Suppository form comprising an acid-labile active compound

Details Suppository form comprising an acid-labile active compound Suppository form comprising an acid-labile active compound

2000-07-06

2002-05-07

Kishore, Gollamudi S. (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Implant or insert

C424S434000

Reexamination Certificate

active

06383510

ABSTRACT:

TECHNICAL FIELD
The present invention relates to the field of pharmaceutical technology and describes a novel administration form comprising an acid-labile active compound. In particular an acid-labile proton pump inhibitor. The novel administration form is a suppository, in particular for rectal administration. Furthermore, the invention also relates to a process for the production of the administration form and preparations which can be used for the production of the administration form.
Prior Art
Acid-labile proton pump inhibitors (H
+
/K
+
ATPase inhibitors), In particular pyridin-2-ylmethylsulfinyl-1H-banzimidazoles, such as are disclosed, for example, In EP-A-0 005 129, EP-A-0 166 287, EP-A-0 174 726 and EP-A-0 268 956, are of great importance on account of their H
+
/K
+
ATPase-inhibiting action in the therapy of diseases which result from increased gastric acid secretion. Examples of already commercially available active compounds from this group are 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methylsulfinyl]-1H-benzimidazole (INN: omeprazole), 5-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridinyl)methylsulfinyl]-1H-benzimidazole (INN: pantoprazole). 2-[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl)methylsulfinyl]-1H-benzimidazole (INN: lansoprazole) and 2-{[4-(3-methoxypropoxy)-3-methylpyridin-2yl]methylsulfinyl}-1H-benzimidazole (INN: rabeprazole).
Because of their strong tendency to decompose in a neutral and, in particular, acidic environment, strongly colored decomposition products being formed, it is necessary to protect the active compounds in pharmaceutical administration forms from the action of acids and moisture and destruction by undesired interaction with pharmaceutical auxiliaries. For example, the strongly acid-labile pyridin-2-ylmethylsulfinyl-1H-banzimidazoles for oral administration forms are processed in the tablet core or in pellets in the form of their alkaline salts, for example as sodium salts, or together with alkaline substances.
The preparation of administration forms for acid-labile proton pump inhibitors for oral administration is described, for example, in EP-A-0 244 380, EP-A-0 519 385, EP-A-0 342 522, EP-A-0 277 741, WO 96/01623, WO 98/01624, WO 98/01626 and WO 97/25030.
In certain groups of patients the oral administration of an active compound is not possible or is made difficult, for example in the case of patients having a hypersensitivity to taste impulses, in the case of difficulty in swallowing, after stomach operations or in patients in intensive care units. In these cases, the administration of an active compound can be affected by means of a suppository.
EP-0 645 140 describes compositions for rectal administration in which pyridin-2-ylmethylsulfinyl-1H-benzimidazoles and salts of fatty acids having 6-20 C atoms are present mixed in a base for rectal administration.
In WO 97/34580, a suppository for acid-labile active compounds is described which, in addition to the active compound, contains poloxamer and hydrophilic natural polymers as auxiliaries.
EP-0 444 625 discloses omeprazole compositions for rectal administration, which contain omeprazole as an active compound, a mixture of polyethylene glycols or a mixture or hard fat and sodium lauryl sulfate as well as a soluble basic amino acid.
DESCRIPTION OF THE INVENTION
It is an object of the present invention to provide a novel, stable suppository form for add-labile active compounds.
It has now surprisingly been found that this object can be achieved by a suppository which comprises a plurality of individual active compound units, the acid-labile active compound in the individual active compound units being surrounded by a mixture or at least one sterol and at least one polymer, by at least one fatty alcohol or by a mixture of at least one fatty alcohol and at least one polymer and/or at least one sterol.
The subject of the invention is a suppository for acid-labile active compounds, comprising at least one pharmaceutical auxiliary and a plurality of individual active compound units, wherein the acid-labile active compound in the individual active compound units is surrounded by a mixture of at least one sterol and at least one polymer, by at least one fatty alcohol or by a mixture of at least one fatty alcohol and at least one polymer and/or at least one sterol.
A preferred subject of the invention is a suppository for acid-labile active compounds, comprising at least one pharmaceutical auxiliary and a plurality of individual active compound units, wherein the acid-labile active compound in the individual active compound units is surrounded by a mixture of at least one sterol and at least one polymer.
Further subjects follow from the patent claims.
The plurality of individual active compound units in the sense of the invention is a plurality of individual units (multiple individual units) in which at least one active compound particle is present surrounded by a mixture of at least one sterol and at least one polymer, by at least one fatty alcohol or by a mixture of at least one fatly alcohol and at least one polymer and/or at least one sterol.
Further subject of the invention is an active compound unit comprising an acid-labile active compound, wherein the acid-labile active compound is surrounded by a mixture of at least one sterol and at least one polymer, by at least one fatty alcohol or by a mixture of at least one fatty alcohol and at least one polymer and/or at least one sterol.
The particle size of the individual units is advantageously less than 200 &mgr;m. In particular less than 100 &mgr;m. Preferably, the particle size is in the range from 2 &mgr;m to 50 &mgr;m, particularly preferably in the range from 4 &mgr;m to 20 &mgr;m.
Acid-labile active compounds in the sense of the present invention are, in particular, acid-labile proton pump inhibitors.
Acid-labile proton pump inhibitors (H
+
/K
+
ATPase inhibitors) which may be mentioned in the sense of the present invention are, in particular, substituted pyridin-2-ylmethylsulfinyl-1H-benzimidazoles, such as are disclosed, for example, in EP-A-0 005 129, EP-A-0 165 287, EP-A-0 174 726, EP-A-0 184 322, EP-A-0 261 478 and EP-A-0 258 956. Preferably, mention may be made here of 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methylsulfinyl]-1H-benzimidazole (INN: omeprazole), 5-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridinyl)methylsulfinyl]-1H-benzimidazole (INN: pantoprazole), 2-[3-methyl-4-2,2,2-trifluoroethoxy)-2-pyridinyl)methylsulfinyl]-1H-benzimidazole (INN: lansoprazole) and 2-{[4(3-methoxypropoxy)-3-methylpyridin-2-yl]methylsulfinyl}-1H-benzimidazole (INN: rabeprazole).
Further acid-labile proton pump inhibitors, for example substituted phenylmethylsulfinyl-1H-benzimidazoles, cycloheptapyridin-9-ylsulfinyl-1H-benzimidazoles or pyridin-2-ylmethylsulfinylthienoimidazoles are disclosed in DE-A-35 31 487, EP-A-0 434 999 or EP-A-0 234 485. Mention may be made by way of example of 2-[2-(N-isobutyl-N-methylamino)benzylsulfinyl]benzimidazole (INN: leminoprazole) and 2-(4-methoxy-6,7,8,9-tetrahydro-5H-clohepta[b]pyridin-9-ylsulfinyl)-1H-benzimidazole (INN: nepaprazole).
The acid-labile proton pump inhibitors are chiral compounds. The term acid-labile proton pump inhibitor also includes the pure enantiomers of the acid-labile proton pump inhibitors and their mixtures in any mixing ratio including the racemates. Enantiomerically pure acid-labile proton pump inhibitors are disclosed, for example, in WO 92/08716. Esomeprazole may be mentioned by way of example.
The acid-labile proton pump inhibitors are present here as such or preferably in the form of their salts with bases. Examples of salts with bases which may be mentioned are sodium, potassium, magnesium or calcium salts. If desired, the salts of the acid-labile proton pump inhibitors with bases can also be present in hydrate form. Such a hydrate of the salt of an acid-labile proton pump inhibitor with a base is disclosed,

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