GB2288117A - Sustained release morphine - Google Patents

Abstract

Morphine preparations for once-a-day dosing are characterised by a W50 for the M-6-Glucuronide metabolite of between 4 and 12 hours and a W50 for morphine of between 4 and 12 hours. The W50 parameter defines the duration over which plasma concentrations are equal or above 50% of the peak concentration.

Description

SUSTAINED RELEASE COMPOSITIONS 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.

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 "twice-a-day" formulations, that is formulations having a duration of activity of 12 hours or more and accordingly requiring to be administered twice a day.

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.

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.

We have found, in accordance with one 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 characterised by a W50 for the M-6-G metabolite of between 4 and 12 hours, and preferably has a tmax 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 W50 parameter defines the width of the plasma profile at 50% Cmax, 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 characterised by a W50 for M-6-G in the range specified, are usually also characterised by a Wso 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 characterised by a W < o for morphine of between 4 and 12 hours, and preferably has a tmax 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 characterised by the foregoing parameters when dosed to patients in the fasted state.

Preferred values for Ws0 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 Cmaxs of formulations in accordance with the invention are dose dependant. For instance, a preferred embodiment containing 60mg morphine sulphate when administered as a single dose is characterised by a Cmax for M-6-G in the range of from 65ng/ml to 150ng/ml. Another such preferred embodiment is characterised by a Cmax for morphine in the range of from 7.5 to 20ng/ml.

One preferred embodiment described herein, after single dosing to 5 fasted volunteers was found to have W505 for morphine and M-6-G in the range 5.5 to 12 hours.

It has been found that in a group eg. n=5, of healthy volunteers one embodiment of such dosage units, when administered in a single dose in the fasted state. gave median tmax 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.

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 500mg 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 200mg of morphine (calculated as above).

A formulation in accordance with the invention will preferably release morphine or salt thereof at a rate substantially independent of pH of the surrounding environment.

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 100rpm in 900ml aqueous buffer (pH 6.5) containing 0.05%w/v Polysorbate 80 at 37 C] are preferably as set out below:

Hours after start of test % Morphine (salt) released suitable preferred 2 5-30 5-20 4 15-50 1 15-35 6 6 20-60 20-45 12 35-75 40-70 18 45-100 50-80 24 55-100 r 60-100 In 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 showns the mean plasma profiles of morphine and M-6-G obtained using a known controlled release morphine preparation in nine volunteers.

The compositions of the invention may be provided in a variety of forms, for example as tablets or capsules or sachets containing granules, spheroids, pellets or multiparticulates. 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 hydrophillic release modifier. In particular, the multiparticulates can be prepared by a process 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 sufficient energy to cause the fusible material to melt or soften it whereby it forms multiparticulates with the active ingredient. The resultant multiparticulates, after cooling, are suitably sieved to give multiparticulates having a particle size range from 0.1 to 3.0mm, preferably 0.25 to 2.0mm. 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 formulated 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 70% 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 1000C, preferably 45 to 900C.

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) Hydrophillic 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), Cl-Ch 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 hydrophillic or hydrophobic polymer.

(b) Digestible, long chain (C8-C50, especially C8-C40), 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 250C and 900C 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,2-C36, preferably C14-C2, aliphatic alcohols and/or one or more hydrogenated vegetable oils.

A particular suitable matrix comprises one or more alkylcelluloses, one or more C11- C36, (preferably C,4-C22) aliphatic alcohols and optionally one or more polyalkylene glycols.

Preferably the matrix contains between 0.5to and 60%, especially between 1% and 50% (by weight) of the cellulose ether.

The acrylic resin is preferably a methacylate 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 coo 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.

A preferred process for the manufacture of a formulation in accordance with the invention comprises (a) mechanically working in a high-speed mixer, a mixture of morphine or a pharmaceutically acceptable salt in particulate form and a particulate, hydrophobic fusible carrier or diluent having a melting point from 35 to 100C 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.

This process is capable of giving a high yield (over 80%) of particles (multiparticulate) in a desired size range, with a desired in vitro release rate of morphine or salt thereof.

The resulting multiparticulates may be sieved to eliminate any over or undersized material then formed into the desired dosage units by for example, compression into tablets, encapsulation into hard gelatin capsules containing the required dose of the active substance.

In a preferred method according to the invention morphine sulphate is used in an amount which results in particles containing between 10 to 70% w/w and more preferably 15 to 60% w/w of morphine.

In the method of the invention all the morphine or salt thereof is added in step (a) together with a major portion of the hydrophobic fusible release control material used.

Preferably the amount of fusible release control material added in step (a) is between 25 % and 45 % w/w of the total amount of ingredients added in the entire manufacturing operation, more preferably between 30% and 40% w/w.

If necessary or desired step (c) can be repeated one or more times with various amounts of the hydrophobic fusible release control materials to which, if desired minor amounts of water soluble fusible material or particulate soluble or insoluble organic or inorganic material can be added.

The total amount of additional fusible release control material added in step (c) or repeated step (c) is preferably between 5% and 30% w/w, more preferably 5-20% w/w of the total amount of ingredients added, most 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 or equivalent mixer. The mixture is processed until a suitable bed temperature e.g. above 400C 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 400C 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 370C may be conveniently used.

The agglomerates are broken down by any suitable means, which will comminute oversize agglomerates and produce a mixture of powder and small particles preferably with a diameter under 2mm. It is currently preferred to carry out the classification using a Jackson Crockatt granulator using a suitable sized mesh, or a Comil with an appropriate sized screen. We have found that if too small a mesh size is used in the aforementioned apparatus the agglomerates melting under the action of the beater or impeller will clog the mesh and prevent further throughput of mixture, thus reducing yield. A mesh size of 12 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 particles 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 multiparticulates have been formed they are cooled or allowed to cool, and may then be sieved to remove any over or undersized material.

The resulting multiparticulates may be used to prepare dosage units in accordance with the invention in the form of e.g. tablets or capsules or filled into sachets in manners known per se.

In order that the invention may be well understood the following examples are given by way of illustration only.

EXAMPLES Multiparticulates, 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 10kg, in the bowl of a 75 litre 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 formed into multiparticulates (iii) discharging the multiparticulates from the mixer and sieving them to separate out the multiparticulates collected between 0.5 and 2mm aperture sieves.

TABLE I EXAMPLE NO. 1 2 3 4 5 6 7 8 Morphine Sulphate (wt%) 15 15 15 23 55 55 55 55 Hydrogenated castor oil 77 76 75 70 - - - - U.S.N.F. (wt.%) Hydrogenated vegetable oil - - - 42.8 45 44.95 42.0 U.S.N.F.(wt. %) Polyethylene glycol 6000 8 9 10 7 0.2 - 0.05 U.S.N.F. (wt.%) Dicalcium phosphate - - - - 2 - - 3 anhydrous 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 100rpm in 900ml aqueous buffer (pH6.5) at 370C. For each of the products, six samples of the multiparticulates, each sample containing a total of 30mg 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 EXAMPLE Hours after 1 2 3 5 start of test (% morphine released) 2 19 25 33 44 4 27 36 49 57 6 34 45 62 66 8 41 52 72 72 12 53 64 86 81 18 66 77 96 89 24 76 86 101 92 Pharmacokinetic studies in health 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 30mg.

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 20kg) in the bowl of a 75 litre capacity Collette Vactron Mixer (or equivalent) equipped with variable speed mixing and granulating blades; ii) Mixing the ingredients at about 150-350rpm whilst applying heat until the contents of the bowl are agglomerated.

iii) Classifying the agglomerated material by passage through a Comill andior Jackson.'Crockatt to obtain controlled release seeds.

iv) Warming and mixing the classified material in the bowl of a 75 litre Collette Vactron, with addition of ingredient (d), until uniform particles of the desired pre-determined size range are formed in yield of greater than 80%. This takes approximately 5 minutes.

v) Discharging the particles from the mixer and sieving them to separate out the pellets collected between 0.5 and 2mm aperture sieves.

TABLE Ill

EXAMPLE 9 10 11 12 a) Morphine Sulphate (Wt%) 55.0 52.19 53.48 53.48 b) Hydrogenated Vegetable Oil USNF (Wt%) 34.95 33.17 33.98 33.98 c) Polyethylene Glycol 6000 USNF (Wt%) 0.05 0.047 0.049 0.049 d) Hydrogenated Vegetable Oil USNF (WL%) 10.0 14.60 12.49 12.49 Yield % 90.5 83.4 90.1 82.5 The in vitro release rates of Examples 9, 10, 11 and 12 were assessed by modified Ph.

Eur. Basket method at 100 rpm in 900ml aqueous buffer (pH 6.5) containing 0.05%w/v polysorbate 80 at 370C. For each of the products, six samples of the particles, each sample containing a total of 60mg 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 EXAMPLES

HOURS AFTER 9 10 11 j 12 START OF TEST % MORPHINE SALT RELEASED 2 21 15 20 15 4 33 25 36 24 6 43 35 49 30 59 43 59 36 12 62 57 72 46 18 71 71 82 57 24 82 81 86 65 30 83 85 89 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 60mg of morphine sulphate. The capsules produced were used in open, randomised crossover studies. As part of these studies patients received after overnight fasting either one capsule according to the invention or one MST CONTINUSR tablet 30mg (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 the capsules containing 60mg of morphine sulphate is produced according to Examples 9 to 12 gave peak plasma levels of morphine 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.

In terms of morphine plasma levels the capsules containing particles produced according to Examples 10 and 12 gave a mean Cmax of 11.9 ng/ml at median tmax 1 hours and mean Cmax of 9.2 ng/ml at median tmax 2.5 hours respectively (these values represent the mean of the individual (Cmax and tmax values). In contrast the Cmax and tmax of morphine for the patients who received MST CONTINUS9 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 these patients given MST CONTINUS &commat;.

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 60mg of morphine sulphate in five volunteers in the fasted state gave the results shown in Table V and Figs. 1 to 6.

TABLE V Volunteer M-6-G M-6-G W5o (h) w, (h) Cm"" (ng/ml) tmax (h) M-6-G Morphine 1 147.7 5.0 7.54 8.18 2 83.8 3.5 5.69 4.24 3 73.4 6.0 11.97 8.45 4 72.8 5.0 7.02 5.99 5 82.5 3.5 6.75 6.67 Mean 92.0 - 7.79 6.71 sd 31.5 - 2.43 1.72 Median - 5.0 Minimum 72.8 3.5 5.69 4.24 Maximum 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 CONTINUSX under a similar test conditions, and analysing 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 3 resulted at 12 hours in mean plasma levels for M-6-G and morphine of about 14ng/ml and 2nglml 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 M-6-G 17.5 ng/ml of morphine 2.5 ng/ml.

Based on the above results the preparations in accordance with the present invention are potentially effective for once a day dosing for the relief of moderate to severe pain.

Claims (2)

CLAIM:

1. A sustained release pharmaceutical formulation, containing an effective amount of morphine or a pharmaceutically acceptable salt thereof.

effective for 24 hourly dosing, characterised by a W50 (as hereinbefore defined) for the M-6-G metabolite of between 4 and 12 hours.

2. A sustained release pharmaceutical formulation, containing an effective amount of morphine or pharmaceutically acceptable salt thereof, effective for at least 24 hour dosing, characterised by a Ws0 (as herein before defined) for morphine of between 4 and 12 hours.