The present invention relates to improvements in the formulation of the histamine H2-receptor antagonist ranitidme, particularly for oral administration

Ranitidme, N-[2-[[[5-(dιmethylamιno)methyl-2-furanyl]methyl]thιo]eth yl]-N'- methyl-2-nιtro-1 ,1-ethenedιamιne, and its physiologically acceptable salts are described and claimed in British Patent Specification No 1565966, and a particular crystalline form of ranitidme hydrochloride is described and claimed in British Patent Specification No 2084580 In both these specifications there is reference to formulations for oral administration, which may take the form of for example tablets, capsules, granules, powders solutions, syrups, suspensions or tablets or lozenges for buccal administration

Oral administration constitutes a preferred route for administering ranitidme Ranitidme, however, in common with many drug substances, has an inherently bitter taste, and this constitutes a disadvantage with certain types of oral preparation The problems resulting from the bitter taste of ranitidme are particularly acute in chewable formulations

Chewing gum compositions for the oral, systemic delivery of H ₂ antagonists have not previously been described, although topical chewing gum compositions for the treatment of gingivitis or peπodontitis containing H ₂ - receptor antagonists are described generally in US5294433 Thus compositions comprising 0 1 % to 10% of an H ₂ antagonist and a chewing gum carrier (comprising a gum base, a flavouring agent and a sweetening agent) are disclosed There is no further teaching as to the nature of the chewing gum carrier, however, and chewing gum compositions containing ranitidme are not specifically disclosed

Chewable formulations are a particularly convenient form of oral presentation for patients who prefer not to take swallowable tablets, or find difficulty in swallowing them A chewing gum formulation would be a particularly convenient way of administering ranitidme systemically, especially in the treatment of minor conditions such as acid indigestion and heartburn However since chewing gums remain in the mouth for an extended period, such a formulation presents particular difficulties if the taste of ranitidme is to be effectively masked

A further problem to be overcome if one is to arhve at a sufficiently stable ranitidine chewing gum is due to ranitidine's tendency to degrade in the presence of moisture. Conventional sugar-free chewing gum compositions contain large amounts of hygroscopic sugar alcohols which result in the gum having a high moisture content, around 3 to 5%, which is further increased by moisture uptake on storage.

An additional problem with conventional chewing gums lies in the method used to prepare them. This involves mixing a heated chewing gum base with an aqueous solution of the sugar alcohol.

Substantially anhydrous chewing gum compositions have been described, for example US3262784 relates to dry, granular chewing gum compositions comprising a chewing gum base and sugar granules which produces chewing gum granules which can be compressed into shape.

US4961935 describes anhydrous chewing gum compositions compπsing a gum base, a non-hygroscopic bulking agent, such as an isomalt, a softening agent and a sweetening agent. The chewing gum is prepared by heating the gum base at 60 to 120°C until molten, mixing with the other ingredients whilst still in the molten state and then forming the gum into shapes.

Thus, according to the method of US4961935, the chewing gum ingredients are exposed to a period of working at elevated temperature which could result in degradation of heat-sensitive components. Since it is known that the degradation of ranitidine is accelerated by heat, it would be advantageous to avoid excess exposure to heat during the formulation process.

A ranitidine chewing gum composition has now been discovered which avoids the problems of exposure to moisture and heat, thus ensuring the stability of ranitidine, and where the bitter taste of ranitidine is effectively masked and which provides a rapid and effective release of ranitidine resulting in advantageous bioavailability.

Thus, the present invention provides a chewing gum composition comprising a gum base, a non-hygroscopic bulking agent, a flavouring, a high-intensity sweetener and ranitidine, or a physiologically acceptable salt thereof.

Ranitidme may be employed in the compositions according to the invention in the form of either its free base or a physiologically acceptable salt Such salts include salts with inorganic or organic acids such as the hydrochloride, hydrobromide, sulphate, acetate, maleate, succinate, citrate, tartrate, fumarate and ascorbate salts A particularly preferred salt of ranitidme is the hydrochloride

The gum base may be selected from any suitable water-insoluble gum base known in the art and includes those gum bases utilised for chewing gums and bubble gums Thus, for example, the gum base may compπse a polymer, such as an elastomeric polymer, resins, waxes, glycerol esters of edible fatty acids plasticizers, mineral adjuvants such as talc and other conventional additives such as antioxidants A particularly suitable gum base is the commercially available "DELTA T"

The gum base suitably comprises 15 to 20% of the total composition, for example around 18% The ratio of gum base to non-hygroscopic bulking agent is suitably in the range 1 3 to 1 5, for example 1 4

The non-hygroscopic bulking agent is preferably an isomalt, i e a mixture such as a racemic mixture of 1-O-alpha-D-glucopyranosyl-D-mannιtol and 6-O-alpha- D-glucopyranosyl-D-glucitol, for example the commercially available "PALATINIT" or "PALATINOL" The non-hygroscopic bulking agent suitably comprises 60 to 80% of the total composition, for example around 70%

The flavouring in the compositions according to the invention ts a strong flavouring such as fruit flavours and natural or synthetic mint or peppermint flavours Strong mint or peppermint flavourings are preferred

The chewing gum composition also optionally contains an acidifiant agent such as sodium citrate

The high intensity sweetener includes saccharine and cyclamic acid and their various salts or, more preferably, dipeptide sweeteners such as aspartame

The chewing gum composition may also include a lubricant such as magnesium stearate

Thus, in a preferred aspect, the present invention provides a chewing gum composition comprising a gum base, a non-hygroscopic bulking agent, e.g an isomalt, a flavouring, e.g. a strong mint or peppermint flavouring, a high intensity sweetener, e.g. aspartame, a lubricant, e.g. magnesium stearate and ranitidine, or a physiologically acceptable salt thereof, e.g. the hydrochloride salt.

It will be appreciated that the chewing gum compositions according to the invention are for the oral, systemic delivery of ranitidine and not topical delivery It will also be appreciated that the instant chewing gum compositions are essentially sugarless.

The chewing gum compositions according to the instant invention are preferably in the form of chewing gum tablets.

The amount of ranitidine, preferably in the form of a physiologically acceptable salt, particularly ranitidine hydrochloride, in the composition according to the invention is preferably in the range of 10 to 800mg per dosage unit (for example per chewing gum tablet), e.g. 20 to 600mg, more preferably 25 to 300mg, such as 25, 75, 125 or 150mg, expressed as the weight of free base.

The unit dose (for example contained in one chewing gum tablet according to the invention) may be administered up to, for example, 6 times a day depending upon the unit dose used, the nature and seventy of the conditions being treated, and the age and weight of the patient Thus, for example, in the treatment of minor conditions where there is an advantage in lowering gastric acidity such as, for example, acid indigestion, over-indulgence of food or drink, acid stomach, sour stomach, waterbrash/regurgitation, heartburn, such as episodic heartburn, nocturnal heartburn, and meal-induced heartburn, gastritis and dyspepsia, lower and more frequent doses of ranitidine may be used, for example doses in the range of 10-150mg, e.g 25-75mg ranitidine expressed as the weight of free base, administered up to 6 times a day as and when required For more serious conditions such as duodenal and gastric ulceration, reflux oesophagitis and Zollinger-Ellison syndrome, higher and less frequent doses of ranitidine will be employed, for example 75-600mg, e g 150mg unit doses administered one to four, preferably once or twice, daily

The chewing gum compositions according to the instant invention may be prepared by heating the gum base until molten according to conventional

procedures, for example at around 70°C, allowing the gum base to cool, yet maintaining it in its molten state, for example at around 40-45°C, adding the preheated bulking agent, for example portion wise, e.g. 60% of the total amount, and at a temperature of, for example 30-35°C, and blending and cooling the mixture, for example at about 30°C. The remaining bulking agent is added, for example the remaining 40%, and the mixture is further blended and cooled, for example at around 25°C, at which stage a free flowing powder is produced.

The step of cooling and blending the gum base/bulking agent mixture to produce a free flowing powder is novel and constitutes a further aspect of the invention.

The free flowing powder is then blended with the ranitidine and other ingredients according to conventional anhydrous blending procedures. Thus, for example the gum base/bulking agent mixture is dry blended or dry granulated with ranitidine followed by the remaining ingredients and then the mixture is compressed into tablet shapes.

The following table illustrates non-limiting examples of the pharmaceutical compositions according to the invention.

In the following examples the gum base used is DELTA T, available from Cafosa Gum SA, Barcelona, Spain, and the isomalt is PALATINIT. DELTA T and PALATINIT are tradenames.

Ingredient Example 1 Example 2 Example 3 Example 4 mg/tablet mg/tablet mg/tablet mg/tablet

Ranitidine HCl 28.0 84.0 84.0 168.0

Gum Base 534 534 534 575

Isomalt 2100 2136 2136 2140

Peppermint Flavour 150 150 150 200

Sodium Citrate - - 30 30

Aspartame 10 22 22 25

Magnesium Stearate 40 44 44 60