Compositions for treatment of disorders of the oesophagus

Details Compositions for treatment of disorders of the oesophagus Compositions for treatment of disorders of the oesophagus

2002-01-07

2003-08-26

Barts, Samuel (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C514S004300, C514S779000, C514S780000, C514S782000, C536S124000, C536S123100, C536S114000, C536S119000, C536S055100

Reexamination Certificate

active

06610667

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention relates to a compositions capable of detachable adherence to a surface. More particularly, the present invention relates to such compositions for use in coating a biological, for example, mucosal surface and/or delivering an active ingredient to the biological surface.
Many compositions are known to be bioadhesive (i.e. able to adhere to biological surfaces, e.g. mucus, the skin, mucosal surfaces, epithelium etc.) and the value of this property is well recognised. For example, bioadhesives may be used to adhere active agents to specific sites in the body for local drug administration, or to coat particular parts of the body.
However, when bioadhesives are applied to such surfaces in aqueous solution they may be easily washed off or mechanically removed because the strength of adhesion of each individual bioadhesive molecule to the surface is not very high. This may lead to further problems if the bioadhesive materials contain active agents intended for use at one particular site, but which are washed away to other sites.
This is especially true where bioadhesives are applied to the upper gastrointestinal (GI) tract where washing off by swallowed saliva and/or mucus is a particular problem.
The prior art does not provide a composition which is able to adhere to biological surfaces and which can provide both physical protection, for example, against episodes of gastric reflux as well as exert a curative effect on the surface, for example, by delivering a pharmaceutically active ingredient to the surface.
A need therefore exists for a bioadhesive pharmaceutical composition which is able to coat a biological surface to protect and heal the surface and/or to deliver an active ingredient to the surface throughout the GI tract.
The need extends to a pharmaceutical composition which is capable of detachably adhering to desired regions of the oesophagus immediately following ingestion and prior to the composition reaching the stomach, the composition being able to exhibit both a protective and a direct healing effect, whether this arises as a result of the barrier properties alone or as a consequence of the incorporation of further active ingredients in the formulation which may have a beneficial effect on the healing process, immediately after ingestion and prior to contact with the stomach.
It is also desirable that the compositions are able to resist washing off by physiological fluids such as saliva or fluids which are subsequently ingested by the user and/or refluxed from the stomach.
In addition to the above, it is important that, when in liquid form, the compositions are of such a viscosity that they are capable of being provided in and reproducibly dispensed from a single container in a form which is immediately ready for use by the consumer.
DISCLOSURE OF THE INVENTION
We have now found a novel composition for detachable adhesion on biological surfaces of mammals which satisfy some or all of the above needs. The viscosity and adhesion of the resulting formulations are such that these compositions show good adhesion, stability and wash-off resistance.
According to a first aspect of the present invention there is provided a pharmaceutical composition for the treatment of disorders of the oesophagus, the composition comprising:
a) 0.1 to 11.0 parts by weight, preferably 2.5 to 8 parts by:weight alginate (hereinafter component a);
b) 0.01 to 3.0 parts by weight, preferably 0.1 to 1.5 parts by weight of gum selected from xanthan gum, carageenan gum and mixtures thereof (hereinafter component b); and
c) 0.01 to 3.0 parts by weight, preferably 0.1 to 1.5 parts by weight of gum selected from a galactomannan, a glucomannan and mixtures thereof (hereinafter component c).
The term ‘alginate’ is intended to encompass alginic acids, salts of alginic acids (alginate salts), derivatives of alginic acid, for example esters such as propylene glycol and mixtures thereof.
The alginate is preferably a monovalent salt of alginic acid, for example the sodium, potassium or ammonium salt, most preferably the sodium salt. Such alginates may be supplied by FMC Biopolymer AS, for example Protonal LFR5/60 and Protonal LF10L.
Preferably, the composition includes 1 to 10 parts by weight of alginate, more preferably between 2 and 9 parts by weight and most preferably between 3 and 8 parts by weight.
Preferably component b) includes a major amount of xanthan gum. Most preferably, component b) consists essentially of xanthan gum.
In the context of this specification, a major amount means that more than 50% by weight, preferably more than 70% by weight, more preferably more than 90% by weight, especially more than 95% by weight of the referenced component is present.
Component c) may be any pharmaceutically acceptable glucomannan or galactomannan, including enzymatically altered derivatives thereof. Preferably, however, component c) includes a major amount of a galactomannan. Preferably, component c) consists essentially of a galactomannan, especially locust bean gum.
Preferably components b) and c) are present in a total amount of from 0.2 to 2.5 parts by weight, more preferably 0.7 to 2 parts by weight, most preferably 1 to 1.6 parts by weight. Preferably components b) and c) are present in amount ratios of from 1:10 to 10:1, most preferably 2:8 to 8:2.
In a preferred embodiment of the present invention, b) is present in an amount greater than c) such that the ratio of b):c) is in the range 1.5:1 to 3.5:1, more preferably in the range 2:1 to 3:1, especially about 2.3:1.
It will be appreciated that the compositions according to the present invention may be presented in solid form, for example as a chewable tablet, in granular or powder form, as a gel or as a liquid. It is preferred however, that the composition is in the form of a liquid, most preferably a pourable liquid.
Pourable means flowable at room temperature (for example, 20-24° C.) (possibly following reasonably vigorous shaking) such that doses of, for example, 5 ml may be measured out with reasonable accuracy. For example, reproducible doses of as low as 5 ml may be dispensed from bottles having neck diameters of 1.5 cm or more.
Preferably the composition has a viscosity of between 500 and 10000 mPa·s, most preferably between 1000 and 8000 mPa·s measured on a Brookfield Viscometer at 20° C. using spindle No. 3.
When in the form of a liquid, it is most preferred that the compositions are aqueous liquids.
In a most preferred embodiment there is therefore provided an aqueous bioadhesive pourable liquid composition for coating a biological surface in the treatment and/or prevention of reflux oesophagitis, gastritis, dyspepsia and disorders of the oesophagus associated with reflux, the composition comprising:
a) 0.1 to 11% weight, preferably 2.5 to 8% weight alginate salt (hereinafter component a);
b) 0.01 to 3.0% weight, preferably 0.1 to 1.5% weight xanthan gum (hereinafter component b); and
c) 0.01 to 3.0% weight, preferably 0.1 to 1.5% weight galactomannan or glucomannan (hereinafter component c).
Any component described herein as being included in a composition according to the invention may be included in the aqueous composition of the most preferred embodiment. Where an amount is stated in parts by weight in relation to an embodiment, the same numerical value or values expressed as “% weight” may be applied to said most preferred embodiment. Thus, by way of example, it is described above that a composition may include 1 to 10 parts by weight alginate. This may be expressed as 1 to 10% weight when applied to said most preferred formulation and so on.
Mixtures of xanthan gum and a glucomannan, or galactomannan for example locust bean gum, have been widely used as thickening and gelling agents in the food industries. However, an aqueous mixture of 1.0% weight xanthan gum and 0.4% weight locust bean gum has a viscosity of approximately 35,000 mPa·s at 20° C. measured on a Brookfield Viscometer using spindle No. 3. In effect, this has a jelly like consistency which is disadvantageous in that it is fir

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