BG99077A - Composition with continuous release and method for the preparation of the pharmaceutical compositions - Google Patents

Abstract

The pharmaceutical form is a tablet or capsule containing granules, spheroids or pellets (multiparticulates). It comprises from 10 to 500 mg of morphine or a pharmaceutically acceptable salt thereof and a controlling carrier release. Morphine or a pharmaceutically acceptable salt thereof is from 10 to 60% wt. The rate of release of the active substance provides a peak plasma level of 1 to 6 hours after administration and the plasma levels are maintain that pain relief is carried out for 24 hours. The pharmaceutical form is also characterized by a W50 parameter defining the the period of time during which the plasma concentration is equal to or higher than

Description

YZObRETENIETO APPLY TO improvement NA'SASTAVI sustained release formulations and in particular dosage form of a sustained-release formulation for oral administration containing as an active ingredient morphine or pharmaceutically acceptable salt thereof.

The present invention also further relates to a method for producing orally administrable dosage forms PREFERRED GRANULES / microgranules, and compressing the microgranules sustained release, such as microgranules have a diameter in the range of 0.1 to 3.0 mm. The method according to the invention provides an unexpectedly high yield of microgranules.

Morphine is an opioid analgesic, widely used for the treatment of pain, and especially for moderate and severe pain. MORPHINE CONTAINING COMPOUNDS PREPARED FOR DOSAGE-FORMED DISPOSAL Forms are available on the commercial network and are known as two-day-a-day preparations, i.e. PREPARATIONS FOR 12 HOURS OR MORE AND SUCH ASSIGNED FOR ACCEPTANCE TWO DAYS.

One of the purposes of the present invention is to provide an ORALLY DOSAGE FORM with constant release, containing morphine, having an effective longitudinal viability,

2.

Surprisingly Oeshe found that an effective therapeutic effect for a period of 24 hours and more can be obtained from MORfINOSADARZhASht sustained release preparation according to the invention that has the IN VIVO Supreme plasma RELATIVELY recent use, IE FROM 1 TO 6 HOURS AFTER TAKING, preferably 1 TO 4 HOURS AND MAXIMUM 1 TO 3.5 HOURS AFTER ADMINISTRATION

Accordingly, one embodiment of the composition according izo6reTENIETO provides an oral administered dosage sustained release formulations comprising as active ingredient morphine or pharmaceutically acceptable salt thereof, which has a peak plasma level of 1 to 6 hours, preferably from 1 to 4 hours, more particularly from 1 UP TO 3.5 HOURS AFTER ACCEPT.

In a group of 5 healthy volunteers, such dosage forms, taken at a single dose in a compressed state, were found to give average b values in the range of 1 to 4.25 hours.

When the morphine is in the form of morphine sulfate, a method for analysis of plasma liquid chromatography, high efficiency, peak plasma level of morphine (LA ML · plasma) is preferably from 0,5 X ^{10, 7} to 7,5 X 10 ~ ⁷ TIMES THE QUANTITY OF ORAL MORPHIN SULPHATE. WHEN USED OSONVA morphine or its salt other than the sulphate, a preferred value of prescriptions to produce peak plasma level to be calculated according to the molecular weight of the salt or base.

The dosage form according to the invention should contain sufficient morphine or a salt thereof to provide a therapeutic effect for a single period of at least 24 hours.

3.

THE SPECIFIC QUANTITY OF MORPHINE (OR ITS SALT) FOR EACH DETERMINED DOSAGE FORM DEPENDS ON THE NUMBER OF VARIABLES / CLT: (i) number of dosage forms to be assigned. It is appropriate that the dosage forms according to the invention contain from 10 to 500 mg of morphine (calculated as morphine sulphate), even if typical dosage forms are in accordance with the invention morphine (MORPHINE SULPHATE BASED).

Morphine - 6 - Glucuronide (hereinafter referred to as M-6-6-) is a known metabolite of morphine and has strong analgesic properties on its own, least of all comparable.

In accordance with the and in accordance with the and in accordance with the in accordance with the enacting according to the invention, it is M _χΑχ ON M-6-G- IN 1 TO 6.5 HOURS, preferably 3 TO 6.5 HOURS; AND EVEN MORE PREFERRED FROM 3.5 TO 6 HOURS,

The parameter W ₅₀ determines the width of the plasma profile at 50% C _mX , i. the duration over which the plasma concentrations are equal to or greater than 50% of the TOP CONCENTRATION. THE PARAMETER IS DETERMINED BY THE LINEAR INTERPOLATION OF THE MONITORED DATA.

It was found with surprise that the preparations according to the INVENTION. WHICH ARE CHARACTERIZED WITH W ^ q FOR M-6- & IN THE SPECIFIED RANGE Usually Characterized With W ^ q For Morphine

А.

WITHIN A SIMILAR RANGE. ACCORDINGLY / According to another preferred aspect of the invention, a pharmaceutical composition comprising an effective amount of morphine or pharmaceutically acceptable salt thereof, effective for at least 24 hour dosing, is characterized by a W ₅ q for morphine of between 4 and 12 hours, and preferably has a T _MST IN A RANGE FROM 1 TO 6.5 HOURS, PREFERREDLY FROM 1 TO 4 HOURS, EXAMPLE FROM 1 TO 3.5 HOURS AFTER TAKING THE PREPARATION.

A preferred preparation according to this aspect of the INVENTION is CHARACTERIZED BY THE FOLLOWING PARAMETERS WHEN DOSED TO PATIENTS AFTER POSTING:

Preferred values of ha W ₅₀ for M-6-6- and morphine are in the range of about 5.5 to 12 or 5.5 to 11 or even 6 to 10 hours.

THE MAXIMUM _{CONCENTRATIONS} OF _MDX OF THE PREPARATIONS IN ACCORDANCE WITH THE INVENTION are dose _dependent . For example, one preferred embodiment containing 60 mg of morphine sulphate, when prescribed in a single dose, is characterized by _mdx for M-6-6-N / ML. OTHER SUCH A PREFERRED EMBODIMENT IS CHARACTERIZED BY _MHDX FOR MORPHINE IN A DISTANCE FROM 7.5 TO 20 NG / ML.

One preferred embodiment described herein after administration of a SINGLE dose of 5 healthy volunteers has been found to have W ₅ Q for morphine and M-6-6- in the range of 5.5 to 12 hours.

It was also found that in a group of 5 healthy volunteers, at a state AFTER fasting, one embodiment of a dosage unit appointed SINGLE DOSE show a mean value T _MST FOR N-6-6- in the range of 3.5 to 6 HOURS, FOR EXAMPLE 4 TO 6 HOURS AND FOR MORPHINE IN A RANGE OF 2.5 TO 5 HOURS.

5.

In addition, and in addition, it is also [6] in addition to, and in addition to, VITRO / MEASURED THROUGH MODIFICATIONS Ph.Eui Bast / ei method at 150 rpm in 900 ml aqueous 6uFer (pH 6.5), containing 0.05% by weight by weight of polysorbate at 37 ° C / CO. Below:

Hours after the start of the TEST % FREE MORPHINE (salt) appropriate PREFERRED 2 5-30 5-20 4 15-50 15-35 6 20-60 20-45 12 35-75 40-70 18 45-100 50-80 24 55-100 60-100

The embodiments of the compositions of the invention are illustrated by the accompanying Figures, of which:

Figures 1 to 5 show the plasma profiles of morphine and M-6-G- FOR ALL OF THE FIVE VOLUNTEERS AFTER TAKING A SINGLE DOSE OF THE PREPARATION ACCORDING TO THE INVENTION;

Figure 6 shows the mean plasma profiles of morphine and M-6-G- derived from the results shown in Figures 1 to 5;

6.

Figure 7 shows the mean plasma profiles of morphine

AND OBTAINED BY USE OF USED NAMED CONTROLLED MORPHINE PREPARATIONS IN NINE VOLUNTEERS.

The compositions according to the invention may be prepared in a plurality of Forms, for example, such as cells or capsules containing Pellets, Spheroids or Spheres. Usually, the composition contains the active ingredient (morphine or its salt) together with a solvent that can be used to change the release of the active ingredient. The preferred form for preparation of the unit dosage of the invention comprises a capsule filled with multiparticulates, comprising essentially the active ingredient, a hydrophobic fusible carrier or diluent and, optionally, - a hydrophilic release modifier. Particularly the number of particles are prepared preferably by a process comprising basically Formation of a mixture of dry active ingredient or soluble controlled release material, followed by a machining blended in a high MykSER with supply of energy sufficient for melting or softening the mixture to a shaping OF THE PARTICULAR PARTICLE FROM ACTIVE INGREDIENT. THE PARTICLES OBTAINED SHALL BE SCREENED AND COOLED SO MANY PARTICULAR SIZES OF 0.1 TO 3 MM ARE PROVIDED FROM 0.25 TO 2.0 MM. A PREFERRED AND NEW PROCESS OF THIS TYPE IS DESCRIBED BELOW AND IS ESPECIALLY SUITABLE FOR INDUSTRIAL PRODUCTION OF DOSAGE FORMS CONTAINING MORPHINE OR OTHER ACTIVE SUBSTANCES.

When using this production technology, it was determined that the desired characteristics were achieved more quickly7.

RELEASE OF RELEASE (like IN vivo, TAIL AND IN VITRO

THE COMPOSITION / SUBJECT TO PROCESSING SHOULD CONTAIN TWO SIGNIFICANT INGREDIENTS:

A / ACTIVE INGREDIENT (MORPHINE OR ITS SALT) AND

B / HYDROPHOBIC TOPIMUM CARRIER OR SOLVENT, A

Optional & c / EXPOSURE CONTROL ELEMENT CONTAINING WATER-SOLUBLE TOXY MATERIAL OR SHALLOW SOLUBLE OR INSOLVED / ORGANIC ORAL ORGANIC OR.

w It has been found that the total amount of Active IngredientsEHT in the PREPARATION CAN VARIABLE IN WIDE LIMITS, FROM 10 TO 60% BY WEIGHT.

The hydrophobic fusible component (B) must be hydrophobic materials such as natural or synthetic waxes or oils, as hydrogenated vegetable oil or hydrogenated castor oil, and suitably has a melting point in the range of 35 to 100 ° C, preferably from 45 Up to 90 ° C.

Component for Modifying Expectations (c) WHEN WATER SOLUBLE MATERIAL is SELECTED.

The use of lower amounts of morphine, for example

FROM 10 TO 30%, requires the inclusion of small quantities of the release modification component, eg 5 to 15%, polyethylene, polyethylene, polyethylene, polyethylene, polyethylene AT 0 HIGH DOSES OF THE MEDICINAL PRODUCT, SUGGESTED FROM 40 TO 60% BY WEIGHT, ESPECIALLY SURPRISING THAT THE INCLUSION OF MANY SMALL QUANTITIES OF POLYETHY

8.

Flax glycol, for example from 0.01 to 1% by weight, is required to change the rate of release in VITRO.

Alternatively, the morphine (or salt thereof) may be incorporated (for example, by DRY OR WET GRANULATION or BY MIXTURE) into a controlled release formulation formed by components, components. Suitable materials for inclusion in a controlled release matrix include, for example: A / hydrophilic or hydrophobic polymers, such as gums, cellulose ethers, PROTEIN DERIVATIVES, nylon, acrylic resins, polylactic acid, polyvinylchloride, starches, polyvinylpyrrolidones, TSELOLUZEN acetate. Of these polymers are preferred cellulose ethers, and especially substituted TSELULOAZNI ethers such as alkylcelluloses (such as ethylcellulose), Cj- Cg hydroxyalkylcelluloses (such as hydroxypropylcellulose and especially, hydroxyethylcellulose) and dkrilni resins (EG methacrylates as METAkRILATkISELINNI copolymer). The control release matrix is suitably comprised of from 1 to 80% by weight of a hydrophilic or hydrophobic polymer.

in / digestible, DALGOZVENNI (Cg - C ₅ q), IN PARTICULAR (Cg - Cn _0), substituted or unsubstituted hydrocarbons, such as fatty acids, hydrogenated vegetable oils such as CUTINA (trade MARkd), fatty alcohols (such as lauryl, myristyl, stearate, cetyl or preferably cetostearyl alcohol, glyceryl esters of fatty acids, as glyceryl monostearate mineral oils and waxes (kdto beeswax, glycowax, castor oil, kdrnAUbski wax). preferred are vaglevodoridi having tochkd MELTING between 25 ° C and 90 ° C. OF THESE LONG-TERM HYDROCARBON MATERIALS ARE BEFORE Eye fatty (aliphatic) alcohols.

9.

The matrix may contain up to 50% by weight of at least one digestible, long-lived hydrocarbon.

c / Polyalkylene glycols. The matrix can contain up to

% By weight of at least one polyethylene glycol.

A suitable matrix comprises one or more cellulose ethers or acrylic resins, one or more preferably ₁ micron -C _22, aliphatic alcohol and / or more hydrogenated vegetable oils.

SPECIFICALLY APPROPRIATE MATRIX INCLUDES ONE OR MORE ALKYCELLULOSE, ONE OR MORE THAN C35 (PREFERRED 0 _{1Ζ |} -0 ₂ 2)

ALPHATE ALCOHOLS AND OPTIONAL - ONE OR MORE POLYALKYL GLY CARS.

Preferably, the matrix comprises between 0.5% and 50%, and more particularly between 1% and 50% (weight) cellulose ether.

DKRILNA.RESOLE METACYLAT IS PREFERRED AS METACRYLIC ACID COPOLYMER AND. SN F, TYPE A (EUDRAGIT L, TRADE MARK), TYPE B (EUDRAGIT S, TK 30D, Eudragit E, Eudragit RL and Eudragit RS.

Preferably, the matrix comprises between 0.5 and 60% by weight, preferably between 1 and 50% by weight of acrylic resin.

In the absence of polyalkyl glycol, the matrix preferably contains between 1 and 40% by weight, in particular between 2 and 36% by weight of aliphatic alcohol. WHEN IN THE ORAL DOSAGE A POLYALKYL GLYCOL IS PRESENTED, THEN THE GENERAL WEIGHT OF THE ALIFATH ALCOHOLS ARE ALSO 2

10.

POLYalkylene glycol may be, for example, polypropylene glycol or, preferably, polyethylene glycol. Number-average molecular weight of at least one polyalkylene glycol is preferred between 250 and 15,000, especially between 400 and 12,000 MORfINOSADARZhAShtATA controlled-release matrix can easily be prepared by dispersing the active ingredients in controlled-release systems using conventional Pharmaceutical technologies such as granulation through melt, wet granulation, dry granulation, dry blending or co-precipitation.

Another form of sustained release formulation includes spheroids obtained by sphingonization of morphine (or salts thereof) with a spheronizing agent such as microcrystalline cellulose.

The present invention also includes a method for the production of a plurality of sustained-release particulates containing morphine or a salt thereof, which METHOD INCLUDES:

and / Mechanical obrdbotkA in a high shear mixer a mixture of morphine or salt thereof in particulate form and crushed hydrophobic fusible excipient, or diluent, having a melting point of 35 to 150 ° C, for example up to 100 ° C, and optionally - a component for controlled release CONTAINING WATER SOLUBLE MATERIAL OR CRUSHED, SOLUBLE OR INSOLUBLE, ORGANIC OR INORGANIC MATERIAL. MECHANICAL PROCESSING IS OF RATE AND QUANTITY OF ENERGY SUPPLIED, ALLOWING THAT TO MAY MAKE OR MOLD THE FILLER OR THE DILUTION THEN IF IT IS.

C / DISTRIBUTION OF Larger Production Agglomerates

GRAINS WITH CONTROLLED RELEASE;

π.

C / CONTINUATION OF MECHANICAL PROCESSING WITH THE CONTINUOUS ADDITION OF SMALL QUANTITIES OF FILLER OR THINNER; And

E / OPTIONAL - REPEAT THE STEP WITH / AND POSSIBLY STEP / B / ONE OR MORE times, for example up to five times.

By this method it is possible to obtain a high yield (over 80%) of particles having a size of a desired range, with desired release rate, IN VITRO, the uniformity of the release rate, preferably forms achieve a EARLY peak plasma level at PREPARATION WITH 24 HOURS DURATION OF IMPACT MU.

The resulting microgranules can be screened to eliminate those larger or smaller sizes, after which they are formed in the desired dosage form, for example, by encapsulating them in solid gelatin CDs, and containing them.

Preferably, the morphine sulfate is used in an amount of 60, which leads to the content of the active ingredient in the microgranules in the range from 10 to 60 60 60 60 60 60 60 60 60 60 60 60 60 60 60 60 60 60 60 60 60 60 60 60 60 60 60 60 60 60 60 60 60 60 60 60 60 60 60 60 60 60 45% by weight for the low dose preparation.

In this method, according to the invention, all LEADING is added in STEP (A), TOGETHER WITH THE BASIC PART OF THE USED HYDROPHOBIC TOPIM CONTROLLED RELEASE MATERIAL. Preferably preferred is the amount of the added to the step (a) (A) OF THE CONTINUOUS CONTROLLATED CONTROLLED SUBSTANCE OF THE PREFERRED PERFORMANCE, A CONTROLLED SUBSTITUTE OF THE CONTINUED PRODUCT, A SUBSTANCE OF THE CONTINENT OF THE INVENTION, %.

12.

IN IN IN IN IN IN IN IN IN IN IN IN IN

STEPKD (A) OF THE METHOD MAY BE IMPLEMENTED IN ORDERED HIGH-SPEED MIXERS WITH STANDARD STAINLESS STEEL INTERIOR / MIXER ELEGER COLLER ACTIVE The mixture is treated to reach a base temperature of 40 ° C. The material (in the case of the embodiments described below) is in the form of agglomerates which, when cooled: under 40 ° C, have a structural uniformity and a stable structure. At this stage, the agglomerates do not have the same size / shape and appearance.

The agglomerates are preferably left to cool. The temperature to which they are cooled is not critical, as it is convenient to use temperatures in the range from room temperature to 45 ° C, for example to 37 ° C.

THE AGLOMERATES SHALL BE CRUSHED THROUGH ANY SUIT AND THE SUGGESTED AGENT THAT SHALL BE GRINDED BY THE BIGGER AGGREGATES, WHETHER THAT THEY MAKE MIXTURE FROM THE POWDER Sorting is preferably performed using a Jackson Crockatt granulator with a suitably sized grid, or Comil also with a suitably sized grid. It was found that if the abovementioned devices employ a grid with too little hole agglomerates, stop the action of RAZbIVAChkATA or shovel, blocked grille and impede passing the mixture through it, thus

13.

THE METHOD IS REDUCING. IT WAS DETERMINED THAT FITS OF 12 OR 94 G-COMILL GATES ARE SUITABLE.

The sorted material is returned to the high-speed mixer and the blender continues. This is thought to result in the adherence of the finer particles into microgranules having dimensions of the same range.

In a preferred embodiment of the inventive method processing of sorting MATERIAL USED continued until the hydrophobic fusible material sTArTIng to soften or melt, then add additional hydrophobic fusible material. Stirring is continued until the blends are converted into microgranules of the dimensions falling into the desired preset range.

In order to ensure the supply of the same amount of energy to the ingredients in the high-speed mixer, it is preferable to supply at least a portion of the energy in the form of microwaves.

Energy can also be supplied by other means, eg via a heating jacket or through the mixer mixer and through the crushing blades.

After spheres are formed, they can be sieved to remove larger or smaller size materials, after which the spheres are cooled or left behind.

The resulting beads can be used to prepare dosage forms such as cells or capsules according to methods known per se.

IN THE METHOD OF THE INVENTION, THE TEMPERATURE OF THE MIXTURE CUP AT THE MECHANICAL PROCESSING TIME IS SELECTED,

14.

WHAT TO AVOID OVERHEADING OF THE MATERIAL ON THE WALLS OF THE CUP.

BASIC was found that the temperature should be neither too high nor too low by Melting NL material and it can easily be optimized to avoid the problems mentioned above. For example, in the methods described below when describing the examples, it was found that a temperature of about 60 ° C was satisfactory for avoiding adhesion.

To produce the tablet according to the invention, microgranules, prepared as described-above may be mixed or mixtures of desired (desired) excipient (filler) using conventional procedures, for example USING Y-cone or bin blender AS THE MIXTURE OBTAINED IS PRESSED THROUGH THE UNDERSTANDING TABLET PROCEDURE USING APPROPRIATELY SIZED TABLET PRESSES. THE TABLETS MAY BE PRODUCED BY USING GENERAL TABLETING MACHINES AS IN THE EXAMPLES TABLETS MADE BY STANDARDS6 STANDARDS

For the sake of better understanding of the invention, the following examples are given, which are ONLY illustrative.

Examples 1 to 8

BALLS OF THE COMPOSITIONS GIVEN IN TABLE I WERE MANUFACTURED BY THE FOLLOWING ACTIONS:

(I) INGREDIENTS OF 10 KG WEIGHT INGREDIENTS IN THE COLLETTE VACTRON MIXER BOX WITH 75 L (OR LIKE IT, WITH MIXER AND MIXER)

15.

(II) Stirring the ingredients by applying heat until the contents of the bowl have been turned into spheres;

(W) REMOVING THE SPHERES FROM THE MIXER AND SIFTING THEM TO SEPARATE THE SPHERES THROUGH THE SITTING WITH SIZE SIZES OF 0.5 MM AND 2 MM.

EXAMPLE No. TABLE 1 MORPHINE SULPHATE (% by weight) 1 2 3 4 5 6 7 8 Hydrogenated beaver- VA MAC U.S.N. F (tem%) 15 15 15 23 55 55 55 55 HYDROGENATED VEGETABLE OIL U.S.N.F (wt.%) 77 76 75 70 - - - - Polyethylene glycol 6000 U.S.N.F (wt.%) - - - - 42.8 45 44.95 42.0 TWO-calcium phosphate anhydrate U.S.P (TErn.% 8 9 10 7 0.2 - 0.05 - - - - - 2 - - 3

The levels of in vitro release of the preparations

OF EXAMPLES 1,2,3 AND 5 WERE ESTIMATED BY THE MODIFIED METHOD

Ph.Eur.Basket at 100 rpm in 900 ml of aqueous 6uFer (pH 6.5) at 37 ° C. For each product, six SPHERIC samples were tested, as each PROBD always contained a total of 30 MG of MORPHIN SULPHATE. THE RESULTS REFERRED TO IN TABLE II GIVE THE AVERAGE VALUES FOR EACH OF THE SIX TESTS.

16.

TABLE II EXAMPLE PRODUCT Hours after the start of the TEST 12 3 5 (% FREE MORPHINE 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

FARMOkINETIChNITE RESEARCH healthy volunteers show peak plasma LEVELS OF 2,2 TO 21,6 NG / ML morphine hourly space between 1 and 3.5 hours after administration of one capsule, W CONTAINING beads prepared according to Example 1,2,3 or 5 ,

IN QUANTITY, IT IS SUFFICIENT TO PROVIDE A MORPHIN SULFATE DOSE OF 30 MG.

Examples 9 to 12

Particles having the compositions listed in Table III below were made through:

(I) DELIVERY OF THE INGREDIENTS (A) TO (c) (TOTAL WEIGHT OF ONE Batch 20 kg) IN THE TANK OF A COLLETTE VACTRON MIXER WITH CAPACITY 75 L. (OR IN EQUIVALENT SIBER)

17.

(Ii) stirring the ingredients at a rate of 150-350 rpm with the application of heating until the contents of the tank are agglomerated;

(III) Sorting agglomerated material by passing MY through COMILL and / or JACKSON CROCKATT to obtain grain with controlled release;

(IV) HEATING AND MIXING THE SORTED MATERIAL IN

75L COLLETTE VACTRON TANK WITH ADDITION TO

INGREDIENT (E) UNDER THE FORMATION OF SINGLE PARTICLES WITH A DIMENSION FALLING IN A PRELIMINARY RANGE OF Yield greater than 80%. THIS TAKES ABOUT ABOUT 15 MINUTES.

(V) DRAINING THE PARTICLES FROM THE MIXER AND SIFTING THEM TO SEPARATE THE COLLECTED PARTICLES THROUGH THE SITTING WITH SIZE OF Apertures between 0.5 and 2 mm.

TABLE I'll - EXAMPLE 9 10 11 A / MORPHINE SULPHATE (% By weight) 55.0 52.19 53.48 B / HYDROGENATED VEGETABLE OIL U.S.N.F (% by weight) 34.95 33.17 33.98 e / Polyethylene glycol 6000 U.S.N.F (% by weight) 0.05 0.047 0.049 D / HYDROGENATED VEGETABLE OIL U.S.F.N (% by weight) 10.0 14.60 12.49 Yield% 90.5 83.4 90.1

18.

Degrees of in vitro release for example

9,10 and 11, as in Example 12 below, were evaluated by the modified Ph.Eur.Basket method at 100 rpm.

IN 900 ML WATER BUFFER (pH 6.5) CONTAINING 0.05 VOLUME% POLYSORBATE 80 AT 37 ° C. FOR EACH PRODUCT WAS TESTED WITH SIX PARTICLE SAMPLES, ALWAYS THE SAMPLE CONTAINED A TOTAL OF 60 MG OF MORPHINE SULPHATE.

The results shown in Table IV below give the average values for each of the six tested samples.

TABLE I PRODUCT FROM V NAME Hours after the start of the TEST 9 10 11 % MORPHINE SULPHATE FREE 2 21 15 20 4 33 25 36 6 43 35 49 8 52 43 59 12 62 57 72 18 74 71 82 24 82 81 86 30 83 85 89

The procedure of Example 11 6 was repeated, but the action was modified by adding the sorted particles to the cold reservoir of the COLLETTE VACTRON mixer, followed by addition and addition. During the stirring, the heating was applied through a heating jacket and microwaves.

19.

The degree of in vivo release is reflected in

TABLE IV-A AND INVITES THAT IT HAS CONTRASTED THE EQUALITY OF THE COMPOSITIONS OF

THE PRODUCTS OF EXAMPLES 11 AND 12, DIFFERENT PROCESSING IS REFLECTED IN CHANGE IN THE RELEASE OF RELEASE.

TABLE IV-A EXAMPLE 12 Hours after test start / % FREE MORPHINE 2 15 4 24 6 30 8 36 12 46 18 57 24 65 30 71

The particles produced according to Examples 9 to 12 were mixed with purified talc and magnesium stearate and used to fill hard gelatin capsules so that each capsule contained 60 mg of capsule. The resulting capsules were used for open-label, randomized, cross-pharmacokinetic studies. As part of these studies, patients received either overnight fasting or one capsule according to the invention or one 30-mg MST CONTINUS tablet (two-day preparation). TAKING LEAK

20.

THE NEWS WAS UNLIMITED 4 HOURS AFTER DOSAGE.

Lunch was provided is low in fat

HOURS AFTER TAKING THE DOSE, EVENING AFTER 10 HOURS AND LIGHT 3 ACUSES AFTER 13.5 HOURS. Until the blood sample was taken at the 24th hour, no other food was allowed. BLOOD SAMPLES WERE TAKEN AT THE FOLLOWING HOURS: 1, 1.5, 2, 2.5, 3, 3.5; 4, 5, 6, 9, 12, 18, 24, 36, 48 and 72 hours after dosing.

PHARMACEUTICAL PHARMACEUTICAL ANALYSIS WHEN USING THESE Capsules SHOWED TOP PLASMA LEVELS OF 3.2 TO 29.2NG / MORMIN IN 2 TIMES MIDI 6

The capsules containing particles produced in accordance with Examples 10 and 12 in particular gave ONE INTERMEDIATE CONCENTRATION with a _max of 11,9 ng / ml at an average T _{max of} 4 HOURS and an intermediate with a _{MAX of} 9,2 NG / ML for a mean T _MAX 2 , 5 HOURS (THESE VALUES REPRESENT THE AVERAGE VALUES OF INDIVIDUALS WITH _{MD) <} AND τ _ΜΑχ ). Contrasting these results, with _mdx and _mdx the patients who received MST CONTINUS ^R tablets were 10.6 - 11.4 ng / ml and 2.0-2.5 hours, respectively. It was found that

PLASMA CONCENTRATIONS OF MORPHINE IN THE BLOOD OF PATIENTS TO WHICH THE Capsules HAVE BEEN ADMINISTRATED IN ACCORDANCE WITH THE INVENTION, AT THE 24TH TIME, HIGHER THAN THOSE MST CONTINUS ^R tablets were given.

FARMOkINETIChNITE ASSAYS BASED PARTICLES PRODUCED IN EXAMPLE 9, and directed to morphine and M-6-6, since the adoption of a capsule containing 60mg of morphine sulphate of six volunteers PRESENT IN POST MODE showing the results depicted in Table V AND FIGURES FROM 1 TO 6.

I *** ·

TABLE V VOLUNTEER M-6-G C _max (ng / ml) M-6-G tmax (b) Wjoih) M-6-G Wsofli) 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 On average 92.0 - 7.79 6.71 sd 31.5 - 2.43 1.72 On average - 5.0 - - minimum 72.8 3.5 5.69 4.24 MAXIMUM 147.7 6.0 11.97 8.45

Figure 1 shows, by counterstick, the mean Plasma Millets FILLETS RECEIVED AFTER ADOPTION OF NINE HEALTHY VOLUNTEERS

Known preparation containing morphine sulphate MST CONTINUS ^ under similar test conditions and analyze blood samples through similar analytical procedure as that used in testing NA'PREPARATA invention which gave the results illustrated in Table V and Fig. 1 TO 6. YOU CAN SEE THAT MST CONTINUS ^r has results at 12 noon

At the mean plasma levels for M-6-G- and MORPHINE about 14 NG / ML and 2 NG / ML respectively.

Mean plasma levels at 24 hours obtained using the preparation according to the present invention

22.

DETECTION AND ILLUSTRATED IN FIGURE 6 WAS: FOR M-6-6 17.5 NG / ML

AND FOR MORPHINE 2.5 NG / ML.

Example 13

Particles analogous to examples were produced

UP TO 12, BUT HAVING THE FOLLOWING INGREDIENTS:.

% By weight morphine sulfate55.0

HYDROGENATED VEGETABLES44,7

BUTTER

Polyethylene glycol 60000,03

The particulate samples were mixed following this with magnesium stearate and purified talc in two batches (1 and 2) using a y-kOHYCEH OR MIXER hopper. EVERY MIX AFTER THIS WAS COMPRESSED THROUGH ONE PRESSING TABLET MACHINE S Wanes / y WITH NORMAL HOLES WITH A DIAMETER OF 7,1 MM. THE INGREDIENTS FOR A SINGLE DOSAGE FORM WAS THE FOLLOWING:

l TABLE VI TVBLET INGREDIENT me / Tablets 1 2 MORPHINE SULPHATE 60.00 60.00 HYDROGENATED VEGETABLE OIL 48.77 48.77 Polyethylene glycol 0.33 0.33 Intermediate total weight 109.1 109.1 Magnesium stearate 1.42 2.0 Purified TLC 2.18 3.0

23.

The dissolution of the unpolluted particulate matter (Each sample contains 60 mg of morphine in sulfate) was evaluated by the modified Ph.Eur.Basket method described above.

For the dissolution of the Ph.Eur.Basket tlBLETs, method 6 was REPLACED by the Ph.EUR method. PADDLE. THE RESULTS ARE

SHOWED IN TABLE VII.

TABLE VII Hours after the TEST begins Particles TABLE 1 TABLET2 % FREE MORPHINE IN SULPHATE 1 27 13 11 2 43 20 17 4 63 29 26 8 82 42 37 12 88 50 44 16 91 57 NR 24 93 65 NR 30 94 70 NR 36 95 74 NR

NR - NOT RECORDED

The above results indicate that as a result of the targeting, a significant reduction in the degree of release of the active ingredient is obtained.

Example 14

The procedure of Example 13 was repeated, but with the following changes:

24.

The particles 6 were made from the following ingredients:

% by weight

MORPHINE SULPHATE55,0

HYDROGENATED VEGETABLE OIL44,4 polyethylene glycol0,6

THE PARTICLES WERE MANUFACTURED BY TWO BATS OF TABLETS (3 AND 4) BY USING A PRESSURE WITH A DIAMETER OF 7.1 MM. THE INGREDIENTS FOR A SINGLE DOSAGE FORM WAS AS FOLLOWS:

TABLE VIII TABLETS Ingredient Me / Tablet 3 4 MORPHINE SULPHATE 60.0 60.0 HYDROGENATED VEGETABLE OIL 48.44 48.44 Polyethylene glycol 600 0.655 0.655 Intermediate total weight 109.1 109.1 PoIoxamer 188 - 5.0 Magnesium stearate 2.0 2.0 Purified TLC 3.0 3.0

The dissolution of the plates and samples of non-compressed particles (each sample containing 60 mg of morphine sulphate) were evaluated by the methods described above. The results are shown in TABLE IX.

25.

5, ^ 5 · =

TABLE IX Hours after the test begins Particles TABLE3 TABLE 4 7o FREE MORPHINE SULPHATE 1 56 16 19 2 75 24 28 4 90 34 38 8 95 46 52 12 97 54 60 16 NR NR 67 24 NR NR 77

These results again show a strong decrease

THE RELEASE OF MORPHINE SULPHATE RELEASE IN RESULT

ON THE PRESSING OF THE PARTICLES TO TAKE TABLETS. COMPARISON BETWEEN release rate of the tablet 3 and 4 also shows that the rate of release may be ^W regulated using a surfactant (in this case POLOXAMER 188 ^R) as a tabletting excipient; THE RELEASE RELEASE FOR TABLE 4 CONTAINS A SURFACE OF ACTIVE SUBSTANCES IS GREATER THAN THOSE FOR A TABLE 3 THAT DOES NOT CONTAIN A SURFACE ACTIVE.

Claims (23)

1. 1. A dosage form with a sustained release for oral administration and containing morphine or pharmaceutically acceptable acceptable salts, such as an active ingredient, characterized in the method of claim 1; UP TO 6 HOURS AFTER ACCEPT. A dosage form according to claim 1, wherein the dosage form is: W COMES ONCE THAT ITS INITIATIVE PRODUCTS ARE ON TOP PLASMA LEVEL FROM 1 TO 3.5 HOURS AFTER ACCEPT. 3. A pharmaceutical composition constant osvo6oZhdavane comprising an effective amount of morphine or pharmaceutically acceptable salt thereof, effective in 24 hour dosing, is characterized by the parameter W ^ q (defined substantially as set forth ALREADY) for M-6-GMETAbOLIT between 4 and 12 hours. 4. Permanent release pharmaceutical composition. containing Effective Amount of Morphine or Pharmaceutically Acceptable Salt thereof, EFFECTIVE AT 24 HOURS DOSAGE, CHARACTERIZING WITH PARAMETER W ^ q (WHEN DETERMINED 12) A pharmaceutical dosage form according to any one of claims 1 to 4, characterized in that it contains 10 TO 500 MH MORPHINE (MORPHINE SULPHATE CONSIDERED). A pharmaceutical dosage form according to any one of PREVIOUS CLAIMS WHICH HAVE SUCH RELEASE CHARACTERISTICS IN VILCO THAT COMPOSE (WHICH IS ESTIMATED BY THE MODIFIED METHOD PH. EUR. BASKET AT 100 rpm 27. WATER BUFFER, (pH 6.5), CONTENTS 0.5% POLYSORBATE AT 37 ° C) LIBERATES 5 TO 30% OF THE ACTIVE INGREDIENT TWO HOURS AFTER TEST START, 15 TO 50% 4 HOURS AFTER 20 60% 6 HOURS AFTER STARTING THE TEST, 35 TO 75% 12 HOURS AFTER STARTING THE TEST, AND 55 TO 100% 24 HOURS AFTER STARTING OF THE EXPERIMENT. A pharmaceutical dosage form according to any one of the preceding claims, including a capsule comprising microgranules, which substantially includes the active ingredient and the hydrophobic outerboron. 8. A pharmaceutical dosage form according to claim 7, characterized in that THAT microgranules also contain from 0.01 to 20 wt.% (Of their total weight) of components for controlled release, water-soluble fusible material or crushed SOLUBLE OR NON-SOLUBLE, ORGANIC OR INORGANIC MATERIAL. A pharmaceutical dosage form according to claim 7 OR 7 Characteristic that the micro-granules include a pharmaceutically active substance in a matrix of hydrophobic materials, having a capacity of 10 to 100 10. A pharmaceutical dosage form which can be 6ade obtained by compression of microgranules containing a pharmaceutical active substance in a matrix of a hydrophobic fusible material with a melting tochkd from 35 to 150 ° C, klto dosage form optionally containing conventional tabletting excipients. 28. A dosage form according to one of the claims of 7 to 10, characterized in that said microparticles are prepared by methods, which include all actions for machining of a mixture comprising particulate drug and particulate hydrophobic fusible carrier or diluent having a melting point of 35 to 150 ° C, at a speed and floor ENERGY THAT ALLOW THE MEDICAL OR DILUTION MIXER OR MOLD AND MOLD THE MICRO GRANULLE WITH THE DESIRED SIZE. 12. A dosage form according to any one of claims 7 to 11, characterized in that THAT microgranules RECEIVED POSRESDTVOM machining of a mixture comprising an active ingredient, a hydrophobic and fusible carrier or diluent and optionally - a release modifier, the processing is carried IN A HIGH-SPEED MIXER AT SPEED AND FEED. ENERGY ENOUGH TO CAUSE MELTING OR MELTING OF TOPICAL MATERIAL BEFORE SHAPING PARTICLES WITH THE ACTIVE INGREDIENT, AFTER WHICH IT TAKES OIL 13. A dosage form according to any one of claims 7 to 12, characterized in that THAT CONTAIN microgranules modifier osvoboZhdlvANEto which is hydrophilic modiFiklTOP OF OSVOboZhDVAVANETO OR WATER INSOLUBLE OR comminuted organic or inorganic material. 14. A method for the production of sustained release microgranules containing morphine or pharmaceutically acceptable salt thereof, characterized in that it includes: A / MECHANICAL PROCESSING IN A HIGH-SPEED MIXER OF MIXED MORPHINE OR PHARMACEUTICALALLY ACCEPTABLE 29. SOL and crushed hydrophobic fusible carrier or diluent having a melting point of 35 to 150 ° C and optionally - control components release comprising a water soluble fusible material or particle, soluble or insoluble, organic or inorganic materials, such as processing is at a rate I. ENERGY SUBMITTED THAT ALLOWS TO Melt OR MIX MEDIUM OR DILUTION OR TO AGGOMERATE; C / EXPOSURE OF THE AGLOMERATES TO OBTAIN CONTROLLED RELEASE PARTICLES; AND optionally with / CONTINUE MECHANICAL PROCESSING BY ADDING A SMALL AMOUNT OF THE CARRIER OR Diluent; AND OPTIONAL E / REPEAT THE STEP (s) AND IT IS POSSIBLE STEP (C) ONE OR MORE TIMES. 15. A method according to claim 14, characterized in that the heat of the mixture is applied by microwave irradiation during the mechanical treatment. A method according to claim 15, characterized in that only a part of the heat energy is supplied by microwave radiation. 17. Method according to any one of Claims 17 to 17, HLEDERATED WITH THAT THE HYDROPHOBIC TOPIM (S) HAD , Microcrystalline wax and glycerol monostearate. A method according to any one of claims 14 to 17, characterized in that the water-soluble material or solution is 30. OPTIONAL DIRECTOR INCLUDED IN STEP (A) IS A PEG-MOLECULAR WEIGHT OF 1000 TO 20000 OR POLOXDMER. A method according to any one of claims 14 to 18, characterized in that. THAT THE STOPMY CARRIER OR Diluent IS ADDED TO PARTS DURING MECHANICAL PROCESSING. A dosage form according to one of the claims of 7 TO 13 CHARACTERIZING THAT THE PARTICLES ARE OBTAINED BY THE METHOD DEFINED IN ONE OF CLAIMS 12 TO 17. 21. The pharmaceutical composition of claim 1, substantially the same as those described in the EXAMPLES set forth herein. A method according to claim 14 for the production of PERMANENTLY RELEASE PARTICLES, substantially the same as the method described in the Examples set forth herein. 23. A method of manufacturing a Dosage Form according to Claim 7 or 10, substantially the same as those described in the EXAMPLES.