Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-12-01
2004-05-04
Henley, III, Raymond (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S398000
Reexamination Certificate
active
06730685
ABSTRACT:
This is a 371 of PCT/SE00/01992 filed Oct. 13, 2000.
FIELD OF THE INVENTION
The present invention relates to a stable liquid formulation comprising an acid labile substituted benzimidazole compound such as a proton pump inhibitor, i.e. a H
+
, K
+
-ATPase inhibitor. The liquid product can be stored refrigerated or stored at room temperature for several months without significant degradation. The invention provides a stable liquid formulation of the H
+
, K
+
-ATPase inhibitor in a water free or almost water free solvent. Such a stable liquid formulation is i.a. suitable as a ready-to-use solution for parenteral administration or as a concentrate for ex tempore preparation of a solution for parenteral administration. Further, the present invention also refers to the manufacture of such stable liquid i.a. parenteral formulations, and their use in medicine.
BACKGROUND OF THE INVENTION AND PRIOR ART
The susceptibility for chemical degradation of the proton pump inhibitors poses special problems in the pharmaceutical formulation of solutions for parenteral administration. The degradation of the proton pump inhibitors in liquid solutions is pH-dependent; the rate of reaction is very high at low pH values.
The proton pump inhibitors have a low solubility in water and a higher solubility in less polar solvents. On the other hand, alkaline salts of the proton pump inhibitors generally have a higher solubility in water and a lower solubility in less polar solvents.
At present pharmaceutical formulations of proton pump inhibitors for parenteral administration are formulated as dry preparations for ex tempore reconstitution in a sterile solvent. The dry preparations are obtained by lyophilisation of sterile filtered solutions. The chemical instability of the proton pump inhibitors precludes heat sterilisation of these compounds.
Thus, at the same time as an enhanced solubility of the active compound is requested for parenteral administration, the stability of the formulations must be maintained and the formulations should have suitable storage stability. Further suitable requirements are easy handling and inexpensive manufacturing.
Proton pump inhibitors are for instance compounds known under the generic names omeprazole, lansoprazole, pantoprazole, rabeprazole, leminoprazole and esomeprazole. Omeprazole and therapeutically acceptable salts thereof are described in EP-A1-0005129. EP-A1-124495 describes certain salts of omeprazole and EP-A1-174726, EP-A1-166287 and GB 2163747 are directed to lansoprazole, pantoprazole and rabeprazole respectively. WO 94/27988 is directed to salts of the single enantiomers of omeprazole.
Proton pump inhibitors are susceptible to degradation/transformation in acidic and neutral media. Due to the stability problems, intravenous formulations of the H
+
, K
+
-ATPase inhibitors are usually made in the form of a dry powder that is to be dissolved in a liquid just before use.
For instance, WO 94/02141 describes an injection of an antiulcerative benzimidazole compound, such as omeprazole. The injection comprises a lyophilised product, which is dissolved in physiological saline just before use. The lyophilised product is prepared from a strong alkaline solution of sodium salt of omeprazole, sodium hydroxide and water, whereafter the solution is lyophilised.
EP 356 143-A1 describes an injectable solution comprising a substituted benzimidazole and at least one of ethanol, propylene glycol and polyethylene glycol. The active compound is either used as such, or preferably as a lyophilised material of an alkaline aqueous solution of the compound, dissolved in the ethanol, propylene or polyethylene glycol. If a lyophilised material is used an acidic substance is also added to the solvent. The examples in Table 2 (EP 356143-A1, page 5) comprising polyethylene glycol have a water content of about 50%.
EP 124 495 describes for instance, see example 13, injectable solutions which are obtained by dissolving omeprazole sodium salt in sterilised water, followed by filtration and lyophilisation to give a lyophilised material. The prepared material is then dissolved in a sterile-filtered mixed solution of polyethylene glycol 400 for injection, sodium dihydrogenphosphate and sterilised water.
The previously described parenteral dosage forms recommend a freeze dried product, which makes the manufacture of intravenous products expensive. The present invention provides a stable liquid formulation which can be used as a ready-to-use solution for parenteral administration or a concentrate for ex tempore preparation of a solution for parenteral administration without using lyophilisation processes/steps in the manufacturing.
SUMMARY OF THE INVENTION
The present invention provides a stable liquid formulation of an acidic susceptible H
+
K
+
-ATPase inhibitor, such as a proton pump inhibitor. The stable liquid formulation can be used as a ready-to-use solution for parenteral administration or as a concentrate for ex tempore preparation of a solution for parenteral administration. The liquid product can be stored refrigerated or stored at room temperature for several months without significant degradation.
According to one aspect of the present invention a water free or almost water-free, polyethylene glycol solution of a sodium or potassium salt of a H
+
,K
+
-ATPase inhibitor of Formula I below or a sodium or potassium salt of a single enantiomer of one of the compounds is provided.
According to another aspect, the sodium or potassium salt of the H
+
, K
+
-ATPase inhibitor may be formed in situ in the polyethylene glycol solution by adding a sodium hydroxide or potassium hydroxide and the active compound, i.e. the H
+
, K
+
-ATPase inhibitor.
Water that has been added with the sodium or potassium salt of the active compound or that has been formed by the in situ formation of the sodium or potassium salt of the active compound, can be evaporated by purging the polyethylene glycol solution with nitrogen. It is by such a procedure possible to remove practically all the water or to obtain a water content of a pre-set value.
Alternatively, the stable liquid formulation may also be filled into capsules which then are enteric coated, and used for oral administration.
According to a further aspect the stable liquid formulation may be filled into a one or two compartment syringe to provide a ready-to-use product or ex tempore preparation product that will be easy to use for parenteral administration.
DETAILED DESCRIPTION OF THE INVENTION
Compounds of interest for the novel stable liquid formulation according to the present invention are a sodium or potassium salt of compounds with the general formula I
wherein
Het
1
is
wherein
N in the benzimidazole moiety means that one of the ring carbon atoms substituted by R
6
-R
9
optionally may be exchanged for a nitrogen atom without any substituents;
R
1
, R
2
and R
3
are the same or different and selected from hydrogen, alkyl, alkoxy optionally substituted by fluorine, alkylthio, alkoxyalkoxy, dialkylamino, piperidino, morpholino, halogen, phenyl and phenylalkoxy;
R
4
and R
5
are the same or different and selected from hydrogen, alkyl and aralkyl;
R
6
′ is hydrogen, halogen, trifluoromethyl, alkyl and alkoxy;
R
6
-R
9
are the same or different and selected from hydrogen, alkyl, alkoxy, halogen, haloalkoxy, alkylcarbonyl, alkoxycarbonyl, oxazolyl, trifluoroalkyl, or adjacent groups R
6
-R
9
form ring structures which may be further substituted;
R
10
is hydrogen or forms an alkylene chain together with R
3
and
R
11
and R
12
are the same or different and selected from hydrogen, halogen or alkyl.
Examples of specifically interesting compounds are a sodium or potassium salt of the following compounds with formula I
The compounds may also be used in the form of a sodium or potassium salt of a single enantiomer. Especially preferred compounds for the present invention are a sodium salt of omeprazole or a sodium salt of (S)-omeprazole.
The stable liquid formulation is pr
AstraZeneca AB
Henley III Raymond
White & Case LLP
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