US20070003620A1

US20070003620A1 - Morphine sulfate microgranules, method for preparing same and compositions containing same

Info

Publication number: US20070003620A1
Application number: US11/441,349
Authority: US
Inventors: Dominique Marechal; Pascal Suplie; Pascal Oury
Original assignee: Ethypharm SAS
Current assignee: Ethypharm SAS
Priority date: 1999-06-09
Filing date: 2006-05-26
Publication date: 2007-01-04
Also published as: CN1267089C; ES2379688T3; CO5160317A1; AU769160C; BRPI0011404B8; HK1045107B; PT1627631E; EP1189602B1; KR20020031338A; EP1627631A2; NZ516077A; PT1189602E; TWI224510B; ATE544448T1; WO2000074659A1; EP1627631B1; KR100676123B1; DE60033519D1; JP2003520770A; CY1107612T1

Abstract

The present invention relates to sustained-release morphine sulfate microgranules each comprising a neutral support grain coated with an active layer and with a sustained-release layer, wherein the sustained-release layer contains a copolymer of methacrylic acid, and a silica selected from hydrophobic fumed silica, as well as pharmaceutical compositions containing them.

Description

The present invention concerns a novel sustained-release morphine sulphate formulation for oral administration.
The present invention also applies to the process for manufacturing this formulation and to the pharmaceutical preparations containing it.
In the present application, “morphine sulphate” is intended to mean the sulphate salt, optionally hydrated, of (5 alpha, 6 alpha)-7,8-didehydro-4,5-epoxy-17-methylmorphinane-3,6-diol.
The oral administration of morphine sulphate is the best suited treatment for relieving chronic pain. Many oral formulations of morphine sulphate have been described in the prior art.
EP 205 282 (EUROCELTIQUE) relates to granules comprising morphine sulphate, an aliphatic alcohol and a water-soluble hydroxyalkylcellulose.
These granules are coated with a derivative of mucoadhesive cellulose, such as hydroxypropylmethyl-cellulose, and present a release profile over 12 hours, with a plasmatic peak situated between 1 and 3 hours.
EP 377 518 (FAULDING) discloses sustained-release granules containing a very water-soluble active principle such as morphine. The granules make it possible to maintain plasmatic levels higher than 75% of the maximum for at least 3 hours.
These granules comprise an active core coated with a polymeric layer which allows a slow release of the active principle at a very acid pH and a constant faster release of the active principle at a pH which is less acid to basic, over an extended period of time.
This polymeric layer contains three compounds: a polymeric matrix which is insoluble whatever the pH, an enteric polymer, the solubility of which is pH-dependent, and a polymer which is soluble in acid medium.
The preparations described in EP 377 518 have a bioavailability requiring an administration which should be at least twice daily.
A subject of EP 553 392 (EUROCELTIQUE) is a process for preparing a stable sustained-release formulation consisting of granules obtained in a fluidized air bed by spraying an aqueous solution of active principle over neutral grains, followed by a coating with HPMC, by a coating with an acrylic polymer and by a protective film required for reducing the agglomeration of the granules.
EP 636 366 (EUROCELTIQUE) discloses sustained-release morphine sulphate microgranules comprising a neutral core coated with an active layer consisting of an active principle/HPMC mixture, of a sustained-release layer consisting of Eudragit® RS D and/or of Eudragit® RL D, and of an HPMC film, which represents 5% of gain in mass.
In documents EP 533 392 and EP 636 366, the granules undergo a heat treatment above the glass transition temperature of the polymeric coating, in order to stabilize its structure. This heat treatment is carried out at 45° C. approximately for at least 24 hours, which considerably lengthens the duration of the process.
EP 647 448 (EUROCELTIQUE) discloses morphine sulphate granules, the in vitro dissolution profile of which stretches over 24 hours. The granules consist of Neutral grains coated with active principle and with lactose. The active layer is covered with a film of Opadry®, and then coated with Aquacoat ECD 30®, Eudragit RS 30 D® or a Eudragit RS®/Eudragit RL® mixture: 97.5/2.5. The titre of the granules described in this document is quite low, of the order of 15%.
U.S. Pat. No. 5,445,829 (KV Pharmaceutical) relates to a formulation which is capable of releasing the active principle exclusively between 12 and 24 hours after the administration.
This formulation contains 0 to 50% of immediate particles and the complement of controlled-release particles consisting of immediate particles coated with a cellulose derivative as delaying polymer.
WO 94/22431 (KAPIPHARMACIA) discloses a controlled-release formulation of a morphine salt.
This formulation can be administered in a single daily dosage intake. At 32 hours, the plasma concentration is higher than Cmax/2 and the fluctuations in the release profile are very small over this period, and so the plasmatic concentration is virtually constant over 24 hours.
The formulation disclosed in WO 94/22431 consists, for example, of granules containing a core of morphine salt, of lactose and of a binder, coated with a film of HPMC/EC and of triethyl citrate.
This formulation uses a mixture of two polymers, one being soluble and the other being insoluble in water.
WO 95/31972 (EUROCELTIQUE) discloses sustained-release morphine sulphate granules consisting of a neutral core coated with active principle and with hydrated lactose, the bulk density of which is between 0.4 and 0.9 g/ml. The delayed-release layer coating the active principle contains for example an acrylic polymer, an alkylcellulose, a hydrogenated vegetable oil or a mixture thereof.
This document teaches that the binding of the morphine sulphate to the neutral cores requires the addition of the lactose as a diluent.
The release profiles of the microgranules given by way of example show that these granules are suitable for one dosage intake per day.
WO 96/14059 (EUROCELTIQUE) discloses a process for extruding spherical particles containing morphine sulphate, a support the melting point of which is between 35 and 150° C. and a sustained-release agent.
The support is a hydrogenated vegetable oil or a PEG (Mw 1000 to 20,000). The in vitro dissolution profile of these particles is 67% at 24 hours. No in vitro result is provided.
WO/960066 (ALZA) describes a composition containing morphine sulphate, polyvinylpyrrolidone and a polyalkylene oxide.
This document claims that the formulation provides a sustained release over time, but gives no example either in vitro or in vivo, and so it is difficult, upon reading the document, to estimate whether the administration should be one or more dosage intakes per day.
The subject of the present invention concerns sustained-release morphine sulphate microgranules each comprising a neutral support grain coated with an active layer and with a sustained-release layer, characterized in that the sustained-release layer contains a copolymer of methacrylic acid, and a hydrophobic fumed silica.
According to the present invention, the preferred copolymers of methacrylic acid are chosen among ammonio-methacrylate copolymers, i.e. fully polymerized copolymers of acrylic acid and methacrylic acid esters with low content of quaterny ammonium groups.
Such polymers are, for example, those sold under the trade names:

- Eudragit® RS (Röhm): (poly(ethyl acrylate methyl methacrylate, trimethylamonioethyl methacrylate chloride) 1:2:0.1, and
- Eudragit® RL (Röhm): (poly(ethyl acrylate methyl methacrylate, trimethylamonioethyl methacrylate chloride) 1:2:0.2

Eudragit® RS are poorly permeable to water whereas Eudragit® RL are highly permeable water. Both polymers are water-insoluble.
Among the grade Eudragit® RS (low permeability to water), methacrylic acid copolymers that can be used are, for example, those sold under the trade names Eudragit® RS 12.5, Eudragit® RS 100 and Eudragit® RS PO.
According to the present invention, the methacrylic acid copolymer is preferably conditionned as an aqueous solution, like the one sold under the trade name Eudragit® RS 30 D (30% aqueous dispersion) as it does not need to be used with organic solvents.
Among the grade Eudragit® RL (high permeability to water), methacrylic acid copolymers that can be used are, for example, those sold under the trade name Eudragit® RL 12.5, Eudragit® RL 100 and Eudragit® RL PO.
According to the present invention, the methacrylic acid copolymer is preferably conditionned as an aqueous solution, like the one sold under the trade name Eudragit® RL 30 D (30% aqueous dispersion) as it does not need to be used with organic solvents.
According to a particular embodiment of the invention, the sustained release layer contains a mixture of two or more different grades of methacrylic acid copolymers.
In particular, the sustained release layer is composed of a mixture of methacrylic acid of low (Eudragit® RS) and high (Eudragit® RL) permeability. Such a mixture is advantageously used to adapt the permeability of the sustained release layer in order to obtain the desired dissolution profile.
Preferably, when the sustained release layer is composed of a mixture of methacrylic acid copolymers of low and high permeability, the ratio between low permeability copolymer and high permeability copolymer is comprised between 95:5 and 60:40.
More preferably, when the sustained release layer is composed of a mixture of such copolymers, the low permeability copolymer is Eudragit® RS 30 D and the high permeability copolymer is Eudragit® RL 30 D.
According to the present invention, the hydrophobic fumed silica represents advantageously 0.2 to 1% by weight of the microgranules.
Said hydrophobic fumed silica (or also called hydrophobic colloidal silica) have the same chemical formula (S_iO₂) than non hydrophobic silica but do present an important hydrophobic character vis à vis water. Hydrophobic silica to be used in the present invention are preferably chosen among the silica called “fumed silica” i.e silica which have undergone a heating treatment (at 400° C.) modifying their surface state, rendering them very hydrophobic. Such silica are practically insoluble in water. Aerosil® R 972 (Degussa) is preferred as hydrophobic fumed silica.
Hydrophobic fumed silicas are produced by chemical treatment of hydrophilic fumed silica (SiO₂) with silanes or siloxanes. In the finished product, the treatment agent is chemically bonded to the previously hydrophilic oxide. This can convert the natural hydrophilic fumed into a hydrophobic material.
One production method of fumed silica involves a continuous flame hydrolysis technique. It involves the conversion of silicon tetra chloride (SiCl₄) to the gas phase using an oxy hydrogen flame. It then reacts with water to yield silica (SiO₂) and hydrochloric acid thus:
SiCl₄+H₂O→SiO₂+HCl
The HCl is easily separated as it remains in the gas phase, while the fumed silica is solid.
Hydrophobic fumed silica of different grades may be provided by Degussa (Aerosil® R972, Aerosil® R974, Aerosil® R104, Aerosil® R106, Aerosil® R202, Aerosil® R805, Aerosil® R812, Aerosil® R812 S, Aerosil® R816, Aerosil® R7200, Aerosil® R8200, Aerosil® R9200) or by Thornley Company (Dumasil®100-FG, Dumasil®100-Z-FG, Dumasil®300-FG).
According to the present invention, the preferred fumed silica is Aerosil® R972.
Aerosil®R972 is a hydrophobic fumed silica after treated with DDS (Dimethyldichlorosilane) based on a hydrophilic fumed silica with a specific surface area of 130 m²/g.
Hydrophobic fumed silica are generally used in pharmaceutical formulations as lubricants or anti-tacking agents. As such, they are commonly used in quantity varying from 2 to 10% by weight of the total weight of the composition.
In the present invention, the hydrophobic fumed silica is used in a much smaller amount (0.1 to 2% by weight of the microgranules). Furthermore, it is not used as an anti-tacking agent but as a hydrophobising agent.
In the present invention, the applicant has discovered that introducing small quantities (0.1 to 2% by weight of the microgranules) of such a hydrophobic fumed silica in the sustained release layer, allow to obtain sustained release microgranules which are less sensitive to pH conditions than other formulations of the prior art. Indeed, dissolution profile of microgranules according to the invention is less subject to change when pH conditions are varying as shown in the example 3 and FIG. 2).
Surprisingly, the microgranules of the invention exhibit the advantage of lacking a protective film coating the sustained-release layer. In addition, it is not necessary to subject the microgranules to a very lengthy heat treatment (longer than 24 hours) as in the prior art to improve the structure of the sustained-release layer.
This surprising effect may be due to the fact that hydrophobic fumed silica has a high specific surface area (BET) thereby providing an excellent protection against water, even with low quantites.
The acrylic copolymer represents advantageously 5 to 15% by weight of the microgranules.
The relative mass proportion of the morphine sulphate and of the neutral support grain is preferably between 40/60 and 60/40.
The morphine sulphate represents advantageously 30 to 40% by mass of the microgranules.
The neutral support grain coated with the active layer contains preferably 40% to 50% of morphine sulphate and 10 to 20% of at least one pharmaceutically acceptable binder. Preferably, the active layer further contains a conventional lubricant.
The sustained-release layer contains preferably a plasticizer and a lubricant. The plasticizer and the lubricant are used in conventional amounts and chosen from the pharmaceutically acceptable plasticizers and lubricants which are well known to persons skilled in the art. The plasticizer is for example triethylcitrate. The lubricant is for example talc.
Advantageously, the lubricant is used both in the active layer and in the sustained-release layer.

The composition of the microgranules according to the invention is advantageously as follows:



	Morphine sulphate	30-42%
	Neutral support grain	30-40%
	Binder	10-20%
	Methacrylic acid copolymer	5-15%
	Plasticizer	1-2.5%
	Lubricant	1-4%
	Hydrophobic fumed silica	0.2-1%

More preferably, The composition of the microgranules according to the invention is as follows:



	Morphine sulphate	30-40%
	Neutral support grain	30-40%
	Binder	10-20%
	Methacrylic acid copolymer	5-15%
	Plasticizer	1-2.5%
	Lubricant	2-4%
	Hydrophobic fumed silica	0.2-1%

The most preferred composition of the microgranules according to the present invention is:



	Morphine sulphate	37.56%
	Neutral support grain (sugar	38.03%
	sphere)
	Binder (HPMC)	13.18%
	Methacrylic acid copolymer	7.08%
	(Eudragit ® RS 30D)
	Plasticizer (Triethylcitrate)	1.42%
	Lubricant (Talc)	2.38%
	Hydrophobic fumed silica	0.35%
	(Aerosil ® R972)

The neutral support grains have a particle size of between 200 and 1000 μm, preferably of between 400 and 600 μm.
The present invention also concerns a process for preparing the microgranules described above. This process is carried out entirely in aqueous medium. It comprises a step of spraying the active principle in aqueous solution and/or suspension (drug-layering solution and/or suspension) on neutral support grains and a step of coating the resulting product with one or more methacrylic copolymer, still in aqueous solution and/or suspension.
The granules are advantageously prepared in a perforated rotary turbomixer or a fluidized air bed. The spraying of the drug-layering solution and/or suspension and the coating of the coating solutions and/or suspensions is preferably continuous and followed by a drying step at a temperature of between 30 and 65° C.
It is not necessary for the granules according to the invention to undergo a heat treatment for the structure of the film to be satisfactory.
The present invention finally concerns the pharmaceutical compositions containing the microgranules of the invention optionally obtained according to the process described above.
Said pharmaceutical composition may be in the form of capsules containing said microgranules or in the form of tablets prepared from said microgranules.
Said pharmaceutical composition has substantially no food effect on the bioavailability of morphine sulfate.
The following examples illustrate the invention without limiting the scope thereof.
The percentages are expressed by weight.
FIG. 1 represents the mean of the in vitro dissolution profile of four formulations according to the invention (curves 1, 2, 3 and 4). The percentage of dissolution is on the x-axis and the time (hours) on the y-axis.
FIG. 2 represents the influence of pH condition on the in vitro dissolution profile of microgranules according to the present invention (curve (∘) is water+NaCl 0.1M; curve (Δ) is pH 6.8+NaCl 0.1M ; curve (X) is pH 4.5+NaCl 0.1M; curve (*) is pH 1.2+NaCl 0.1M).
FIG. 3 represents plasma concentrations of morphine following a single dose of ZOMORPH 60 mg in fasting (▪) or fed (▴) conditions and of SKENAN LP 60 mg in fasting condition (●)
FIG. 4 represents plasma concentrations of morphine-6-glucuronide following a single dose of ZOMORPH 60 mg in fasting (▪) or fed (▴) conditions and of SKENAN LP 60 mg in fasting condition (●)

EXAMPLE 1 (Batch A)

Preparation of the Granules
A drug-layering solution containing 74.7% of purified water, 6.6% of Pharmacoat 603® (hydroxy-propylmethylcellulose) and 18.7% of morphine sulphate is prepared. Stirring is maintained until the solution is homogeneous, and then throughout the emplacing.
Neutral support grains (400 to 600 μm) are placed in a rotating perforated turbomixer. The emplacing of the active principle on the neutral grains is carried out by continuous spraying of the emplacing solution described above, with a support of hot air at a temperature of between 35 and 60° C.
The mass of the active microgranules obtained is sieved through a screen of mesh size ranging from 0.71 to 0.85 mm.
A coating solution is prepared by successively adding Eudragit® RS 30 D (an aqueous dispersion containing 30% of poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1:2:0.1), triethyl citrate, talc and Aerosil® R 972 (hydrophobic fumed silica) to the purified water. Stirring of the suspension is maintained until the mixture is homogeneous, and then throughout the coating.
The active microgranules are placed in a rotating perforated turbomixer and continuously sprayed with the coating suspension described above, at a temperature of 30° C. The mass of microgranules obtained is sieved through a screen of mesh size ranging from 0.8 to 1 mm.
This step can be repeated one or more times. The granules are then lubricated with an amount of talc which is equivalent to 0.5% of the coated mass obtained.

The microgranules obtained have the following composition:



	Batch A

	Amount	%
	mg	by mass

Morphine sulphate	12.5	37.3
Neutral grains	12.5	37.3
Pharmacoat 603 ®	4.4	13.0
Eudragit RS 30 D ®	2.7	8.2
Triethylcitrate	0.5	1.6
Talc	0.7	2.1
Aerosil R972 ®	0.1	0.4

	Content (mg/g)	371

In vitro Dissolution Tests

The previously obtained microgranules are dissolved in 500 ml of water at 37° C. in a machine with paddles revolving at 100 revolutions/min. The U.V. absorbance reading is measured at two wavelengths, 285 nm and 310 nm.

Batch A

Time (hours)

1 2 3 4 5 6 7 8 9 10 15 20

Percentage 6.6 20.8 38.8 55.8 69.9 79.9 86.3 90.7 93.2 94.8 97.8 98.3

of dissolution
The in vitro dissolution profile of Batch A is represented by Curve 3 of the figure.
Tests for Stability of the Gelatin Capsules of Microgranules (Batch A1)
The stability properties of the microgranules which have been previously obtained and packaged in size 3 gelatin capsules each containing 60 mg of morphine sulphate are measured under storage conditions of at 25° C. and 60% relative humidity, for 24 months.
It is observed that the water content of the microgranules is stable at 6% on average, that the appearance of the gelatin capsules is satisfactory and that the active principle titre is in compliance and homogeneous.
The dissolution profiles are fairly stable over time.
After 24 months, the content of pseudomorphine and ampomorphine impurities is in compliance with standards (i.e. less than 0.5%).
The stability of the same gelatin capsules is also studied for 6 months at 40° C. and 75% relative humidity.
It is observed that the active principle titre is in compliance and homogeneous. The dissolution is stable at 6 months. Moreover, the water content is stable.

The stability results are presented in the following tables.

Percentage of dissolution in vitro (Batch A1)

Storage conditions 25° C., 60% RH

Hours	T0	1M	3M	6M	9M	12M	18M	24M

1	7.8	7.4	7.7	7.1	6.1	6.5	6.4	5.5
2	21.6	21.9	23.2	22.4	18.9	19.7	20.1	17.0
4	55.2	57.3	60.2	58.1	52.7	53.1	52.9	50.6
6	78.9	81.7	83.7	81.0	77.8	76.1	73.4	76.1
8	89.9	93.4	93.8	90.8	90.1	86.7	81.9	88.5
12	96.0	100.2	98.8	95.9	97.5	93.0	86.2	95.4
16	96.4	100.6	99.8	96.9	98.7	94.6	86.9	95.4

Percentage of dissolution in vitro (Batch A1)

Storage conditions 40° C., 75% RH

	Hours	T0	1M	2M	3M	6M

1	7.8	6.0	5.9	6.1	6.3
2	21.6	19.8	19.7	19.7	21.0
4	55.2	57.1	57.3	57.0	58.7
6	78.9	83.1	81.8	81.9	83.2
8	89.9	94.3	92.1	92.9	94.0
12	96.0	100.1	97.5	98.7	100.3
16	96.4	101.5	98.0	99.6	102.4



	Active principle content (Batch A1)

	T0	1M	2M	3M	6M	9M	12M	18M	24M

25° C.,	mg/gelatin	59.0	58.4	—	56.7	59.3	58.1	58.0	57.6	57.0
60% RH	capsule
	Variation	—	−1.0	—	−3.9	0.5	−1.5	−1.7	−2.4	−3.4
	in %
40° C.,	mg/gelatin	59.0	57.4	58.7	57.5	58.4	—	—	—	—
75% RH	capsule
	Variation
	0	2.7	−0.5	−2.5	−1.0	—	—	—	—
	in %

Water content (Karl Fisher) (Batch A1)

T0 1M 2M 3M 6M 9M 12M 18M 24M

25° C., 6.1% 5.9% — 5.9% 6.1% 4.8% 6.1% 6.1% 5.9%

60%

RH

40° C., 6.1% 6.6% 6.0% 5.3% 6.8% — — — —

75%

RH

Pharmacokinetic Study No. 1.
The bioavailability of gelatin capsules of Batch A1 is compared to that of a reference morphine formulation (containing a dose of 30 mg), after 7-day repeated dose administration in 24 healthy volunteers.

Plasmatic concentration of

Morphine 6(glucuronide) morphine

Gelatine Gelatin

capsules of Reference capsules of Reference

microgranules (Batch microgranules (Batch S

(Batch A1) S 1079) (Batch A1) 1079)

60 mg 30 mg 60 mg 30 mg

C_max(ng/ml)* 18.3 12.8 77.6 59.2

C_min(ng/ml)** 7.9 6.8 31.0 30.4

T_max(h)* 5 5 6 3

*means

**medians
It is noticed that at Day 7, the plasmatic concentrations of morphine from the gelatin capsules of the invention at 24 hours are higher than the plasmatic concentrations from the reference at 12 hours (+1.1 ng/ml), which is a sign of good cover over 24 hours.
Pharmacokinetic Study No. 2
The bioavailability of gelatin capsules of Batch A2 is compared to that of a reference morphine formulation, after administration of a single dose of 60 mg in healthy volunteers.

The gelatin capsules of Batch A2 are of size 3 and contain a dose of 60 mg of morphine sulphate per gelatin capsule.



	Plasmatic concentration of

morphine

6(glucuronide) morphine

Gelatine		Gelatin
capsules of	Reference	capsules of	Reference
microgranules	of the	microgranules	of the
of the	prior art	of the	prior art
invention	(Batch	invention	(Batch
(Batch A2)	S 1055)	(Batch A2)	S 1055)

C_max(ng/ml)*	6.97	13.16	64.0	114.8
C_min(ng/ml)**	6.0	2.0	5.0	3.0
T_max(h)*	218.9	186.9	1471.49	1536.5

*means
**medians

The formulation of the invention and the reference are bioequivalent over the area under the curve parameters, which demonstrates an equivalent absorption of both products. Conversely, the release profile of the formulation of the invention appears more delayed than the reference, with a later T_maxand a lower C_max.

EXAMPLE 2 (Batches B, C and D)

Preparation of the Granules

Granules of the following composition are prepared according to the protocol of Example 1.



Batch B	Batch C	Batch D

Amount	% by	Amount	% by	Amount	% by
(kg)	mass	(kg)	mass	(g)	mass

Morphine sulphate	13.7	35.1	31.0	40.9	728.8	41.9
Neutral grains	15.4	39.7	26.0	34.3	573.7	33.0
Pharmacoat 603 ®	4.8	12.3	10.8	14.3	204.1	11.7
PEG 4000	—	—	—	—	51.0	2.9
Eudragit RS 30 D ®	3.2	8.2	5.1	6.7	126.5	7.3
Triethylcitrate	0.6	1.6	1.0	1.3	24.9	1.4
Talc	1.0	2.6	1.7	2.2	24.9	1.4
Aerosil ® R972	0.1	0.40	0.2	0.3	6.2	0.4

Content (mg/g)	371.3	368.5	397.9

Batch B is prepared as in Example 1 in a Glatt perforated turbomixer, whereas Batches C and D are respectively prepared in an O'Hara perforated turbomixer or in a Laf Huttlin.

Tests for in vitro Dissolution of the Microgranules



	Time (h)

	1	2	3	4	5	6	7	8	9	10	15	20	24

% of	Batch B	11.0	29.0	46.2	60.4	71.5	79.9	86.0	90.3	93.4	95.5	98.7	—	—
dissolution	Batch C	5.3	22.2	42.1	58.5	71.6	81.6	88.5	93.0	95.9	97.8	100.4	—	—
	Batch D	7.1	20.2	34.8	47.9	58.7	67.4	74.5	80.2	85.0	88.7	97	99.6	100.5

The in vitro dissolution profiles of Batches B, C and D are represented by curves 2, 1 and 4, respectively, of the figure.
Tests for Dissolution of the Gelatin Capsules of Microgranules
The gelatin capsules of Batches B2, B1, D1 and C1 contain a dose of 60 mg of morphine sulphate.

Time (h)

1 2 3 4 5 6 8 10 12 14

% dissolution Batch B1 15.2 34.1 51.1 64.8 75.3 83.2 93.3 — 100.4 —

Batch C1 6.5 24.1 — 60.3 — 81.9 92.2 96.3 97.4 98.5

Tests for Stability at 25° C., 60% RH of Gelatin Capsule Batch B2 (Microgranules of Batch B)



T0	15 D	1M	2M	3M	6M

Water	—	5.50%	6.00%	6.16%	6.00%	6.02%
content (%)
Dissolution
(hours)
1	21.2	19.2	14.7	6.9	15.6	16.6
2	45.1	43.1	29.5	22.1	35.7	37.9
3	63.5	62.0	42.9	36.7	53.3	55.8
4	76.1	75.7	54.4	49.4	67.1	69.3
5	85.2	85.2	64.0	60.1	77.3	79.3
6	91.3	91.6	71.9	68.8	84.8	86.5
7	95.5	95.7	78.2	76.0	90.3	91.5
8	98.2	98.4	83.6	81.5	94.1	95.0
12	102.2	102.9	96.3	93.1	101.2	101.0

Tests for Stability at 40° C., 75% RH of Gelatin Capsules Batch D1 (Microgranules of Batch D)



T0	15 D	1M	2M	3M	6M

Water	6.19%	6.40%	6.29%	6.20%	6.30%	6.38%
content (%)
Dissolution
(hours)
1	11.8	11.9	12.2	12.6	11.6	12.5
2	28.7	28.7	31.0	33.1	31.6	34.3
3	45.8	45.2	48.1	50.6	49.1	51.8
4	59.3	58.4	61.2	63.9	62.5	64.9
5	69.8	68.8	71.5	74.1	72.8	75.2
6	77.9	77.1	79.6	82.1	80.7	83.0
8	88.5	88.8	90.3	91.9	90.8	88.7
10	94.2	95.5	95.4	96.0	95.0	95.7
12	97	98.7	97.6	97.5	96.7	97.1

EXAMPLE 3

pH Independency

The aim of this example was to analyse the dissolution behavior of microgranules according to the present invention in dissolution media exhibiting different pH.
Four different pH conditions were tested (Water; pH 6.8; pH 4.5 and pH 1.2). The dissolution results are presented on the following FIG. 2.
In order not to be influenced by the nature of the different ions used in the buffer solution (chloride, acetate, phosphate, citrate . . . ), all the media were saturated with NaCl, used at a concentration of 0.1 M.
Sustained release microgranules of morphine sulfate were manufactured according to the method described in example 1.
Dissolution measurements were performed using the Paddle method at 100 rpm, at 37° C. in a 500 mL media. Each measurement was repeated 6 times.

These microgranules have the following composition:



	Amount
Material	(kg)	% by mass

Morphine Sulfate	51.87	38.08
Neutral cores #30	52.00	38.17
HPMC 603	18.20	13.36
Eudragit ® RS30D (v.s)	8.84	6.49
Triethyl citrate	1.76	1.29
Aerosil ® R972	0.43	0.32
Talc	3.13	2.30
Purified water	238.49	N/A
Total dry mass	136.23	100.0

FIG. 2 shows that microgranules according to the invention present a dissolution profile independent from the pH conditions of the dissolution medium.

EXAMPLE 4

Reduced “Food-Effect”

a) Aim of the Study
This example presents pharmacokinetic studies realized on the microgranules according to the present invention in order to determine the influence of food on the bioavailability of morphine sulfate.
b) Preparation of the Formulations
Five capsules of different strengths, each filled with morphine sulfate sustained release microgranules prepared according to the process described in example 1 (20 mg, 40 mg, 60 mg, 120 mg and 200 mg) were prepared. The percentage composition of each strength is the same.

The relative proportion of each constituents is indicated in the following table:



Name of	Capsule

ingredients

Amount (mg)

%

Strengh

	20	40	60	120	200	formula	Function

Morphine

	20	40	60	120	200	37.55	Active
sulfate							ingredient
Sucrose	15.59	31.185	46.78	93.555	155.925	29.28	Ingredient
							of core
							granules
Maize starch	4.66	9.315	13.97	27.945	46.575	8.75	Ingredient
							of core
							granules
Hypromellose	7.00	14.00	21.05	42.10	70.20	13.18	Binder
Eudragit ® RS	3.80	7.55	11.30	22.70	37.70	7.08	Coating
30D*							agent
Triethyl	0.75	1.50	2.30	4.55	7.60	1.42	Plasticiser
citrate
Talc	1.25	2.50	3.80	7.55	12.70	2.38	Lubricant
Hydrophobic	0.20	0.40	0.60	1.20	1.90	0.35	Hydrophobic
fumed silica							agent
Purified water**	NQ	NQ	NQ	NQ	NQ	NQ	Solvent
Total mass	53.25	106.45	159.80	319.60	532.60	100.00

(Quantities expressed as dry material; *This solvent is eliminated during manufacture; NQ: not quantified)

c) Pharmacokinetic Study
This study was conducted in two different conditions: when microgranules are taken with food (“fed state”) and without food (“fast state”) in order to determine the influence of food intake on pharmacokinetic properties of the microgranules according to the present invention (“food effect”).
This study was conducted with a single dose of sustained-release morphine sulphate. Morphine and its metabolite, morphine-6-glucuronide, were assayed by Algorithme Pharma (Montreal, Canada) using HPLC with a Limit of Quantification of 1 and 2.5 ng/mL for morphine and morphine-6-glucuronide respectively.
The pharmacokinetic parameters were compared by ANOVA except median of Tmax, which were compared by Friedman's test. The 90% confidence interval of the ratio of log transformed geometric means of test/reference were calculated for AUCT, AUC∞ (single administrations) and Cmax.
The statistical analysis of each pharmacokinetic parameter was conducted using the Kinetic program (version 1.02). This software consists in an in-house application developed, tested and verified by the CRO Algoritme Pharma.

Pharmacokinetics data obtained for this study in fasting state versus fed state are shown in the following table:



				Fast/fed ratio
				of log-
	Fast			transformed
	mean	Fed mean		geometric
Parameter	(CV %)	(CV %)	p***	mean (90% CI)

Morphine

Cmax (ng/mL)	10.76	11.88	NS	90
	(32.41)	(30.90)		(80-100)
Tmax (hour)	5.50*	5.50*	NS**	—
	(4-8)	(5-9)
AUCT (ng · h/mL)	177.78	169.54	NS	104
	(24.33)	(21.17)		(98-111)
AUC∞ (ng · h/mL)	229.45	218.98	NS	105
	(21.17)	(20.40)		(98-112)
Kel (hour⁻¹)	0.0377	0.0412	NS	—
	(23.86)	(43.15)
t½el (hour)	19.62	19.79	NS	—
	(29.25)	(42.55)

Morphine-6-glucuronide

Cmax (ng/mL)	65.01	80.68	<0.01	81
	(24.70)	(30.07)		(73-90)
Tmax (hour)	6.00*	6.00*	NS**
	(4-9)	(5.50-9)
AUCT (ng · h/mL)	1081.44	1098.09	NS	98
	(19.51)	(13.10)		(93-103)
AUC∞ (ng · h/mL)	1245.34	1343.39	NS	93
	(18.63)	(24.01)		(87-100)
Kel (hour⁻¹)	0.0467	0.0442	NS
	(27.24)	(49.75)
t½el (hour)	16.05	22.84	NS
	(30.99)	(97.39)

The pharmacokinetics profiles obtained in fed state and fast state for morphine sulphate and morphine-6-glucuronide for the microgranules according to the invention (Zomorph® 60 mg) are represented with the pharmacokinetic profile of one sustained release formulation of the prior art (Skenan® LP 60 mg) on FIGS. 3 and 4 respectively.
These data show that the concomitant administration of a high fat content meal (“fed state”) does not modify the pharmacokinetic profile of morphine, the 90% confidence limit of the fast versus fed ratio of mean AUCT, AUC∞ and C_maxvalues being in the 0.80-1.25 bioequivalence interval.
Regarding the metabolite, fast and fed administrations provide equivalent AUC and median T_maxare similar.
In spite of the moderately higher mean Cmax value induced by concomitant food absorption, one can conclude that overall, microgranules according to the invention have a pharmacokinetic profile that is not clinically significantly affected by food and that this microgranules may be equally administered with or without food.

Claims

1. Sustained-release morphine sulfate microgranules each comprising a neutral support grain coated with an active layer and with a sustained-release layer, wherein the sustained-release layer contains a copolymer of methacrylic acid, and a silica selected from hydrophobic fumed silica.

2. The microgranules according to claim 1, wherein the hydrophobic fumed silica is a hydrophobic fumed silica after treated with dimethyldichlorosilane based on a hydrophilic fumed silica with a specific surface area of 130 m²/g.

3. The microgranules according to claim 1, wherein the hydrophobic fumed silica represents from 0.2 to 1% by weight of the microgranules.

4. The microgranules according to claim 1, wherein the copolymer of methacrylic acid represents from 5 to 15% by weight of the total weight of the microgranules.

5. The microgranules according to claim 1, wherein the copolymer of methacrylic acid is selected from the group consisting of fully polymerized copolymers of acrylic acid and methacrylic acid esters with low content of quaterny ammonium groups, or mixtures thereof.

6. The microgranules according to claim 1 wherein the copolymer of methacrylic acid is selected from the group consisting of poly(ethyl acrylate methyl methacrylate, trimethyamonioethyl methacrylate chloride) with a (1:2:0.1) ratio or with a (1:2:0.2) ratio, and mixtures thereof.

7. The microgranules according to claim 1, wherein the sustained-release layer contains a mixture of two or more different grades of said copolymer of methacrylic acid.

8. The microgranules according to claim 1, wherein the neutral support grain coated with the active layer contains 40% to 50% of morphine sulfate and 10 to 20% of at least one pharmaceutically acceptable binder.

9. The microgranules according to claim 1, wherein the sustained-release layer contains a plasticizer and a lubricant.

10. The microgranules according to claim 1 whose composition is as follows:

Morphine sulfate: 30 to 42% Neutral support grain: 30 to 40% Binder: 10 to 20% Copolymer of methacrylic acid: 5 to 15% Plasticizer: 1 to 2.5% Lubricant: 1 to 4% Hydrophobic silica: 0.2 to 1%

11. The microgranules according to claim 10 whose composition is as follows:

Morphine sulfate: 30 to 40% Neutral support grain: 30 to 40% Binder: 10 to 20% Copolymer of methacrylic acid: 5 to 15% Plasticizer: 1 to 2.5% Lubricant: 2 to 4% Hydrophobic silica: 0.2 to 1%

12. The microgranules according to claim 1, wherein the relative mass proportion of the morphine sulfate to the neutral support grain is between 40/60 and 60/40.

13. The microgranules according to claim 1, wherein the morphine sulfate represents 30 to 40% by mass of the microgranules.

14. The microgranules according to claim 1, whose composition is as follows:

Morphine sulphate 37.56% Neutral support grain (sugar sphere) 38.03% Binder (HPMC) 13.18% Methacrylic acid copolymer 7.08% (Eudragit ® RS 30D) Plasticizer (Triethylcitrate) 1.42% Lubricant (Talc) 2.38% Hydrophobic fumed silica 0.35% (Aerosil ® R972)

15. A process for preparing the microgranules according to claim 1, wherein the active layer and the sustained-release layer are applied onto the neutral grains by spraying.

16. A pharmaceutical composition containing microgranules according to claim 1.

17. The pharmaceutical composition according to claim 16, having substantially no food effect on the bioavailability of morphine sulfate.

18. The pharmaceutical composition according to claim 16, in the form of capsules or tablets.