Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Reexamination Certificate
1997-05-09
2001-10-23
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
C424S451000, C424S464000, C424S465000, C424S469000, C424S489000
Reexamination Certificate
active
06306439
ABSTRACT:
The present invention relates to mixtures of polyvinyl-lactams and polyacrylates in the preparation of pharmaceutical systems having controlled release of active compound, which are characterized in that they swell strongly in the aqueous environment of the stomach and reside in the stomach for an extended period of time. Optionally, the gastric residence time of the system according to the invention can also be affected by additional incorporation of a gas-forming mixture, as the gas formed reduces the density of the system, by means of which it floats on the stomach contents and thus cannot very easily reach the pylorus, which is located in the lower region of the stomach.
In comparison with the administration of a number of rapidly releasing individual doses at certain intervals, the administration of an individual dose of a medicament from which the active compound is released in a controlled manner over a prolonged period (sustained-release formulation) has the advantage that over a prolonged period a constant and uniform blood level of the active compound is guaranteed. In pharmacy, sustained-release formulations of all sorts of types are known. There are, for example, sustained-release formulations which are based on the controlled erosion of a matrix containing active compound or those from which a water-soluble active compound is released by controlled diffusion through one or more polymer layers surrounding the formulation. In another sustained-release administration form, the controlled release is based on displacement of a layer containing active compound from the osmotically active administration form surrounded by a water-permeable membrane as a result of osmotic water absorption. Pressure equalization or release of active compound in this case takes place through a hole in the membrane.
The sustained-release administration forms briefly described above, however, are only utilizable for active compounds which are absorbed effectively in all regions of the gastrointestinal tract. They are unsuitable for active compounds which on account of their physicochemical properties or due to microbial degradation have so-called absorption windows, i.e. are only absorbed in certain regions of the gastrointestinal tract (GI tract), because they pass through the gastrointestinal tract continuously and their residence time in the absorbing part of the GI tract is thus too short to guarantee a long-term action. Examples of substances whose bioavailability is strongly dependent on the local physiology in the GI tract and which preferably are absorbed in the higher sections of the intestine are ciprofloxacin and nimodipine. Ciprofloxacin is readily soluble in the acidic environment of the stomach. In the intestine, where neutral to slightly alkaline pH conditions prevail, however, precipitation of the active compound occurs, which adversely affects absorption in the lower sections of the intestine. Nimodipine is degraded by the bacterial flora prevailing in the colon, and can therefore only be effectively absorbed in the upper region of the intestine. Further active compounds which have absorption windows in the upper GI tract are captopril and ranitidine. Other active compounds in turn, such as, for example, certain antacids and pepstatin, are locally active and can display their action only if they are released at the site of action, the stomach.
In view of the above explanations, it is clear that a large number of active compounds are unsuitable for conventional sustained-release formulations and that there is a need for systems which reside in the stomach over a relatively long time and release the active compound there in a controlled manner.
Various mixtures which are based on swellable or floatable administration forms are described in the patent literature for prolonging the residence time.
Thus U.S. Pat. Nos. 3,574,820 and 4,434,153, for example, describe tablets which swell in the stomach and thereby become so large that due to their bulkiness they can no longer pass through the pylorus.
In addition to bulkiness, reduction in density is also used as a measure for prolonging the gastric residence time. Administration forms whose density is lower than that of the stomach content float and are thus kept away from the stomach exit, which is located in the lower region of the stomach. JP 62283919 describes, for example, a tablet comprising a part containing active compound and a part which contains a gas-forming mixture. In contact with aqueous media, carbon dioxide is formed, whereby the average density of the administration form is reduced and the tablet floats on the stomach contents. The reduction of the density by gas formation was also used, as described in EP-A 0235718, with granules of an active compound and a gas-forming mixture coated with a permeable flexible lacquer layer. The abovementioned effects of bulkiness and density reduction due to gas formation are also employed in combination, as shown in Japanese Patent Application 284093/91.
Other administration forms described in the patent literature are not dependent on gas formation for reducion of the density and as a result of their construction already have a density on administration which guarantees the ability to float on the stomach contents. Thus U.S. Pat. No. 3,976,764 describes systems in all types of embodiments which are constructed such that a hollow core, or a core of low density, was coated with a layer containing active compound. Based on this, EP 0326816 describes administration forms in which the reduction of the density is achieved by the use of structural elements having hollow spaces, such as foams or hollow bodies. Administration forms are described in U.S. Pat. No. 4,167,558 which essentially consist of a mixture of active compound and gel-forming polymers in a capsule. A gel body which still contains dry powder mixture is formed in the stomach by swelling of the powder mixture after dissolution of the capsule. The active compound is released in the course of time by erosion of the gel covering. New gel is in this case formed continuously by further swelling of the dry core. The administration form remains capable of floating until the entire powder mass is soaked through.
Despite the versatility of the mixtures for prolonging the gastric residence time, their conversion to practical pharmaceutical forms is difficult for various reasons. Pure floating pharmaceutical forms such as the pellets presented above (EP-A-0235718) or systems having an inherent low density (U.S. Pat. No. 3,976,764, EP-A-0326816 and U.S. Pat. No. 4,167,558) can only reside in the stomach for a relatively long time if the stomach contains food. In the fasting state, administration forms of this type, due to their relatively small size, leave the stomach within a short time. In addition, the said administration forms having a low inherent density, due to their relatively low active compound content relative to the volume of the total administration form, are only suitable for low-dose active compounds. The granules described in EP 0235718 B1 can in turn only be used for water-soluble active compounds, which greatly restricts their use range.
The swellable tablets described in U.S. Pat. Nos. 3,574,820, 4,434,153 and in JP 284093/91 suffer from the properties of the swelling matrix used. A good swelling matrix can absorb many times its original weight of moisture. At the same time, however, it must also have a certain dimensional stability in the swollen state in order to stand up to the mechanical stress to which it is subject in the stomach. Normal linear gel-forming agents such as modified celluloses, polyoxyethylene and polyvinylpyrrolidone (PVP), or alternatively crosslinked polymers, for example based on PVP or polyacrylates, are indeed distinguished by good liquid absorption, but their dimensional stability greatly decreases with increasing degree of swelling because of the poor association between the hydrated linear polymer chains or crosslinked polymer particles, which leads to the erosion or to the dissolution
Lustig Klemens
Penners Gunther
Petersen-von Gehr Jorg
Bayer Aktiengesellschaft
Norris & McLaughlin & Marcus
Page Thurman K.
Tran S.
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