Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Reexamination Certificate
2001-08-20
2003-12-23
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
C424S424000, C514S282000, C514S226500, C514S284000
Reexamination Certificate
active
06667056
ABSTRACT:
BACKGROUND OF THE INVENTION
Field of the Invention
This invention relates to orally administered, solid, fast-soluble pharmaceutical compositions containing an effervescent acid-base couple, suitable for dissolving in water or an aqueous solution and for sucking.
The effervescent tablets occupy an important position among dosage forms, being the form of choice not only for adults but also for children. Many drugs, and in particular analgesics, vitamins and antibiotics were designed in this kind of formulations.
The effervescent tablets, when added to cold water, generate a gas which causes effervescence and produces a clear sparkling solution. The gas which gives the effervescence is always carbon dioxide which derives from the reaction between an acid and a base like carbonate or bicarbonate. The effervescent tablet consists of at least three components:
the active ingredient;
an acid;
an alkali compound (basic ingredient) constituted by a carbonate or a bicarbonate.
The acid and the alkali are the essential components which provide the effervescence and the disintegration of the tablet when is contacted with water. As acidic component the citric acid both in the hydrated and anhydrous forms is more often used, but other edible acids like tartaric, fumaric, adipic, malic acid can be used as well. The carbonate, which represents the source of carbon dioxide which generates the effervescence, generally is a water-soluble alkaline carbonate. The choice of the carbonate is very important since, besides provoking the effervescence, it can influence the stability of the tablet. Sodium bicarbonate is one of the most used carbonate because it is very soluble and of low cost. Alternatively, modified sodium bicarbonate can be used, obtained by heating common sodium bicarbonate in order to convert the surface of its particles to sodium carbonate so increasing its stability.
Other physiologically acceptable alkaline or alkaline earth metal carbonates may be used, such as potassium or calcium (bi)carbonate, sodium carbonate, or sodium glycine carbonate.
Compositions of effervescent tablets may also include a lubricant which has to be necessarily selected from the totally water soluble compounds forming a clear solution. Examples of this kind of lubricants are sodium. benzoate, sodium acetate, fumaric acid, polyethylenglycols (PEG) higher than 4000, alanine and glycine.
Conventional excipients such as diluents, ligands, bufferings, sweeteners, flavourings, colorings, solubilizers, disintegrants, wetting agents and other excipients of common use may be added to the formulation. Effervescent tablets are convenient, attractive, easy to use premeasured dosage forms. These advantages, however, are balanced by some technological problems, the two most important of which are hygroscopicity and lubrication.
The instability of effervescent tablets, their tendency to absorb moisture and lose reactivity are generally known. Due to this instability in the presence of water, conventional wet granulation and the subsequent granulate compression are very hardly applicable.
Sometimes the granulation has been carried out using very low amounts of water, for example through the fusion of the citric acid monohydrate, which upon heating releases part of the water of crystallisation which acts as the granulating fluid. Then the granulate has to be processed in conditions of severely controlled relative humidity, normally lower than 20%.
Alternatively, techniques of anhydrous granulation, in the absence of aqueous phases, have been applied using volatile organic solvents like ethanol. However such techniques require special manufacturing environments with strictly controlled relative humidity conditions (normally lower than 20%) and with explosion proof equipment.
Another technique, which is more time-consuming and more laborious, is represented by the separated wet granulation of acidic and alkali granules, which are subsequently mixed and compressed to give the final pharmaceutical composition.
The direct compression of the simple physical blend of the components of the formulation represented an attempt to obviate the above technological difficulties. However such an operation has been carried out in controlled thermo-hygrometric conditions, for example at temperatures lower than 20-25° C. and with relative humidity lower than 30%, using tabletting machines with tapered dies and punches faced with chromium alloys.
Because of the operating and stability problems, this type of manufacturing method cannot be easily applied to the preparation of effervescent tablets of particular active ingredients which cannot be wet granulated or which contain a residual percentage of water of crystallisation which. is hardly eliminated. Typical examples of this kind of medicaments are drug cyclodextrin complexes, hydrated active ingredients and their salts, which may present stability problems in the presence of water. Similar problems are encountered when the composition contains excipients having hydration water or residual-hardly eliminable moisture. Typical examples of this kind of excipients are cyclodextrins.
The other important technological problem affecting the manufacture of effervescent tablets is lubrication, as the lubricant must not only have lipophilic properties for good lubrication, but also high water solubility, to give adequate disintegration and produce quickly a clear solution. Most substances used as lubricants, such as magnesium stearate, are effective, but are water insoluble. The resulting solution after disintegration is cloudy and often has a soapy taste. Ideally, non toxic lubricants with high water solubility and acceptable taste are required. Moreover, the effervescent base is inherently difficult to lubricate, partly due to the nature of the raw materials used and partly due to the rapid tablet disintegration usually required which limits the use of high percentage of lubricants.
BRIEF SUMMARY OF THE INVENTION
Now it has been found, and this is an object of the present invention, that effervescent tablets can be prepared through simple techniques which have direct-industrial application and which are based on the use of a particular effervescent blend of acids and sodium glycine carbonate, provided in a sufficient amount to rapidly disperse and assist dissolution of the components of the formulation.
In particular, according to a second aspect of the invention, it was found that the use of a blend of certain acids with sodium glycine carbonate allows to prepare effervescent tablets by direct compression in normal thermohygrometric conditions and with standard tabletting equipment.
It has been even more surprisingly found that this technology applies also to active ingredients and/or excipients which cannot be wet-granulated or which contain a residual percentage of hardly eliminable crystallisation water.
According to a further aspect of the invention, it was found that the use of certain acids/sodium glycine carbonate blend is particularly advantageous in the preparation of effervescent tablets which contain a cyclodextrin as the component of an inclusion complex or as an excipient, despite of the fact that cyclodextrins have hydration water and tend to absorb moisture very easily.
DESCRIPTION OF RELATED ART
The characteristics of excipients which can be used in the preparation of effervescent tablets, have been described in Aiache J M, Pharm Acta Helv 49 (5/6), 169-178, 1974 and in Boymond C, Labo-Pharma Probl Tech 25(271), 987-995, 1977.
Anyway, Faguet J P et al. in Labo-Pharma Probl Tech 26(274), 207-210, 1978, after evaluating the effects of moisture on the stability of acids, carbonates and bicarbonates, conclude that when sodium glycine carbonate, which is per se moisture—sensitive, is blended with an acid, specifically citric acid, the resulting carbonate is very moisture—unstable, much more than sodium glycine carbonate alone.
In some patents, sodium glycine carbonate is simply mentioned, among various different excipients, as a possible component of effervescent combinations which ca
Acerbi Daniela
Brambilla Gaetano
Chiesi Paolo
Mezzadri Rosa
Ventura Paolo
Chiesi Farmaceutici S.p.A.
Oblon, Spivak, McClelland, Maier & Neustadst, P.C.
Page Thurman K.
Pulliam Amy E
LandOfFree
Pharmaceutical compositions containing an effervescent... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Pharmaceutical compositions containing an effervescent..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Pharmaceutical compositions containing an effervescent... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3134310