CA2135639C - Controlled release preparation containing a salt of morphine - Google Patents

Controlled release preparation containing a salt of morphine Download PDF

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Publication number
CA2135639C
CA2135639C CA002135639A CA2135639A CA2135639C CA 2135639 C CA2135639 C CA 2135639C CA 002135639 A CA002135639 A CA 002135639A CA 2135639 A CA2135639 A CA 2135639A CA 2135639 C CA2135639 C CA 2135639C
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morphine
preparation according
barrier layer
preparation
salt
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CA2135639A1 (en
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Birgitta Olsson
Maritta Anneli Chefrad
Gert Ragnarsson
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Pfizer Health AB
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Pharmacia AB
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/48Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005Wall or coating material
    • A61K9/5021Organic macromolecular compounds
    • A61K9/5036Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
    • A61K9/5047Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47Quinolines; Isoquinolines
    • A61K31/485Morphinan derivatives, e.g. morphine, codeine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/04Centrally acting analgesics, e.g. opioids

Abstract

A new pharmaceutical preparation containing a number of coated particles comprising a salt of morphine coated with a barrier membrane providing a controlled, preferably pH-independent, 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. Also disclosed is 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.

Description

Controlled relase preparation containing a salt of morphine.
Field of invention The present invention relates to a new pharmaceutical preparation containing a num-ber 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 fluc-tuation 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 half-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-b times daily to achieve a satisfactory analgesic effect.
This has led to a development of various oral controlled release formulations of mor-phine.
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 espeoally pro-nounc!ed 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 control-led release matrix partly in the form of a salt and partly as a free base.
This prepara-tion increases dissolution time and biovailabilty without the need of applied coating membranes.
It is known that morphine gives rnnsiderable problems in the development of matrix tablets which have been considered to be due to poor absorption properties of mor phine in the distal parts of the gastrointestinal tract, see Proceed. Intern.
Symp.
Control. Rel. Bioact. Mater.,18,1991, pag. 433-434, (B. Olsson et al).
There are several examples of formulations which are designed to overcome tl°.e 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 gas-trointestinal tract and having a lower transit rate especially in the colon, compared to matrix tablets, see Drug Delivery to the Gastrointestinal Tract, Ed. By JG
Hardy Et. al., Chichester, Ellis Howard Ltd,1989, pages 75-81: "Colonic transit rate and drug deli-very". 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 pro-parties which will give greater flexibility in selection of the size of the dose, will faci-litate administration of the drug to patients having problems to swallow and will con-siderably 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-518 exhibit a limited bioavailibility, restricting the administration fio 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 ingre-dient 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 present invention provides a once-daily preparation of morphine i.e. a preparation with an even blood rnncentration profile when the preparation is administered once daily, without any substantial loss in bioavailability.
The preparation should preferably also have a release rate of morphine which is sulr stantially independent of its position in the gastrointestinal tract.
Such a preparation represents an improvement in the treatment of severe opioid sen-sitive 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 rnnsisting of small particles of morphine salts and a coated barrier layer which preferably provi-des 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 admini-stration.
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 I5 - 24 hours for all possible strengths of the preparation in the prefer-red interval of IO-400 mg moiphine (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',aspects of the present invention are low peak plasma concentration of morphi ne, release of 50% of the total dose within 4-10 hours and more than about 80%, pre ferably more than 90%, bioavailability of the preparation when compared to traditio nal preparations as instant release tablets and oral solutions.
It has been found that these demands are met surprisingly well by a preparation con-taining a large number of small particles comprising a salt of morphine which are mated 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 acsds. The particles are prepared with conventional methods such as mixing and gra-nulation of the morphine salt with the excspient or excipients, extrusion, spheroniza-tion, drying and sieving the particles to an acceptable size range.
Examples of suitable barrier mating 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 diffe-rent 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 mating 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 hydroxypropylmethyl 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 thetrade-mark 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. Eudragit RL and RS differ in the molar ratios'of the ammonium groups to the remaining neutral (meth)acrylic aced 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 characteristic.
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 mating constituents.
Plasticizers and pigments may optionally be used to modify the technical properties or change the permeability of the mating. The coating membrane is made of one or more polymers and has preferably a virtually pH independent permeability proper-ties within the pH range of 1.0 to 7Ø At higher pH a reduction in the release of mor-phine 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 mating composition within the scope of invention consi-sts of ethyl cellulose and hydroxypropylmethyl cellulose ands certain amount of tri-~ethyl citrate as plasticizes. A specific example of the coating composition is ethyl cel-lulose and hydroxypropylmethyl cellulose in relations from 55/35°!o to 80/10% w/w with 10°r6 triethyl citrate as a plasticszer.
Each coated morphine particle represents an individual controlled release unit, releas ing the drug at a predetermined rate preferably independent of its position in the gas trointestinal 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.

4a In one aspect, the invention provides an oral pharmaceutical preparation for administration once daily, comprising a therapeutically effective amount of a salt of morphine in the form of at least 50 individual particles with an individual particle size in the range of 0.7 to 1.4 mm, wherein each particle has a core comprising the salt of morphine coated with a barrier layer, wherein the barrier layer is derived from a solution, dispersion, suspension, emulsion or melt and comprises at least one water insoluble component selected from the group consisting of ethyl cellulose, a copolymer synthesised from acrylic and methacrylic esters, and natural or synthetic waxes, and a plasticizer, for providing drug release through the barrier layer which is substantially independent of pH in the range of 1.0 to 7.0 and wherein the mean serum concentration of morphine obtained is at least 50% of the maximum serum concentration during at least 12 hours after the administration of a single dose of the preparation.
In a further aspect, the invention provides a process for the manufacture of a preparation according to the invention, wherein the morphine containing particles are subjected to a spray coating procedure in a fluidized bed with a coating liquid in the form of a solution comprising at least one water insoluble barrier layer forming component, a plasticizer and a solvent selected from the group consisting of ethanol, acetone and methyl isobutylketone (MIBK), for providing a pH-independent barrier coating on the particles, and thereafter drying, size fractionating and collecting the coated particles.
In a still further aspect, the invention provides a process for the manufacture of a preparation according to the invention, wherein the morphine containing particles are subjected to a spray coating procedure in a fluidized bed 4b with a coating liquid in the form of a dispersion, suspension or emulsion comprising at least one water insoluble barrier layer forming component, a plasticizer and a solvent selected from the group consisting of ethanol, acetone and methyl isobutylketone (MIBK), for providing a pH-independent barrier coating on the particles, and thereafter drying, size fractionating and collecting the coated particles.
The invention also provides uses of the preparations of the invention for preparing a medicament for a once daily oral treatment of a severe opioid sensitive pain which demands a low plasma fluctuation of morphine, and for treatment of a severe opioid sensitive pain which demands a low plasma fluctuation of morphine; as well as a commercial packing comprising a preparation according to the invention and associated therewith instructions for use thereof for treatment of a sever opioid sensitive pain which demands a low plasma fluctuation of morphine.
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.
Manufacturing of morphine pellets Morphine hydrochloride pellets to be used in a controlled release preparation accord-ing to the present invention can be manufachued 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 criti-cally 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 96 w/w), lact~e (40 %
w/w) and microcrystalline cellulose (Avieel PH-l0I) (20 % w/w) totally 1500 gram were dry-mixed in a planetary type mixer (Kenwood Major) at a low mixing speed (speed adjustment <I) 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 L0 mm diameter.
The speed of the agitator and the feeder were set on the lowest values.
3. Spheronization: Spheronization was conducted in a marumerizer (Ferro Mecano AB, Sweden). The speed of the marumerizer plate was adjusted to 450 rpm. The num-ber 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 Vl~est Germany) at an IN-temperature of 50°C. The batch was divided into sub-batches of 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 OLTT-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°k of the cores had a size between 0.7I and 1.0 mm. A crushing strength analysis showed that the mean crushing strength of 1.0 mm particles was 4.71 N. 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.
Coating of morphine ~rdrochloride pgllets Morphine hydrochloride cores manufactured in accordance with Example I 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 filin formers together with triethyl citrate (1'EC) as a plastiozer.
The coating solution contained 99.59~o ethanol and methyl isobutyl ketone (MIBK).
The coating was performed using a spray coating equipment QVICA FB-water, Sweden). The spray gun used was a Binks ds 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 mm.
Ethanol/MIBK mixture was pumped through the system prior to the start of the coating, and there was wnsequently liquid present between the pump housing and the spray gun. The morphine hydrochloride cores prepared as in Example 1 were loaded The tyres were pre-heated at 55°C with an air velocity of 20-25 m3/h for 4 minutes: At the start of the coating, the bed temperature was 32 36°C.
The orating was started using the following process parameters: atomising pressure 500 kPa, air velocity 85 m3/h and a solution flow of about 24 ml/min. The regisfiered IN-temperature varied between 53 and 56°C, the OUT fiemperature between 34 and 38°C during the coating.
Morphine hydrochloride cores from the same batch were orated with different pro-portions of EC/HPMC in the film orating solution. Different amounts of the polymer solution was also tested in order to obtain a suitable in-vitro dissolution rate at a suit-able film thickness ( too thin a film may give reproducibility problems), see Table 1 below.
A mixture of S.5 parts of EC and 3.5 pans of HPMC was selected and an amount of appro~dmately 8 mg of coating material per capsule wntent (appro~dmatelY
7.596w/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 L4 mm sieve and spheres with a size less than 1.4 mm are collected. The collected spheres were filled into hard gelatine capsu-les (Hard gelatine capsule, velour 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 ~.13~~~9, Ph. Eur. The mean rnntent of active component in the capsules are between 36 and 44 mg.
The composition per capsule was:
Morphine hydrochloride 40 mg Lactose 40 mg Microcrystalline cellulose 20 mg Water (purified), evaporated during the q.s.
process Ethyl cellulose (EC) 3.5-5.3 mg Hydroxypropyl methylcellulose (HI'MC) 2.2-3.4 mg Triethyl citrate (TC) 0.6-10 mg Ethanol 99.5% (evaporated) ,s.

Methyl isobutylketone (evaporated) q.s.

~d g~atine capsule, white, No. 2 approx.
60 mg The film components are selected to give release properties that are virtually indepen-dent 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 fiest is carried out with the USP dissolution apparatus No. II
(paddle) at 50 rpm, 3T°C, in a phosphate buffer solution, pH 6.8. Six individual capsu-les are tested.
The amount released (% of labelled amount) is calculated <I5% released after 1 h 35-65% released after 6 h 55-80% released after I2 h not less than 80% released 24 after h ~13~~~~
t< t Table T
d., In vitro dissolution rate. Morphine hydrochloride pellets according to above, but with different amounts 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.
1Gi Amount of film (%w/w) 1.4 2.7 8.0 2.7 Prop:EC: HPMC:TEC 8:1:1 8:1:1 8:/:I 7:2:I
Time per cent dissolved morphine (hours) hydrochloride, n=2 10 - _ _ _ I2 - - _ _ EC; ethylcellulose HPMC; hydroxypropyl methylcellulose TEC; triethyl citrate *) n~

~l~a~~~~
94/22431 ~ PCT/SE94/00264 Table I continuation Amount of film (%w/w) 4.2 4.6* 7.5'~
Prop:EC: HPMC:TEC 7:2:1 5.5:3.5:1 5.5:3.5:1 Time per cent dissolved morphine (hours) hydrochloride, n=2 IS I I6 I6 . g 7 ~ ~ 55 EC; ethylcellulose HPMC; hydroxypropyl methylcellulose 30 TEC; triethyl citrate *) n=6 ~i3 ~~3 WO 94/22431 PCTISE94/00264~

to Table 2 ;..., .

In vitro dissolution rate: Morphine hydroc.~iloride pellets according to above with a coating of EC : HPMC : TEC = 5.5 : 3.5.: I at different agitation speed and pH.

Method: USP dissolution apparatus No. II (paddle), 37C. ' Dissolution pH 6.8 pH 6.8 pH L2 pH 4.0 pH 7.6 media n=6 n=6 n=3 n=4 n=3 Agitation 50 rpm I00 rpm 50 rpm 50 rpm 50 rpm speed Time per cent dissolved morphine hydrochloride (hours) ~13~~:~~
Table 3 In order to compare the in vitro dissolution rate at different pH, mating film thickness, agitation speed and temperature, the preparation of the following composition was prepared in a comparable manner to the manufacturing procedures " above.
proportion of EC : HPMC : TEC = 8 : 0.5 : L5 Active constituent Morphine hydrochloride 20 mg Inactive constituents Lactose 60 mg Microcrystalline cellulose 20 mg Water. purified* q.s.

Ethylcellulose 5.0-7.4 mg Hydroxypropyl methylcellulose 0.3-0.5 mg Triethyl citrate 0.9-L3 mg Ethano195%* q,s.

Acetone* q.s.

Water' purified* q.s.

*Evaporated during the manufacturing process ~1~
WO 94/22431 . ~ > , . ' ~ ~ ~CT/SE94/00264 Table 4 In vitro dissolution rate. Morphine hydrochloride CR pellets with different amount of polymers in the coating.
Proportions EC : HPMC : TEC = 8: 0.5 :1.5 Method: USP dissolution apparatus No. II (paddle), 37°C
dissolution medium phosphate buffer, pH=6.8, agitation speed 50 rpm.
fount of film 5.8* 6.9 8.6 9.2 (%w/w) Time per cent dissolved morphine hydrochloride, n=6 (hours) EC; ethylcellulose HPMC; hydroxypropyl methylcellulose TEC; triethyl citrate * n=3 ~~.3~~~~
Table 5 In vitro dissolution tests: Morphine hydrochloride CR according to Table 3 at different pH.
Method: USP dissolution apparatus No. II (paddle), 37°C, dissolution agitation speed 50 rpm.
Dissolution Medium pH pH 2.0 pH 5.8 pH 6.8 pH
L2 7.4 Time per sent solved morphine dis hydrochloride, n=6 (hours) ~1~~6~~ ~~,:.y:, ;;~ .
.. .. .
WO 94/22431 PCT/SE94/00264~
Table 6 In vitro dissolution rate. Morphine hydrochloride CR pellets batch 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 40rpm 50rpm 100rpm Time per cent dissolved morphine (hours) hydrochloride, n=6 R

....

Table 7 In vitro dissolution rate. Morphine hydrochloride CR pellets batch 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 in dissolution medium 35°C 37°C 40°C
Time per cent dissolved morphine (hours) hydrochloride, n=6 g 65 62 67 ,.;
~13~~~~ v ._ WO 94/22431 PCT/SE94/00264~
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 fulf'~l the requirements set on the preparations.
The film components were selected to give release properties that are virtually inde-pendent of pH and agitation. By testing the in vitro dissolution rates of the pellets of different batches (see Tables I-~, the rnmposition 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 pHa appear and that changes in agitation speed and temperature had no significant effect on the release rate.
Example 3 Bioavailability sfudX
A single dose, 3-way crossover bioavailability study was performed in 6 healthy individuals. Two prototypes of Morphine controlled release (CR) capsules manu-factured in accordance with Examples I and 2 of the present invention were studied, see also Tables 8 and 9, below. A morphine oral solution was used as a reference pre-paration. The subjects receaved either 30 mg of CR capsule A, 40 mg of CR
capsule B
or I5 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 concen-tration, tmax, fine width of the serum concentration vs time curve at half the Cmax concentration (W50) and the relative bioavailability of the CR capsules, (Fret) w~
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 I and 2; morphine CR capsules 40 mg formulation B, prepared according to Examples I
and 2 and morphine oral solution formulation C, 5 mg/ml, as a reference.

213~~3~
Table 8 Constituent CR capsule A CR capsule B

Morphine hydrochloride 30 mg 40 mg Lactose 30 mg 40 mg Microcrystalline cellulose I5 mg 20 mg Water (purified), evaporated in the q.s. q.s.
process Ethylcellulose (EC) L6-2.4 mg 3.5-5.3 mg Hydroxypropyl methylcellulose (HPMC) 1.0-L6 mg 2.2-3.4 mg Triethyl citrate (TC) 0.3-0.5 mg 0.6.1.0 mg Ethano199.5% (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 6.8 Time % dissolved ours CR ca sp uIe A CR capsule B

WO 94/22431 ~ ~ ~ ~ '1 '~ ~ ~CT/SE94/00264 Table 10 Results of a bioavailability study of healthy volunteers:
Parameter Capsule A 30 mg ~' q~ Capsule B 40 mg Solution I5 mg AUC (nmol/1*h)1 252.8t115.9 304.1t158.6 129.478.5 Cm~(nmol/1)1 20.9t14.8 I5.4t9.8 34.1t25.8 tm~(h)2 4.5 (4 - 5) 4.5 (4 - I6) 0.5 (0.5 - 0.5) W50 ~)2 7.73 (5.85 -19.4)>24.3 L53 (0.65 - 2.65) (14.1->28.8) Frej (%~ 104.1 (83.8 92.0 (68.1 -124.4) -129.4) 1 = mean t SD 2 = median (range) 3 = mean (90 % mnfadence interval) The results of the study show very good bioavailability of both CR capsule prepara-tions tested. Capsule A with a dissolution rate profile which makes it suitable for twice daily administration, showed a bioavailability of approximately 100%
compar-ed 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 rnncentrations were, in this case, still above half the Cmax concentration and the true bioavailability was thus higher than the cal-culated figure.
The curve width at half the Cmax concentration W50 was about 5 times larger for Capsule A than for the solution. For capsule B W50 was at least I5 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 Figure 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.

Claims (17)

CLAIMS:
1. An oral pharmaceutical preparation for administration once daily, comprising a therapeutically effective amount of a salt of morphine in the form of at least 50 individual particles with an individual particle size in the range of 0.7 to 1.4 mm, wherein each particle has a core comprising the salt of morphine coated with a barrier layer, wherein the barrier layer is derived from a solution, dispersion, suspension, emulsion or melt and comprises at least one water insoluble component selected from the group consisting of ethyl cellulose, a copolymer synthesised from acrylic and methacrylic esters, and natural or synthetic waxes, and a plasticizer, for providing drug release through the barrier layer which is substantially independent of pH in the range of 1.0 to 7.0 and wherein the mean serum concentration of morphine obtained is at least 50% of the maximum serum concentration during at least 12 hours after the administration of a single dose of the preparation.
2. A preparation according to claim 1, wherein the mean serum concentration of morphine obtained is at least 50% of the maximum serum concentration during at least 18 hours after the administration of a single dose of the preparation.
3. A preparation according to claim 1 or 2, wherein the barrier layer further comprises at least one water soluble component selected from the group consisting of hydroxypropylmethyl cellulose, hydroxypropyl cellulose, and a copolymer synthesised from acrylic and methacrylic acid esters.
4. A preparation according to claim 1, 2 or 3, wherein the barrier layer further comprises a pigment.
5. A preparation according to any one of claims 1 to 4, wherein the barrier layer comprises ethyl cellulose and hydroxypropylmethyl cellulose, and, as a plasticizer, triethyl citrate.
6. A preparation according to claim 6, wherein the ratio between ethyl cellulose, hydroxypropylmethyl cellulose and triethyl citrate is in the range from 55:35:10%
to 80:10:10%.
7. A preparation according to any one of claims 1 to 6, wherein the viscosity of the ethyl cellulose is in the range of from 5 to 15 cps.
8. A preparation according to any one of claims 1 to 7, wherein the salt of morphine is selected from the group consisting of morphine hydrochloride, morphine sulphate and a morphine salt of an organic carboxylic acid.
9. A preparation according to any one of claims 1 to 8, in the form of a tablet, a capsule or a sachet.
10. A process for the manufacture of a preparation according to any one of claims 1 to 9, wherein the morphine containing particles are subjected to a spray coating procedure in a fluidized bed with a coating liquid in the form of a solution comprising at least one water insoluble barrier layer forming component, a plasticizer and a solvent selected from the group consisting of ethanol, acetone and methyl isobutylketone (MIBK), for providing a pH-independent barrier coating on the particles, and thereafter drying, size fractionating and collecting the coated particles.
11. A process for the manufacture of a preparation according to any one of claims 1 to 9, wherein the morphine containing particles are subjected to a spray coating procedure in a fluidized bed with a coating liquid in the form of a dispersion, suspension or emulsion comprising at least one water insoluble barrier layer forming component, a plasticizer and a solvent selected from the group consisting of ethanol, acetone and methyl isobutylketone (MIBK), for providing a pH-independent barrier coating on the particles, and thereafter drying, size fractionating and collecting the coated particles.
12. A process according to claim 10 or 11, wherein the morphine containing particles are prepared by granulating a salt of morphine together with an excipient and a granulating fluid, extruding the granulated product and thereafter subjecting the granulated product to spheronization, drying and size fractionating.
13. A process according to any one of claims 10 to 12, wherein the coating barrier layer further comprises a water soluble component selected from the group consisting of hydroxypropylmethyl cellulose, hdroxypropyl cellulose, and copolymers synthesised from acrylic methacrylic acid esters.
14. A process according to claim 13, wherein the coating barrier layer further comprises a pigment.
15. Use of a preparation according to any one of claims 1 to 9, for preparing a medicament for a once daily oral treatment of a severe opioid sensitive pain which demands a low plasma fluctuation of morphine.
16. Use of a preparation according to any one of claims 1 to 9, for treatment of a severe opioid sensitive pain which demands a low plasma fluctuation of morphine.
17. A commercial package comprising a preparation according to any one of claims 1 to 9, and associated therewith instructions for use thereof for treatment of a sever opioid sensitive pain which demands a low plasma fluctuation of morphine.
CA002135639A 1993-03-30 1994-03-24 Controlled release preparation containing a salt of morphine Expired - Lifetime CA2135639C (en)

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