Abstract:
An oral controlled release pharmaceutical preparation in the form of a tablet, capsule or sachet containing a plurality of coated particles comprising a therapeutically effective amount of a salt of morphine coated with a barrier membrane providing a controlled, preferably pH-independent, release of morphine in that the serum concentration of morphine obtained is at least 50% of the maximum serum concentration during at least 12 hours after administration of a single dose, and providing a significantly reduced plasma concentration fluctuation compared to known morphine preparations. A method for the manufacture of such a preparation and the use of such preparations for the manufacture of an analgesic useful in the treatment of severe chronicle pain are also provided.

Description:
FIELD OF INVENTION 
     The present invention relates to a new pharmaceutical preparation containing a number of coated particles comprising a salt of morphine coated with a barrier membrane with a controlled release of morphine over the main part of the dose interval when administered once daily, providing a significantly reduced plasma concentration fluctuation compared to known morphine preparations. The invention is also related to a method for the manufacture of such a preparation and the use of such preparations for the manufacture of an analgesic useful in the treatment of severe chronical pain. 
     BACKGROUND OF THE INVENTION 
     Morphine has a serum haft-life of 2-4 hours and the duration of its analgesic effect is about 4-6 hours after oral administration. The short duration makes it necessary to administer morphine orally 4-6 times daily to achieve a satisfactory analgesic effect. This has led to a development of various oral controlled release formulations of morphine. Oral controlled release products containing morphine on the market e.g. MST Continus® or MS Contin® and Dolcontin®, are in general administered 2-3 times a day in order to give a sufficient pain relief over the entire dosage interval. Conventional matrix tablets consisting of morphine and an inert carrier composition are characterized by a fast initial drug release leading to an early peak of morphine plasma concentration followed by a decrease in release, which will be especially pronounced in the lower intestinal system where more neutral or weakly basic conditions prevail. There has been a demand to find a way to obtain an oral drug preparation having a more even release of morphine in order to get smoother blood concentration and effect profiles over the entire dosage interval when administered once daily. 
     EP-B-0 097 523 discloses such a preparation where the drug is distributed in a controlled release matrix partly in the form of a salt and partly as a free base. This preparation increases dissolution time and biovailabilty without the need of applied coating membranes. 
     It is known that morphine gives considerable problems in the development of matrix tablets which have been considered to be due to poor absorption properties of morphine in the distal parts of the gastrointestinal tract, see Proceed. Intern. Syrup. Control. Rel. Bioact. Mater., 18, 1991, pag. 433-434, (B. Olsson et al). 
     There are several examples of formulations which are designed to overcome the drawbacks of oral matrix tablets by providing a constant or controlled release rate over a more extended period. An example of such formulations is multiple unit (MU) formulations as disclosed previously in EP-A-0 080 341 and in WO-A-91/01722. 
     The depot preparation consisting of a large number of small units is considered to promote good absorption properties by being dispersed over a large area in the gastrointestinal tract and having a lower transit rate especially in the colon, compared to matrix tablets, see Drug Delivery to the Gastrointestinal Tract, Ed. By J G Hardy Et. al., Chichester, Ellis Howard Ltd, 1989, pages 75-81: &#34;Colonic transit rate and drug delivery&#34;. In addition multiple unit formulations are preferable to one single unit as they may be divided into smaller portions all having the same release and absorption properties which will give greater flexibility in selection of the size of the dose, will facilitate administration of the drug to patients having problems to swallow and will considerably reduce the risk of dose dumping. 
     Also in EP-A-0 377 518 there is described a sustained release pellet formulation, but with core elements which may comprise the salt of a morphine compound coated with a hybrid coating admitting a slow release at an acidic pH and relatively constant higher release at a less acidic to basic pH. The preparations according to EP-A-0 377 518 exhibit a limited bioavallibility, restricting the administration to at least twice daily. 
     ZA-A-921366 relates to a solid controlled release dosage form for improved storage stability at elevated temperature and/or elevated relative hunidity. The controlled release is obtained by overcoating a substrate including a therapeutically active ingredient with a coating derived from an aqueous dispersion of ethylcellulose and then curing the coated substrate at an elevated relative humidity and at a temperature above the glass transition temperature for the coating. There is no indication in ZA-A-921366 that any of the preparations would be suitable for a once daily administration. 
     DESCRIPTION OF THE INVENTION 
     The object of the present invention is to provide a once-daily preparation of morphine i.e. a preparation with an even blood concentration profile when the preparation is administered once daily, without any substantial loss in bioavallability. The preparation should preferably also have a release rate of morphine which is substantially independent of its position in the gastrointestinal tract. Such a preparation represents an improvement in the treatment of severe opioid sensitive pain and supplies a convenient oral dosage form which gives an even effect and reduced risk of pain breakthrough. 
     The present invention is related to a multiple unit preparation of morphine consisting of small particles of morphine salts and a coated barrier layer which preferably provides a pH independent release, methods for their manufacture and the use of such preparations for the treatment of severe opioid sensitive pain by a once daily administration. 
     In general, a multiple unit preparation contains of at least 50, and suitably of at least 150, individual drug including particles, e.g. crystals, beads or pellets. A multiple unit preparation in accordance with the present invention has a controlled rate of drug release during 15-24 hours for all possible strengths of the preparation in the preferred interval of 10-400 mg morphine (salt). However, higher total dosages of morphine are conceivable in certain applications and those will also be possible to administer with the multiple unit preparation according to the present invention. This means that a multiple unit preparation to fulfil the criteria of the invention shall give serum concentrations greater than or equivalent to 50% of the maximum concentration during at least 12 hours, suitably for at least 18 hours and preferably for at least 24 hours. A multiple unit preparation according to the present invention should suitably give a serum concentration greater than or equivalent to 40% of the maximum concentration during at least 18 hours, and preferably for at least 24 hours. This means that the preparations of the present invention can be advantageoulsy used for dosage intervals up to 24 hours, most preferably for once-daily administration, less preferably for twice-daily administration. 
     Other objects of the present invention are low peak plasma concentration of morphine, release of 50% of the total dose within 4-10 hours and more than about 80%, preferably more than 90%, bioavailability of the preparation when compared to traditional preparations as instant release tablets and oral solutions. 
     It has been found that these demands are met surprisingly well by a preparation containing a large number of small particles comprising a salt of morphine which are coated with a barrier layer containing at least one component insoluble in the fluids of the gastrointestinal system to provide high serum concentrations for a prolonged period of time. 
     The particles contain a salt of morphine and optionally pharmaceutically acceptable excipients such as lactose and microcrystalline cellulose and have a size of 0.2 to 3 mm, preferably 0.7 to 1.4 mm. Suitable salts of morphine are soluble salts, such as morphine hydrochloride, morphine sulphate, and salts of certain organic carboxylic acids. The particles are prepared with conventional methods such as mixing and granulation of the morphine salt with the excipient or excipients, extrusion, spheronization, drying and sieving the particles to an acceptable size range. 
     Examples of suitable barrier coating materials which are substantially insoluble in the fluids of the gastrointestinal tract are natural and synthetic polymers such as ethyl cellulose, Eudragit RS, polyvinyl chloride, natural or synthetic waxes as carnauba wax. Ethyl cellulose is an especially suitable insoluble material which is available in different grades and in special qualities for aqueous based barrier coatings. According to the invention it is preferable to use ethyl cellulose having a viscosity of 5 to 15 cps, but also other types of cellulose may be used. 
     In a barrier coating preferred according to the present invention, the water insoluble component or components will be mixed with one or several components soluble in water. Suitable water soluble components are polymers like hydroxypropyimethyl cellulose, hydroxypropyl cellulose, Eudragit RL and Eudragit NE. Instead of water soluble polymers other water soluble substances as sugar, lactose and different salts can be used in the formation of a partly erodable film with a pH-independent release rate. Eudragit is the trade name of a substance useful for film coating of controlled release particles, which can be both soluble and insoluble in the fluids of the gastro intestinal tract (see above). Eudragit RL and RS (Rohm Pharma) are copolymers synthesised from acrylic and methacrylic esters with a low content of quaternary ammonium groups. Euciragit RL and RS differ in the molar ratios of the ammonium groups to the remaining neutral (meth)acrylic add esters (1:20 and 1:40 respectively). Eudragit NE is the aqueous dispersion of a neutral copolymer based on ethyl acrylate and methyl methacrylate. These above mentioned properties result in different permeability characteristics. 
     The coating procedure can be performed by conventional means such as a spraying equipment, a fluidised bed and equipment for drying and size fractionating. The liquid used in the coating procedure contains one or several barrier layer forming components and one or several solvents, such as ethanol, acetone, methyl isobutyl ketone (MIBK), water and others well known in this technical field. The coating liquid can be in the form of a solution, a dispersion, an emulsion or a melt, depending on the specific nature of the coating constituents. 
     Plasticizers and pigments may optionally be used to modify the technical properties or change the permeability of the coating. The coating membrane is made of one or more polymers and has preferably a virtually pH independent permeability properties within the pH range of 1.0 to 7.0. At higher pH a reduction in the release of morphine may be observed but this is not due to the properties of the polymeric layer but depends on the reduced solubility of morphine salts at high pH values. 
     A characteristic and suitable coating composition within the scope of invention consists of ethyl cellulose and hydroxypropylmethyl cellulose and a certain amount of triethyl citrate as plasticizer. A specific example of the coating composition is ethyl cellulose and hydroxypropylmethyl cellulose in relations from 55/35% to 80/10% w/w with 10% triethyl titrate as a plasticizer. 
     Each coated morphine particle represents an individual controlled release unit, releasing the drug at a predetermined rate preferably independent of its position in the gastrointestinal tract. Coated pellets according to the invention can be used in different types of dosage forms such as gelatine capsules, compressed tablets or sachets. 
     The invention makes it possible to obtain a dosage form of morphine salts that can be given once daily and still produce almost constant plasma concentrations of the drug and a high biological availability. 
    
    
     BRIEF DESCRIPTION OF THE DRAWING 
     FIG. 1 is a graph showing mean serum concentrations in tested individuals versus time. 
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     The following examples are intended to illustrate suitable preparations within the scope of invention, which meet the demands set on the oral morphine formulations in the previous text. The examples shall not be regarded as limiting for the scope of invention and alterations and modifications of parameters and ingredients can be made without departing from the context of the present invention. 
     EXAMPLE 1 
     Manufacturing of morphine pellets 
     Morphine hydrochloride pellets to be used in a controlled release preparation according to the present invention can be manufactured by the following measures. 
     Morphine hydrochloride was selected as a suitable salt for the formulation work. It has very similar properties to the most common alternative morphine sulphate, regarding e.g. water solubility. Further studies showed that the solubility is not critically dependent on the pH-value of the dissolution medium (within the physiological range). This is in accordance with its high pKa-value (7.5). Microcrystalline cellulose is a common diluent in pellet formulations as it gives very good technical properties. Lactose is used as a soluble constituent. 
     1. Mixing and granulating: Morphine hydrochloride (40% w/w), lactose (40% w/w) and microcrystalline cellulose (Avicel PH-101) (20% w/w) totally 1500 gram were dry-mixed in a planetary type mixer (Kenwood Major) at a low mixing speed (speed adjustment &lt;1) for 10 minutes. Water (585 gram ) was added and the mass was granu-lated for 5 minutes at speed adjustment 2. 
     2. Extrusion: Extrusion was performed in a NICA E-140 extruder (Lejus Medical AB, Sweden) through a perforated screen with drilled orifices of 1.0 mm diameter. The speed of the agitator and the feeder were set on the lowest values. 
     3. Spheronization: Spheronization was conducted in a mammerizer (Ferro Mecano AB, Sweden). The speed of the marumerizer plate was adjusted to 450 rpm. The number of spheronization rounds were 5, with about 400 grams of wet extrudates on the plates at each run. 
     4. Drying: Drying was performed in a fluid bed dryer (Aeromatic AG West Germany) at an IN-temperature of 50° C. The batch was divided into sub-batches of 600-700 grams wet particulate cores. Each sub-batch was dried for 5 minutes at the air velocity adjustment 20 in order to obtain individual cores rather than aggregates. The sub-batches were then mixed and the whole batch was dried at adjustment 12 for 65 minutes. The end OUT-temperature was 36° C. The yield of dry cores after drying was 1437 gram and 96% w/w. 
     5. Sieving: Sieving was performed by using analytical sieves with sieve sizes of 0.71 mm and 1.40 mm, respectively. The yield of dry cores after sieving was 1337 gram and 89% w/w. 
     The yields were 96 and 89% w/w after drying and sieving, respectively. The mass was lost during the extrudation and sieving procedures. A sieving analysis before and after abrasion of the cores showed that about 93% of the cores had a size between 0.71 and 1.0 mm. A crushing strength analysis showed that the mean crushing strength of 1.0 mm particles was 4.71N. A hardness value at this level makes it possible to coat the particles in a small as well as in a larger equipment. The obtained morphine hydrochloride cores are well suitable for production in large scale. 
     EXAMPLE 2 
     Coating of morphine hydrochloride pellets 
     Morphine hydrochloride cores manufactured in accordance with Example 1 can be coated with controlled release membranes to prepare multiple unit formulations within the scope of the present invention. 
     Hydroxypropylmethyl cellulose (HPMC) E5 and ethyl cellulose (EC) 10 cps were used as film formers together with triethyl citrate (TEC) as a plasticizer. The coating solution contained 99.5% ethanol and methyl isobutyl ketone (MIBK). 
     The coating was performed using a spray coating equipment (NICA FB-coater, Sweden). The spray gun used was a Binks &amp; Bullows with a J92R liquid nozzle and a J930 air nozzle. A net device was placed in the top of the fluidised bed to avoid loss of cores to the cyclone output. The spray gun was mounted on a height over the bottom of the bed of 185 min. Ethanol/MIBK mixture was pumped through the system prior to the start of the coating, and there was consequently liquid present between the pump housing and the spray gun. The morphine hydrochloride cores prepared as in Example 1 were loaded. The cores were pre-heated at 55° C. with an air velocity of 20-25 m 3  /h for 4 minutes: At the start of the coating, the bed temperature was 32°-36° C. The coating was started using the following process parameters: atomising pressure 500 kPa, air velocity 85 m 3  /h and a solution flow of about 24 ml/min. The registered IN-temperature varied between 53° and 56° C., the OUT-temperature between 34° and 38° C. during the coating. 
     Morphine hydrochloride cores from the same batch were coated with different proportions of EC/HPMC in the film coating solution. Different amounts of the polymer solution was also tested in order to obtain a suitable in-vitro dissolution rate at a suitable film thickness (too thin a film may give reproducibility problems), see Table 1 below. A mixture of 5.5 parts of EC and 3.5 parts of HPMC was selected and an amount of approximately 8 mg of coating material per capsule content (approximately 7.5%w/w per dose) was found to be suitable. 
     It is well known, however, that the amount of polymer will vary considerably with rather small variations in the mean pellet size (or surface area), which means that a careful optimisation must be done for each produced pellet quality to ensure an adequate dissolution rate. 
     The coated spheres were sieved through a 1.4 mm sieve and spheres with a size less than 1.4 mm are collected. The collected spheres were filled into hard gelatine capsules (Hard gelatine capsule, colour white, No. 2) with a normal weight of 0.17 g (net weight 108 mg). The capsules meet the requirements of the mass uniformity test in Ph. Eur. The mean content of active component in the capsules are between 36 and 44 mg. 
     The composition per capsule was: 
     
         ______________________________________Morphine hydrochloride   40 mgLactose                  40 mgMicrocrystalline cellulose                    20 mgWater (purified), evaporated during the process                    q.s.Ethyl cellulose (EC)     3.5-5.3 mgHydroxypropyl methylcellulose (HPMC)                    2.2-3.4 mgTriethyl citrate (TC)    0.6-1.0 mgEthanol 99.5% (evaporated)                    q.s.Methyl isobutylketone (evaporated)                    q.s.Hard gelatine capsule, white, No. 2                    approx. 60 mg______________________________________ 
    
     The film components are selected to give release properties that are virtually independent of pH and agitation. At very high pH-values, the release rate is reduced as expected when considering the pKa-value of morphine hydrochloride (see Tables 2 and 5). The agitation speed had no significant effect on the release rate (see Tables 2 and 6) 
     The in-vitro dissolution test is carried out with the USP dissolution apparatus No. II (paddle) at 50 rpm, 37° C., in a phosphate buffer solution, pH 6.8. Six individual capsules are tested. 
     The amount released (% of labelled amount) is calculated: 
     
         ______________________________________&lt;15% released after       1 h35-65% released after     6 h55-80% released after     12 hnot less than 80% released after                     24 h______________________________________ 
    
     
                       TABLE 1______________________________________In vitro dissolution rate. Morphine hydrochloride pelletsaccording to above, but with differentamounts and proportions of polymers in the coating.Method: USP dissolution apparatus No. II (paddle)at 50 rpm, 37° C., in a phosphate buffer solution, pH______________________________________6.8.Amount of film (% w/w)            1.4    2.7      8.0  2.7Prop:EC:HPMC:TEC 8:1:1  8:1:1    8:1:1                                 7:2:1Time             percent dissolved morphine(hours)          hydrochloride, n = 2______________________________________1                45     17       5    262                75     30       9    473                91     40       14   644                98     51       17   765                101    59       21   856                104    65       25   907                105    71       28   938                106    74       31   9510               --     --       --   --12               --     --       --   --24               106    97       64   102______________________________________Amount of file (% w/w)           4.2      4.6*     7.5*Prop:EC:HPMC:TEC           7:2:1    5.5:3.5:1                             5.5:3.5:1Time            percent dissolved morphine(hours)         hydrochloride, n = 2______________________________________1               16       16        82               29       32       173               40       48       264               51       60       345               60       69       426               67       78       497               72       83       558               76       87       6010              --       92       7012              --       96       7424              100      99       93______________________________________ EC; ethylcellulose HPMC; hydroxypropyl methylcellulose TEC; triethyl citrate *) n = 6 
    
     
                       TABLE 2______________________________________In vitro dissolution rate: Morphine hydrochloride pelletsaccording to above with a coating of EC:HPMC:TEC =5.5:3.5:1 at different agitation speed and pH.Method: USP dissolution apparatus No. II (paddle), 37° C.   Dissolution media   pH 6.8         pH 6.8   pH 1.2   pH 4.0                                 pH 7.6   n = 6 n = 6    n = 3    n = 4 n = 3   Agitation speed   50 rpm         100 rpm  50 rpm   50 rpm                                 50 rpmTime (hours)     percent dissolved morphine hydrochloride______________________________________1          8       8        4      5     32         17      16       10     13    103         26      24       16     21    164         34      33       24     28    245         42      40       29     35    306         49      46       35     41    367         55      51       40     47    418         60      57       45     52    4710        70      --       54     60    5524        93      91       82     89    85______________________________________ 
    
     
                       TABLE 3______________________________________In order to compare the in vitro dissolution rateat different pH, coating film thickness, agitation speedand temperature, the preparation of the followingcomposition was prepared in a comparable manner tothe manufacturing procedures above.Proportion of EC:HPMC:TEC = 8:0.5:1.5______________________________________Active constituentMorphine hydrochloride  20 mgInactive constituentsLactose                 60 mgMicrocrystalline cellulose                   20 mgWater purified*         q.s.Ethylcellulose          5.0-7.4 mgHydroxypropyl methylcellulose                   0.3-0.5 mgTriethyl citrate        0.9-1.3 mgEthanol 95%*            q.s.Acetone*                q.s.Water purified*         q.s.______________________________________ *Evaporated during the manufacturing process 
    
     
                       TABLE 4______________________________________In vitro dissolution rate. Morphine hydrochloride CRpellets with different amount of polymers in the coating.Proportions EC:HPMC:TEC = 8:0.5:1.5Method: USP dissolution apparatus No. II (paddle), 37° C.dissolution medium phosphate buffer, pH = 6.8, agitationspeed 50 rpm.      Amount of film (% w/w)      5.8* 6.9        8.6    9.2        percent dissolvedTime (hours) morphine hydrochloride, n = 6______________________________________1            13      8          6    62            30     20         13   113            43     30         21   184            53     38         28   256            68     51         40   358            78     62         51   4710           85     71         61   5612           90     78         69   6315           94     87         78   7418           96     92         84   8221           98     95         90   8924           99     97         93   91______________________________________ EC; ethylcellulose HPMC; hydroxypropyl methylcellulose TEC; triethyl citrate *n = 3 
    
     
                       TABLE 5______________________________________In vitro dissolution tests: Morphine hydrochloride CRaccording to Table 3 at different pHMethod: USP dissolution apparatus No. II (paddle),37° C., dissolution agitation speed 50 rpm.   Dissolution Medium   pH 1.2         pH 2.0   pH 5.8  pH 6.8 pH 7.4     persentTime (hours)     dissolved morphine hydrochloride, n = 6______________________________________1          6      10       10     8      62         15      21       22    20     153         23      30       32    30     224         29      36       40    38     316         41      49       55    51     478         51      60       66    62     5910        58      68       75    71     6812        65      74       81    78     7415        74      82       88    87     8518        81      88       93    92     8921        85      90       95    95     8924        89      94       96    97     92______________________________________ 
    
     
                       TABLE 6______________________________________In vitro dissolution rate. Morphine hydrochloride CR pelletsbatch according to Table 3 at different agitation speed.Method: USP dissolution apparatus No. II (paddle),37° C., dissolution medium phosphate buffer, pH 6.8.Agitation speed       40 rpm      50 rpm  100 rpmTime        percent dissolved morphine(hours)     hydrochloride, n = 6______________________________________1           10           8      122           23          20      253           33          30      354           42          38      446           55          51      588           66          62      6710          73          71      7512          81          78      8015          89          87      8818          91          92      9021          93          95      9224          97          97      96______________________________________ 
    
     
                       TABLE 7______________________________________In vitro dissolution rate. Morphine hydrochloride CR pelletsbatch according to Table 3 at different temperatures.Method: USP dissolution apparatus No. II (paddle),dissolution medium phosphate buffer, pH 6.8,agitation speed 50 rpm.Temperature indissolution medium         35° C.                    37° C.                            40° C.Time          percent dissolved morphine(hours)       hydrochloride, n = 6______________________________________1             12          8      112             23         20      243             33         30      344             41         38      436             52         51      568             65         62      6710            70         71      7512            79         78      8115            85         87      8818            91         92      9021            94         95      9124            93         97      92______________________________________ 
    
     As shown in Table 4 it is possible to control the release rate by varying the amount of film coating on the pellets. These experiments show that adequate dissolution rates are obtained and thus makes it possible to fulfil the requirements set on the preparations. 
     The film components were selected to give release properties that are virtually independent of pH and agitation. By testing the in vitro dissolution rates of the pellets of different batches (see Tables 1-7), the composition of which can be seen in Table 3. By testing the pellets under different conditions (see Tables 2 and 5-7) it is verified that only small variations in dissolution at pH:s appear and that changes in agitation speed and temperature had no significant effect on the release rate. 
     EXAMPLE 3 
     Bioavailability study 
     A single dose, 3-way crossover bioavailability study was performed in 6 healthy individuals. Two prototypes of Morphine controlled release (CR) capsules manufactured in accordance with Examples 1 and 2 of the present invention were studied, see also Tables 8 and 9, below. A morphine oral solution was used as a reference preparation. The subjects received either 30 mg of CR capsule A, 40 mg of CR capsule B or 15 mg of the solution after an overnight fast. Venous blood samples were drawn prior to and during 32 hours after drug administration. Determination of morphine in serum was performed using a specific LC-method with electron capture detection. The area under the serum concentration of morphine vs. the time curve (AUC), the maximum serum concentration, Cmax, the time to reach maximum serum concentration, tmax, the width of the serum concentration vs time curve at half the Cmax concentration (W 50 ) and the relative bioavailability of the CR capsules, (F rel ) was calculated. The results are presented in Table 10 below. 
     The following preparations were used in the study: 
     Morphine CR capsules 30 mg formulation A, prepared according to Examples 1 and 2; morphine CR capsules 40 mg formulation B, prepared according to Examples 1 and 2 and morphine oral solution formulation C, 5 mg/ml, as a reference. 
     
                       TABLE 8______________________________________Constituent        CR capsule A                         CR capsule B______________________________________Morphine hydrochloride              30 mg      40 mgLactose            30 mg      40 mgMicrocrystalline cellulose              15 mg      20 mgWater (purified), evaporated in the              q.s.       q.s.processEthylcellulose (EC)              1.6-2.4 mg 3.5-5.3 mgHydroxypropyl methylcellulose              1.0-1.6 mg 2.2-3.4 mg(HPMC)Triethyl citrate (TC)              03-0.5 mg  0.6.1.0 mgEthanol 99.5% (evaporated)              q.s.       q.s.Methyl isobutylketone (evaporated)              q.s.       q.s.______________________________________ 
    
     The in vitro dissolution rates at pH 6.8 are presented in Table 9. 
     
                       TABLE 9______________________________________In vitro dissolution rate of the CR capsules at pH 6.8Time         % dissolved(hours)      CR capsule A                   CR capsule B______________________________________1            15          82            37         163            56         254            69         345            --         426            87         498            95         6010           --         7012           102        --14           --         8324           --         95______________________________________ 
    
     
                       TABLE 10______________________________________Results of a bioavailability study of healthy volunteers:      Capsule    CapsuleParameter  A 30 mg    B 40 mg    Solution 15 mg______________________________________AUC (nmol/l*h).sup.1      252.8 ± 115.9                 304.1 ± 158.6                            129.4 ± 78.5C.sub.max (nmol/l).sup.1      20.9 ± 14.8                 15.4 ± 9.8                            34.1 ± 25.8t.sub.max (h).sup.2      4.5 (4-5)  4.5 (4-16) 0.5 (0.5-0.5)W.sub.50 (h).sup.2      7.73       &gt;24.3      1.53 (0.65-265)      (5.85-19.4)                 (14.1-&gt;28.8)F.sub.rel (%).sup.3      104.1      92.0       --      (83.8-129.4)                 (68.1-124.4)______________________________________ .sup.1 = mean ± SD .sup.2 = median (range) .sup.3 = mean (90% confidence interval) 
    
     The results of the study show very good bioavailability of both CR capsule preparations tested. Capsule A with a dissolution rate profile which makes it suitable for twice daily administration, showed a bioavailability of approximately 100% compared to the solution. Capsule B, with a dissolution rate profile intended for once daily administration showed a slightly lower bioavailability (approx. 90% ). However, at the last sampling point (32 hours) the serum concentrations were, in this case, still above half the Cmax concentration and the true bioavailability was thus higher than the calculated figure. 
     The curve width at half the Cmax concentration W 50  was about 5 times larger for Capsule A than for the solution. For capsule B W 50  was at least 15 times larger than for the solution. This, in combination with the excellent bioavailability shows that morphine can be administered once daily in a multiple unit preparation according to the invention and that such a preparation will result in low fluctuations in the serum concentration profiles. 
     This can be seen in FIG. 1 which shows mean serum concentrations in the six tested individuals versus time for the three preparations A, B, and C. It is obvious from this figure that preparation B, according to the invention, gives almost constant plasma concentrations during 24 hours.