Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Food or edible as carrier for pharmaceutical
Reexamination Certificate
1999-06-24
2002-07-23
Travers, Russell (Department: 1617)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Food or edible as carrier for pharmaceutical
C424S048000, C424S195110, C426S005000, C514S002600
Reexamination Certificate
active
06423336
ABSTRACT:
TECHNICAL FIELD
This invention relates to chewing gums and in particular to their use in the delivery of active ingredients, including liquid solutions of active ingredients, thermolabile active ingredients in solid or liquid form and homeopathic medicines.
BACKGROUND ART
The use of chewing gum as a drug delivery vehicle is well known and under extensive investigation by many researchers (see, for example, “Chewing gum as a drug delivery system”, Margrethe Romer Rassing,
Advanced Drug Delivery Reviews,
13, 89-121 (1994)). Apart from the fact that chewing gum offers a convenient and easily used vehicle for active ingredient administration, it presents additional features of pharmacological importance including the fact that absorption of active ingredients through the oral mucosa avoids hepatic first pass metabolism, and may therefore offer an opportunity to reduce therapeutic dose requirements.
The primary disadvantage of chewing gum is a difficulty in regulating the total dose administered. In many cases it is impossible to formulate gum such that the total dose contained is released and made available for absorption.
While buccal absorption of active ingredients avoids liver metabolism, the act of chewing produces saliva which necessitates swallowing and there is no way of regulating the amount of active ingredient which is swallowed and the amount absorbed through the buccal mucosa. Furthermore, active ingredients which are poorly water-soluble are not easily absorbed when present in chewing gum in solid form.
Another problem is thermal stability: the industry standard method of formulating any chewing gum involves a hot melt process in which the temperature of the gum base (to which active ingredients, flavours and excipients are added as a dry powder) may be of the order of 80° C. Thermolabile active ingredients are denatured by the high processing temperatures and thus cannot be formulated for delivery using the industry standard process technology.
A solution to this problem has been proposed which avoids the high temperatures of the hot melt process. By freezing the gum it can be comminuted by grinding, and then an active ingredient can be added in powdered form. The mixture of powdered active ingredient and frozen gum particles can be compressed together and thawed. Processes of this type are disclosed in: U.S. Pat. No. 4,000,321, U.S. Pat. No. 4,161,544 and U.S. Pat. No. 4,737,366.
WO 96/03111 discloses details of comminution of gum to a powdered form followed by blending with liquid ingredients, before compression to the form of tablets which are then subsequently dried by hot air.
Despite the disadvantages, there are many suitable active ingredient candidates some of which are already available in the market in chewing gum form. These active ingredients include nicotine, anti-microbials for local oral infection, fluoride gums for prevention of dental caries, vitamins and some functional foods. The common feature of all commercial products is that they are intended for local oral application of the active ingredient and, like ointments or other conventional topical medicaments, the total dose administered is not critical to the therapeutic value.
The delivery of liquids presents its own problems, particularly where aqueous solutions are involved. A major problem in entrapping water in chewing gums is that water (and liquids such as water/ethanol solutions which are often used as a base for homeopathic dilutions) are not compatible with conventional chewing gum processing. There is no point in enclosing a discrete volume of water en masse in a gum envelope because the volume bursts out in the first bite. So a problem exists in finding some way of dispersing the aqueous solution in the gum such that it is released slowly over a period of about twenty minutes, without subjecting the active ingredient to some incompatible conditions such as extreme heat, shearing, electromagnetic forces or chemical manipulation.
If a liquid must be encapsulated, other methods can be used, such as using a resin which holds a polar liquid therein by charge attraction (such as the nicotine gums marketed by Kabi Pharmacia as “Nicorette”); or the liquid can be encapsulated in liposomes (also referred to as nanospheres/microspheres depending on size) and these particles can be entrapped in a gum in much the same way as with a powder. The use of “micro-sponges”, containing encapsulated liquids is disclosed in U.S. Pat. No. 5,154,927. Using these methods the total volume of liquid which can be encapsulated is very small, being approximately 0.1 ml for a standard sized piece of gum.
The present invention aims to provide gums in which significantly more liquid (e.g. up to 1.0 ml or more) can be formulated in each piece of gum.
Therefore, it is an object of this invention to provide a chewing gum product giving improved sustained release of active ingredients and one which is particularly suitable for thermolabile biological ingredients and other medicaments some of which may be required to be in liquid solution.
DISCLOSURE OF INVENTION
The invention provides a method of manufacturing a chewing gum comprising the steps of:
a) entrapping a liquid within a mass of gum;
b) cooling the gum by an amount sufficient to freeze the entrapped liquid and thereby form entrapped frozen liquid crystals within the gum; and
c) regulating the temperature of the gum so as to manipulate the size and/or morphology of the frozen liquid crystals, and thereby manipulate the internal structure of the gum to provide a gum having spaces therein of a plate-like or sheet-like shape.
It has been found that by controlling the size and/or morphology of the frozen crystals inside the gum matrix, it is possible to obtain good control of the internal spaces inside the gum. The distribution of an active ingredient in the liquid is thus controllable, and this has a significant impact on the release characteristics of the gum.
Preferably, a step a) comprises comminuting the gum to a particulate form and adding the liquid thereto.
The liquid can thus act as a binder for the particulate gum. The liquid may be an active ingredient in itself, or it may contain an active ingredient (or a flavouring) in solution, suspension or homeopathic dilution. Alternatively, a simple liquid such as water may be added simply in order to use the frozen crystals of water to control the internal structure of the gum. If the water is subsequently removed, one is left with “blanks” which are adapted to absorb a liquid in the internal spaces vacated by the water.
Preferably, the comminution of the gum is achieved by a process selected from jet milling, homogenisation in a suspending liquid, and cryogenic milling.
The operation of a jet mill is well known to those skilled in the art. In jet milling, particle size reduction occurs from collisions between particles driven at high speeds by cold nitrogen gas. As a starting material, commercially available gum base is supplied in particulate form of a size suitable for feeding into a jet mill. Particles whose size is sufficiently reduced exit the mill chamber automatically.
In homogenisation in a suspending liquid, pieces of gum are suspended in a liquid such as a saturated aqueous salt solution. A commercially available homogeniser is used to reduce the gum particles to an extremely fine suspension. The operation occurs at a suitably low temperature to allow the gum to be effectively chopped. As an alternative to a salt solution, any liquid having a low enough freezing point may be used.
In cryogenic milling, the gum is frozen and ground to a suitable size by any known method of comminuting a brittle mass.
Alternatively, step a) may comprise melting the gum, adding a liquid thereto, and forming an emulsion of the liquid in the melted gum.
This method is less preferred as it is unsuitable for substances which are denatured at high temperatures. However, it may be suitable for robust ingredients, or for simple liquids such as water when water is added on its own.
Preferably, step b) comprises blast freezing the
Travers Russell
Wang Shengjun
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