Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Capsules
Reexamination Certificate
2000-01-12
2003-06-10
Spear, James M. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Capsules
C424S457000, C424S461000, C424S468000, C424S474000, C424S490000, C424S494000, C424S462000, C424S497000, C424S480000, C424S482000, C514S772300, C514S781000, C514S785000, C514S970000
Reexamination Certificate
active
06576258
ABSTRACT:
TECHNICAL FIELD
(A61K31/44,A61K 45/06,A61K 9/20,A61K 9/48)
The invention belongs to the field of pharmaceutical industry and relates to a novel medicinal formulation with controlled release of active substances on the basis of anhydrous (i.e. non-aqueous) granulation of the active substances and dried pharmaceutically acceptable auxiliary substances. By the invention a technologically simple manufacture of a stable pharmaceutical formulation with controlled release of active substances is made possible.
More specifically, the invention relates to a novel pharmaceutical formulation with controlled release of active substances that are unstable in acidic medium, unstable when stored for longer periods of time in the presence of water and at the same time sensitive to heating. Further, the invention relates to a novel method of stabilization of such unstable active substances and to a process for the preparation of the novel pharmaceutical formulation of such unstable active substances.
TECHNICAL PROBLEM
There exists a constant need for developing pharmaceutical formulations wherein in a technologically simple way there would be achieved a good stability of active substances that are unstable in acidic medium unstable when stored for longer periods of time in the presence of water and at the same time sensitive to hearing. For the manufacture of hitherto known pharmaceutical formulations containing such active substances, technological processes have been used, wherein also water, wherein such active substances are not stable, has been used as a solvent and therefore the required stability has been achieved especially by the addition of basic substances to the active substance or by using the active substance in the form of a salt thereof. Namely, basic substances create a basic pH in the environment of the active substance, whereat such active substances are more stable.
PRIOR ART
The first literature data upon stabilization of active substances that are unstable in acidic medium, unstable when stored for longer periods of time in the presence of water and at the same time sensitive to heating, relate to the transformation of such active substances to salts thereof, e.g. the transformation of omeprazol, which is a substance unstable in acidic medium, to different salts of omeprazol is disclosed in EP-A-124495. A pharmaceutical formulation with a magnesium salt of omeprazol is disclosed in WO 95/01783 and in WO 96/01622.
The use of basic inorganic salts of magnesium and/or calcium for stabilization of benzimidazoles is disclosed in EP-A-237200. A stable pharmaceutical formulation is prepared by a homogenous blending of the active substance with basic inorganic salts of magnesium and/or calcium and pharmaceutically acceptable auxiliary substances. The obtained granules, pellets or tablets are then coated with a gastro-resistant (i.e. enteric) coating.
The stabilization of omeprazol as disclosed in EP-A-247983 is achieved by means of a pharmaceutical formulation, wherein the active substance or a salt thereof is blended with different alkaline substances in the core and thereon one or more intermediate coatings (i.e. separating layers) are applied, followed by a gastro-resistant coating. In EP-A496437, which is a divisional of above EP-A-247983, a pharmaceutical composition comprising a benzimidazole active compound, a binder, a cellulose derivative, and a surfactant is disclosed. The stabilization of active substances that are unstable in acidic medium by adding different alkaline compounds is disclosed in several patent applications, e.g. in WO 94/02140 the addition of a coprecipitate Al(QH)
3
-NaHCO
3
is disclosed, in U.S. Pat. No.5,232,706 the addition of different alkaline compounds is disclosed and in EP-A-519365 there is disclosed a pharmaceutical formulation with pantoprazol, which is a substance unstable in acidic medium, and with alkaline compounds in the core. Additionally, the stability at prolonged storage is enhanced with the addition of TiO
2
to the core with omeprazol (WO 96/37195).
The formation of a complex of active substances unstable in an acidic medium, with cyclodextrins in an alkaline solution is disclosed in U.S. Pat. No. 5,399,700. The stabilization is achieved by incorporating a particular molecule of the active substance into a cyclodextrin molecule. Similarly, in WO 96/38175 the incorporating of molecules of benzimidazole derivatives into branched derivatives of cyclodextrin-carboxylic acid is disclosed.
In WO 93/25204 there is disclosed a stable pharmaceutical formulation of omeprazol microgranules containing a neutral core of sugar and starch, onto which core a layer of omeprazol and mannitol in equal quantities is applied. Similar pharmaceutical formulation for benzimidazole derivatives is also disclosed in WO 96/23500 and WO 97/12581. In a pharmaceutical formulation, disclosed in WO 97/12581, in an aqueous suspension a layer of omeprazol and hydroxypropylmethylcellulose is applied to inert cores of lactose. Other technologies of spraying an active substance onto inert cores are known as well (U.S. Pat. No. 5,246,714, EP-A-519144).
WO 96/24375 discloses a fixed formulation comprising an acid susceptible proton pump inhibitor and one or more antibacterial compounds. WO 83/03756 discloses the usage of anhydrous granulation to achieve rapid action of clometacine and to increase the biodisponibility of clometacine. EP-A-391374 relates to methods for the preparation of formulation of bromocriptine, which is very sensitive to moisture, light and temperature, by the incorporation of bromocriptine in an inert excipient.
THE INVENTIVE SOLUTION
The basic object of the invention is an improved stability of active substances that are unstable in acidic medium, unstable when stored for longer periods of time in the presence of water and at the same time sensitive to heating. This object is achieved by anhydrous granulation of the active substances and of dried pharmaceutically acceptable auxiliary substances for the preparation of pellet cores or granules. Pellet cores or granules thus prepared may under addition of dried pharmaceutically acceptable auxiliary substances be compressed into tablets, which are in the further procedure coated with a gastro-resistant coating. Between the tablet and the gastro-resistant coating one or more intermediate coatings may be optionally applied. Alternatively, the pellet cores or granules prepared by anhydrous granulation may be coated with a gastro-resistant coating and then filled into capsules, bags or compressed into tablets under the addition of dried pharmaceutically acceptable auxiliary substances. Between the pellet core or granules and a gastro-resistant coating one or more intermediate coatings may be optionally applied.
The object of the invention is a method for stabilizing active substances that are unstable in acidic medium, unstable when stored for longer periods of time in the presence of water and at the same time sensitive to heating, by means of anhydrous granulation of active substances and dried pharmaceutically acceptable auxliay substances for the preparation of pellet cores or granules.
In active substances that are unstable in the presence of water, stability at prolonged storage is a special problem. Hitherto known technological processes for the preparation of pharmaceutical formulations with controlled release of active substances are based upon the use of water or a mixture of water and organic solvents for the granulation of active substances and pharmaceutically acceptable auxiliary substances. During the process of drying the pellet cores or granules, water and other solvents are removed by heating. However, a complete removal of water from a pharmaceutical formulation is not possible according to hitherto known and disclosed processes. In active substances that are unstable when stored for longer periods of time in the presence of water and at the same time sensitive to heating, a prolonged heating when drying should be avoided, which makes the removal of water even more difficult. Thus it w
Kofler Bojan
Rebi{haeck over (c)} Ljubomira Barbara
Venturini Peter
{haeck over (S)}irca Judita
Burns Doane , Swecker, Mathis LLP
Lek, Tovarna Farmacevtskih In Kemicnih Izdelkov, D.D.
Spear James M.
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