US006143328A Ulllted States Patent   Patent Number: Hea?eld et al.   6,143,328 Date of Patent: SUSTAINEI) RELEASE COMPOSITIONS AND A METHOD OF PREPARING 3,634,584 3,845,770 PHARMACEUTICAL COMPOSITIONS 3,870,790 3,916,889 Inventors: John Joanne Kn0tt> Hea?eld, Bishop’s Fenstanton; Stortford; Trevor *Nov. 7, 2000 1/1972 Poole ...................................... .. 424/21 11/1974 Theeuwes et al . 128/260 3/1975 LoWey et al. 11/1975 ..... .. 424/19 Russell ......... .. .. 128/1458 (List continued Theeuwes on et next al. page.) ................. .. Stewart Thomas Leslie, Cambridge; Sandra Therese Antoinette FOREIGN PATENT DOCUMENTS Malkowska> Ely’ an of Unite? 9047732 7/1990 Australia . Klngdom; Ronald Brown Mlller, Basel, Switzerland; Derek Allan 9341654 2082573 2/1995 5/1993 Prater, Milton; Kevin John Smith, _ Histon, both of United Kingdom Australia . Canada _ _ (L15t Connnued on next page)  Assignee: Euro-Celtique, S.A., Petrusse, OTHER PUBLICATIONS Luxembourg Abraham Sunshine, et al., “Analgesic or al ef?cacy of tramadol hydrochlorine in postoperative pain”, Clin. Phar mam] The“ Jun' 1992, pp 74()_746_ E. Beubler, “Medikamentose SchmerZtherapie: Kriterien, [*] Notice: This patent is subject to a terminal dis- Clalmer- Moglichkeiten, Risken”, Therapiewoche Osterreich, 7, 2  APPL NO-I 09/264,399 (1992), pp. 90—96 With English Translation.  Filed, N. YokokaWa, et'al., “Relationship DCIWG'GII plasma concen Man 8’ 1999 tration of morphine and analgesic effectiveness”, Postgraa' Med J» (1991) 67 (Suppl 2), PP- 550—554~ Related US. Application Data  Continuation of application No. 08/843,571, Apr. 18, 1997, Pat. No. 5,879,705, which is a continuation of application No. 08/269,208, Jun. 30, 1994, abandoned.  Jul. 27, 1993 [GB] "mary - J M S x“m‘”e’_ @165 ' ,Pear _ LLC United Kingdom ................. .. 9315467 Mal 1: 1994 [GB] E Attorney, Agent, or Fzrm—Davldson, Davidson & Kappel, Foreign Application Priority Data Nov. 23, 1993 [GB] (Llst Connnued on next page) P - United Kingdom 9324045 United Kingdom  ABSTRACT 9403922 Sustained release pharmaceutical formulations containing United Kingdom ................. .. 9404928 morphine, or a pharmaceutically acceptable Salt thereof, as  Int. cl.7 ............................. .. A61K 9/14; A61K 9/26; A61K 9/52 active ingrediem> Suitable for administration on a Once daily basis, are disclosed. In a ?rst aspect, an orally administrable  US. Cl. ........................ .. 424/489; 424/484; 424/469; 424/457; 424/486 Sustained release “nit dosage, for“? gives a Peak Plasma level at 1.0 to hours after administration. In a second aspect, the Mar. 14, 1994 [GB]  Field of Search 424/464 451 424 469 489’ 452’ ’ ’ ’ ’ ’ 465’ 457’ ’  morphine of betWeen and 12 hours. AthlTd aspect concerns the pharmaceutical unlt dosage form obtained by compress ing multiparticulates comprising a pharmaceutically active References Cited substance in a matrix of hydrophobic fusible material having U S PATENT DOCUMENTS 2,738,303 formulation provides a W5O for the M-6-G metabolite for a melting point of from 35 to 150° C. 3/1956 Blythe ..................................... .. 167/82 13 Claims, 7 Drawing Sheets g 160 - 16 '5 =5 14o — 14 *9’ ‘EC 120 M—6—-G "12 “5,4 g 5 100 8 g 80 o v 60 “I:I 40 20 - 10 g g -8 8 E _ Morphlne 2 - 6 e v _- 4 2 ~ 1 _ O l l I l 12 24 48 6O Time (h) O O 72 2 6,143,328 Page 2 U.S. PATENT DOCUMENTS 4,063,064 12/1977 Saunders et al. ..................... .. 219/121 4,088,864 5/1978 Theeuwes 9191- 4,132,753 1/1979 4,310,483 1/1982 Dorfel 9191- ~- 4,377,568 3/1983 Chopra 4,385,078 5/1983 onda 9t 91- - 4,389,393 6/1983 Schoret 91- 0108218 5/1984 European Pat. Off. ....... .. A61K 9/22 0147780 7/1985 European Pat. 0235986 9/1987 European pat Off_ _______ __ A61K 9/16 European Pat. on. ....... .. A618 9/00 . . .. A61K 9/32 - 219/121 LM 0253104 1/1988 264/75 0267702 5/1988 European pat ~- 264/117 0271193 6/1988 European Pat. on. A618 31/485 424/31 0327295 1/1989 European Pat. on. .. A618 9/52 Blichare et al. .. __ A61K 9/14 -- 427/3 0361910 4/1990 European Pat. on. .. A618 9/16 424/19 424/19 0377517 0377518 7/1990 7/1990 European Pat. on. European Pat. on. .. A618 31/52 .. A618 9/52 4,421,736 12/1983 4,483,847 11/1984 A118art ----- -- -- 424/470 0388954 9/1990 European Pat. on. .. A618 9/14 4,520,172 4,548,990 5/1985 Lehmann 9t 9110/1985 Mueller 9t a1~ -- 525/369 ~- 525/123 0415693 0452145 3/1991 10/1991 European Pat. on. European Pat. on. .. A618 37/02 .. A618 9/14 4,557,925 12/1985 4,600,645 4,708,874 4,728,513 4,797,410 4,806,337 Walters ---- - _ _ Lindahl et al. ..... .. 7/1986 Ghebre-sellassie 9t 9111/1987 De H99“ 91 a1~ ~~~~~~ ~- 424/19 0533297 3/1993 European pat Om _ __ A61K 9/16 -- 428/403 0534628 3/1993 European Pat. on. A618 31/485 - 424/470 9532348 3/1993 European Pat. on. A618 31/135 424/461 514/356 71/65 424/419 424/488 0535841 0546676 0548448 0580860 0361680 4/1993 6/1993 6/1993 2/1994 7/1994 European European European European European 424/488 424/465 0609961 0430287 8/1994 10/1994 3/1988 Ventouras ----- -1/1989 El-Fakahany -2/1989 Snipes 9t 91- -- 4,828,836 5/1989 E18er 9t 91 4,834,984 5/1989 Goldie 9191- -- Pat. on. Pat. Pat. Pat. Pat. A618 31/485 .. A618 31/60 .. A618 9/50 .. A618 9/14 .. A618 9/46 4,834,985 5/1989 E18er 9t 91- - 4,844,907 4,844,909 7/1989 E18er 9t 91 7/1989 Goldie 9t 91- 424/480 0636370 2/1995 European Pat. on. 4,861,598 4,894,234 8/1989 Oshlack 1/1990 Sharma et al 424/468 424/440 0665010 377518 8/1995 2/1996 European Pat. on. ....... .. A618 9/26 European pat Off_ _ 4,935,246 4,967,486 6/1990 Ahreris ----- -11/1990 139911198 - 424/490 34/1 2053681 2178313 2/1981 2/1987 United Kingdom United Kingdom . 4,970,075 11/1990 424/451 9201446 2/1992 WIpO _________ __ A61K 9/5O 536/69 9202209 2/1992 WIpO _ A61K 9/22 Oshlack ....... .. European Pat. . . . A618 31/485 European Pat. on. ....... .. A618 9/54 A618 31/485 A618 9/22 A618 9/14 4,983,730 1/1991 Domeshek et al. 4,990,341 2/1991 Goldie et al. .. 424/484 9206679 4/1992 WIpO _ A61K 9/16 5,007,790 4/1991 Shell ............ .. 424/451 9304675 3/1993 WIpO _ A61K 31/16 5,023,089 5,024,842 6/1991 Sakamoto et al. 6/1991 Edgren et al. 424/502 424/473 9307859 W0 93 07861 4/1993 4/1993 WIpO _ WIpO _ A61K 9/16 __ A61K 9/5O 5,026,560 6/1991 M91999 9191 -- 424/494 9310765 6/1993 WIPO ............................ .. A618 9/22 Danielsen et al. .................... .. 264/101 Malkowska 9t a1~ ----------------- ~- 424/497 9318753 W0 94 03160 9/1993 2/1994 WIpO _ WIPO ............................ .. A618 9/32 5,122,384 5,126,145 6/1992 Paradissis et al. .. 6/1992 Evenstad et al. ..................... .. 424/465 W0 94 03161 W0 94 05262 2/1994 3/1994 WIpO _ WIpO _ 5,132,142 7/1992 5,133,974 7/1992 Paradissis 9191 5,030,400 5,071,646 5,167,964 5,169,645 7/1991 12/1991 12/1992 12/1992 Jones et al. ........................... .. 427/196 9422431 10/1994 WIpO _ -- 424/480 9423700 10/1994 WIPO ............................ .. A618 9/16 Muhammed 9t a1~ ---------------- ~- 424/482 Shukla et al. ......................... .. 424/499 9600066 9601629 1/1996 1/1996 WIPO ........................ .. A618 31/485 WIpO _ _ A61K 31/485 9614058 3/1996 WIPO ............................ .. A618 9/14 5,178,863 1/1993 lvlalrnquiSt 9t 91- 5,196,203 3/1993 5,202,128 5,266,331 -- 424/490 Boehm .................................. .. 424/469 4/1993 Morella ................................. .. 424/469 11/1993 Oshlack et al. . 424/468 5,273,760 12/1993 Oshlack et al- 424/480 5,283,065 5,286,493 " OTHER PUBLICATIONS Physicians Desk Reference 1994, 48th Edition, pp. 2/1994 Doyon etal. ......................... .. 424/467 2/1994 Oshlack et al. .. 424/468 18214824 5,292,461 3/1994 Juch et al. .............................. .. 264/37 Abstracts.from the Twelfth Annual Congress of the Oncol' 5,321,012 5,330,766 6/1994 Mayer et al. ........................... .. 514/25 7/1994 Morella et a1_ _ 424/490 Ogy Nursmg S°C1ety> May 1987 J. Lapin et al., “Cancer Pain Management With a Controlled 5,378,474 1/1995 Morella et al. 424/469 Release Oral Morphine Preparation”, Journ. of Pain and 5,403,593 5’411’745 4/1995 Royce ................................... .. 424/489 5/1995 Oshlack et a1‘ " 424/456 Sympton Manag., v 4 (3), pp. 146—151, 1989. J. Lapin et al., “Guidelines for use of Controlled Release 5,453,283 9/1995 ........................ .. 424/489 5,456,923 10/1995 Nakamichi et al. .................. .. 5,460,826 10/1995 Merrill et al. .. 5,472,712 12/1995 Oshlack et al. ....................... .. 5,500,227 3/1996 Oshlack et al. ....................... .. 5,508,042 4/1996 Oshlack et a1~ ~~ Munch et al. 424/489 424/470 424/480 424/476 424/468 gerglsoiettall' """""""""""" " , , 5 ac e a. ....................... .. 575807578 12/1996 Oshlack et a1‘ " 424/468 5,601,842 2/1997 5,614,218 5,672,360 3/1997 Olsson .................................. .. 424/456 9/1997 Sackler .................................. .. 424/490 Bartholomaeus ..................... .. 424/464 . . . ,, Oral Morphme 1“ Cancer Pam Management ?ancer Nurs' 1ng> V 12 (4% W 202—8> 1989 R.F. Kaiko, “The Pre— and Postoperative Use of Controlle d—Release Morphine (MS Contin Tablets); A Review of the Published Literature”, Medical Department, The Purdue Frederick Company, Royal Society of Medical Services, - - - l1I2;iIi36I(1)OE11a;8C9;)ngr€SS, Symposium Services, No. 149, PP. ' H-F- Slowey et 211-, “Effect of Premedioation With Controlle d—Release Oral Morphine on Postoperative Pain”, Anaes thesia, 1985, vol. 40, pp. 438—40. FOREIGN PATENT DOCUMENTS 2131350 0097523 3/1995 1/1984 Canada ...................... .. A618 31/135 European Pat. Off. ....... .. A61K 9/26 McTaggart, C.M., et al., “The Evaluation of Formulation and Processing Conditions of a Melt Granulation Process”, Int. J. Pharm., vol. 19, No. 2, Issued 1984 pp. 139—148. 6,143,328 Page 3 El—ShanaWany, S., “Sustained Release of Nitrofurantoin From Inert Wax Matrixes”, J. Controlled Release vol. 26, No. 1, Issued 1993, pp. 11—19. ment and Industrial Pharmacy, vol. 13, No. 6, pp. Kinget, Renaat and Roger KenZel “Preparation and Proper 1001—1022 (1987). ties of Granulates Containing Solid Dispersions” Acta Phar rnaceutica Technologica 31 (2) 1985, pp. 57—62. Kaiko, et al. “A single—dose study of the effect of food ingestion and timing of dose administration on the pharma cokinetic pro?le of 30 mg sustained—release rnorphine sul fate tablets”, Current Therapeutic Research, pp. 869—878, vol. 47, No. 5, May 1990. Kaiko, et al. “Controlled—release rnorphine bioavailability (MS Contin® tablets) in the presence and absence of food” The Hospice Journal, pp. 17—30, vol. 6(4) 1990. Gourlay, et al. “The reproducibility of bioavailability of oral rnorphine from solution under fed and fasted conditions”, Journal of Pain and Symptom Management, pp. 431—436, vol. 6, No. 7, Oct. 1991. Gourlay, et al., “In?uence of a high—fat meal on the absorp tion of morphine from oral solutions”, C lin Pharmacol Ther, pp. 403—468, Oct. 1989. R. West et al. World Congress on Pain Abstracts 997—1001, Aug. 26, 1993. Advertisement: Roxanol SR., @1988 Roxane Labs, Inc. R. Kaiko and T. Hunt, “Comparison of the Pharrnacokinetic Pro?les of TWo Oral Controlled—Release Morphine Forrnu lations in Healthy Young Adults”, Clin. Thera. vol. 13, No. 4, pp. 484—488. S. Bloorn?eld, et al., “Analgesic ef?cacy and potency of tWo Flanders, P., et al., “The Control of Drug Release Frorn Conventional Melt Granulation Matrices”, Drug Develop Kaiko, Robert, et al., “A single—dose study of the effect of food ingestion and timing of dose administration on the pharrnacokinetic pro?le of 3—rng sustained release rnorphine sulfate tablets”, Current Therapeutic Research, vol. 47, No. 5, pp. 869—876 (May 1990). Thornsen, L. Juul, “Utilizing rnelt pelletiZation technique for the preparation of prolonged release products”, Pelletiza tion, (rnaterial elaborated by assistant prof. Lars Juul Thorn sen, Department of Pharmaceutics, Royal Danish School of Pharmacy for the DIE course “PelletiZation Technology”, Nov. 1992, 106 pages plus 3 appendices. Schaefer, T., et al., “Melt granulation in a laboratory scale high shear rnixer”, Drug Development and Industrial Phar macy, vol. 16, No. 8, pp. 1249—1277 (1990). Thornsen, L. Juul, et al., “Prolonged Release Matrix Pellets Prepared by Melt PelletiZation I. Process Variables”, Drug Development and Industrial Pharmacy, vol. 19, No. 15, pp. 1867—1887 (1993). Thornsen, L. Juul, et al., “Prolonged Release Matrix Pellets Prepared by Melt PelletiZation II. Hydrophobic Substances as Meltable Binders”, Drug Development and Industrial Pharmacy, vol. 20, No. 7, pp. 1179—1197 (1994). oral controlled—release rnorphine preparations”, Clin. Phar rnacol. Ther.. vol. 53, No. 4, pp. 469—478, 1993. Advertisement: MS Contin® ©1986, 1987 The Purdue pared by Melt PelletiZation. Part IV: Drug Conent, Drug Frederick Cornpany. Technology Europa, pp. 19—24 (Oct. 1994). Thornsen, L. Juul, “Prolonged Release Matrix Pellets Pre Particle SiZe, and Binder Cornposition”, Pharmaceutical U.S. Patent Nov. 7,2000 Sheet 2 of7 (lw/?u) uogoquaauoo augqdjow @LOQ'NO 2: ("11/5") uop‘mlueouoo Q-Q-W 6,143,328 U.S. Patent Nov. 7, 2000 Sheet 3 0f 7 6,143,328 ("11/5") uogonuaouoo augqdmw 72 3 (h)Time UOQDJWGOUOO Q-Q-W FIG. U.S. Patent Nov. 7, 2000 Sheet 4 0f 7 6,143,328 (lw/bu) uogonueauoo GUllJdJOW 72 4 48 36 (h)Time Morphilne uogonuaauoo g-g-w 24 12 FIG. U.S. Patent Nov. 7,2000 Sheet 5 of7 (Wu/5") uogonuaouoa 9U!L|dJOW ‘d'NO l (D I cm 2: (Wu/5“) uogonuaouoo g-g-w 6,143,328 U.S. Patent Nov. 7,2000 Sheet 6 of7 (Nu/5") uogoqueouoo augqdJow NO PPQCDQ'NO o9 ("u/5“) uogonueouoo g-g-w 6,143,328 U.S. Patent Nov. 7, 2000 Sheet 7 0f 7 6,143,328 (Wu/5“) uononuaouoo augqdJow LD'Q-PONFCD | I | l | T‘ 24 7 (h)Time G. Fl (Iw/ E"1) UOQDJlUSOUOO 9-9-W 6,143,328 1 2 SUSTAINED RELEASE COMPOSITIONS AND A METHOD OF PREPARING PHARMACEUTICAL COMPOSITIONS The dosage unit form in accordance With the invention should contain suf?cient morphine, or salt thereof, to give therapeutic activity over a period of at least 24 hours. The actual amount of morphine, or salt, in any particular dosage This application is a continuation of US. Ser. No. form Will of course depend upon a number of variables 08/843,571, ?led Apr. 18, 1997, issued as US. Pat. No. 5,879,705, Which is a continuation application of US. Ser. No. 08/269,208 ?led Jun. 30, 1994 (abandoned). including the number of dosage forms intended to be administered at any one time and (ii) the intended dosage for any particular patient. Conveniently, hoWever, dosage unit forms in accordance With the invention Will contain from 10 BACKGROUND OF THE INVENTION This invention is concerned With improvements in and relating to sustained release compositions and, more particularly, is concerned With sustained release orally administrable dosage unit forms containing morphine, or a pharmaceutically acceptable salt thereof, as active ingredi 10 15 The present invention also relates generally to a method of manufacturing an orally administrable dosage form, pref erably sustained release granules/multiparticulates and com metabolite of morphine and, itself,, has poWerful analgesic properties, at least comparable With those of morphine. ent. pressed multiparticulates, such multiparticulates having to 500 mg of morphine (calculated as morphine sulphate) and thus, for example, typical dosage unit forms in accor dance With the invention are those containing 20, 30, 60, 90, 120, 150 and 200 mg of morphine (calculated as above). Morphine-6-glucuronide (hereinafter M-6-G) is a knoWn 20 diameters ranging from 0.1 to 3.0 mm; the method of the invention provides multiparticulates in an unexpectedly high We have found, in accordance With another aspect of the invention, that a pharmaceutical formulation, containing an effective amount of morphine or pharmaceutically accept able salt thereof, effective for at least 24 hourly dosing, is characteriZed by a W5O for the M-6-G metabolite of betWeen 4 and 12 hours, and preferably has a Tmwc of M-6-G in the range 1 to 6.5 hours, more preferably 3 to 6.5 hours, and yield. even more preferably 3.5 to 6 hours. Morphine is an opioid analgesic Well established for use in the treatment of pain, especially moderate to severe pain. 25 Morphine-containing compositions in sustained release form are currently commercially available as so-called “tWice-a-day” formulations, that is formulations having a duration of activity of 12 hours or more and accordingly requiring to be administered tWice a day. 30 time betWeen the ?rst (or only) upslope crossing and the last (or only) doWnslope crossing in the plasma pro?le. We have observed that, surprisingly, formulations in OBJECTS AND SUMMARY OF THE INVENTION It is one object of the present invention to provide a The W5O parameter de?nes the Width of the plasma pro?le at 50% Cmwc, ie the duration over Which the plasma concentrations are equal to or greater than 50% of the peak concentration. The parameter is determined by linear inter polation of the observed data and represents the difference in 35 accordance With the invention, Which are characteriZed by a W5O for M-6-G in the range speci?ed, are usually also characteriZed by a W5O for morphine Within a similar range. morphine-containing sustained release orally administrable Accordingly, in accordance With another, preferred, aspect dosage unit form Which has an effective duration of activity of the invention a pharmaceutical formulation, containing an effective amount of morphine or pharmaceutically accept able salt thereof, effective for at least 24 hour dosing, is characteriZed by a W5O for morphine of betWeen 4 and 12 hours, and preferably has a Tmwc in the range of 1 to 6.5 hours, more preferably 1 to 4 hours eg. 1 to 3.5 hours after administration. Apreferred formulation in accordance With this aspect of of 24 hours or more and, hence, is suitable for administration on a once daily basis. It has surprisingly been found, in accordance With the present invention, that effective therapeutic activity over a 40 period of 24 hours or more may be obtained from a morphine-containing sustained release formulation Which gives an in vivo peak plasma level relatively early after administration, that is from 1.0 to 6 hours after administra tion preferably 1 to 4 hours eg 1 to 3.5 hours. Accordingly, one embodiment of the composition of the invention provides an orally administrable sustained release dosage unit form containing morphine, or a pharmaceuti cally acceptable salt thereof, as active ingredient Which formulation gives a peak plasma level from 1 to 6 hours, preferably 1 to 4 hours eg. 1 to 3.5 hours, after adminis tration. It has been found that in a group eg. n=5, of healthy volunteers such dosage units, When administered in a single dose in the fasted state, gave median Tmax values in the range of 1 to 4.25 hours. 45 the range of about 5.5 to 12 or 5.5 to 11 or even 6 to 10 50 ment containing 60 mg morphine sulphate When adminis 55 60 When morphine base or a salt other than the sulphate is molecular Weight of the base or salt. in the range of from 65 ng/ml to 150 ng/ml. Another such preferred embodiment is characteriZed by a Cmax for mor phine in the range of from 7.5 to 20 ng/ml. One preferred embodiment described herein, after single (per ml of plasma) is preferably from 0.5><10_7 to 75x10“7 times the amount of morphine sulphate orally administered. administered, the preferred ratio of drug administered to peak plasma level should be adjusted according to the hours. The Cmwcs of formulations in accordance With the inven tion are dose dependant. For instance, a preferred embodi tered as a single dose is characteriZed by a Cmwc for M-6-G When the morphine is administered as morphine sulphate and the method of plasma analysis is high performance liquid chromatography, the peak plasma level of morphine the invention is characteriZed by the foregoing parameters When dosed to patients in the fasted state. Preferred values for W5O for M-6-G and morphine are in 65 dosing to 5 fasted volunteers Was found to have W50, for morphine and M-6-G in the range 5.5 to 12 hours. It has been found that in a group eg. n=5, of healthy volunteers one embodiment of such dosage units, When administered in a single dose in the fasted state, gave median Tmwc values of M-6-G in the range of 3.5 to 6 hours, eg. 4 to 6.0 hours and for morphine in the range of 2.5 to 5 hours. It has further been found, in accordance With the present invention, that in order to achieve the desired time of peak 6,143,328 4 3 plasma level of morphine and M-6-G and to provide effec We have found that the total amount of active ingredient the modi?ed Ph. Eur. Basket method at 100 rpm in 900 ml in the composition may vary Within Wide limits, for example from 10 to 60% by Weight thereof. The hydrophobic fusible component (b) should be a aqueous buffer. (pH 6.5) containing 0.05% W/v Polysorbate hydrophobic material such as a natural or synthetic Wax or tive activity over a period of at least 24 hours, the in vitro release characteristics of the formulation [When measured by oil, for example hydrogenated vegetable oil or hydrogenated 80 at 37° C.] are preferably as set out beloW: Hours After % Morphine salt released Start of Test Suitable Preferred 2 4 6 12 18 24 5-30 15-50 20-60 35-75 45-100 55-100 5-20 15-35 20-45 40-70 50-80 60-100 10 castor oil, and suitably has a melting point of from 35 to 100° C., preferably 45 to 90° C. The release modifying component (c), When a Water soluble fusible material, is conveniently a polyethylene glycol and, When a particulate material, is conveniently a pharmaceutically acceptable material such as dicalcium phosphate or lactose. Incorporation of loWer levels of morphine, for example 15 betWeen 10 and 30% by Weight, necessitate inclusion of loW levels of a release modifying component, for example 5 to 15% by Weight polyethylene glycol 6000, to achieve a satisfactory in vitro release rate. At higher drug loadings, for 20 that only incorporation of very small amounts of polyeth ylene glycol, for example 0.01 to 1% by Weight are required example 40 to 60% by Weight it is particularly surprising BRIEF DESCRIPTION OF THE DRAWINGS FIGS. 1 to 5 are plasma pro?les of morphine and M-6-G in each of ?ve volunteers after dosing them With a formu lation in accordance With the invention; FIG. 6 shoWs the mean plasma pro?les of morphine and to modify the in vitro release rate. Alternatively the morphine (or salt thereof) may be for 25 mulated (eg by dry or Wet granulation or by blending) in a controlled release mixture formed of components other than M-6-G derived from the results illustrated in FIGS. 1 to 5; fusible components. Suitable materials for inclusion in a FIG. 7 shoWs the mean-plasma pro?les of morphine and controlled release matrix include, for example (a) Hydrophilic or hydrophobic polymers, such as gums, M-6-G obtained using a knoWn controlled release morphine preparation in nine volunteers. cellulose ethers, protein derived materials, nylon, acrylic 30 DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT polyvinylpyrrolidones, cellulose acetate phthalate. Of these polymers, cellulose ethers especially substituted cellulose ethers such as alkylcelluloses (such as ethylcellulose), The compositions of the invention may be provided in a variety of forms, for example as tablet or capsules contain ing granules, spheroids or pellets. Commonly, the compo 35 copolymers) are preferred. The controlled release matrix thereof) together With a diluent Which may serve to modify the release of the active ingredient. Apreferred form of unit dose form in accordance With the invention comprises a may conveniently contain betWeen 1% and 80% (by Weight) of hydrophilic or hydrophobic polymer. 40 acids, hydrogenated vegetable oils such as Cutina (Trade Mark), fatty alcohols (such as lauryl, myristyl, stearyl, cetyl 45 50 (c) Polyalkylene glycols. The matrix may contain up to 60% (by Weight) of at least one polyalkylene glycol. the commercial production of dosage units containing mor When using such a processing technique it has been found that, in order to most readily achieve the desired release characteristics (both in vivo and in vitro as discussed above) the composition to be processed should comprise tWo essen tial ingredients namely: beesWax, glycoWax, castor Wax or carnauba Wax). Hydro carbons having a melting point of betWeen 25° C. and 90° C. are preferred. Of these long chain hydrocarbon materials, fatty (aliphatic) alcohols are preferred. The matrix may contain up to 60% (by Weight) of at least one digestible, long chain hydrocarbon. mm, preferably 0.25 to 2.0 mm. A preferred and novel process of this kind is described beloW Which is suitable for phine or other active substances. or preferably cetostearyl alcohol), glyceryl esters of fatty acids for example glyceryl esters of fatty acids for example glyceryl monostearate mineral oils and Waxes (such as a rate and energy input such that sufficient energy is supplied to the fusible material to melt or soften it Whereby it forms multiparticulates With the active ingredient. The resultant multiparticulates are suitably sieved and cooled to give multiparticulates having a particle siZe range from 0.1 to 3.0 (b) Digestible, long chain (Cs-C50, especially C8-C4O), substituted or unsubstituted hydrocarbons, such as fatty the active ingredient, a hydrophobic fusible carrier or diluent and optionally a hydrophilic release modi?er. In particular, the multiparticulates are preferably prepared by a process essentially comprising forming a mixture of dry active ingredient and fusible release control materials folloWed by mechanically Working the mixture in a high speed mixer at Cl-C6 hydroxyalkylcelluloses (such as hydroxypropylcel lulose and especially hydroxyethyl cellulose) and acrylic resins (for example methacrylates such as methacrylic acid sition Will comprise the active ingredient (morphine or salt capsule ?lled With multiparticulates essentially comprising resins, polylactic acid, polyvinylchloride, starches, 55 A suitable matrix comprises one or more cellulose ethers or acrylic resins, one or more C12-C36, preferably C14-C22, aliphatic alcohols and/or one or more hydrogenated veg etable oils. A particular suitable matrix comprises one or more 60 alkylcelluloses, one or more C12C36, (preferably C14-C22) aliphatic alcohols and optionally one or more polyalkylene (a) active ingredient (morphine or salt thereof); and (b) hydrophobic fusible carrier or diluent; optionally together With glycols. Preferably the matrix contains betWeen 0.5% and 60%, especially betWeen 1% and 50% (by Weight) of the cellulose soluble fusible material or a particulate soluble or ether. The acrylic resin is preferably a methacrylate such as insoluble organic or inorganic material. methacrylic acid copolymer USNF Type A (Eudragit L, (c) a release control component comprising a Water 65 6,143,328 5 6 Trade Mark), Type B (Eudragit S, Trade Mark), Type C (Eudragit L 100-55, Trade Mark), Eudragit NE 30D, Eudragit E, Eudragit RL and Eudragit RS. Preferably the In step (c) the amount of additional fusible release control material added is preferably betWeen 5% and 20% W/W of the total amount of ingredients added, more preferably betWeen 8 and 17% W/W. Stage (a) of the process may be carried out in conven tional high speed mixers With a standard stainless steel matrix contains between 0.5% and 60% by Weight, prefer ably betWeen 1% and 50% by Weight of the acrylic resin. In the absence of polyalkylene glycol, the matrix prefer ably contains betWeen 1% and 40%, especially betWeen 2% and 36% (by Weight) of the aliphatic alcohol. When poly alkylene glycol is present in the oral dosage form, then the combined Weight of the aliphatic alcohol and the polyalky lene glycol preferably constitutes betWeen 2% and 40%, especially betWeen 2 and 36% (by Weight) of the matrix. interior, eg a Collette Vactron 75 or equivalent mixer. The mixture is processed until a bed temperature above 400 C. is achieved and the resulting mixture acquires a cohesive 10 The polyalkylene glycol may be, for example, polypro pylene glycol or, Which is preferred, polyethylene glycol. The number average molecular Weight of the at least one polyalkylene glycol is preferably betWeen 200 and 15000 especially betWeen 400 and 12000. The morphine containing controlled release matrix can readily be prepared by dispersing the active ingredient in the controlled release system using conventional pharmaceutical techniques such as melt granulation, Wet granulation, dry blending, dry 15 20 spheroids obtained by spheroniZing the morphine (or salt cellulose. The present invention also includes a process for the manufacture of sustained release multiparticulates contain ing morphine or a salt thereof Which comprises (a) mechanically Working in a high-speed mixer, a mix ture of morphine or salt thereof in particulate form and mm to ?ne poWder in the case of non-aggregated original material. Such material, in the case of the embodiments described beloW, has the appearance of agglomerates Which upon cooling beloW 40° C. have structural integrity and resistance to crushing betWeen the ?ngers. At this stage the agglomerates are of an irregular siZe, shape and appearance. The agglomerates are preferably alloWed to cool. The temperature to Which it cools is not critical and a tempera ture in the range room temperature to 45° C. eg to 37° C. granulation or coprecipitation. Another form of sustained release formulation comprises thereof) With a spheroniZing agent such as microcrystalline granular texture, With particle siZes ranging from about 1—3 25 may be conveniently used. The agglomerates are broken doWn by any suitable means, Which Will comminute oversiZe agglomerates and produce a mixture of poWder and small particles preferably With a diameter under 2 mm. It is currently preferred to carry out the classi?cation using a Jackson Crockett granulator using a suitable siZed mesh, or a Comil With an appropriate siZed screen. We have, found that if too small a mesh siZe is used in the aforementioned apparatus the agglomerates melting under the action of the beater or impeller Will clog the mesh and prevent further throughput of mixture, thus 30 a particulate, hydrophobic fusible carrier or diluent reducing yield. Amesh siZe of 12 or greater or a 94G Comill screen have been found adequate. The classi?ed material is returned to the high speed mixer and processing continued. It is believed that this leads to cementation of the ?ner particles into multiparticulates of having a melting point from 35 to 150° C., e.g., to 100° C. and optionally a release control component com prising a Water soluble fusible material, or a particulate 35 uniform siZe range. soluble or insoluble organic or inorganic material at a In a preferred form of the method of the invention speed and energy input Which alloWs the carrier or diluent to melt or soften, Whereby it forms agglomer ates; (b) breaking doWn the larger agglomerates to give con 40 trolled release seeds; and (c) continuing mechanically Working With a further addi In order to ensure uniform energy input into the ingredi tion of loW percentage of the carrier or diluent; and ents in the high speed mixer it is preferred to supply at least (d) optionally repeating step (c) and possible (b) one or more eg up to ?ve times. processing of the classi?ed materials is continued, until the hydrophobic fusible materials used begin to soften/melt and additional hydrophobic fusible material is then added. Mix ing is continued until the mixture has been transformed into multiparticulates of the desired predetermined siZe range. 45 The process is capable of giving a high yield (over 80%) of multiparticulates in a desired siZe range, With a desired in part of the energy by means of microWave energy. Energy may also be delivered through other means such as by a heating jacket or via the mixer impeller and chopper blades. vitro release rate, uniformity of release rate and in its After the pellets have been formed they may then be preferred form surprisingly an early peak plasma level for a sieved to remove any over or undersiZed material and are product With a 24 hour duration of activity. The resulting multiparticulates may be sieved to eliminate 50 cooled or alloWed to cool. The resulting pellets may be used to prepare dosage units any over or undersiZed material then formed into the desired such as tablets or capsules in manners knoWn per se. dosage units by for example, encapsulation into hard gelatin In this process of the invention the temperature of the mixing boWl throughout the mechanical Working is chosen capsules containing the required dose of the active sub stance. 55 so as to avoid excessive adhesion of the material to the Walls Preferably morphine sulphate is used in an amount Which results in multiparticulates containing betWeen 10% and 60%, especially betWeen about 45% and about 60% W/W active ingredient for a high dose product and 10 and 45% for a loW dose product. In this method of the invention all the drug is added in step of the boWl. We have generally found that the temperature should be neither too high nor too loW With respect to the 60 drug and particulate hydrophobic fusible carrier in a high speed mixture ?rst mentioned above. For example in the (a) together With a major portion of the hydrophobic fusible release control material used. Preferably the amount of fusible release control material added in step (a) is betWeen 25% and 45% W/W of the total amount of ingredients added in the entire manufacturing operation, more preferably betWeen 30% and 40%. melting temperature of the material and it can be readily optimiZed to avoid the problems mentioned above. The same applies to the process of mechanically Working a mixture of 65 processes described beloW in the Examples a boWl tempera ture of approximately 60° C. has been found to be satisfac tory and avoid adhesion to the boWl. To produce tablets in accordance With the invention, multiparticulates produced as described above may be 6,143,328 7 8 mixed or blended With the desired excipient(s), if any, using conventional procedures eg using a Y-Cone or bin-blender and the resulting mixture compressed according to conven EXAMPLES 9 TO 12 tional tabletting procedure using a suitably siZed tabletting Particles, having the formulations given in Table III beloW, Were prepared by the steps of: tooling. Tablets can be produced using conventional tablet ting machines, and in the embodiments described beloW kg) in the boWl of a 75 liter capacity Collette Vactron i) Placing the ingredients (a) to (c) (total batch Weight 20 Mixer (or equivalent) equipped With variable speed mixing and granulating blades; Were produced on a standard single punch F3 Manesty machine or Kilian RLE15 rotary tablet machine. In order that the invention may be Well understood the folloWing examples are given by Way of illustration only. ii) Mixing the ingredients at about 150—350 rpm While 10 EXAMPLES 1 TO 8 applying heat until the contents of the boWl are agglom erated. iii) Classifying the agglomerated material by passage Pellets, having the formulations given in Table I beloW, Were prepared by the steps of: (i) placing the ingredients, in a total amount by Weight of iv) Warming and mixing the classi?ed material in the 10 kg, in the boWl of a 75 liter capacity Collette Vactron boWl of a 75 liter Collette Vactron, With addition of through a Comill and/or Jackson Crockett to obtain controlled release seeds. Mixer (or equivalent), equipped With variable speed mixing and granulating blades; (ii) mixing the ingredients While applying heat until the contents of the boWl are pelletiZed; ingredient (d), until uniform particles of the desired pre-determined siZe range are formed in a yield of greater than 80%. This takes approximately 15 minutes. 20 (iii) discharging the pellets from the mixer and sieving v) Discharging the particles from the mixer and sieving them to separate out the particles collected betWeen 0.5 them to separate out the pellets collected betWeen 0.5 and 2 mm aperture sieves. and 2 mm aperture sieves. TABLE III 25 TABLE I EXAMPLE EXAMPLE NO. 1 Morphine Sulfate 2 3 4 5 15 15 23 55 76 75 70 6 7 55 55 (Wt %) Hydrogenated castor 30 Hydrogenated 42.8 44.95 0.2 0.05 42.0 vegetable oil U.S.N.F. (Wt %) 8 9 10 7 6000 U.S.N.F. 35 (Wt %) Dicalcium phosphate anhydrous USP The in vitro release rates of the products of Examples 1, 40 2. 3 and 5 Were assessed by the modi?ed Ph. Eur. Basket method at 100 rpm in 900 ml aqueous buffer (pH 6.5) at 37° C. For each of the products, six samples of the pellets, each sample containing a total of 30 mg of morphine sulphate, Were tested. The results set out in Table II beloW give the mean values for each of the six samples tested. a) Morphine Sulphate (Wt %) 55.0 52.19 53.48 b) Hydrogenated Vegetable Oil USNF (Wt %) c) Polyethylene Glycol 6000 34.95 33.17 33.98 0.05 0.047 0.049 d) Hydrogenated Vegetable Oil USNF (Wt %) 10.0 14.60 12.49 Yield % 90.5 83.4 90.1 The in vitro release rates of Examples 9, 10 and 11 as Well as Example 12 beloW Were assessed by modi?ed Ph. Eur. the products, six samples of the particles, each sample containing a total of 60 mg of morphine sulphate Were tested. The results set out in Table IV beloW give the mean values for each of the six samples tested. TABLE IV 45 PRODUCT OF EXAMPLE Hours After Start of TABLE II 1 Test 2 3 2 4 6 8 12 18 24 30 4 (% morphine released) 19 27 34 41 53 66 76 25 36 45 52 64 77 86 33 49 62 72 86 96 101 44 57 66 72 81 89 92 55 60 10 11 (% morphine released) 21 33 43 52 62 74 82 83 15 25 35 43 57 71 81 85 20 36 49 59 72 82 86 89 The procedure of Example 11 Was repeated but the operation varied by adding the classi?ed particles to a cold boWl of the Collette Vactron, folloWed by adding ingredient (d) and mixing, heating by jacket heating and microWave Pharmacokinetic studies in healthy human volunteers have indicated peak plasma levels of from 2.2 to 21.6 ng/ml of morphine at median times betWeen 1.0 and 3.5 hours folloWing administration of a single capsule containing 9 Test 50 PRODUCT OF EXAMPLE 2 4 6 8 12 18 24 11 Basket method at 100 rpm in 900 ml aqueous buffer (pH 6.5) containing 0.05% W/v polysorbate 80 at 37° C. For each of (Wt %) Hours After Start of 10 USNF (Wt %) oil U.S.N.F. (Wt %) Polyethylene glycol 9 8 being applied during mixing. The in vivo release rate is given in Table IVa and demonstrates that although the 65 composition of the products in Examples 11 and 12 are the pellets of Examples 1, 2, 3 or 5 in an amount suf?cient to same the different processing results in modi?ed release provide a morphine sulphate dose of 30 mg. rates. 6,143,328 9 10 knoWn bid morphine sulphate-containing preparation MST CONTINUS® under a similar test conditions, and analyZing TABLE IVa the blood samples using a similar analytical procedure, as PRODUCT OF EXAMPLE Were used in the tests carried out With the formulations in accordance With the invention and Which gave the results Hours After Start of Test % of Morphine Released 2 4 6 8 12 18 24 30 15 24 30 36 46 57 65 71 illustrated in Table V and FIGS. 1 to 6. it can be seen MST CONTINUS® resulted at 12 hours in mean plasma levels for M-6-G and morphine of about 14 ng/ml and 2 ng/ml respectively: the mean values for plasma levels at 24 hours 10 obtained using the preparation in accordance With the present invention, and as illustrated in FIG. 6 Were M-6-G 17.5 ng/ml and morphine 2.5 ng/ml. EXAMPLE 13 Particles Were produced analogously to Examples 9 to 12 Particles produced according to Examples 9 to 12 Were each blended With puri?ed talc and magnesium stearate and 15 but having the folloWing ingredients: used to ?ll hard gelatin capsules such that each capsule contains 60 mg of morphine sulphate. The capsules pro Wt % duced Were used in open, randomized crossover pharmaco kinetic studies. As part of these studies patients received after overnight fasting either one capsule according to the 20 invention or one MST CONTINUS® tablet 30 mg (a tWice a day preparation). Fluid intake Was unrestricted from 4 hours after dosing. AloW-fat lunch Was provided four hours Morphine sulphate 55.0 Hydrogenated vegetable oil Polyethylene glycol 6000 44.7 0.3 Samples of the particles Were then blended With magne after dosing, a dinner at 10 hours post dose and a snack at 25 sium stearate and puri?ed talc in tWo lots (1 and 2) using a 13.5 hours post-dose. No other food Was alloWed until a 24 Y-Cone or bin-blender-machine. The blended mixtures Were hour post-dose blood sample had been Withdrawn. Blood samples Were taken at the folloWing times 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 9, 12, 18, 24, 36, 48 and 72 hours post-dose. The pharmacokinetic studies using these capsules gave then each compressed on a 7.1 mm diameter normal concave 30 tooling on a single punch F3 Manestr tabletting machine. The ingredients per dosage unit amounted to the folloWing: peak plasma levels of from 3.2 to 29.2 ng/ml of morphine at median times between 2 and 6 hours folloWing administra tion and blood sampling according to the above protocol. TABLE VI Mg! lablet The capsules containing particles produced according to Examples 10 and 12 in particular gave a mean Cmax of 11.9 ng/ml at median Tmwc 4 hours and mean Cmwc of 9.2 ng/ml at median Tmwc 2.5 hours respectively (these values repre sent the mean of the individual Cmax and Tmax values). In contrast the Cmax and Tmwc for the patients Who received MST CONTINUS® tablets Were 10.6—11.4 ng/ml and 2.0—2.5 hours respectively. It Was found, however, that the 35 Morphine Sulphate Hydrogenated Vegetable Oil Polyethylene Glycol Sub Total 40 plasma concentrations of morphine in the blood of patients given capsules according to the invention at 24 hours Were greater than the concentrations at 12 hours in those patients given MST CONTINUS® tablets. The pharmacokinetic studies based on the particles pro duced in Example 9, and directed to morphine and morphine-6-glucuronide folloWing administration of a cap Tablet Ingredient 45 Volunteer W50 (h) Morphine 1 2 3 4 5 147.7 83.8 73.4 72.8 82.5 5.0 3.5 6.0 5.0 3.5 7.54 5.69 11.97 7.02 6.75 8.18 4.24 8.45 5.99 6.67 Mean 92.0 — 31.5 — 7.79 2.43 6.71 sd Median — 5.0 — — Minimum Maximum 72.8 147.7 3.5 6.0 5.69 11.97 4.24 8.45 1.72 60.00 48.77 0.33 109.1 109.1 1.42 2.0 Puri?ed Talc 2.18 3.0 ticles (each sample containing 60 mg of morphine sulphate) Was assessed by the modi?ed Ph. Eur Basket method described above. For the dissolution of the tablets the Ph. Eur. Basket Was replaced by the Ph. Eur. Paddle Method. The results are shoWn in Table VII beloW: TABLE VII Hours After Start of TABLE V W50 (h) M-6-G 60.00 48.77 0.33 Magnesium Stearate teers in the fasted state gave the results shoWn in Table V and 50 FIGS. 1 to 6. M-6-G Tmax (h) 2 The dissolution of the samples of non-compressed par sule containing 60 mg of morphine sulphate in ?ve volun M-6-G Cmax (ng/ml) 1 Test 55 60 1 2 4 8 12 16 24 30 36 Particles Tablet 1 Tablet 2 % morphine sulphate released 27 43 63 82 88 91 93 94 95 13 20 29 42 50 57 65 70 74 11 17 26 37 44 NR" NR" NR" NR" "NR = Not recorded The above results shoW that the tabletting procedure FIG. 7, by contrast shoWs the mean plasma pro?les obtained after dosing nine healthy volunteers With the results in a considerable reduction in the release rate of the active ingredient. 6,143,328 11 12 EXAMPLE 14 for 24 hourly dosing, characteriZed by a Width of the plasma pro?le at 50% CmaX (W50) for the morphine-6-glucoronide metabolite of morphine of betWeen 4 and 12 hours, said The procedure of Example 13 Was repeated but With the following variations. multparticulates being prepared by miXing together said The particles Were made With the following ingredients. 5 morphine or salt thereof and said natural or synthetic Wax or oil at a rate and energy input suf?cient to cause said natural or synthetic Wax or oil to melt or soften Whereby it forms said multiparticulates containing said morphine or salt Wt % Morphine Sulphate 55.0 Hydrogenated Vegetable Oil Polyethylene Glycol 6000 44.4 0.6 10 thereof. 2. An oral sustained release pharmaceutical formulation comprising multiparticulates including morphine or a phar maceutically acceptable salt thereof dispersed in a matriX of a natural or synthetic Wax or oil With a melting point of from TWo lots of tablets (3 and 4) Were produced from the particles using a 7.1 mm diameter concave tooling. The ingredients per dosage unit Were as folloWs; 15 about 35 degrees C. to about 100 degrees C., said multpar ticulates having in vitro release characteristics such that the multiparticulates, When assessed by the modi?ed European Pharmacopeia Basket Method at 100 rpm in 900 ml aqueous buffer at pH 6.5 containing 0.5% polysorbate at 37 degrees TABLE VIII MgZTablet Tablet Ingredient Morphine Sulphate Hydrogenated Vegetable Oil Polyethylene Glycol 6000 Sub Total 20 3 4 60.00 48.44 0.655 60.00 48.44 0.655 109.1 109.1 PoloXamer 188 — 5.0 Magnesium Stearate 2.0 2.0 Puri?ed Talc 3.0 3.0 C., releases from 5 to 30% of morphine tWo hours after start of test, 15 to 50% at 4 hours after start of test; 20% to 60% at 6 hours after start of test; 35 to 75% at 12 hours after start of test, from 45 to 100% at 18 hours after start of test and 55 and 100% at 24 hours after start of test such that the multiparticulates provide a time to peak plasma level of 25 morphine in about 1.0 to about 6.0 hours after administration, and When administered in an effective amount, provide morphine plasma levels effective for 24 hourly dosing, characteriZed by a Width of the plasma pro?le at 50% CmaX (W50) for the morphine-6-glucoronide compressed particles (each sample containing 60 mg of metabolite of morphine of betWeen 4 and 12 hours, Wherein said multiparticulates are prepared by a process comprising the steps of a) miXing together a particulate form of said morphine or morphine sulphate) Were assessed by the methods described pharmaceutically acceptable salt thereof, a particulate 30 The dissolution of the tablets and samples of non above. The results are shoWn in Table IX beloW: 35 soften Whereby it forms agglomerates; and (b) breaking doWn the agglomerates to give said multi TABLE IX Hours After Start of Test Particles Tablet 3 particulates. Tablet 4 3. An oral sustained release pharmaceutical formulation % morphine sulphate released 40 1 2 4 8 12 16 24 56 75 90 95 97 NR* NR* form of said natural or synthetic Wax or oil, at a speed and energy input Which alloWs the carrier to melt or 16 24 34 46 54 NR" NR" 19 28 38 52 60 67 77 maceutically acceptable salt thereof and a natural or syn thetic Wax or oil, said multiparticulates characteriZed by a Width of the plasma pro?le at 50% CmaX (W50) for said morphine of betWeen 4 and 12 hours after administration 45 and When administered in an effective amount, provide suf?cient analgesia for about 24 hours after administration. 4. The oral sustained release pharmaceutical formulation of claim 3, Wherein said multiparticulates are prepared by a process comprising the steps of miXing together said mor 50 phine or salt thereof and said natural or synthetic Wax or oil at a rate and energy input suf?cient to cause said natural or synthetic Wax or oil to melt or soften Whereby it forms said *NR = Not recorded These results demonstrate again a dramatic reduction in the release rate of the morphine sulphate resulting from compression tabletting of the particles; comparison of the release rates for Tablets 3 and 4 also shoW that the release rate can be adjusted by use of a surface active agent (in this case PoloXamer 188) as a tabletting eXcipient, the release rate for tablet 4 Which contains the surface active agents multparticulates containing said morphine and thereafter separating said multiparticulates having a siZe range from 55 about 0.1 mm to about 3 mm. 5. The oral sustained release pharmaceutical formulation as claimed in claim 1, Wherein said multiparticulates provide a time to peak plasma level of morphine in about 1.0 to about being greater than that for tablet 3 Without the surface active agent. We claim: 1. An oral sustained release pharmaceutical formulation comprising multiparticulates including morphine or a phar comprising multiparticulates including morphine or a phar 60 maceutically acceptable salt thereof dispersed in a matriX of 3.5 hours after administration. 6. The oral sustained release pharmaceutical formulation a natural or synthetic Wax or oil With a melting point of from as claimed in claim 2, Wherein said multiparticulates provide a time to peak plasma level of morphine in about 1.0 to about about 35 degrees C. to about 100 degrees C., such that the multiparticulates provide a time to peak plasma level of 3.5 hours after administration. 7. The oral sustained release pharmaceutical formulation morphine in about 1.0 to about 6.0 hours after administration, and When administered in an effective amount, provide morphine plasma levels Which are effective 65 as claimed in claim 3, Wherein said multiparticulates provide a time to peak plasma level of morphine in about 1.0 to about 3.5 hours after administration. 6,143,328 13 8. The oral sustained release pharmaceutical formulation as claimed in claim 1, Wherein said multiparticulates further comprise a release modi?er. 14 12. The oral sustained release pharmaceutical formulation as claimed in claim 9, Wherein said release modi?er com prises a material selected from the group consisting of a 9. The oral sustained release pharmaceutical formulation Water soluble fusible material, a particulate soluble organic as claimed in claim 2, Wherein said multiparticulates further 5 material, a particulate insoluble organic material, a particu comprise a release modi?er. late inorganic soluble material, a particulate inorganic insoluble material and miXtures thereof. 10. The oral sustained release pharmaceutical formulation 13. The oral sustained release pharmaceutical formulation as claimed in claim 3, Wherein said multiparticulates further comprise a release modi?er. as claimed in claim 10, Wherein said release modi?er 11. The oral sustained release pharmaceutical formulation 10 comprises a material selected from the group consisting of as claimed in claim 8, Wherein said release modi?er com a Water soluble fusible material, a particulate soluble organic prises a material selected from the group consisting of a material, a particulate insoluble organic material, a particu Water soluble fusible material, a particulate soluble organic late inorganic soluble material, a particulate inorganic insoluble material and miXtures thereof. material, a particulate insoluble organic material, a particu late inorganic soluble material, a particulate inorganic 15 insoluble material and miXtures thereof.
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