding. Compressed tablets may be prepared by compressing in a suitable machine the mixture of one or more components described abosve. Molded tablets may be made by molding in a suitable machine the above components, which can be optionally moisteried with an inert liquid diluent. The tablets may optionally be coated and/or have other identifying indicia visible to the consumer. A tablet can also be in a variety of forms, e.g., uncoated , dry coated, or filun coated, etc. A tablet can also be in a variety of shapes (e.g., oval, sphere, etc.) and sizes. A comprehensive discussion of tablets can be found in references such as The Theory and Practice of Industrial Pharmacy by Lachman et al., 3° Ed. (Lea & Febiger, 1986).

Dissolution Profile of Sustaineci-Release Composition : 36 | oo

[00169] The active agent of the composition exhibits the following in vitro dissolution profile when measured with a USP Type | apparatus in 50 mM phosphate, pH 6.8, and stirring between 50 and 150 rpm: ;

[00170] an average rate of between 10% a nd 30% per hour of the agent is "5 released between 0 and 2 hours when tested in vitro using a USP Type | apparatus in 50 mM phosphate, pH 6.8, and stirring between 50 and 150 rpm; or E

[00171] between 10% and 40% of the agermt is released from the formulation between 0 and about 2 hours of measurement, bestween about 30% and 60% of the agent is released from the formulation betweesn 2 and about 7 hours of the measurement, between about 50% and 80% of the agent is released from the formulation between 7 and about 12 hours of meassurement, and between about 80% and 100% of the agent is released from the fosrmulation after about 20 hours of measurement; or more preferably

[00172] between 15% and 35% of the agernt is released from the formulation between at 2 hours of measurement, between albout 40% and 60% of the agent is released from the formulation between at 7 homurs of the measurement, between about 60% and 80% of the agent is released from the formulation at 12 hours of measurement, and between about 85% and 100%% of the agent is released from the formulation after about 20 hours of measurement, or :

[00173] between 20% and 40% of the agemnt is released from the formulation between at 2 hours of measurement, between about 40% and 60% of the agent is released from the formulation between at 7 ho urs of the measurement, between about 60% and 80% of the agent is released frrom the formulation at 12 hours of measurement, and between about 85% and 100=4 of the agent is released from the formulation after about 20 hours of measurement.

[00174] The present invention will be mores readily understood by referring to the following examples which are given to illustrate the invention rather than to limit its scope.

EXAMPLES -

[00175] The cross-linked high amylose starch used in the these examples Is made by a process comprising the ‘steps of crosslinking and chemically madifying, followed by gelatinization and drying. Such process is described in more detail in

U.S. Patent No. 6,607,748 (Lenaerts et al), which issued August 18; 2003, and known in the marketplace under the name Contramid®. and described in Examples and Il. _

Example | :

A. Cross-Linking :

[00176] High amylose starch (30.0 kg) containing about 70% w/w of amylose (Cl AmyloGel 03003) is placed in a reactor. To this reactor is added water (55.0 1) containing sodium hydroxide (30.0 g) and sodium sulfate (2.40 kg). The resulting slurry is heated to a temperature of 30°C. Phosphorus oxychloride (22.5 g) is added . to the reaction mixture which is reacted for one hour. \ :

B. Chemical Modification, Hydroxyproylation ’

[00177] The crude reaction mixture from Part A is transferred into a hydroxypropylation reactor. The reaction mixture is heated to 40°C. over 30 minutes and the reaction is purged with nitrogen. After a full purge, propylene oxide (1.80 kg) is added. The reaction mixture is kept at 40°C. for 20 hours. The reaction mixture is neutralized with 0.1N H.SO, (1:2 v/v) to a pH of 5.5. The starch slurry is washed with a basket-centrifuge at a speed of 1200 rpm. The obtained starch cake is re-sturrified

In 35 | of water and centrifuged a second time. The resulting starch cake is dried In a . flash dryer at an inlet temperature of 160°C. and an outlet temperature of 60°C.

C. Gelatinization

[00178] The modified granular starch cake Is diluted in demineralized water in order to form a slurry at a concentration of about 8% calculated on dry substance.

The resulting slurry has a relative density of 1.032 kg/l compared to water. The pH of the modified starch slurry is adjusted to 6.0. The slurry is then heated to 160°C. by direct steam injection (Schlick Model 825). The temperature variation is not higher than *1°C. The sluny is held in a holding column for a period of 4 minutes at a temperature of 160°C. and a pressure of about 5.5 bar. The pressure is then reduced to atmospheric by passin g through a flash. The slurry is then contained at 95°C. in a hold tank. .

D. Spray-Drying . . | :

[00179] The drying of the sluny from Part C is carried out using a Niro FSD 4 ‘5 spray-drying tower equipped with a 0.8 mm nozzle and fed at 10 Vhour. The: inlet temperature is fixed at 300°C. ard the outlet temperature of 120°C. The obtained powder is a controlled release exclipient with the following properties: . —————————————————————aae A ———————— reise ee err ee erm } - Properties ..

Moisture Content . 4.5% : Co “Bulk Density : 150 g/l : ~ Packed Density 210 gh . pH 5.4

Particle Size Peak Value - 50 um (Laser Particle Sizer-SSympatec) teeter eee een eee ete ee eee? :

Example ll :

A. Cross-Linking

[00180] "High amylose starc h (30.0 kg) containing about 70% w/w of anweylose (Cl AmyloGel 03003) is placed ir a reactor. To this reactor is added water (55.01) containing sodium hydroxide (30.0 g) and sodium sulfate (2.40 kg). The resulting slurry is heated to a temperature of 30°C. Sodium trimetaphosphate (45 g) is aadded to the reaction mixture which is re=acted for one hour.

B. Chemical Modification, Hydwoxyproylation

[00181] The crude reaction mixture from Part A is transferred rato a hydroxypropylation reactor. The reaction mixture is heated to 40°C. over 30 mimutes and the reactio n is purged with nitrogen. After a full purge, propylene oxide 1.80 kg) is added. The reaction mixture is kept at 40°C. for 20 hours. The reaction mixture is neutralized with 0.1N H.S04 (1:2 viv) to a pH of 5.5. The starch slurry is wasshed with a basket-centri fuge at a speed of 1200 rpm. The obtained starch cake is re—slurrified in 351 of water and centrifuged a second time. The resulting starch cake Is ciried ina flash dryer at an inlet temperature of 160°C. and an outlet temperature of 60° C.

C. Gelatinization

[00182] The modified granular starch cake is diluted in demineralized water in order to form a slurry at a concentration of about 8% calculated on dry swabstancs.

The resulting Slurry has a relative density of 1.032 kg/l compared to water. T he pH of the modified starch slurry is adjusted to 6.0. The slurry is the heated to 1 60°C. by direct steam imjection (Schlick Model 825). The temperature variation is n-ot higher than £1°C. T he slurry is held in a holding column for a period of 4 minustes at a - temperature of 160°C. and a pressure of about 5.5 bar. The pressure is then reduced to atrmospheric by passing through a flash. The slurry is then cormtained at 95°C. in a hold tank.

D. Spray-Dryiing :

[00183] ~The slurry from Part C is carried out using a Niro FSD 4 spraay-drying tower equipped with a 0.8 mm nozzle and fed at 10 Vhour. The inlet temperature is fixed at 300°C. and the outlet temperature of 120°C. The obtained powder is a controlled relerase excipient with the following properties:

Properties CL -

Moisture Content 5.2%

Bulk Density ~ 103gN So

Packed Density 155 gl pH 5.83

Particle Size Peak Value | 70 um ee

Properties « iN ret tet ent een St . ( Laser Particle Sizer-Sympatec) Co -—

[00184] Lubritab® Is a product sold by Penwest Pharmaceuticals Co. (Cedar

Rapids, IA, USA). Kolidon™ SR is a product producecd by BASF (Germany).

Encompress '™ is a dicalcium phosphate dihydrate which can be purchased from

Mendell (Patterson, NY). Tramadol hydrochloride can be osbtained from Chemagls

Ltd., 3 Hasknlosha Street, P.O. Box 9091, 61090, Tel Aviv, Israel. Methods of synthesis amd purification of tramadol are described in, for example, U.S. Patent

Nos., 3,652,589, 5,414,129, 5,672,755, 5,874,620, 5,877,351. and 6,169,205.

Manufacturing Procedure : - [00185] Tablets of the invention can be manufactured according to the process set out gene rally in the flow chart of Figure 1, and described ir more detail below.

[00186] Weighing: Raw materials are dispensed into clearly labeled containers.

[00187] Core Pre-Blend: Blend a portion of the Coeniramid® and Colloidal 16 Silicon Dioxide and pass through #30 mesh screen into a suitable container. :

[00188] Core Blend: Place a portion of the Contramidl® into a blender. Pass

Tramadol H-ydrochloride through a #30 mesh screen and add to blender. Rinse container with a portion of Contramid® and add to blender. Sieve Hydrogenated

Vegetable Oil Type | through a #30 mesh screen and add to the blender. Add the

Core Pre-Bleend into the blender. Add the remaining Contramid® into the blender, and blend al 1 ingredients. Sieve the Magnesium Stearate through a #30 mesh screen and add blend with other ingredients. Dispense blend in suitable container and identify as Core Blend.

[00189] Dry Coated Pre-Blend: Blend a portion of the Xanthan Gum and all of the Colloidal Silicon Dioxide and pass through #30 mesh screen.

WE 2004/038428 PC'I/CA2003/001637 [©0190] Dry Coated Blend: Place a portion of the Kollidon® S:R into a blender.

P ass Tramadol Hydrochloride through Kason Separator with a #30 rnesh screen into switable container and add to blender. Rinse container with remaining xanthan gum and add to blender. Sieve Hydrogenated Vegetable Oil Type 1 through a #30 mesh screen and add to the blender. Place Diy Coated Pre-Blend and “the remainder of the Kollidon® SR into the blender, and blend with all ingredieants. Sieve the rnagnesium stearate through a #30 mesh screen and biend with Other ingredients.

Dispense granulation in suitable container and identify as Dry Coated Blend. [o0191] - Compression: ‘Use a Manesty Dry-Cota press to produce compression-coated tablets.

Example 1 00192]. ~ Formulations A, B, and C, as shown in Table 3, were ‘manufactured . @&ccording to the process set out above. :

T/CA2003/001637

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[00193] Dissolution profiles of formulations A, B =and C are shown in Figure 2.

BIOAVAILABILITY

SINGLE ADMINISTRATION

Example 2

The plasma pharmacokinetic profile of tramadol and its principal metabolite, O- desmethyltramadol, after a single oral administration of 200 mg, (formulation B) was determined in comparison to a currently available 100 mg formulation, Topalgic® administered two times a day, and after a double dose administration of 200 mg, (formulation B) was determined in comparison tos a currently available 200 mg formulation, Topalgic® administered two times a day . The study was an open, single dose, randomized, three-way cross-over design with at least a 7 day wash-out period between each administration. Results are shown in Figures 3(a) and 3(b).

Example 3

[00194] The plasma pharmacokinetic profile of tramadol and its principal metabolite, O-desmethyltramadol, after a single ora | administration of 100, 200 and 300 mg, formulations A, B and C, respectively, wass determined. The study was an open, single dose, randomized, three-way cross-ower design with at least a 7 day wash-out period between each administration. Re-sults are shown in Figures 4(a) and 4(b).

[00195] A median time to tramadol peak plasma concentration (Tmax) Of between 2 and 8 hours and 2 mean peak tramaedol plasma concentration (Cmax) which is less than three times the mean plasma concentration obtained 24 hours after administration (Cz) Of a single dose of the scomposition was obtained. In a narrower sense, the peak tramadol plasma concentration (Cmax) obtained in each case is less than two times the plasma concen tration obtained 24 hours after administration (Caan) of a single dose of a compositiosn of the invention.

Example 4

Steady-State

[00196] The steady state plasma pharmacokinetic profile of tramadol and its principal metabolite, O-desmethyltramadciol, following daily administration of 200 mg, formulation B, was determined. The profile was obtained in an open-label, two- period crossover randomized study. Res ults obtained are shown in Figure 5.

[00197] The invention provides am oral tramadol pharmaceutical composition suitable for successive administration, once daily, comprising an effective amount of tramadol in vivo in a steady state In whi ch, during a given 24 hour period, a tramadol maximum plasma concentration (Cmax) Of between 2 and 3 times a tramadol minimum plasma concentration (Cin) 1S obtained. More particularly, an average Cmax of no greater than 350 ng/ml is achievable. Further, a plasma concentration of tramadol of less than 90 percent of Cmax for at least 18 hours of the 24 hour period can be achieved, on average.

[00198] The term “A is the apparent terminal elimination rate constant, determined by the slope of the regression during the log-linear phase.

[00199] The term “AUCq1may” IS th € mean area under the plasma concentration- time curve from time 0 to Tmax and is used as an indicator of the rate of drug absorption, or metabolite formation. It is calculated as the arithmetic mean of the area under the plasma concentration-time curve from time 0 to Tmax calculated for each individual participating in the bioavailability study.

[00200] The term "AUC." is the mean area under the plasma concentration- time curve extrapolated to infinity. It is calculated as the arithmetic mean of the area under the plasma concentration-time curve from time 0 extrapolated to infinity, for each individual participating in the bioavailability study.

[00201] The term “C'mac is the maximum observed plasma concentration, calculated as the mean of the individual maximum blood plasma concentrations.

[00202] The term “half-life” is the aapparent terminal elimination half-life.

[00203] The term “HVD” is the ha If value duration, that is, the time during which tramadol concentrations are above ones half the Cmax. This parameter is an indicator of the shape of the plasma concentration time curve, that is, the larger the value of

HVD, the better the controlled release.

[00204] The term “MRT” is the mean residence ti me, which is an estimate of the average time that a tramadol molecule resides in the body following oral administration.

[00205] The term “max” is the time at which Coax 3s achieved.

[00206] The term “Tmax ” is the time at which the maximum blood plasma concentration is observed for each individual participating in the bioavailability study.

[00207] The term “Rstart” is the time at which plasma concentrations begin to decline in a log-linear fashion, that is, the time at which either drug absorption or metabolite formation is complete.

[00208] Tramadol pharmacokinetic paramete rs of the controlled release composition are presented in Table 4, and O-desrmethyltramadol pharmacokinetic parameters of the controlled release composition are presented in Table 5.

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[00-209] The present invention is not limited im scope by the specific em bodiments disclosed in these examples which are inteanded to illustrate the most preferred embodiments of the invention. Indeed, various modifications of the inv ention or other embodiments which are functionally equivalent to those shown and described herein will become apparent to those skilled in the art and are intended to be covered by the appended claims. Further, although various examples of coxmbined elements of the invention have been described, it will also be understood that these are not intended to be exhaustive and features of one embodiment may be cosmbined with those of another, and such other combinations are contemplated to be within the scope of the invention disclosed herein.

[00210] A number of references have been cited, the entire disclosures of which ares incorporated herein by reference.

Claims (58)

1. A solid dosage formulation comprising: a core co mprising a pharmacological agent dispersed in a first controdlled- release matrix comprising cross-linked high amylose starch, from which ma=atrix release of the agesnt is relatively slow; and a coat forrmed over the core and comprising said agent dispersed in a second controlled-releases matrix from which release of the agent is relatively fast.

2. The formulatiosn of claim 1, wherein the coat and core comprise relative amoursts of the agent such that release of the agent from the formulation is biphasic.

3. The formulation of claim 1 or 2, wherein the agent is soluble in water, and the= first matrix is relatively hydrophilic relative to the second matrix.

4. The formulation of any of claims 1 to 3, wherein the agent is present im the formulation as arm ionic salt.

5. The formulation of claim 4, wherein the agent contains an amino group.

6. The formulati-on of claim 5, wherein the agent is present in the formulation as a hydrochloride sa.it.

"7. The formulati on of any of claims 2 to 6, wherein the rate of release of the agent from the coat iss at least twice the rate of release of the agent from the cor-e, or wherein the rates of release of the agent from the coat is at least three times thes rate of release of thes agent from the core, and preferably, wherein the rate of releamse of the agent from t he coat is up to fifteen times the rate of release of the agent frorm the core, or whereir the rate of release of the agent from the coat is up to twelve times the rate of relezase of the agent from the core, or wherein the rate of release of the agent from the oat is up to ten times the rate of release of the agent from the core, or wherein the rate of release of the agent from the coat is up to eight times thes rate of release of thes agent from the core, or wherein the rate of release of the agen& from the coat is up to six times the rate of release of the agent from the core, or wiherein the rate of release of the agent from the coat is about four times the rate of release of the agent from t he core.

8. The formulation of any preceding claim, wherein between 10% and 30% per hour of the agent is released between 0 and 2 hours when tested in vitro using a USP Type | apparatus in 50 mM phosphate, pH 6.8, and stirring betweera 50 and 150 rpm.

9. The formulation of any preceding claim, wherein between 104 and 40% of the agent is releasexd from the formulation between 0 and about 2 hours of measurement, between about 30% and 60% of the agent is released from the forrnulation between 2 and about 7 ho urs of the measurement, between about 50% and 80% of the agent is released from the formulation between 7 and about 12 hours of measurement, and between about 80% and 100% of the agent is released from trme formulation after about 20 hours of measurement.

10. The formulation of any preceding claim wherein the active agent is an analgesic.

11. The formulzation of claim 10, wherein the active agent is tramaclol.

12. The formulation of any preceding claim, wherein each of the agent is soluble in water at least to the extent of 1 g/L, or more than 10 g/L, or more than 100 g/L, or more than 500 g/L, or more than 1000 g/L, or more than 2000 g/L.

13. The formuBRation of any preceding claim, wherein the ratio of &he core to the coat (w/w) is between about 1 and about 0.1, or between about 0.9 and about 0.2, or between about 0.8 and about 0.2, or between about 0.7 and abeout 0.2, or between about 0.5 and -about 0.2, or between about 0.4 and about 0.2, or a®out 0.35.

14. The formu lation of any preceding claim, wherein the ratio of “the agent In core to . the agent in thme coat (w/w) is between about 0.1 and about 10, ow between about 0.1 and about 8, oer between about 0.2 and about 7, or between about 0.3 and about 6, or between about 0.4 and about 5, or between about 0.5 and about 4, or between about

0.6 and about 3, or between about 0.6 and about 2, or between about 0.6 and about

1.5, or between about 0.6 and about 1.3, or between about ©O.7 and about 1, or between about 0.7 and about 0.9 or about 0.8.

15. The formulation of any preceding claim wherein the core is between about 10% and about 90% by weight agent, or between about 20% and about 80%4 by weight agent, or between about 30% and about 70% by weight agent, or between about 40% and about 60% by weight agent, or about 50% by weight agent.

16. The formulation of any preceding claim, wherein the coat is betwee=n about 5% and about 90% by weight agent, or between about 5% and about 802% by weight agent, or ketween about 10% and about 70% by weight agent, or beftween about 10% and =mabout 60% by weight agent, or between about 15% and aboout 50% by weight ageant, or between about 15% and about 45% by weight agent, or between about 15% and about 40% by weight agent, or between about 20% ancd about 35% by weight aagent, or between about 20% and about 30% by weight agent.

17. The fo-rmulation of any preceding claim wherein the ratio of the matrix of the coat to the age-nt of the coat (w/w) is between about 0.1 and about 10, or between about

0.2 and about 9, or between about 0.2 and about 8, or between about 08.3 and about 7, or between about 0.4 and about 6, or between about 0.5 and about 5, or between about 0.6 and about 4, or between about 0.7 and about 4 or between about 1 and about 4, o r between about 1 and about 3 and about 1.5 and about 2.5.

18. The formulation of any of claims 1 to 13 wherein the ratio of the matrix of the core to the agent of the core (w/w) is between about 0.1 and about 10, or beetween about

0.2 and about 9, or between about 0.3 and about 7, or between about O.4 and about 8, or betwseen about 0.5 and about 5, or between about 0.5 and about <4, or between about 0.5 and about 3, or between about 0.6 and about 3, or between about 0.7 and about 2 o r between about 0.8 and about 1.5, or between about 0.9 and about 1.5, or between about 0.9 and about 1.3, or about 1, or is about 0.55.

19. The foomulation of any of claims 1 to 3, wherein the agent is solubole in water at room tem perature (about 21°C) to the extent of at least 0.5 gm per mL.

20. The formulation of any of claims 1 to 4, wherein the agent contains &n acid group, a base group or both an acid group and a base group, and the agent is present inthe form of a salt thereof.

21. The formulation of claim 21, wherein the agent contains a base grou p.

22. The formulation of any of claims 1 to 4, wherein the2 agent contains an ionizable group and said group is at least 90% ionized in gastric jut ces (0.1M HCI).

23. The formulation of any of claims 1 to 11 and 13 to 22, wherein the agent is selected from the group consisting of isonicotinic acid hydrazide, sodium salicylate, pseudoephedrine hydrochloride, pseudoephedrine sulfate, acetaminophen or diclofenac sodium, verapamil, glipizide, nifedipine, felosdipine, betahistine, albuterol, acrivastine, omeprazole, misoprostol, tramadol, oxybutynin, trimebutine, ciprofloxacin, and salts thereof. In addition, the pharmmaceutical agent can be an antifungal agent, such as ketoconazole, or an analgesics agent such as acetylsalicylic acid, acetaminophen, paracetamol, ibuprofen, ketopro¥en, indomethacin, diflunisal, naproxen, ketorolac, diclofenac, tolmetin, sulindac, phenacetin, piroxicam, mefamanic acid, dextromethorphan, other non-sterolidal anti-inflammatory drugs including salicylates, pharmaceutically acceptable salts thereof or mixtures thereof.

24. The formulation of any preceding claim, wheredin the core is prepared by compression.

25. The formulation of any preceding claim, where in the coat is prepared by compression.

26. The formulation of claim 25, wherein coat is co mpressed over a separately prepared said core.

27. The formulation of any preceding claim, wherein the coat comprises an admixture of polyvinyl acetate, polyvinylpyrrolidone.

28. The formulation of claim 27, wherein the ratfo of polyvinyl acetate and polyvinylpyrrolidone in the coat (w/w) is between about 6:4 and 9:1, or 7:3 and 9:2, or about 8:2.

29. The formulation of claim 27 or 28, wherein the coaat further comprises a binding agent.

30. The formulation of claim 29, wherein the binding age=nt is xanthan gum.

31. The fosrmulation of claim 30, wherein the formulation is a tablet, and wherein said cross-linkead high amylose starch comprises a chemically-modified, cross-linked high amylose s-tarch prepared by a method comprising: (a) cross-l inking high amylose starch, followed by (b) chemiczally modifying the cross-linked high amylose starch, follow-ed by “(c) gelatinsization, and (d) drying to obtain a powder of said controlled release excipient; wherein said cross-linked high amylose starch is characterized in that upon solubilization in 90% DMSO at 80°C. for about three days ancd gel permeation chromato graphy, the height of the peak corresponding to amylo:se in said cross- linked high amylose starch is at least 90% of that of the peak corresponding to amylose #in said high amylose starch prior to (a).

32. The —formulation of any preceding claim, wherein the core fumrther comprises a " jubricant; and wherein the lubricant is optionally hydrogenated vegetable oil.

33. The formulation of any preceding claim, wherein the coat furrther comprises a jubricant, and wherein the lubricant is optionally hydrogenated vege&able oll.

34. The formulation of any preceding claim, wherein the formulation is a tablet formulated for oral administration.

35. A solid dosage formulation comprising: a core comprising a pharmacological agent dispersed in a first controlled- release rmatrix from which release of the agent is relatively slow; anad a coat formed over the core and comprising said agent dispoersed in a second controlleed-release matrix, the second controlled-release matrix cormprising a physical mixture eof polyvinyl acetate and polyvinylpyrrolidone and from winich release of the agent is welatively fast.

36. A sollid dosage formulation comprising:

a core comprising a pharmacologica! agent dispersed in a first controlied- release matrix comprising cross-linked high amylose starch, from which matrix release of the agent is relatively slow; and a coat formed over the core and comprising a pharmacological agent ina second controlled-release matrix, the second controlled-release matrix comprising a physical mixture of polyvinyl acetate and polyvinyipyrrolidone, and wherein: release of the agent from the mairix of the core is relatively slow with respect to release of the agent from the matrix of the coat.

37. A solid dosage formulation comprising: a core comprising a pharmacological agent in a first controlled-release matrix; and a coat formed over the core and comprising a pharmacological agent in a second controlled-release matrix, the secorad controlled-release matrix comprising a physical mixture of polyvinyl acetate and polyvinylpyrrolidone, and wherein: release of the agent from the matrix of the core is relatively slow with respect to release of the agent from the matrix of thes coat.

38. A solid dosage formulation comprising a pharmacological agent for release thereof over an extended period of time, the formulation comprising: a core comprising agent in a first controlled-release release matrix, the controlled-release matrix comprising cross-limked high amylose starch; and a coat formed over the core and comprising the agent in a second controlled- release matrix, the second controlled-releas.e matrix comprising a physical mixture of polyvinyl acetate and polyvinylpyrrolidone, amd wherein: the agent is present in the core suffficient to obtain release into an aqueous environment, e.g. gastric juices, of no nnore than 50% of the agent from the formulation within one quarter of the period.

30. The formulation of claim 38, wherein the period is betwee about 12 and about 24 hours, and between about 30% and about 70% of the agent iss in the core.

40. T he formulation of any of claims 36 to 39, wherein each off the agent in the first matriix and the agent in the second matrix is soluble in water at | east to the extent of 1 g/L, wor more than 10 g/L, or more than 100 g/L, or more than £500 g/L, or more than 10008 g/L, or more than 2000 g/L.

41. T he formulation of any of claims 36 to 40, wherein the agent: is an analgesic.

42. A controlled released tablet comprising: a compressed core comprising cross-linked high armylose starch having tram.adol, or a salt thereof, embedded therein; and a coat formed over the core by compression, and comprising a physical mixtwure of polyvinyl acetate, polyvinyipyrrolidone, a binder, tram adol; and wherein: the ratio of the core/coat (w/w) is between about 0.2 and 0.6; the ratio of the tramadol in the core to the tramadol im the coat is between : about 0.7 and about 1; the ratio of polyvinyl acetate/polyvinylpyrrolidne (w/w) is between about 6:4 and 9:1; and the rate of release of tramadol from the coat matrix is att least twice the rate of rele=ase of tramadol from the core when measured by a USP “Type | apparatus in 50 mM phosphate, pH 6.8, and between 50 and 150 rpm.

43. A method of manufacturing a controlled-release medication, the method comprising: 0] blending a pharmacological agent and a first matrix material comprising a cross-linked high amylose starch; (ii) forming the resultant blend of step (i) into a core;

(ii) blending a pharmacological agent and a second matrix material comprising 2 relatively fast release material with respect to the first matrix material; (v) forming the resultant blend of step (iii) as a coat orto the exterior of the core.

44. A method of manufacturing a controlled-releasse medication, the method comprising: ()] blending a pharmacological agent and a first matriix material; (ii) forming the resultant blend of step (i) into a core; (iii) blending a pharmacological agent and a second matrix material, the second matrix material comprising a physical mixture of polyvinyl acetate and polyvinylpyrrolidone and being a relatively fast release material with respect to the first matrix material, (iv) forming the resultant blend of step (iii) as a coat osnto the exterior of the core.

45. The method of claim 43 or 44, wherein step (ii) comprises compressing the resultant blend of step (i).

46. The method of claim 43, 44 or 45, wherein step (ill) comprises compressing the resultant blend of step (iii) onto the exterior of the core.

47. The method of any of claim 43 to 46, wherein the agent in the core and the coat is tramadol, the total amount of tramadol in the med cation is effective as a daily dosage, and wherein the medication comprises a fo rmulation, as appropriate as defined, in any of claims 1 to 42.

48. An oral tramadol pharmaceutical compositiom suitable for once daily administration comprising an effective amount of trammadol or a pharmaceutically acceptable salt thereof providing after a single adminis=tration in vivo, a median time to tramadol peak plasma concentration (Tmax) betweer 2 and 8 hours and a mean peak tramadol plasma concentrations (Cmax) Which a re less than three times the mean plasma concentration obtained 24 hours after administration (C2an) of a single dose of such composition.

49. The ceomposition of claim 48, wherein said mean peak tramadol plasma concentrations (Cmax) are less than two times the mean plasm a concentration obtained 24- hours after administration (Caan) of a single dose of such ecomposition. :

50. An oral tramadol pharmaceutical composition suitable for successive administrati on, once daily, comprising an effective amount of tramadol or a pharmaceutically acceptable salt thereof providing in vivo a steady state in which, during a gi ven 24 hour period, a tramadol maximum mean plasma concentration (Cmax) Of bestween 2 and 3 times a tramadol minimum mean plasnma concentration (Cmin) is obtained.

51. The coemposition of claim 50, wherein said mean Cmax is NO greater than 350 ng/ml.

52. The cormposition of claim 51, wherein the mean plasma concentration of tramadol is less than 90 percent of Cpa for at least 18 hours of a said 24 hour gperiod.

53. The ceomposition of any of claims 48 to 52, comprising a formulation, as appropriate , of any of claims 1 to 42.

54. A solid sdosage formulation comprising: a coere comprising a pharmacological agent dispersed in a_ first controlled- release maftrix comprising cross-linked high amylose starch; and a co=at formed over the core and comprising said agent dispersed in a second controlled-reelease matrix, different from the first such that release o-f the agent from the formula-tion is biphasic.

55. A solid edosage formulation comprising: . a coere comprising a pharmacological agent dispersed in a first controlled- release matrix; and a coaat formed over the core and comprising said agent dispersed in a second controlled-reelease matrix comprising a physical mixture of polyvinyl acetate and polyvinylpyr-rolidone such that release of the agent from the formulation is biphasic.

586. A solid dlosage formulation comprising: a core comprising a pharmacological agent dispersed in a «controlled-release matrix comprising a cross-linked high amylose starch; and a coat formed over the core and comprising a pharmacol ogical agent in a second controlled-release matrix comprising a physical mixture of polyvinyl acetate and polyvinysipyrrolidone.

57. A solid dosage formulation comprising: a core comprising about 50 mg, or about 75 mg or about 100 mg or about 125 mg or about 150 mg or about 175 mg or about 200 mg or about 2255 mg or about 250 mg or about 275 mg or about 300 mg or about 325 mg or about 35@ mg or about 375 mg or about 400 mg tramadol dispersed in a controlled-release m afrix comprising a cross-linked high amylose starch; and a coat formed over the core and comprising a pharmaco logical agent in a second con trolled-release matrix comprising a physical mixture off polyvinyl acetate and polyvinylpyrrolidone.

58. Use of a composition of any preceding claim in the preparation of a medicament.