Abstract:
Sustained release pharmaceutical formulations containing morphine, or a pharmaceutically acceptable salt thereof, as active ingredient, suitable for administration on a once daily basis, are disclosed. In a first aspect, an orally administrable sustained release unit dosage form gives a peak plasma level at 1.0 to 6 hours after administration. In a second aspect, the formulation provides a W 50  for the M-6-G metabolite for morphine of between 4 and 12 hours. A third aspect concerns the pharmaceutical unit dosage form obtained by compressing multiparticulates comprising a pharmaceutically active substance in a matrix of hydrophobic fusible material having a melting point of from 35 to 150° C.

Description:
This application is a continuation of U.S. Ser. No. 08/843,571, filed Apr. 18, 1997, issued as U.S. Pat. No. 5,879,705, which is a continuation application of U.S. Ser. No. 08/269,208 filed Jun. 30, 1994 (abandoned). 
    
    
     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 ingredient. 
     The present invention also relates generally to a method of manufacturing an orally administrable dosage form, preferably sustained release granules/multiparticulates and compressed multiparticulates, such multiparticulates having diameters ranging from 0.1 to 3.0 mm; the method of the invention provides multiparticulates in an unexpectedly high yield. 
     Morphine is an opioid analgesic well established for use in the treatment of pain, especially moderate to severe pain. Morphine-containing compositions in sustained release form are currently commercially available as so-called &#34;twice-a-day&#34; formulations, that is formulations having a duration of activity of 12 hours or more and accordingly requiring to be administered twice a day. 
     OBJECTS AND SUMMARY OF THE INVENTION 
     It is one object of the present invention to provide a morphine-containing sustained release orally administrable dosage unit form which has an effective duration of activity 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 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 administration 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 pharmaceutically acceptable salt thereof, as active ingredient which formulation gives a peak plasma level from 1 to 6 hours, preferably 1 to 4 hours e.g. 1 to 3.5 hours, after administration. 
     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 T max  values in the range of 1 to 4.25 hours. 
     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 (per ml of plasma) is preferably from 0.5×10 -7  to 7.5×10 -7  times the amount of morphine sulphate orally administered. When morphine base or a salt other than the sulphate is administered, the preferred ratio of drug administered to peak plasma level should be adjusted according to the molecular weight of the base or salt. 
     The dosage unit form in accordance with the invention should contain sufficient 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 form will of course depend upon a number of variables including (i) 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 to 500 mg of morphine (calculated as morphine sulphate) and thus, for example, typical dosage unit forms in accordance 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 metabolite of morphine and, itself,, has powerful analgesic properties, at least comparable with those of morphine. 
     We have found, in accordance with another aspect of the invention, that a pharmaceutical formulation, containing an effective amount of morphine or pharmaceutically acceptable salt thereof, effective for at least 24 hourly dosing, is characterized by a W 50  for the M-6-G metabolite of between 4 and 12 hours, and preferably has a T max  of M-6-G in the range 1 to 6.5 hours, more preferably 3 to 6.5 hours, and even more preferably 3.5 to 6 hours. 
     The W 50  parameter defines the width of the plasma profile at 50% C max , i.e. the duration over which the plasma concentrations are equal to or greater than 50% of the peak concentration. The parameter is determined by linear interpolation of the observed data and represents the difference in time between the first (or only) upslope crossing and the last (or only) downslope crossing in the plasma profile. 
     We have observed that, surprisingly, formulations in accordance with the invention, which are characterized by a W 50  for M-6-G in the range specified, are usually also characterized by a W 50  for morphine within a similar range. Accordingly, in accordance with another, preferred, aspect of the invention a pharmaceutical formulation, containing an effective amount of morphine or pharmaceutically acceptable salt thereof, effective for at least 24 hour dosing, is characterized by a W 50  for morphine of between 4 and 12 hours, and preferably has a T max  in the range of 1 to 6.5 hours, more preferably 1 to 4 hours e.g. 1 to 3.5 hours after administration. 
     A preferred formulation in accordance with this aspect of the invention is characterized by the foregoing parameters when dosed to patients in the fasted state. 
     Preferred values for W 50  for M-6-G and morphine are in the range of about 5.5 to 12 or 5.5 to 11 or even 6 to 10 hours. 
     The C maxs  of formulations in accordance with the invention are dose dependant. For instance, a preferred embodiment containing 60 mg morphine sulphate when administered as a single dose is characterized by a C max  for M-6-G in the range of from 65 ng/ml to 150 ng/ml. Another such preferred embodiment is characterized by a C max  for morphine in the range of from 7.5 to 20 ng/ml. 
     One preferred embodiment described herein, after single dosing to 5 fasted volunteers was found to have W 50 , for morphine and M-6-G in the range 5.5 to 12 hours. 
     It has been found that in a group e.g. n=5, of healthy volunteers one embodiment of such dosage units, when administered in a single dose in the fasted state, gave median T max  values of M-6-G in the range of 3.5 to 6 hours, e.g. 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 plasma level of morphine and M-6-G and to provide effective activity over a period of at least 24 hours, the in vitro release characteristics of the formulation [when measured by the modified Ph. Eur. Basket method at 100 rpm in 900 ml aqueous buffer. (pH 6.5) containing 0.05% w/v Polysorbate 80 at 37° C.] are preferably as set out below: 
     
         ______________________________________Hours After    % Morphine (salt) releasedStart of Test  Suitable Preferred______________________________________2               5-30     5-204              15-50    15-356              20-60    20-4512             35-75    40-7018              45-100  50-8024              55-100   60-100______________________________________ 
    
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS 
     FIGS. 1 to 5 are plasma profiles of morphine and M-6-G in each of five volunteers after dosing them with a formulation in accordance with the invention; 
     FIG. 6 shows the mean plasma profiles of morphine and M-6-G derived from the results illustrated in FIGS. 1 to 5; 
     FIG. 7 shows the mean-plasma profiles of morphine and M-6-G obtained using a known controlled release morphine preparation in nine volunteers. 
    
    
     DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT 
     The compositions of the invention may be provided in a variety of forms, for example as tablet or capsules containing granules, spheroids or pellets. Commonly, the composition will comprise the active ingredient (morphine or salt thereof) together with a diluent which may serve to modify the release of the active ingredient. A preferred form of unit dose form in accordance with the invention comprises a capsule filled with multiparticulates essentially comprising the active ingredient, a hydrophobic fusible carrier or diluent and optionally a hydrophilic release modifier. 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 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 mm, preferably 0.25 to 2.0 mm. A preferred and novel process of this kind is described below which is suitable for the commercial production of dosage units containing morphine or other active substances. 
     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 essential ingredients namely: 
     (a) active ingredient (morphine 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 active ingredient 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 hydrophobic material such as a natural or synthetic wax or oil, for example hydrogenated vegetable oil or hydrogenated 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 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 example 40 to 60% by weight it is particularly surprising that only incorporation of very small amounts of polyethylene glycol, for example 0.01 to 1% by weight are required to modify the in vitro release rate. 
     Alternatively the morphine (or salt thereof) may be formulated (e.g. by dry or wet granulation or by blending) in a controlled release mixture formed of components other than fusible components. Suitable materials for inclusion in a controlled release matrix include, for example 
     (a) Hydrophilic or hydrophobic polymers, such as gums, cellulose ethers, protein derived materials, nylon, acrylic resins, polylactic acid, polyvinylchloride, starches, polyvinylpyrrolidones, cellulose acetate phthalate. Of these polymers, cellulose ethers especially substituted cellulose ethers such as alkylcelluloses (such as ethylcellulose), C 1  -C 6  hydroxyalkylcelluloses (such as hydroxypropylcellulose and especially hydroxyethyl cellulose) and acrylic resins (for example methacrylates such as methacrylic acid copolymers) are preferred. The controlled release matrix may conveniently contain between 1% and 80% (by weight) of hydrophilic or hydrophobic polymer. 
     (b) Digestible, long chain (C 8  -C 50 , especially C 8  -C 40 ), substituted or unsubstituted hydrocarbons, such as fatty acids, hydrogenated vegetable oils such as Cutina (Trade Mark), fatty alcohols (such as lauryl, myristyl, stearyl, cetyl 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 beeswax, glycowax, castor wax or carnauba wax). Hydrocarbons 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. 
     (c) Polyalkylene glycols. The matrix may contain up to 60% (by weight) of at least one polyalkylene glycol. 
     A suitable matrix comprises one or more cellulose ethers or acrylic resins, one or more C 12  -C 36 , preferably C 14  -C 22 , aliphatic alcohols and/or one or more hydrogenated vegetable oils. 
     A particular suitable matrix comprises one or more alkylcelluloses, one or more C 12  C 36 , (preferably C 14  -C 22 ) aliphatic alcohols and optionally one or more polyalkylene glycols. 
     Preferably the matrix contains between 0.5% and 60%, especially between 1% and 50% (by weight) of the cellulose ether. 
     The acrylic resin is preferably a methacrylate such as methacrylic acid copolymer USNF Type A (Eudragit L, 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 matrix contains between 0.5% and 60% by weight, preferably between 1% and 50% by weight of the acrylic resin. 
     In the absence of polyalkylene glycol, the matrix preferably contains between 1% and 40%, especially between 2% and 36% (by weight) of the aliphatic alcohol. When polyalkylene glycol is present in the oral dosage form, then the combined weight of the aliphatic alcohol and the polyalkylene glycol preferably constitutes between 2% and 40%, especially between 2 and 36% (by weight) of the matrix. 
     The polyalkylene glycol may be, for example, polypropylene 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 granulation or coprecipitation. 
     Another form of sustained release formulation comprises spheroids obtained by spheronizing the morphine (or salt thereof) with a spheronizing agent such as microcrystalline cellulose. 
     The present invention also includes a process for the manufacture of sustained release multiparticulates containing morphine or a salt thereof which comprises 
     (a) mechanically working in a high-speed mixer, a mixture of morphine or salt thereof in particulate form and a particulate, hydrophobic fusible carrier or diluent having a melting point from 35 to 150° C., e.g., to 100° 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 a further addition of low percentage of the carrier or diluent; and 
     (d) optionally repeating step (c) and possible (b) one or more e.g. up to five times. 
     The process is capable of giving a high yield (over 80%) of multiparticulates in a desired size range, with a desired in vitro release rate, uniformity of release rate and in its preferred form surprisingly an early peak plasma level for a product with a 24 hour duration of activity. 
     The resulting multiparticulates 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. 
     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 (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%. 
     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 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 above 40° C. is achieved and the resulting mixture acquires a cohesive granular texture, with particle sizes ranging from about 1-3 mm 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 45° C. e.g. 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 2 mm. It is currently preferred to carry out the classification 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 reducing yield. A mesh size of 12 or greater or a 94G Comill screen have 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 multiparticulates of uniform size range. 
     In a 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 additional hydrophobic fusible material is then added. Mixing is continued until the mixture has been transformed into multiparticulates of the desired predetermined size range. 
     In order to ensure uniform 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 pellets have been formed they may then be sieved to remove any over or undersized material and are cooled or allowed to cool. 
     The resulting pellets may be used to prepare dosage units such as tablets or capsules in manners known per se. 
     In this process of the invention the temperature of the mixing bowl throughout the mechanical working is chosen so as to avoid excessive adhesion of the material to the walls of the bowl. We have generally found that the temperature should be neither too high nor too low with respect to the 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 drug and particulate hydrophobic fusible carrier in a high speed mixture first mentioned above. For example in the processes described below in the Examples a bowl temperature of approximately 60° C. has been found to be satisfactory and avoid adhesion to the bowl. 
     To produce tablets in accordance with the invention, multiparticulates produced as described above 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 suitably sized tabletting tooling. Tablets can be produced using conventional tabletting machines, and in the embodiments described below 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. 
     EXAMPLES 1 TO 8 
     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 10 kg, in the bowl of a 75 liter capacity Collette Vactron 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; 
     (iii) discharging the pellets from the mixer and sieving them to separate out the pellets collected between 0.5 and 2 mm aperture sieves. 
     
                       TABLE I______________________________________EXAMPLE NO. 1     2     3    4   5    6    7    8______________________________________Morphine Sulfate       15    15    15   23  55   55   55   55(wt %)Hydrogenated castor       77    76    75   70  --   --   --   --oil U.S.N.F. (wt %)Hydrogenated       --    --    --   --  42.8 45   44.95                                           42.0vegetable oilU.S.N.F. (wt %)Polyethylene glycol        8     9    10    7  0.2  --   0.05 --6000 U.S.N.F.(wt %)Dicalcium phosphate       --    --    --   --  2    --   --   3anhydrous USP(wt %)______________________________________ 
    
     The in vitro release rates of the products of Examples 1, 2. 3 and 5 were assessed by the modified 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. 
     
                       TABLE II______________________________________PRODUCT OF EXAMPLEHours AfterStart of     1     2           3    4Test         (% morphine released)______________________________________2            19    25          33   444            27    36          49   576            34    45          62   668            41    52          72   7212           53    64          86   8118           66    77          96   8924           76    86          101  92______________________________________ 
    
     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 pellets of Examples 1, 2, 3 or 5 in an amount sufficient to provide a morphine sulphate dose of 30 mg. 
     EXAMPLES 9 TO 12 
     Particles, having the formulations given in Table III below, were prepared by the steps of: 
     i) Placing the ingredients (a) to (c) (total batch weight 20 kg) in the bowl of a 75 liter capacity Collette Vactron Mixer (or equivalent) equipped with variable speed mixing and granulating blades; 
     ii) Mixing the ingredients at about 150-350 rpm while applying heat until the contents of the bowl are agglomerated. 
     iii) Classifying the agglomerated material by passage through a Comill and/or Jackson Crockett to obtain controlled release seeds. 
     iv) Warming and mixing the classified material in the bowl of a 75 liter Collette Vactron, with addition of 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. 
     v) Discharging the particles from the mixer and sieving them to separate out the particles collected between 0.5 and 2 mm aperture sieves. 
     
                       TABLE III______________________________________EXAMPLE          9        10      11______________________________________a) Morphine Sulphate (Wt %)            55.0     52.19   53.48b) Hydrogenated Vegetable            34.95    33.17   33.98Oil USNF (Wt %)c) Polyethylene Glycol 6000            0.05     0.047   0.049USNF (Wt %)d) Hydrogenated Vegetable            10.0     14.60   12.49Oil USNF (Wt %)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 modified Ph. Eur. 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 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______________________________________PRODUCT OF EXAMPLEHours AfterStart of    9            10    11Test        (% morphine released)______________________________________2           21           15    204           33           25    366           43           35    498           52           43    5912          62           57    7218          74           71    8224          82           81    8630          83           85    89______________________________________ 
    
     The procedure of Example 11 was repeated but the operation varied by adding the classified particles to a cold bowl of the Collette Vactron, followed by adding ingredient (d) and mixing, heating by jacket heating and microwave being applied during mixing. The in vivo release rate is given in Table IVa and demonstrates that although the composition of the products in Examples 11 and 12 are the same the different processing results in modified release rates. 
     
                       TABLE IVa______________________________________PRODUCT OF EXAMPLEHours AfterStart of Test        % of Morphine Released______________________________________2            154            246            308            3612           4618           5724           6530           71______________________________________ 
    
     Particles produced according to Examples 9 to 12 were each blended with purified talc and magnesium stearate and used to fill hard gelatin capsules such that each capsule contains 60 mg of morphine sulphate. The capsules produced were used in open, randomized crossover pharmacokinetic studies. As part of these studies patients received after overnight fasting either one capsule according to the invention or one MST CONTINUS® tablet 30 mg (a twice a day preparation). Fluid intake was unrestricted from 4 hours after dosing. A low-fat lunch was provided four hours after dosing, a dinner at 10 hours post dose and a snack at 13.5 hours post-dose. No other food was allowed until a 24 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 peak plasma levels of from 3.2 to 29.2 ng/ml of morphine at median times between 2 and 6 hours following administration and blood sampling according to the above protocol. 
     The capsules containing particles produced according to Examples 10 and 12 in particular gave a mean C max  of 11.9 ng/ml at median T max  4 hours and mean C max  of 9.2 ng/ml at median T max  2.5 hours respectively (these values represent the mean of the individual C max  and T max  values). In contrast the C max  and T max  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 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 produced in Example 9, and directed to morphine and morphine-6-glucuronide following administration of a capsule containing 60 mg of morphine sulphate in five volunteers in the fasted state gave the results shown in Table V and FIGS. 1 to 6. 
     
                       TABLE V______________________________________     M-6-G     M-6-G     W.sub.50 (h)                               W.sub.50 (h)Volunteer C.sub.max (ng/ml)               T.sub.max (h)                         M-6-G Morphine______________________________________1         147.7     5.0       7.54  8.182         83.8      3.5       5.69  4.243         73.4      6.0       11.97 8.454         72.8      5.0       7.02  5.995         82.5      3.5       6.75  6.67Mean      92.0      --        7.79  6.71sd        31.5      --        2.43  1.72Median    --        5.0       --    --Minimum   72.8      3.5       5.69  4.24Maximum   147.7     6.0       11.97 8.45______________________________________ 
    
     FIG. 7, by contrast shows the mean plasma profiles obtained after dosing nine healthy volunteers with the known bid morphine sulphate-containing preparation MST CONTINUS® under a similar test conditions, and analyzing the blood samples using a similar analytical procedure, as were used in the tests carried out with the formulations in accordance with the invention and which gave the results 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 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 but having the following ingredients: 
     
         ______________________________________            wt %______________________________________Morphine sulphate  55.0Hydrogenated vegetable oil              44.7Polyethylene glycol 6000              0.3______________________________________ 
    
     Samples of the particles were then blended with magnesium stearate and purified talc in two lots (1 and 2) using a Y-Cone or bin-blender-machine. The blended mixtures were then each compressed on a 7.1 mm diameter normal concave tooling on a single punch F3 Manestr tabletting machine. The ingredients per dosage unit amounted to the following: 
     
                       TABLE VI______________________________________             Mg/TabletTablet Ingredient   1       2______________________________________Morphine Sulphate   60.00   60.00Hydrogenated Vegetable Oil               48.77   48.77Polyethylene Glycol 0.33    0.33Sub Total           109.1   109.1Magnesium Stearate  1.42    2.0Purified Talc       2.18    3.0______________________________________ 
    
     The dissolution of the samples of non-compressed particles (each sample containing 60 mg of morphine sulphate) was assessed by the modified 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 AfterStart of   Particles    Tablet 1                           Tablet 2Test       % morphine sulphate released______________________________________1          27           13      112          43           20      174          63           29      268          82           42      3712         88           50      4416         91           57      NR*24         93           65      NR*30         94           70      NR*36         95           74      NR*______________________________________ *NR = Not recorded 
    
     The above results show that the tabletting procedure results in a considerable reduction in the release rate of the active ingredient. 
     EXAMPLE 14 
     The procedure of Example 13 was repeated but with the following variations. 
     The particles were made with the following ingredients. 
     
         ______________________________________             wt %______________________________________Morphine Sulphate   55.0Hydrogenated Vegetable Oil               44.4Polyethylene Glycol 6000               0.6______________________________________ 
    
     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; 
     
                       TABLE VIII______________________________________             Mg/TabletTablet Ingredient   3       4______________________________________Morphine Sulphate   60.00   60.00Hydrogenated Vegetable Oil               48.44   48.44Polyethylene Glycol 6000               0.655   0.655Sub Total           109.1   109.1Poloxamer 188       --       5.0Magnesium Stearate  2.0     2.0Purified Talc       3.0     3.0______________________________________ 
    
     The dissolution of the tablets and samples of non-compressed particles (each sample containing 60 mg of morphine sulphate) were assessed by the methods described above. The results are shown in Table IX below: 
     
                       TABLE IX______________________________________Hours AfterStart of   Particles    Tablet 3                           Tablet 4Test       % morphine sulphate released______________________________________1          56           16      192          75           24      284          90           34      388          95           46      5212         97           54      6016         NR*          NR*     6724         NR*          NR*     77______________________________________ *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 being greater than that for tablet 3 without the surface active agent.