Europäisches Patentamt
(19) European Patent Office *EP001294372B1*
Office européen des brevets (11) EP 1 294 372 B1
(12) EUROPEAN PATENT SPECIFICATION
(45) Date of publication and mention (51) Int Cl.7: A61K 31/223, A61K 9/16,
of the grant of the patent: A61P 1/12
17.08.2005 Bulletin 2005/33
(86) International application number:
(21) Application number: 01969310.0 PCT/EP2001/007086
(22) Date of filing: 22.06.2001 (87) International publication number:
WO 2001/097801 (27.12.2001 Gazette 2001/52)
(54) DRY POWDER FORMULATION COMPRISING RACECADOTRIL
RACECADOTRIL ENTHALTENDE TROCKENE PULVERFORMULIERUNG
FORMULATION PULVERENTE SECHE CONTENANT DU RACECADOTRIL
(84) Designated Contracting States: (56) References cited:
AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU EP-A- 0 914 822 WO-A-01/97803
MC NL PT SE TR WO-A-92/10173
(30) Priority: 23.06.2000 EP 00401799 • " DICTIONNAIRE VIDAL" 1998 , DITIONS DU
VIDAL , PARIS (FR) XP002195794 228450 tiorfan
(43) Date of publication of application: page 1838, column 2
26.03.2003 Bulletin 2003/13 • "TIORFAN 30 mg ENFANTS poudre orale en
sachet-dose" BIAM, [Online] 15 November 2000
(73) Proprietor: BIOPROJET (2000-11-15), XP002195795 Retrieved from the
75003 Paris (FR) Internet:
<URL:www.biam2.org/www/spe29406.htm>
(72) Inventors: ;
• LECOMTE, Jeanne-Marie
F-75003 Paris (FR) Remarks:
• SCHWARTZ, Jean-Charles The file contains technical information submitted
F-75003 Paris (FR) after the application was filed and not included in this
specification
(74) Representative: Bernasconi, Jean Raymond et al
c/o Cabinet Lavoix,
2, Place d’Estienne d’Orves
75441 Paris Cedex 09 (FR)
EP 1 294 372 B1
Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give
notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in
a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art.
99(1) European Patent Convention).
Printed by Jouve, 75001 PARIS (FR)
EP 1 294 372 B1
Description
[0001] The present invention relates to a novel formulation of the compound racecadotril, and its use in the treatment
of diarrhoea, in particular in paediatric patients.
5 [0002] Racecadotril, is the compound of structure (I) in the form of a racemate.
10
15
[0003] The compound is generically and specifically disclosed in EP 038758 B1 (equivalent to US 4 513 009) and
is indicated to have inter alia, enkephalinase inhibiting and anti-diarrhoea activity. These patents indicate that the
compounds may be administered to humans by the oral, parenteral or rectal route, but no details of specific formulations
20 of the claimed compounds is provided. Furthermore, a number of test results are provided indicating the biological
activity of the compounds, but in all cases, reference is made only to intravenous formulations of compound.
[0004] In seeking to provide suitable formulations for administration to patients it is important to ensure that the
formulations are in the most acceptable form to the patient, for example in terms of the nature and appearance of the
dosage form, and the ease of ingestion. These features are important in providing a formulation which assists in en-
25 suring patient compliance with the desired dosing regimen. When considering dosage forms for paediatric patients
(that is to say children of age 14 or under) the dosage form is particularly critical in ensuring patient compliance. For
example, children may often find difficulties in swallowing a tablet or capsule formulation, with the result that liquid or
suspension formulations are generally more desirable and are often regarded as the formulation of choice for paediatric
patients.
30 [0005] In respect of the present invention, the compound racecadotril is on the market in a number of countries for
adult nse in the form of a capsule filled with dry powder formulation (and sold as TIORFAN - a trademark of Société
Civile de Recherche Bioprojet), but to date a suitable paediatric form (for example a liquid or suspension formulation)
has not been provided due to inherent difficulties in formulating the compound. More particularly, the compound is very
hydrophobic, ie. water hating, and as such is not readily formulated into a suspension for paediatric use. As noted
35 above, tablets and capsules are not regarded as preferred dosage forms for children, especially younger children for
whom a liquid/suspension form is generally regarded as more acceptable.
[0006] In order to overcome the problem of providing a suitable paediatric dosage form, Applicants have found racec-
adotril can be formulated into a dry powder form which can be provided for direct dosing to the patient, or added, for
example to food and then ingested by the patient.
40 [0007] The present invention therefore provides, in a first aspect, a dry powder pharmaceutical composition suitable
for oral use, comprising coated granules comprising racecadotril and a pharmaceutically acceptable carrier, blended
with sweetening/flavouring agents.
[0008] Suitably, the dry powder composition comprises granules of racecadotril. Granules of racecadotril can be
prepared to the desired particle size by standard granulation techniques as described hereinafter in the examples.
45 Typically, the racecadotril granules are prepared and coated with a coating to assist in taste masking of the composition,
and then blended with sweetening/flavouring agents to provide the final composition.
[0009] Suitably, the granules of racecadotril comprise racecadotril together with a sweetening agent to assist in taste
masking of the final composition. Suitable sweetening agents include for example aspartame and sucrose, preferably
sucrose. The granules of racecadotril and sucrose, are then coated to assist further with the taste masking of the final
50 product. Film coating of the granules can be achieved using standard techniques. Suitable coatings include for example
hydroxypropyl cellulose, acrylate and/or methacrylate co-polymers, resins etc. Preferably, the coating is a polymeric
acrylate or methacrylate compound, most preferably EUDRAGIT NE 3OD. The coated granules of racecadotril can
then optionally be further blended with a lubricant to improve powder flow, and further taste masking or sweetening
agents to improve palatability to produce the final composition.
55 [0010] Suitable lubricants will be apparent to those skilled in the art, and include for example, long chain fatty acids
such as stearic acid and salts thereof, in particular group II metal salts such as magnesium or calcium, or anhydrous
colloidal silica. Either a single lubricant or combination of lubricants can be used to achieve the desired flow charac-
teristics. Preferred in the present invention is a single diluent, most preferably anhydrous colloidal silica.
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EP 1 294 372 B1
[0011] Suitable sweetening and flavouring agents will again be apparent to the skilled person, and include for example
sucrose or aspartame as sweeteners, and standard fruit flavouring agents.
[0012] It is generally necessary to mill and sieve the granulate to obtain a suitable size fraction. In particular, a particle
size from 0.630 to 1.58 is preferred, most preferred the particles are milled and sieved to a fraction size of nearly
5 1.01mm.
[0013] The dry powder formulations of the present invention are preferably provided in the unit dosage formulation
for administration to patients. Suitably, unit dosages comprise from 1 to 50mg of racecadotril, more suitably 5 to 30mg
of racecadotril. Preferably, unit dosages comprise 6, 10, 18 or 30 mg of racecadotril. In a preferred aspect of the present
invention, the unit dose of the dry powder composition is provided in a sachet. The individual sachets ensure the
10 composition is retained dry prior to use, and provide a convenient form form which to dispense the powder.
[0014] The dry powder of the present invention can be ingested direct by the patient ie. direct into the patients mouth,
or sprinkled onto food prior to ingestion. In addition even though the granules do not form a suspension due to the
hydrophobic nature of racecadotril, the powder may also be added to a small amount of clean water prior to adminis-
tration, ensuring that the water and granules are stirred together vigorously and then provided to the patient before the
15 granules have settled to the bottom of the glass.
[0015] As hereinbefore indicated the present composition in particular is advantageous for dosages to paediatric
patients, since the only current known formulation is a capsule, and as such not preferred for administration to children,
in particular, young children. The present composition of a palatable powder is far more acceptable and effective, either
via the direct route into the patient's mouth, or for example sprinkled onto food.
20 [0016] The examples serve to illustrate the invention.
EXAMPLES
1. Preparation of a 250 kg batch of dry powder formulation of racecadotril for subsequent filling onto sachets.
25
[0017]
Component Percentage Amount
(%) (kg)
30
Racecadotril 1.00 2.50
Sucrose 96.65 241.625
Eudragit NE 30D* (as dry weight) 0.15 0.375
35
Apricot flavouring 2.00 5.000
Colloidal silica 0.20 0.500
40 Purified water 1.250
* equivalent to 1.250kg of solution for a 250kg batch size
[0018] The racecadotril and 10% of the sucrose awere mixed together on a Fielder type granulating mixer for 10
minutes.
45
[0019] The Eudragit was dissolved in purified water and mixed to obtain a homogenous dispersion, then added to
the racecadotril/sucrose mixture to form the granules. The granules so formed were then dried in an air-fluidised bed
dryer (such as a Franco Moran or Aeromatic type of drier), with a drying temperatre of between 45 and 55 C until
granules were obtained with a moisture content of less than 1 %. The dry granules were then mixed with the remainder
of the sucrose, the colloidal silica and the flavouring in a mixer (such as a Robotianer inverting type of mixer) and then
50
sized on a Frewitt type oscillating granulator equipped wth a screen mesh of aperture 1.01 mm. The resulting sized
mixture was then mixed again in a Robotainer inverting container mixer until homogenous.
[0020] The final granule containing 1 % of active principle is packaged in a sachet dosage strength of from 6-30mg
racecadotril, by filling sachets with 0.6g/sachet to 3.0g /sachet of final granule.
55
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EP 1 294 372 B1
Claims
1. A dry powder pharmaceutical composition, suitable for oral use, comprising coated granules comprising raceca-
dotril in association with a pharmaceutically acceptable carrier, blended with sweetening/flavouring agents.
5
2. A dry powder pharmaceutical formulation according to claim 1 in which the pharmaceutically acceptable carrier
comprises a sweetening agent.
3. A dry powder pharmaceutical formulation according to claim 1 or 2 in which the sweetening/flavouring agents
10 comprise sucrose.
4. A dry powder pharmaceutical composition according to claims 1, 2 or 3, in which the granules of racecadotril are
coated with a coating agent.
15 5. A dry powder composition according to claim 4 in which the granulate coating agent is a polymeric acrylate or
methacrylate.
6. A dry powder pharmaceutical composition according to claim 5 in which the granulate coating agent is EUDRAGIT
NE 30D.
20
7. A dry powder pharmaceutical composition according to any one of claims 1 to 6 comprising a unit dose of from 1
to 50mg of racecadotril.
8. A pharmaceutical composition according to claim 7, comprising a unit dose of from 5 to 30mg of racecadotril.
25
9. A pharmaceutical composition according to claim 8 comprising, 6, 10, 18 or 30 mg of racecadotril.
10. A dry powder pharmaceutical composition according to any one of claims 1 to 9, contained in a sachet form.
30 11. A dry powder pharmaceutical composition comprising racecadotril as claimed in any one of claims 1 to 10 for use
as in therapy.
12. Use of a composition as claimed in any one of claims 1 to 10 for the preparation of a medicament for treating
diarrhoea in mammals.
35
13. A process for preparing the dry powder formulation of racecadotril according to any one of claims 1 to 11 comprising:
- preparing granules of racecadotril together with a pharmaceutically acceptable carrier,
- coating said granules with a coating agent; and
40 - blending said coated granules with sweetening/flavouring agents.
Patentansprüche
45 1. Eine pharmazeutische Zusammensetzung in Trockenpulverform, die für die orale Verwendung geeignet ist, die
beschichtete Granula, umfassend Racecadotril in Assoziation mit einem pharmazeutisch annehmbaren Träger,
gemischt mit Süß-/Geschmacks-Stoffen, umfasst.
2. Eine pharmazeutische Zusammensetzung in Trockenpulverform nach Anspruch 1, bei der der pharmazeutisch
50 annehmbare Träger einen Süßstoff umfasst.
3. Eine pharmazeutische Zusammensetzung in Trockenpulverform gemäß Anspruch 1 oder 2, bei dem die Süß-/
Geschmacks-Stoffe Sucrose umfassen.
55 4. Eine pharmazeutische Zusammensetzung in Trockenpulverform nach Ansprüchen 1, 2 oder 3, bei dem die Ra-
cecadotril-Granula mit einem Beschichtungsmittel beschichtet sind.
5. Eine Zusammensetzung in Trockenpulverform nach Anspruch 4, bei dem das Beschichtungsmittel für die Granula
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EP 1 294 372 B1
ein polymeres Acrylat oder Methacrylat ist.
6. Eine pharmazeutische Zusammensetzung in Trockenpulverform nach Anspruch 5, bei dem das Beschichtungs-
mittel für die Granula EUDRAGIT NE 30D ist.
5
7. Eine pharmazeutische Zusammensetzung in Trockenpulverform nach einem der Ansprüche 1 bis 6, das seine
Einheitsdosis von 1 bis 50mg Racecadotril umfasst.
8. Eine pharmazeutische Zusammensetzung nach Anspruch 7, die eine Einheitsdosis von 5 bis 30mg Racecadotril
10 umfasst.
9. Eine pharmazeutische Zusammensetzung nach Anspruch 8, die 6, 10, 18 oder 30mg Racecadotril umfasst.
10. Eine pharmazeutische Zusammensetzung in Trockenpulverform nach einem der Ansprüche 1 bis 9, die in einer
15 Beutelform enthalten ist.
11. Eine pharmazeutische Zusammensetzung in Trockenpulverform, die Racecadotril umfasst, wie in einem der An-
sprüche 1 bis 10 beansprucht zur Verwendung bei der Therapie.
20 12. Verwendung einer Zusammensetzung wie in einem der Ansprüche 1 bis 10 beansprucht zur Herstellung eines
Medikaments zur Behandlung von Diarrhoe bei Säugetieren.
13. Ein Verfahren zur Herstellung der Trockenpulverformulierung von Racecadotril nach einem der Ansprüche 1 bis
11, das umfasst:
25
- Herstellung von Granula aus Racecadotril mit einem pharmazeutisch annehmbaren Träger,
- Beschichten der Granula mit einem Beschichtungsmittel; und
- Mischen der beschichteten Granula mit Süß/Geschmacks-Stoffen.
30
Revendications
1. Composition pharmaceutique pulvérulente sèche, adaptée à un usage oral, comprenant des granules enrobés
comprenant du racécadotril associé à un véhicule pharmaceutiquement acceptable, mélangés à des agents édul-
35 corants/aromatiques.
2. Formulation pharmaceutique pulvérulente sèche selon la revendication 1, dans laquelle le véhicule pharmaceuti-
quement acceptable comprend un agent édulcorant.
40 3. Formulation pharmaceutique pulvérulente sèche selon la revendication 1 ou 2, dans laquelle les agents édulco-
rants/aromatiques comprennent du saccharose.
4. Composition pharmaceutique pulvérulente sèche selon les revendications 1, 2 ou 3, dans laquelle les granules
de racécadotril sont enrobés avec un agent d'enrobage.
45
5. Composition pulvérulente sèche selon la revendication 4, dans laquelle l'agent d'enrobage des granules est un
acrylate ou méthacrylate polymère.
6. Composition pharmaceutique pulvérulente sèche selon la revendication 5, dans laquelle l'agent d'enrobage des
50 granules est l'EUDRAGIT NE 30D.
7. Composition pharmaceutique pulvérulente sèche selon l'une quelconque des revendications 1 à 6 comprenant
une dose unitaire allant de 1 à 50 mg de racécadotril.
55 8. Composition pharmaceutique selon la revendication 7, comprenant une dose unitaire allant de 5 à 30 mg de ra-
cécadotril.
9. Composition pharmaceutique selon la revendication 8, comprenant 6, 10, 18 ou 30 mg de racécadotril.
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EP 1 294 372 B1
10. Composition pharmaceutique pulvérulente sèche selon l'une quelconque des revendications 1 à 9, contenue sous
forme de sachet.
11. Composition pharmaceutique pulvérulente sèche comprenant du racécadotril selon l'une quelconque des reven-
5 dications 1 à 10 destinée à être utilisée en thérapie.
12. Utilisation d'une composition selon l'une quelconque des revendications 1 à 10 pour la préparation d'un médica-
ment destiné à traiter la diarrhée chez les mammifères.
10 13. Procédé pour préparer la formulation pulvérulente sèche de racécadotril selon l'une quelconque des revendications
1 à 11 comprenant :
- la préparation de granules de racécadotril conjointement avec un véhicule pharmaceutiquement acceptable,
- l'enrobage desdits granules avec un agent d'enrobage ; et
15 - le mélange desdits granules enrobés avec des agents édulcorants/aromatiques.
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