Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Reexamination Certificate
2002-01-03
2003-08-05
Rose, Shep K. (Department: 1614)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
C424S044000, C424S465000, C264S340000, C264S344000, C034S381000, C034S382000, C034S385000
Reexamination Certificate
active
06602520
ABSTRACT:
The invention relates to a process for the production of solid preparations which contain active pharmaceutical ingredient and rapidly disintegrate in aqueous liquids (such as, for example, water, saliva).
Pharmaceutical formulations which act immediately are required to disintegrate rapidly in liquids and quickly release the active ingredient. It is often attempted to achieve this aim by processing the active ingredient without binder but with excipients which promote disintegration of the preparations after the liquid gains access to give formulations such as, for example, tablets. However, satisfactory results are not obtained in all cases.
A new generation of pharmaceutical preparations which act immediately are expected to disintegrate and release the active ingredient in the shortest possible time. In addition, however, it would also be advantageous for the preparations to disintegrate in the presence of only small amounts of liquid, as are present, for example, on oral administration without addition of liquid, within a very short time without coarse granule particles remaining, which cause a “gritty feeling” in the mouth.
Effervescent preparations such as effervescent powders and effervescent tablets are a formulation form which can distinctly improve the disadvantageous properties of active ingredients when the active ingredients have a long absorption time and/or limited gastric tolerability. Pharmaceutical-containing effervescent preparations are therefore enjoying increasing popularity. It would therefore be desirable for the solution to be found to the problem also to be applicable to pharmaceutical effervescent preparations.
The required pharmaceutical preparations ought also to take appropriate account of the properties of the individual active ingredients such as, for example, the frequently encountered sensitivity to water. The solution to be found to the problem ought, of course, to lead to mechanically stable formulations (low friability, high hardness and compressive strength), which can be packaged without difficulty and can be stored and transported under usual conditions.
There have been diverse attempts to achieve this aim:
JP-A 08291051 discloses a process for producing tablets in which initially the active ingredients, water-soluble binder and water-soluble bulking agent are tabletted under very low pressure; the resulting tablets are then moistened and subsequently dried.
EP-A 192 460 describes tablets with a relatively hard shell of compressed material which is relatively resistant to liquids, there being rapid dissolution of the tablet ingredients after crushing of the tablet in the presence of liquid.
EP-A 352 190 describes the production of porous tablets which rapidly disintegrate in water and whose pores are produced by freeze drying a dispersion. The moulding composition for producing the tablets contains a defined amount of water to adjust the required viscosity.
EP-A 450 141 relates to a rapidly dissolving carrier material, inter alia for active pharmaceutical ingredients, with porous water-soluble, hydratable gel or foam material which has been hydrated with water, cured in the hydrated state and then dehydrated in such a way that cavities remain in place of the hydration liquid.
EP-B 548 356 discloses tablets containing disintegrating agents and/or swelling agents or soluble substances, where the (unpleasant-tasting) active ingredient is multiparticulate and is in the form of coated microcrystals or coated microgranules.
EP-A 553 777 describes a process for producing porous, rapidly disintegrating tablets in which granules containing active ingredient and carbohydrate are moistened with water, and a tablet is shaped therefrom and dried. The dissolving times (in the mouth) are between 0.2 and 1.5 minutes.
U.S. Pat. No. 2,926,121 discloses a process for producing medicinal sweets in which sugar is added to a highly concentrated aqueous aluminium hydroxide suspension, a solid protective colloid is added to the resulting mixture, the mixture is homogenized and air is introduced, and the resulting pasty composition is allowed to dry at room temperature without exposure to heat.
U.S. Pat. No. 4,946,684 describes rapidly disintegrating tablets based on a matrix network structure composed of mannitol and a natural gum such as guar gum or gum acacia.
U.S. Pat. No. 5,851,553 describes a process for producing rapidly disintegrating tablets in which a mixture containing active ingredient and amorphous sugar is subjected to a so-called flash flow process where the sugar crystallizes in the form of a type of candyfloss. The candyfloss-containing voluminous composition can be shaped to tablets with small forces (preferably not more than 80 psi) and then subjected, where appropriate in a moist atmosphere, to a curing.
WO 98/23656 relates to a freeze-drying process for producing rapidly disintegrating tablets using lipids and structure-forming agents.
WO 98/29137 describes rapidly disintegrating tablets which comprise a solid dispersion of an active ingredient of low solubility in a gel-forming water-soluble polymer, and contain an alkali metal salt of a weak acid or of a strong acid with an endothermic standard dissolution enthalpy or dissolution heat.
WO 98/46215 discloses a technology in which granulation is dispensed with, and the active ingredients and a matrix containing a non-direct compression filler, for example mannitol, and a glidant are compressed to tablets. The tablets are intended to disintegrate quickly in the mouth and, during this, cause a minimal “gritty feeling”.
It is furthermore known to make sucrose crystals slightly moist (residual moisture less than 2% by weight) and to follow compaction under high pressure by drying, resulting in porous but stable shaped articles.
The processes mentioned are either technically complicated or lead to products which do not have the expected short disintegration times or which have inadequate mechanical stability so that to protect from damage in some cases even special packaging techniques are proposed. Thus, whereas the known processes usually provide partial solutions for particular problems, there has to date been no economic process for preparations which meet all the abovementioned requirements to a high degree.
It has now been found, surprisingly, that the stated object can be achieved by a technically very simple process.
The invention relates to a process for the production of preparations containing A) at least one active pharmaceutical ingredient and B) at least one excipient but—apart from an effervescent composition which is present where appropriate—no disintegrant, in which at least the predominant part of the complete composition of the ingredients for the preparation to be produced is granulated, the resulting granules and, where appropriate, the remainder of the ingredients are shaped in the presence of 2.5 to 15% by weight of liquid C), based on the total of solid ingredients and liquid, preferably water, ethanol and/or isopropanol, under a pressure of up to 100, preferably 0.1 to 50, in particular 1 to 20, N/cm
2
with a degree of compaction of 30 to 80%, based on moist complete composition to be shaped, and the resulting shaped articles are dried.
The solid preparations obtainable in this way are porous and are immediately moistened throughout on contact with aqueous liquid. The disintegration and the dissolution of preparations produced according to the invention and containing effervescent compositions take place virtually simultaneously within a few seconds. As a rule, disintegration and dissolution are complete within 2 to 12 sec, preferably within less than 8 sec, in particular within less than 5 sec (measured in a vessel charged with 150 ml of water at 20° C. or on the tongue without additional liquid being added); preparations produced according to the invention without effervescent compositions have completely disintegrated in this time and are at least one half dissolved.
The mechanical stability of the preparations obtainable according to the invention makes transport,
Schroeder Marco
Steffens Klaus-Jürgen
Bayer AG
Rose Shep K.
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