Active ingredient-containing floating forms comprising...

Details Active ingredient-containing floating forms comprising... Active ingredient-containing floating forms comprising...

2001-03-20

2003-10-21

Spear, James M. (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Tablets, lozenges, or pills

C424S465000, C424S457000, C424S470000, C424S472000, C424S474000

Reexamination Certificate

active

06635279

ABSTRACT:

The present invention relates to active ingredient-containing dosage forms comprising polyvinyl acetate and polyvinylpyrrolidone which float on gastric fluids after intake and thus result in delayed release of active ingredient. These forms can be produced by simple processes and exhibit exceptional mechanical strengths.
Slow-release dosage forms are becoming increasingly important, firstly because the frequency of administration can be reduced, and secondly because they lead to a reduction in the fluctuations in the levels in the blood. The lower maximum level in the blood may reduce the severity of dose-dependent side effects and thus, for example for drug products, improve the tolerability. The higher minimum plasma concentration increases the efficacy, especially of active ingredients for which the concentration ought not to fall below a particular threshold.
After intake of the slow-release dosage form it reaches the stomach, where it is normally transported after 0.5-3 h into the small intestine. The time to pass through the small intestine is usually 3-6 h. The result of this is that absorption of the active ingredient must be complete within about 3-6 h because most active ingredients are absorbed in the colon to only a negligible extent or not at all. It is therefore possible to adjust a longer release-slowing period only with difficulty. The bioavailability of active ingredients which are not completely absorbed in this period decreases because part of the dose is lost. An additional factor is that certain active ingredients have an absorption window, which is very quickly passed through with conventional dosage forms, in the small intestine.
A system which remains in the stomach for a longer time and continuously releases active ingredient would avoid these disadvantages, since the active ingredient would continuously pass through the pylorus in dissolved form and could be taken up in the small intestine. It is possible in this way on the one hand to extend the bioavailability but also, on the other hand, to extend the duration of action, for example of a drug product.
In addition, there are some active ingredients intended to act locally in the stomach. An extended duration of action is frequently desired for these too.
There have been frequent approaches to extending the residence time by tablets which swell in the stomach and become so large that they are no longer able to pass through the pylorus. Such forms are described in U.S. Pat. Nos. 4,871,548; 4,767,627; 5,443,843; 5,007,790; 5,582,873; 4,851,232; WO 99/07342. In most of these, hydroxyalkylated celluloses are used as swelling agents. All these forms have the disadvantage that they may block the outlet from the stomach and may cause health problems. In addition, the swelling depends greatly on the contents of the stomach and the osmolarity of the medium. These eventially also influence the release-slowing action and the residence time.
Another possibility for extending the residence time in the stomach is to produce floating forms. These float on the contents of the stomach and, because the pylorus is located in the lower part of the stomach, are not discharged into the small intestine for a lengthy period.
Various processes are known for producing such forms. Thus, it is possible to incorporate substances which have per se a low density, such as, for example, fats, oils or waxes. Such forms are described in the Applications EP 198769 (Forest Laboratories Inc.), U.S. Pat. No. 4,424,235, U.S. Pat. No. 8,343,47, U.S. Pat. No. 3,014,98, BE 839604 (Hoffmann-LaRoche). However, relatively large amounts are necessary for this and increase the volume of the dosage forms and make them more difficult to swallow and, in addition, these substances have a very disadvantageous effect on the strength of the shaped products. Compression results in tablets with low hardnesses, and the tablets frequently adhere to the punch during production. The Application DE 3527852 (Nippon Shinyaku KK) describes fat-containing mixtures which are packed into a capsule and must be heated for solidification. This is complicated and entirely unsuitable for temperature-labile active ingredients. Shaped articles are produced in the US Application U.S. Pat. No. 4,814,179 (Univ. of St.Johns) by cooling and gelling and drying. This process is even more elaborate.
Another method makes use of the evolution of gas from salts of carbonic acid. This entails these salts being incorporated together with gel formers into the dosage forms and, after exposure to gastric acid, CO
2
is produced and inflates the form and leads to the floating. In order to be independent of gastric acid there is frequently incorporation of physiologically tolerated acids such as, for example, citric acid or tartaric acid. These preparations are very sensitive to moisture, so that humidity must be low during production and no water-containing excipients can be employed. The packaging material for the dosage forms must be very leakproof so that the forms do not effervesce even during storage. The evolution of gas on contact with acid often also affects the structure of the dosage forms and the release-slowing effect is reduced. Since these preparations are often difficult to compress, and tablets with adequate mechanical stability are not obtained, such preparations are frequently and inconveniently packed in hard or soft gelatin capsules. Examples thereof are described in the Applications GB 2283172 (Scherer LTD), GB 2283171 (Reckitt & Colman Prod LTD).
The production of tablets is described in WO 99/45887 (Temple Univ), U.S. Pat. No. 4,167,558 (Hoffmann-LaRoche), and the production of two-layer tablets is described in U.S. Pat. No. 4,140,755 (Hoffmann-LaRoche). Besides the disadvantages already mentioned above, with these tablets there are enormous problems with reproducibility of the release. It is generally known that the gel-forming capacity and the gel strength of polysaccharides varies from batch to batch because of the variation in the chain length and the degree of substitution, and this is exacerbated by the disturbance of the gel structure through evolution of CO
2
. In addition, the gel formers react very sensitively to differences in the osmolarity of the release media, with alterations in the release.
Even more delicate and complicated are preparations in which coating layers are applied to a core able to evolve CO
2
. In some cases, the coating itself contains a salt of carbonic acid. These coatings must be applied using organic solvents. Such preparations are described in EP 235718 (Eisai KK), US 4,101,650 (Microbiochemical Research Foundation), WO 99/49868 (Yuhan Corp).
A powder which comprises active ingredient, hydrocolloid, pH-dependent polymer and binder and is packed into a capsule is described in U.S. Pat. No. 5,169,638 (Squibb & Sons Inc). However, the gelling and release depend very greatly on the surrounding conditions.
U.S. Pat. No. 5,232,704 describes forms consisting of 2 layers, one of which contains active ingredient and the other is responsible for the floating. The production is elaborate and high-dose drugs cannot be processed.
Aerogels, foams and air-containing microcapsules are likewise described in WO 96/25950 (Hoechst AG), EP 326816 (LTS Lohmann), WO 95/05809 (Nippon Shinyaku), but the disadvantage of these microcapsules is often that the substances are not pharmaceutically approved, very complicated to process or difficult to tablet. The lyophilization of active ingredients or additives to produce a porous shaped article is enormously time-consuming and costly.
Using porous shaped articles as starting material and applying active ingredient or other excipients thereto increases the volume of the dosage form correspondingly.
The use of solvents in the production moreover increases costs and, in addition, is not environmentally friendly.
It is an object of the present invention to develop a suitable composition for a slow-release dosage form which does not have the abovementioned disadvantages.
We have found that this object is achieved by

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