CA2123160C

CA2123160C - Controlled release formulation

Info

Publication number: CA2123160C
Application number: CA002123160A
Authority: CA
Inventors: Ronald Brown Miller; Stewart Thomas Leslie; Sandra Therese Antoinette Malkowska; Kevin John Smith; Walter Wimmer; Horst Winkler; Udo Hahn; Derek Allan Prater
Original assignee: Euro Celtique SA
Current assignee: Euro Celtique SA
Priority date: 1993-05-10
Filing date: 1994-05-09
Publication date: 2003-04-29
Anticipated expiration: 2014-05-09
Also published as: NO993484L; US6254887B1; ATE303140T1; HUT75703A; ES2159591T3; NO941719L; AU3995797A; SG67347A1; EP1527775B1; EP1468679B1; NO993484D0; PT1527775E; US6326027B1; US7074430B2; DE729751T1; DK0699436T3; DK0699436T4; US20010036477A1; DE09004973T1; JP2002154954A

Abstract

A controlled release preparation for oral administration contains tramadol, or a pharmaceutically acceptable salt thereof, as active ingredient.

Description

ONTROLLED RELEASE FORMULATION
The present irmention relates to a controlled release preparation for oral administration, to processes for its preparation and to its medical use. In particular, the invention relates to a controlled release preparation comprising tramadol or a pharmaceutically acceptable salt thereof.
Tramadol, which has the chemical name (~-traps-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl) cyclohexanol, is an orally active opioid analgesic.
Conventional release preparations in the form of capsules, drops and suppositories containing tramadol, or more particularly its hydrochloride salt, have been commercially available for many years for use in the treatment of moderate to severe pain; Such preparations, however, do not provide a controlled release of the tramadol. Moreover, despite tramadol's long-standing use, controlled release preparations for oral adminisaation containing tramadol as active ingredient have not even previously been described in the literature.
The present in~rention provides an oral controlled release tramadol preparation comprising tramadol or a pharmaceutically acceptable salt thereof suitable for at least twelve-hourly (e.g. up to twenty-four hourly) administration for the treatment of pain.
Suitable pharmaceutically acceptable salts of tramadol for use according to the present invention are those conventionally known in the art such as pharmaceutically acceptable acid addition salts. The hydrochloride salt is particularly preferred.
A controlled release preparation according to the present invention is one that achieves slow release of a drug over an extended period of time, thereby extending the duration of drug action over that achieved by conventional delivery. Preferably such a preparation maintains a drug concentration in the blood within the therapeutic range for 12 hours or more.

'The present inventors have found that in order to allow for controlled release tramadol over at least a twelve hour period following oral administration, the in vitro release rate preferably corresponds to the following % rate of tramadol released:
TABLE 1 i T-- IME (lEln % RELEASED

4 _ 3_95 36 > 80 Another preferred preparation especially suited for twice-a-day dosing has an in vitro release rate corresponding to the following % rate of tramadol released:

TABLE 2 . I

T~ % RELEASED

Yet another preferred preparation particularly suited for once-a-day dosing has an in-vitro release rate corresponding to the following % rate of tramadol released:

T~ % RELEASED

I

24 > 90 A still further preferred preparation in accordance with the invention also particularly suited for once-a-day dosing has an in vitro release rate corresponding to the following rate of tramadol released.

25-RPR-1994 16:16 MRRKS 8: CLEPK L01~lUCah! 071 404 4910 P.02 ~8l~r~iBEp 2 p-4p 12 2o-~s _ ~
. ___ More pretenbly a prepindon for oace-t.d'y doeing~ hwr ra in vitro releue rAte substaatially as follow:
w~mr~--~e TII~ (~ 9i T>ElANIADOL R~~

8 40.60 lx 49-69 i6 57-Tl 25-RPR-1994 16:16 f'1RRKS ~. CLERK LCh~ILiC~i~i X71 4G~4 4910 P. ~~
2123.160 Another preFenod diccolution rate in :~ upon release of the controlled release preparation for administration twice deity according to the invention, is betWaen 5 and 50 % (by weight) tra~dol released after 1 hour, between 10 sad 75 % (by weight) tramadol releaeod after 2 hours, between 20 and 95 % (by weight) tramadol released after 4 hours, betwoea 40 and 10096 (by weight) tran~adol nleaaed after 8 bouts, more than 50% (by weight) tramadal released altar 12 hours, more thane 70% (by weight) released agar 18 hours and more than 80% (by weight) tramadol released after hours.
lrlrwermore, it is preferred in the rest of a conaolled reiease preparation for adminietratioa twice daily that rafter 8 hours failowls~ oral administrwaoll between ~0 sad 9196 (by weight) tramadol is absorbed , between 77 and 47 % (by weight) ~~ol is absorbed after 10 homre and betareea 80 and 100 % (by weight) ~l it absorbed after 12 hours.
A tormttlatlan fa accordance with the inv~on cuitable for twice-a-day dosing tray have a tmau of 1.3 to 8 hours, preferabiy 2 w 7.houre, and a W~ value in the ranfge 7 to I6 hours.
A formulation is accowith tho invead4a suitable for ouce~aday doai~ may have a tnwx is the range of 3 to 6 hours, preferably 4 to. s boars sad a Wa, value is the rtwgt of 10 to 33 twun.
T~ Wso Pw~ter det~tes the width of the plaarna profile at 50 % G~a~t, s. e.
the dutatiori over which the plasma coace~ ~, oq~ to or greater than SO % of the peak cotrceratratioa. The parameter is determined by linear Interpolation of the observed data aril represents the dltfereace in time between the first (or only) upsl~
ct~iag and the test (or only) downalope ceoraaina in the plaiuna profile.
~ ~ relearjp rate! lnenfi0ned hCrela arC, CXCCpt WherC 0t11Crw16C 6peCi0ed, those obtained by measurement u:ia$ the Pb. >;ur. Pr;iddle Method at 100rpm iuf 900m10.1 N hydrochloric acid at 37°C and usir~ UV detection at 270nm.

25-APR-1994 16:17 hIRRKS & c~LERIE Lr_y~lL:~r!~! 071 404 4910 P.04 The controlled release preparation according to the Invention preferably contafttr: an aaalgesicatlly , effective autount of tra>uadol or a pharmaceutically acceptable silt th~of, conveniently in the ratlga of from s0 to 800 mg, especially 1U0, Zap, 30p, q~p t0 6001>C!g (Calculated ae tramadol hydrochloride) per dosage unit.
Tire controlled release preparation according to the invention raay be prersnted, for ~ple, as $raaules, spheroids, pellets. muitipatticuJatea, capsules, tabteu, sachets, corsfirolled release suspensions, or in auy other suitable dosage form incorporating such lnanuks, spheroids, pellets or multiparticulates.
The active ingredient in the preparation accordlr>fg to the iapention may suirably be iacOrporated in a matrix. This stay be any matrix that affords controlled release tt'amadol over at least a twelve hour period a~ preferably that afford~c dlet4ludon rates and ]~jyQ a~orption rates of tramadol within tire rare tpecif'ted above. Pretierably the taatrix is a controlled release matrix. Alteraaavely, aortnal ~l~ BRCS's having a coadttg which providva for coturolla! release of the tctive ittgrediettt nay be used.
Suitable materials for iraclueioa in a conttvltod reieasa ~t~ h~lude (a) l;ydrophiltic or hydrophobic polymers, each ~ g>ams. ce:lulose others, acrylic resins and protein dorlved , Ot these polytaer9. the cellulose ether, especially. alkylcelluloaes rre preferred. The preparatiaa may eo>avsnisntly contain between 1 % a>Ad 80% (by weight) of one or more hydrophiUic or hydrophobic polymers. , (b) b3ge:dble. long chain (C,-Cue, aap~ially C~z.G~~ ~bstituted or uaeubr<titbted hydrocarbons, such as fatty acids, fatty alcohole, glyeeryl estete of fatty odds, mineral and vogetable oils and waxes, Hydrveubonr having a melting point of ~123~.60 between 25 and 90°C are preferred. Of these long chain 'hydrocarbon materials, fatty (aliphatic) alcohols are preferred. The preparation may conveniently contain up to 60 % (by weight) of at least one digestible, long chain hydrocarbon.
(c) Polyalkylene glycols. The preparation may suitably contain up to 60% (by weight) of one or more polyalkylene glycols.
One particularly suitable controlled release , matrix comprises one or more alkylcelluloses and one or more C,2-C36 aliphatic alcohols. The alkylcellulose is preferably C,-C6 alkyl cellulose, especially ethyl cellulose. The controlled release preparation according to the invention preferably contains from 1 to 20% (by weight), especially from 2 to 15 % (by weight) of one or more alkylcelluloses.
The aliphatic alcohol may conveniently be lauryl alcohol, myristyl alcohol or stearyl alcohol but is preferably cetyl alcohol or more preferably cetostearyl alcohol. The controlled release preparation suitably contains from S to 30% (by weight) of aliphatic alcohol, especially from 10 to 25 % (by weight) of aliphatic alcohol.
Optionally the controlled release matrix may also contain other pharmaceutically acceptable ingredients which are conventional in the pharmaceutical art such as diluents, lubricants, binders, granulating aids, colourants, flavourants, surfactants, pH
adjusters, anti-adherents and glidants, e.g. dibutyl sebacate, ammonium hydroxide, oleic acid and colloidal silica.
The controlled release preparation according to the invention may conveniently be film coated using any film coating material conventional in the pharmaceutical art.
Preferably an aqueous film coating is used.
Alternatively, the controlled release preparation according to the invention may comprise a nornnal release matrix having a controlled release coating.
Preferably the preparation comprises film coated spheroids containing the active ingredient and a ~~2~~so spheronising agent.
The spheronising agent may be any suitable pharmaceutically acceptable material which may be spheronised together with the active ingredient to form spheroids. A
preferred spheronising agent is microcrystalline cellulose. The microcrystalline cellulose used may suitably be, for example, Avicel PH 101 or Avicel PH 102 (Trade Marks, FMC
Corporation).
Optionally the spheroids may contain other pharmaceutically acceptable ingredients conventional in the pharmaceutical art such as binders, bulking agents and colourants.
Suitable binders include water soluble polymers, water soluble hydroxyalkyl celluloses such as hydroxypropylcellulose or water insoluble polymers (which may also contribute controlled release properties) such as acrylic polymers or copolymers for example ethylcellulose. Suitable bulking agents include lactose.
The spheroids are coated with a material which permits release of the active ingredient at a controlled rate in an aqueous medium. Suitable controlled release coating materials include water insoluble waxes and polymers such as polymethacrylates (for example Eudragit polymers, Trade Mark) or water insoluble celluloses, particularly ethylcellulose. Optionally, water soluble polymers such as polyvinylpyrrolidone or water soluble celluloses such as hydroxypropylmethylcellulose or hydroxypropylcellulose may be included. Optionally other water soluble agents such as polysorbate 80 may be added.
Alternatively the drug may be coated onto inert non-pareil beads and the drug loaded beads coated with a material which permits control of the release of the active ingredient into the aqueous medium.
In a further aspect the present invention provides a process for preparing a controlled release preparation according to the present invention comprising incorporating tramadol or a pharmaceutically acceptable salt thereof in a controlled release matrix, for example by (a) granulating a mixture comprising tramadol or a pharmaceutically acceptable salt thereof and one or more alkylcelluloses, (b) mixing the alkylcellulose containing granules with one or more C,2_36 aliphatic alcohols; and optionally (c) shaping and compressing the granules, and film coating, if desired; or (d) granulating a mixture comprising tramadol or a pharmaceutically acceptable salt thereof, lactose and one or more alkylcelluloses with one or more 02_36 aliphatic alcohol; and, optionally, (e) shaping and compressing the granules, and film coating, if desired.
The controlled release preparation according to the invention may also be prepared in the form of film coated spheroids by (a) granulating the mixture comprising tramadol or a pharmaceutically acceptable salt thereof and a spheronising agent;
(b) extruding the granulated mixture to give an extrudate;
(c) spheronising the extrudate until spheroids are formed; and (d) coating the spheroids with a film coat.
One preferred form of unit dose form in accordance with the invention comprises a capsule filled with controlled release particles essentially comprising the active ingredient, a hydrophobic fusible carrier or diluent and optionally a hydrophillic release modifier. In particular, the controlled release particles are preferably prepared by a process which comprises forming a mixture of dry active ingredient and fusible release control materials followed by mechanically working the mixture in a high speed mixer 2~.23~.~0 to with an energy input sufficient to melt or soften the fusible material whereby it forms particles with the active ingredient. The resultant particles, after cooling, are suitably sieved to give particles having a size range from 0.1 to 3.Omm, preferably 0.25 to 2.Omm. An example according to the invention is described below which is suitable for the commercial production of dosage units.
When using such a processing technique it has been found that, in order most readily to achieve the desired release characteristics (both in vivo and in vitro as discussed above) the composition to be processed should comprises two essential ingredients namely:
(a) tramadol or salt thereof; and (b) hydrophobic fusible carrier or diluent; optionally together with (c) a release control component comprising a water-soluble fusible material or a particulate soluble or insoluble organic or inorganic material.
We have found that the total amount of tramadol or pharmaceutically acceptable salt thereof in the composition may vary within wide limits, for example from 10 to 90%
by weight thereof.
The hydrophobic fusible component (b) should be a hydrophobic material such as a natural or synthetic wax or oil, for example hydrogenated vegetable oil, hydrogenated castor oil, microcrystalline wax, Beeswax, Carnauba wax or glyceryl monostearate, and suitably has a melting point of from 35 to 140°C, preferably 45 to 110°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.

-, 2123160 Another preferred process for the manufacture of a formulation in accordance with the invention comprises (a) mechanically working in a high-speed mixer, a mixture of tramadol or a pharmaceutically acceptable salt in particulate form and a particulate, hydrophobic fusible carrier or diluent having a melting point from 35 to 140°C
and optionally a release control component comprising a water soluble fusible material, or a particulate soluble or insoluble organic or inorganic material at a speed and energy input which allows the carrier or diluent to melt or soften, whereby it forms agglomerates, (b) breaking down the larger agglomerates to give controlled release seeds;
and (c) continuing mechanically working with optionally a further addition of low percentage of the carrier or diluent.
(d) optionally repeating steps (c) and possibly (b) one or 'more times.
This process is capable of giving a high yield (over 80%) of particles in a desired size range, with a desired uniformity of release rate of tramadol or salt thereof.
The resulting particles may be sieved to eliminate any over-or undersized material then formed into the desired dosage units by for example, encapsulation into hard gelatin capsules containing the required dose of the active substance or by compression into tablets.
In this method in accordance with the invention preferaby all the tramadol or salt thereof is added in step (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 10% and 90% w/w of the total amount of ingredients added in the entire manufacturing operation, more preferably between 20 % and 70% w/w.

Stage (a) of the process may be carried out in conventional high speed mixers with a standard stainless steel interior, e.g. a,Collette Vactron 75 or equivalent mixer. The mixture is processed until a bed temperature about 40°C or above is achieved and the resulting mixture acquires a cohesive granular texture, with particle sizes ranging from about 1-3mm to fine 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 fingers. 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 temperature in the range room temperature to 37°C
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 2mm. It is currently preferred to carry out the classification using a Jackson Crockatt 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 reducing yield. A mesh size of 12 has been found adequate.
The classified material is returned to the high speed mixer and processing continued.
It is believed that this leads to cementation of the finer particles into particles of uniform size range.
In one preferred form of the method of the invention processing of the classified materials is continued, until the hydrophobic fusible materials used begin to soften/melt and optionally additional hydrophobic fusible material is then added. Mixing is continued until the mixture has been transformed into particles of the desired predetermined size range.

In order to ensure uniforrn_ energy input into the ingredients in the high speed mixer it is preferred to supply at least 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.
After the particles have been formed they are cooled or allowed to cool, and may then be sieved to remove any over or undersized material.
The resulting particles may be used to prepare dosage units in accordance with the invention in the form of e.g. tablets or capsules in manners known er se.
We have also mound that particles containing tramadol or salt thereof produced by a melt processing as described in WO 93/18753, published September 30, 1993 as well as the process described herein are particularly useful for processing into the form of tablets.
We have found that by suitable selection of the materials used in forming the particles and in the tabletting and the proportions in which they are used, enables a significant degree of control in the ultimate dissolution and release rates of the tramadol or salt thereof from the compressed tablets.
Usually, to form a tablet in accordance with the invention, particles prepared as described above will be admixed with tabletting excipients e.g. one or more of the standard excipients such as diluents, lubricants, binding agents, flow aids, disintegrating agents, surface active agents or water soluble polymeric materials.
Suitable dilue:nts are e.g. microcrystalline cellulose, lactose and dicalcium phosphate.
Suitable lubricants are e.g. magnesium stearate and sodium stearyl fumarate.
Suitable binding agents are e.g. hydroxypropyl methyl cellulose, polyvidone and methyl cellulose.

14 212~3160 Suitable disintegrating agents are starch, sodium starch glycolate, crospovidone and croscarmalose sodium.
Suitable surface active are Poloxamer 188~, polysorbate 80 and sodium lauryl sulfate.
Suitable flow aids are talc colloidal anhydrous silica.
Suitable water soluble polymers are PEG with molecular weights in the range 1000 to 6000.
To produce tablets in accordance with the invention, particles produced in accordance with the invention may be mixed or blended with the desired excipient(s), if any, using conventional procedures, e.g. using a Y-Cone or bin-blender and the resulting mixture compressed according to conventional tabletting procedure using a suitable size tabletting mould. Tablets can be produced using conventional tabletting machines, and in the embodiments described below were produced on standard single punch F3 Manesty machine or Kilian RLE15 rotary tablet machine.
Generally speaking we find that even with such a highly water soluble active agent as tramadol or salt thereof tablets formed by compression according to standard methods give very low release rates of the active ingredient e.g. corresponding to release over a period of greater than 24 hours, say more than 36. We have found that the release profile can be adjusted in a number of ways. For instance a higher loading of the drug will be associated with increased release rates; the use of larger proportions of the water soluble fusible material in the particles or surface active agent in the tabletting formulation will also be associated with a higher release rate of the active ingredient.
By controlling the relative amounts of these ingredients it is possible to adjust the release profile of the tramadol or salt thereof.
In order that the invention may be well understood the following examples are given by way of illustration only.

14a BRIEF DESCRIPTION OF THE DRAWINGS
The present invention is further illustrated in connection with the accompanying drawings in which:
FIG. 1 is a graphical depiction of the serum levels of tramadol following administration of one tablet according to Example 2 in 12 healthy volunteers;
and FIG. 2 is a graphical depiction of the plasma profile resulting from single dose administration of the tablet of Example 8 in comparison to the administration of a commercial preparation of tramadol drops 100 mg in a trial involving five healthy male volunteers.

Example 1 Tablets having the following formulation were prepared:
mg/tablet Tramadol Hydrochloride 100 Lactose Ph. Eur. 68.0 Ethylcellulose (Surelease~ 15 % solids) Purified Water Ph. Eur. 13.3 Cetostearyl Alcohol Ph. Eur. 42.00 (Dehydag wax 0) Magnesium Stearate Ph. Eur. 2,00 Purified Talc Ph. Eur. ' 3,00 230.00 * Removed during processing.
Tramadol hydrochloride ( 100mg) and lactose (68mg) were granulated, transferred to a fluid bed granulator and sprayed with ethylcellulose (l5mg) and water. The granules were then dried at 60°C and passed through a 1mm screen.
To the warmed tramadol containing granules was added molten cetostearyl alcohol (42mg) and the whole was mixed thoroughly. The granules were allowed to cool and sieved through a l.6mm screen. Purified talc and magnesium stearate were added and mixed with the granules. The granules were then compressed into tablets.
The tablets were coated with a film coat having the formulation given below mg/tablet Hydropropylmethylcellulose 0.770 Ph. Eur. 15 cps (Methocel E15) Hydroxypropylmethylcellulose 3 , g7 (Ph. Eur. 5 cps (Methocel ES) Opaspray M-1-7111B (33% solids) 2.57 Polyethylene glycol 400 0.520 USNF

Purified Talc Ph. Eur. 0.270 Purified Water Ph. Eur. 55.52*

* Remove during processing.
Example 2 Tablets having the following formulation were prepared:
mg/tablet Tramadol hydrochloride 100.0 Lactose Ph. Eur. 58.0 Ethylcellulose USNF 15.0 (Ethocel 45 CP) Cetostearyl alcohol Ph. 52.0 Eur.

(Dehydag wax O) Magnesium stearate Ph. 2,00 Eur.

Purified talc Ph. Eur. 3,00 A mixture of tramadol hydrochloride (100mg), lactose (58mg) and ethylcellulose ( l5mg) was granulated whilst adding molten cetostearyl alcohol (52mg) and the whole was mixed thoroughly. The granules were allowed to cool and sieved through a l.6mm screen. Purified talc and magnesium stearate were added and mixed with the granules. The granules were then compressed into tablets which were coated with a film coat having the formulation given in Example 1.
Example 3 Film coated tablets were produced following the procedure described in Example 2 and having the following formulation:

mg/tablet Tramadol hydrochloride 1~,~

Lactose Ph. Eur. 70.50 Iiydroxyethylcellulose Ph. 12.50 Eur.

Cetostearyl alcohol Ph. 42.00 Eur.

Magnesium stearate Ph. Eur.2.00 Purified talc Ph. Eur.

In vitro dissolution studies In vitro dissolution studies were conducted on tablets prepared as described above.
Results are given in Table 1.

WT % TRAMADOL
RELEASED

Time (hl Example 1 Example 2* Example 3 * Measured on tablet core In a trial involving 12 healthy volunteers the serum levels of tramadol following administration of one tablet according to Example 2 was found to be as illustrated in Figure 1.

is Example 4 and 5 Particles having the formulations given in Table II below , were prepared by the steps of:
i. Placing the ingredients (a) and (c) (total batch weight 0.7kg) in the bowl of a litre capacity Collette Gral Mixer (or equivalent) equipped with variable speed mixing and granulating blades;
ii. Mixing the ingredients at about 150-1000rpm whilst applying heat until the contents of the bowl are agglomerated.
iii. Classifying the agglomerated material by passage through a Comil and/or Jackson Crockatt to obtain controlled release seeds.
iv. Warming and mixing the classified material in the bowl of a 10 litre Collette Gral, until uniform multiparticulates of the desired pre-determined size range are formed in yield of greater than 80%. This takes approximately 5 minutes.
v. Discharging the multiparticulates from the mixer and sieving them to separate out the multiparticulates collected between 0.5 and 2mm aperture sieves.
TABLE II

Examle 4 5 (a) Tramadol HCl (Wt%) 50 75 (b) Hydrogenated Vegetable Oil (Wt%)50 25 Example 6 Samples of the particles from Example 4 were blended with magnesium stearate and purified talc using a Y-Cone or bin-blender. The blended mixture was then compressed using either (1) 14 x 6mm, (2) 16 x 7mm or (3) 18.6 x 7.Smm capsule shaped tooling on a single punch F3 Manesty tabletting machine to give tablets giving 200, 300 and 400mg of tramadol HCI. The ingredients per dosage unit amounted to the following:
TABLE III

TABLET MGlTABLET
INGREDI

ENT
2 ~ 3 Tramadol Hcl 200 300 400 Hydrogenated Vegetable Oil 200 300 400 Sub Total 400 600 800 Purified Talc 12.63 18.95 25.26 Magnesium Stearate 8.42 12.63 16.84 The tablets were assessed by the dissolution using Ph. Eur. Paddle Method 100 rpm, 0.1 N HCI.
To assess the non-compressed particles the Ph Eur. Paddle was replaced by a modified Ph Eur. Basket.
The resslts are shown in Table IV below;

~l2mso ., TABLE IV

HOURS AFTER Particles Table 1 Table Ta 1e EST

% TRAMADOL
HCl RELEASED

i 12 98 55 49 49 These results confirm the effectiveness of the tabletting in reducing the release rate.
Exam~de 7 Samples of the particles from Example 5 were then tabletted using a procedure similar to Example 3 and the ingredients per unit dosage amounted to:

~12~1.~0 TABLE V

TABLET MG/TABLET
INGREDIEN

T

Tramadol Hcl 200 300 400 Hydrogenated Vegetable 66.7 100 133 Oil Sub Total 266.7 400 533 Purified Talc 7.63 11.44 15.25 Magnesium Stearate 5.16 7.63 10.17 The tablets and samples of non-compressed multiparticulates (each sample containing 400mg of tramadol hydrochloride) were assessed by the dissolution method also described above. The results are shown in Table VI below;
TABLE VI

HOURS AFTER P icl Tablet Tablet ~ Tablet START OF TEST
% TRAMADOL
HCl RELEASED

6 102 94 83 ~ 84 These results show that by increasing the loading of the highly water soluble tramadol hydrochloride (75% w/w in this example compared with 50% w/w in Example 6) a significantly faster release rate of the active ingredient can be achieved.
Examule 8 Example 4 was repeated but with the following formulation:
Tramadot HCl 200 mg/tablet Hydrogenated Vegetable Oil 163.0 mg/tablet The resulting multiparticulates were blended as described in Example 6 with the following;
Purified Talc 11.5 mg/tablet Magnesium Stearate 7.66 mg/tablet The blend was then compressed as described in Example 6 but using l5mm x 6.Smm normal concave capsule shaped plain/plain punches.
The resulting tablets were then assessed by the dissolution method described above.
The results are shown in Table V.

2~.23~,60 HOURS AFTER START OF TEST % TRAMADOL HC1 RELEASED

In a trial involving five healthy male volunteers the plasma profile resulting from single dose administrations of the above tablet are shown in Figure 2 in comparison to the administration of a commercial preparation of Tramadol drops 100mg.

Claims

1. A controlled release oral pharmaceutical preparation suitable for dosing every 24 hours containing from about 50 mg to about 800 mg of tramadol or a pharmaceutically acceptable salt thereof, calculated as hydrochloride salt, in a controlled release matrix, the matrix comprising from about 1 to about 80% w/w of one or more hydrophilic or hydrophobic polymers, and having a dissolution rate in vitro when measured using the Ph. Eur. Paddle Method at 100 rpm in 900 ml 0.1N
hydrochloric acid at 37°C and using UV detection at 270 nm, from about 0 to about 50% tramadol released after 1 hour; from about 0 to about 75% tramadol released after 2 hours; from about 3 to about 95% tramadol released after 4 hours; from about 10 to about 100% after 8 hours; from about 20 to about 100% tramadol released after 12 hours; from about 30 to about 100%
tramadol released after 16 hours; from about 50 to about 100% tramadol released after 24 hours;
and greater than 80%
tramadol released after 36 hours, by weight.

2. A controlled release preparation as claimed in claim 1, having an in-vitro dissolution rate measured by the Ph. Eur. Paddle Method at 100 rpm in 900 ml 0.1N hydrochloric acid at 37°C and using UV detection at 270 nm as set forth below:
TIME (H)~~% RELEASED
1~~~20-50 2~~~40-70 4~~~60-95 8~~~80-100 12~~~90-100

3. A controlled release preparation as claimed in claim 1, having an in-vitro dissolution rate measured by the Ph. Eur. Paddle Method at 100 rpm in 900 ml 0.1N hydrochloric acid at 37° C and using UV detection at 270 nm as set forth below:

TIME (H)~~~% RELEASED
1~~~~0-50 2~~~~0-75

4~~~~10-95 8~~~~35-100 12~~~~55-100 16~~~~70-100 24~~~~>90 4. A controlled release preparation as claimed in claim 1, having an in-vitro dissolution rate measured by the Ph. Eur. Paddle Method at 100 rpm in 900 ml 0.1N hydrochloric acid at 37° C and using UV detection at 270 nm as set forth below:
TIME (H)~~~% RELEASED
1~~~~0-30 2~~~~0-40 4~~~~3-55 8~~~~10-65 12~~~~20-75 16~~~~30-88 24~~~~50-100 36~~~~>80

5. A dosage form according to any one of claims 1 to 4, wherein said matrix comprises a cellulose ether.

6. A dosage form according to claim 5, wherein said matrix comprises a controlled release matrix comprising at least one alkylcellulose, and at least one C12 to C36, aliphatic alcohol.

7. A dosage form according to claim 6, wherein said matrix further comprises at least one polyalkylglycol.

8. A dosage form according to claim 7, wherein said polyalkylglycol is polyethylene glycol.

9. A dosage form according to claim 6, 7 or 8, wherein said at least one C12 to C36 aliphatic alcohol is a C14 to C22 aliphatic alcohol.

10. A dosage form according to any one of claims 6 to 9, wherein said alkylcellulose is a C1-C6 alkylcellulose.

11. A dosage form according to any one of claims 6 to 10, wherein the dosage form contains from about 1 to about 20% w/w of said alkylcellulose.

12. A dosage form according to any one of claims 6 to 11, wherein said aliphatic alcohol is selected from the group consisting of lauryl alcohol, myristyl alcohol, stearyl alcohol, cetyl alcohol, cetostearyl alcohol, and mixtures thereof.

13. The dosage form of claim 12, wherein said aliphatic alcohol is cetyl alcohol or cetostearyl alcohol.

14. A dosage form according to any one of claims 6 to 13, wherein said dosage form contains from about 5 to about 30% w/w of said aliphatic alcohol.

15. A dosage form according to claim 14, wherein said dosage form contains from about 10 to about 25% w/w of said aliphatic alcohol.

16. A dosage form according to any one of claims 1 to 15, in the form of film coated spheroids, wherein said spheroid matrix comprises a spheronizing agent.

17. A dosage form according to any one of claims 1 to 15, in the form of multi-particulates wherein said matrix comprises a hydrophobic fusible carrier or diluent having a melting point from 35 to 140°C.

18. A dosage form according to claim 17, wherein said matrix further comprises a release control component comprising a water soluble fusible material, or a particulate soluble or insoluble organic or inorganic material.

19. A dosage form which comprises a tablet formed by compressing a multiparticulate according to claim 17 or 18.

20. A dosage form according to claim 5, wherein said cellulose ether is an alkylcellulose.

21. A dosage form according to claim 20, wherein said alkylcellulose is ethylcellulose.

22. A dosage form according to any one of claims 1 to 21, which provides a t max from about 3 to about 6 hours.

23. A dosage form according to any one of claims 1 to 22, which provides a W50 from about 10 to about 33 hours.

24. A controlled release preparation suitable for dosing every twelve hours containing from about 50 to about 400 mg tramadol or pharmaceutically acceptable salt thereof, calculated as the hydrochloride salt, in a controlled release matrix containing from about 1 to about 80% w/w of one or more hydrophilic or hydrophobic polymers, said preparation exhibiting an in vitro dissolution rate when measured by the Ph. Eur. Paddle Method at 100 rpm in 900 ml 0.1N
hydrochloric acid at 37°C
and using UV detection at 270 nm, such that between 5 and 50% by weight tramadol is released after 1 hour, between 10 and 75% by weight tramadol is released after 2 hours, between 20 and 95% by weight tramadol is released after 4 hours, between 40 and 100% by weight tramadol is released after 8 hours, more than 50% by weight tramadol is released after 12 hours, more than 70% by weight tramadol is released after 18 hours and more than 80% by weight tramadol is released after 24 hours.

25. A dosage form according to claim 24, wherein said controlled release matrix comprises a cellulose ether.

26. A dosage form according to claim 25, wherein said cellulose ether is an alkyl cellulose.

27. A dosage form according to claim 25, wherein said controlled release matrix comprises at least one C1 to C6 alkyl cellulose.

28. A dosage form according to claim 27, wherein said controlled release matrix further comprises at least one C12 to C36 aliphatic alcohol.

29. A dosage form according to claim 28, wherein said controlled release matrix comprises at least one C14 to C22 aliphatic alcohol.

30. A dosage form according to claim 29, wherein said controlled release matrix further comprises at least one polyalkylglycol.

31. A dosage form according to claim 30, wherein said polyalkylglycol is polyethylene glycol.

32. A dosage form according to any one of claims 26 to 31, wherein said dosage form contains from about 1 to about 20% w/w of said alkyl cellulose.

33. A dosage form according to claim 32, wherein said dosage form contains from about 2 to 15%
w/w of said alkyl cellulose.

34. A dosage form according to claim 28, wherein said aliphatic alcohol is selected from the group consisting of lauryl alcohol, myristyl alcohol, stearyl alcohol, cetyl alcohol, cetostearyl alcohol, and mixtures thereof.

35. A dosage form according to claim 28, 29 or 34, wherein said dosage form contains from about to about 30% w/w of said aliphatic alcohol.

36. A dosage form according to claim 35, wherein said dosage form contains from about from to 25% w/w of said aliphatic alcohol.

37. A dosage form according to any one of claims 24 to 36, in the form of multiparticulate spheroid matrices, wherein said spheroid matrix comprises a spheronizing agent.

38. A dosage form according to claim 37, wherein said spheronizing agent comprises microcrystalline cellulose.

39. A dosage form according to any one of claims 24 to 36, in the form of multiparticulates wherein said matrix comprises a hydrophobic fusible carrier or diluent having a melting point from 35 to 140°C.

40. A dosage form according to claim 39, wherein said matrix further comprises a release control component comprising a water soluble fusible material, or a particulate soluble or insoluble organic or inorganic material.

41. A dosage form according to any one of claims 24 to 40, which provides a t max from about 1.5 to about 8 hours.

42. A dosage form according to any one of claims 24 to 41, which provides a W50 from about 7 to about 16 hours.

43. A controlled release oral pharmaceutical preparation suitable for dosing every 24 hours, comprising:
a substrate comprising a pharmaceutically effective amount of tramadol or a salt thereof;
said substrate coated with a controlled release coating;
said preparation having a dissolution rate in vitro when measured using the Ph. Eur.
Paddle Method at 100 rpm in 900 ml. 0.1 N hydrochloric acid at 37°C and using UV detection at 270 nm, between 0 and 50% tramadol released after 1 hour; between 0 and 75%
tramadol released after 2 hours; between 3 and 95% tramadol released after 4 hours;
between 10 and 100% tramadol released after 8 hours; between 20 and 100% tramadol released after 12 hours;
between 30 and 100% tramadol released after 16 hours; between 50 and 100%
tramadol released after 24 hours; and greater than 80% tramadol released after 36 hours, by weight.

44. A controlled release preparation as claimed in claim 43, having an in vitro dissolution rate measured by the Ph. Eur. Paddle Method at 100 rpm in 900 ml 0.1 N
hydrochloric acid at 37 °C and using UV detection at 270 nm as set forth below:

TIME (H) % RELEASED

45. A controlled release preparation as claimed as claim 43, having an in vitro dissolution rate measured by the Ph.Eur. Paddle Method at 100 rpm in 900 ml 0.1 N
hydrochloric acid at 37°C and using UV detection at 270 nm as set forth below:

TIME (H) % RELEASED

24 >90

46. A controlled release preparation as claimed in claim 43, having an in vitro dissolution rate measured by the Ph. Eur. Paddle Method at 100 rpm in 900 ml 0.1 N
hydrochloric acid at 37°C and using UV detection at 270 nm as set forth below:

TIME (H) % RELEASED

36 >80

47. A controlled release preparation according to any one of claims 43 to 46, wherein said substrate comprises a plurality of spheroids.

48. A controlled release preparation according to claim 47, wherein said spheroids comprise a spheronizing agent.

49. A controlled release preparation suitable for dosing every twelve hours, comprising:
a substrate comprising an effective amount of tramadol or pharmaceutically acceptable salt thereof, calculated as the hydrochloride salt; and said substrate coated with a controlled release coating;
said preparation exhibiting an in vitro dissolution rate when measured by the Ph. Eur.
Paddle Method at 100 rpm in 900 ml 0.1 N hydrochloric acid at 37°C and using UV detection at 270 nm, such that between 5 and 50% by weight tramadol is released after 1 hour, between 10 and 75% by weight tramadol is released after 2 hours, between 20 and 95% by weight tramadol is released after 4 hours, between 40 and 100% by weight tramadol is released after 8 hours, more than 50% by weight tramadol is released after 12 hours, more than 70% by weight tramadol is released after 18 hours and more than 80% by weight tramadol is released after 24 hours.

50. A controlled release preparation according to claim 49, wherein said substrate comprises a plurality of spheroids.

51. A controlled release preparation according to any one of claims 43 to 50, which provides a t max at 2 to 7 hours after oral administration.

52. A controlled release preparation according to any one of claims 43 to 50, which provides a t max at 1.5 to 8 hours after oral administration.

53. A controlled release preparation according to any one of claims 49 to 52, which provides a W50 in the range of 7 to 16 hours when orally administered.

54. A controlled release preparation according to any one of claims 49 to 53, wherein said substrate is a tablet.

55. A controlled release oral pharmaceutical tablet suitable for dosing every 24 hours, comprising:

a tablet containing a pharmaceutically effective amount of tramadol or a salt thereof;
said tablet coated with a controlled release coating;
said coated tablet having a dissolution rate in vitro when measured using the Ph. Eur.
Paddle Method at 100 rpm in 900 ml 0.1 N hydrochloric acid at 37°C and using UV
detection at 270 nm, between 0 and 50% tramadol released after 1 hour; between 0 and 75% tramadol released after 2 hour; between 3 and 95% tramadol released after 4 hours;
between 10 and 100% tramadol released after 8 hours; between 20 and 100%
tramadol released after 12 hours; between 30 and 100% tramadol released after 16 hours;
between 50 and 100% tramadol released after 24 hours; and greater than 80% tramadol released after 36 hours, by weight, and providing a W50 in the range of 10 to 33 hours when orally administered.

56. A controlled release oral pharmaceutical tablet suitable for dosing every 24 hours, comprising:
a tablet containing a pharmaceutically effective amount of tramadol or a salt thereof;
said tablet coated with a controlled release coating;

said coated tablet having an in vitro dissolution rate measured by the Ph.
Eur. Paddle Method at 100 rpm in 900 ml 0.1 N hydrochloric acid at 37°C and using UV detection at 270 nm as set forth below:

TIME (H) % RELEASED

57. A controlled release oral pharmaceutical tablet suitable for dosing every 24 hours, comprising:
a tablet containing a pharmaceutically effective amount of tramadol or a salt thereof;
said tablet coated with a controlled release coating;
said coated tablet having an in vitro dissolution rate measured by the Ph.
Eur. Paddle Method at 100 rpm in 900 ml 0.1 N hydrochloric acid at 37°C and using UV detection at 270 nm as set forth below:

58. A controlled release preparation according to any one of claims 43 to 52, which when orally administered provides a W50 value in the range of 10 to 33 hours.

59. A controlled release preparation according to claim 43, having an in vitro dissolution rate measured by the Ph. Eur. Paddle Method at 100 rpm in 900 ml 0.1 N
hydrochloric acid at 37°C and using UV detection at 270 nm as set forth below:

TIME (H) % RELEASED

60. A controlled release preparation according to any one of claims 43 to 50, which when orally administered provides a t max at 4-5 hours after oral administration.

61. A controlled release oral pharmaceutical preparation suitable for dosing every 24 hours, comprising:
a substrate comprising a pharmaceutically effective amount of an opioid analgesic consisting essentially of tramadol or a salt thereof;
said substrate coated with a controlled release coating;
said preparation having a dissolution rate in vitro when measured using the Ph. Eur. Paddle Method at 100 rpm in 900 ml 0.1 N hydrochloric acid at 37°C and using UV detection at 270 nm, between 0 and 50% tramadol released alter 1 hour; between 0 and 75% tramadol released after 2 hours; between 3 and 95% tramadol released after 4 hours; between 10 and 100%
tramadol released after 8 hours; between 20 and 100% tramadol released after 12 hours;
between 30 and 100% tramadol released after 16 hours; between 50 And 100% tramadol released after 24 hours;
and greater than 80% tramadol released after 36 hours, by weight, said preparation providing a therapeutic effect for about 24 hours after oral administration.

62. A controlled release preparation according to any one of claims 43 to 46, 49, 59 and 61, wherein said substrate comprises inert non-pareil beads coated with said tramadol.

63. A controlled release preparation according to any one of claims 43 to 46, 49, 59 and 61, wherein said substrate is a tablet.

64. A controlled release preparation according to claim 59 or 61, wherein said substrate comprises spheroids.

65. A controlled release preparation according to any one of claims 43 to 50, 55 to 57, 59 and 61, which provides a t max from 3 to 6 hours after orally administered to a human patient.

66. A controlled release preparation according to claim 65, which provides a W50 value in the range from 10 to 33 hours.

67. A controlled release preparation in accordance with any one of claims 43 to 66, wherein said controlled release coating comprises a material selected from the group consisting of a water insoluble wax, a water insoluble polymer, a water insoluble cellulose and mixtures of any of the foregoing.

68. A process for the preparation of a solid, controlled release oral dosage form, comprising incorporating a therapeutically effective amount of tramadol or a pharmaceutically acceptable salt thereof in a controlled release matrix such that said dosage form provides a therapeutic effect for at least about 12 hours after oral administration.

69. A process according to claim 68, wherein from about 50 to about 800 mg tramadol, calculated as tramadol hydrochloride is incorporated in the dosage form.

70. A process according to claim 68 or 69, wherein the dissolution rate measured by the Ph.
Eur. Paddle Method at 100 rpm in 900 ml 0.1 N hydrochloric acid at 37°C
and using UV detection at 270 nm is set forth below:

71. A process according to claim 68 or 69, wherein the dissolution rate measured by the Ph.
Eur. Paddle Method at 100 rpm in 900 ml 0.1 N hydrochloric acid at 37°C
and using UV detection at 270 nm is set forth below:

72. A process according to claim 68 or 69, wherein the dissolution rate measured by the Ph.
Eur. Paddle Method at 100 rpm in 900 ml 0.1 N hydrochloric acid at 37°C
and using UV detection TIME (H) % RELEASED

36 >80

73. A process according to any one of claims 68 to 72, wherein said controlled release matrix comprises at least one C1 to C6 alkylcellulose and at least one C12 to C36 aliphatic alcohol.

74. A process according to claim 73, further comprising at least one polyalkylglycol.

75. A process according to claim 73 or 74, wherein said aliphatic alcohol is a C4to C22 aliphatic alcohol.

76. A process according to claim 74, wherein said polyalkylglycol is polyethylene glycol.

77. A process according to any one of claims 73 to 76, wherein said alkylcellulose is ethylcellulose.

78. A process according to any one of claims 73 to 77 wherein said dosage form comprises from about 1 to about 20% w/w of one or more alkylcelluloses.

79. A process according to claim 78, wherein said dosage form comprises from about 2 to about 15% w/w of one or more alkylcelluloses.

80. A process according to any one of claims 73 to 80, wherein said aliphatic alcohol is selected from the group consisting of lauryl alcohol, myristyl alcohol, stearyl alcohol, and mixtures thereof.

81. A process according to any one of claims 73 to 80, wherein said aliphatic alcohol is selected from the group consisting of cetyl alcohol, cetostearyl alcohol, and mixtures thereof.

82. A process according to any one of claims 73 to 80, wherein said dosage form comprises from about 5 to about 30% w/w of at least one aliphatic alcohol.

83. A process according to claim 82, wherein said dosage form comprises from about 10 to about 25% w/w of at least one aliphatic alcohol.

84. A process according to claim 73, further comprising:

(a) granulating a mixture comprising said tramadol or a pharmaceutically acceptable salt thereof and one or more alkylcelluloses; and (b) mixing the resultant alkylcellulose containing granules with one or more aliphatic; alcohols.

85. A process according to claim 73, comprising granulating a mixture comprising said tramadol or a pharmaceutically acceptable salt thereof, lactose and one or more alkylcelluloses with one or more C12-36 aliphatic alcohols.

86. A process according to any one of claims 68 to 85, further comprising:

(a) granulating said tramadol or a pharmaceutically acceptable salt thereof with a spheronizing agent;

(b) extruding the resultant granulate to provide an extrudate;

(c) spheronizing said extrudate to produce spheroids; and (d) coating said spheroids with a controlled release film coat.

87. A process according to any one of claims 68 to 85, comprising:

(a) mechanically working in a high-speed mixer, a mixture of said tramadol or a pharmaceutically acceptable salt thereof in particulate form and a particulate, hydrophobic fusible material having a melting point from 35 to 140°C at a speed and energy input which allows said matrix to melt or soften, whereby it forms agglomerates;

(b) breaking down the larger of said agglomerates to give controlled release seeds; and (c) continuing mechanically working.

88. A process according to claim 87, further comprising:

(a') using a release control component comprising a material selected from the group consisting of water soluble fusible materials, a particulate fusible organic material, a particulate fusible inorganic material and a mixture thereof;

(c') using a low percentage of said hydrophobic fusible material; and (d) repeating steps (c) or (c'), or steps (b) and (c) or step (b) and (c') one or more times.

89. A process according to claim 87 or 88, further comprising the step of forming a drug mixture of said tramadol or pharmaceutically acceptable salt thereof and said fusible material and mechanically working said mixture in a high speed mixer with an energy input sufficient to melt or soften the fusible material whereby it forms particles comprising said tramadol or pharmaceutically acceptable salt thereof.

90. A process according to claim 87, 88 or 89, further comprising compressing the resultant controlled release particles to form a tablet.

91. A process according to claim 84, further comprising film coating said granules prepared in step (b).

92. A process according to any one of claims 87 to 90, in which said mixture further comprises a release control component taken from the group consisting of a water soluble fusible material, a particulate soluble organic material. a particulate soluble inorganic material, a particulate insoluble organic material and a particulate insoluble inorganic material.

93. A process according to any one of claims 87 to 90 and 92, further comprising adding an additional amount of carrier or diluent during step (c) or (c').

94. A process according to any one of claims 68 to 93, wherein said dosage form is suitable for 12 hour administration.

95. A process according to any one of claims 68 to 93, wherein said controlled release matrix is prepared such that said dosage form provides a therapeutic effect for about 24 hours when said dosage form is orally administered to human patients.

96. A process for the preparation of a solid, controlled release oral dosage form of tramadol, comprising incorporating a therapeutically effective amount of tramadol or a pharmaceutically acceptable salt thereof in a matrix comprising an effective amount of a controlled release material selected from the group consisting of hydrophilic polymers, hydrophobic polymers, fatty acids, fatty alcohols, glycerol esters of fatty acids, mineral oil, vegetable oils, waxes, polyalkylene glycols, and mixtures thereof, such that said dosage form has a dissolution rate measured by the Ph. Eur. Paddle Method at 100 rpm in 900 ml 0.1 N hydrochloric acid at 37°C and using UV
detection at 270 nm of between 0-50% after 1 hour; between 0-75% after 2 hours; between 3-95%
after 4 hours; between 10-100% after 8 hours; between 20-100% after 12 hours;
between 30-100%
after 16 hours; between 50- 100% after 24 hours; and greater than 80% after 36 hours; said dosage form providing a therapeutic effect for at least about 12 hours after administration.

97. The process of claim 47, wherein said dosage form has an in vitro dissolution rate when measured by the Ph. Eur. Paddle Method at 100 rpm in 900 ml 0.1 N hydrochloric acid at 37°C
and using UV detection at 270 nm, such that between 5 and 50% by weight tramadol is released after 1 hour, between 10 and 75% by weight tramadol is released after 2 hours, between 20 and 95% by weight tramadol is released after 4 hours, between 40 and 100% by weight tramadol is released after 8 hours, more than 50% by weight tramadol is released after 12 hours, more than 70% by weight tramadol is released after 18 hours and more than 80% by weight tramadol is released after 24 hours.

98. The process of claim 96 or 97, wherein said dosage form provides a t max at 2 to 7 hours after oral administration.

99. The process of claim 96 or 97, wherein said dosage form provides a t max at 1.5 to 8 hours after oral administration.

100. The process of any one of claims 96 to 99, wherein said dosage form provides a W50 in the range of 7 to 16 hours when orally administered.

101. The process of any one of claims 96 to 100, further comprising manufacturing the dosage form as a tablet.

102. A process for the preparation of a solid, controlled release oral dosage form of tramadol suitable for a dosing every 24 hours, comprising incorporating a therapeutically effective amount of tramadol or a pharmaceutically acceptable salt thereof in a matrix comprising an effective amount of a controlled release material comprising (a) between 1% and 80% by weight hydrophillic polymers, hydrophobic polymers, or mixtures thereof, (b) from 0-60% by weight digestible C8-C50 substituted or unsubstituted hydrocarbons selected from the group consisting of fatty acids, fatty alcohols, glycerol esters of fatty acids, mineral oils, vegetable oils, waxes, and mixtures thereof; and (c) from 0-60% by weight polyalkylene glycol, such that said dosage form has a dissolution rate measured by the Ph. Eur. Paddle method at 100 rpm in 900 ml 0.1 N
hydrochloric acid at 37°C and using; UV detection at 270 nm of between 0 and 50% tramadol released after 1 hour: between 0 anti 75% tramadol released after 2 hours;
between 3 and 95%
tramadol released after 4 hours; between 10 and 100% tramadol released after 8 hours; between 20 and 100% tramadol released after 12 hours; between 30 and 100% tramadol released after 16 hours; between 50 and 100% tramadol released after 24 hours; and greater than 80% tramadol released after 36 hours, by weight and provides a W50 in the range of 10 to 33 hours and a therapeutic effect for about 24 hours when orally administered to human patients.

103. The process of claim 102, wherein said dosage form has a dissolution rate measured by the Ph. Eur. Paddle Method at 100 rpm in 900 ml 0.1 N hydrochloric acid at 37°C and using UV
detection at 270 nm, as set forth below;

TIME (H) % Released

104. The process of claim 102, wherein said dosage form has a dissolution rate measured by the Ph. Eur. Paddle Method at 100 rpm in 900 ml 0.1 N hydrochloric acid at 37°C and using UV
detection at 270 nm, as set forth below:

TIME (H) % RELEASED

2 0.75 4 10.95 24 >90

105. A process for the preparation of a solid, controlled release oral dosage form, comprising incorporating a therapeutically effective amount of an opioid analgesic consisting essentially of tramadol or a pharmaceutically acceptable salt thereof in a controlled release matrix such that said dosage form provides a therapeutic effect for at least about 12 hours after oral administration.

106. The process of any one of claims 102 to 105, where said preparation provides a t max from about 3 to about 6 hours when orally administered to human patients.

107. A process for the preparation of a solid, controlled release oral dosage form of tramadol suitable for dosing every 12 hours, comprising incorporating a therapeutically effective amount of tramadol or a pharmaceutically acceptable salt thereof in a matrix comprising an effective amount of controlled release material comprising (a) between 1% and 80% by weight hydrophilic polymers, hydrophobic polymers, or mixtures thereof; (b) from 0-60% by weight digestible C8-C50 substituted or unsubstituted hydrocarbons selected from the group consisting of fatty acids, fatty alcohols, glycerol esters of fatty acids, mineral oils, vegetable oils, waxes, and mixtures thereof;
and (c) from 0-60% by weight polyalkylene glycol, such that said preparation contains up to 60%
by weight of said polyalkylene glycol; such that said dosage form has a dissolution rate measured by the Ph. Eur. Method at 100 rpm in 100 ml 0.1 N hydrochloric acid at 37°C and using UV
detection at 270 nm of between 0 and 50% tramadol released after 1 hour;
between 0 and 75%
tramadol released after 2 hours; between 3 and 95% tramadol released after 4 hours; between 10 and 100% tramadol released after 8 hours; between 20 and 100% tramadol released after 12 hours;
between 30 and 100% tramadol released after 16 hours: between 50 and 100%
tramadol released after 24 hours; and greater than 80%, tramadol released after 36 hours, by weight, and provides a t max from about 1.5 to about 8 hours and a therapeutic effect for at least about 12 hours when orally administered to human patients.

108. The process of claim 107, where said preparation provides a W50 from 7 to 16 hours.

109. A process for the preparation of a solid, controlled release oral dosage form, comprising incorporating from about 50 to about 800 mg tramadol or a pharmaceutically acceptable salt thereof in a controlled release matrix to obtain a granular product containing said tramadol; and incorporating said granular product into an orally administrable dosage form such that said dosage form provides a dissolution rate measured by the Ph. Eur. Paddle Method at 100 rpm in 900 ml 0.1 N hydrochloric acid at 37°C and using UV detection at 270 nm of between 0-50% after 1 hour;
between 0-75% after 2 hours; between 3-95% after 4 hours; between 10-100%
after 8 hours;
between 20-100% after 12 hours; between 30-100% after 16 hours; between 50-100% after 24 hours; and greater than 80% after 36 hours and provides a therapeutic effect for at least about 12 hours after oral administration.

110. The process of claim 109, where said preparation provides a therapeutic effect for about 24 hours after oral administration.

111. The process of claim 109 or 110, where said preparation provides a W50 from 7 to 16 hours.

112. The process according to claim 111, wherein said dosage form provides a t max from 1.5 to about 8 hours.

113. The process according to any one of claims 109 to 112, wherein said granular product comprises agglomerated particles.

114. The process according to claim 113, wherein said matrix comprises an effective amount of a controlled release material comprising (a) between 1% and 80% by weight hydrophilic polymers, hydrophobic polymers, or mixtures thereof; (b) from 0-60% by weight digestible substituted or unsubstituted hydrocarbons selected from the group consisting of fatty acids, fatty alcohols, glycerol esters of fatty acids, mineral oils, vegetable oils, waxes, and mixtures thereof;
and (c) from 0-60% by weight polyalkylene glycol, such that said preparation contains up to 60%
by weight of said polyalkylene glycol; such that said dosage form has a dissolution rate measured by the Ph. Eur. Paddle Method at 100 rpm in 900 ml 0.1 N hydrochloric acid at 37°C and using UV detection at 270 nm of between 0 ;end 50% tramadol released after 1 hour;
between 0 and 75%
tramadol.