INCLUSION COMPLEXES OF RANITIDINE

Abstract: An inclusion complex of Ranitidine in cyclodextrin or one of its pharmaceutically acceptable derivatives is provided. The complex is characterised by the fact that the Ranitidine is in its free base form. Processes for the manufacture of the complex and pharmaceutical preparations embodying same are also described.

Description: INCLUSION COMPLEXES OF RANITIDINE FIELD OF THE INVENTION This invention relates to Ranitidine cyclodextrin inclusion complexes which are particularly suitable for the production of pharmaceutical preparations of a wide variety and which exhibit improved properties over Ranitidine hydrochloride, particularly as regards stability, release, versatility and ease of working into preparations. BACKGROUND TO THE INVENTION Ranitidine is a potent histamine-2 receptor antagonist extensively used in the treatment of gastric and duodenal ulcers among other pathological conditions. The Ranitidine molecule incorporates a basic dimethylamino functionality which may react with a variety of inorganic and organic acids to form corresponding salts. South African Patent No. 77/4500 to Allen and Hanburys Limited discloses the synthesis of Ranitidine as the free base (Example 15) which is singularly characterised by a melting point of between 69 and 70 * C. Example 32 of the same patent describes the conversion of Ranitidine to the hydrochloride salt which is characterised by a melting range of between 133-134 * C. This particular crystalline hydrochloride of Ranitidine has become known as the "Form 1" polymorph. This patent claims a variety of pharmaceutical compositions containing Ranitidine or salts thereof. South African Patent No. 81/6809 in the name of Glaxo Group Limited teaches a crystal polymorph of Ranitidine hydrochloride designated "Form 2", identified by a melting range of 139-142'C, its unique infrared spectrum, and a unique X-ray powder diffraction pattern. The latter patent states that Form 1 Ranitidine hydrochloride has unsuitable filtration and drying characteristics, whereas Form 2 is superior in these respects. The patent claims several crystallisation processes carried out in hydroxylic solvents to obtain Form 2 Ranitidine hydrochloride, and discloses pharmaceutical compositions containing this form. Ranitidine hydrochloride (Form 2) has been reported to be unstable against humidity (Teraoka, R. et al, Journal of Pharmaceutical Sciences 1991 , 82, 601-604) thus necessitating precautionary measures in the manufacture and packaging of tablet compositions containing Form 2 Ranitidine hydrochloride. Ranitidine hydrochloride is, furthermore, bitter tasting, with the accompanying clinical disadvantages. British Patent No. 2218333 and European Patent No. 0431759 are particularly aimed at overcoming the disadvantage of this bitter taste. Ranitidine as the free base has been commercially less useful than the salts of Ranitidine owing to very poor solid state characteristics. For example, it is difficult to obtain Ranitidine free base in crystalline form. On exposure to the atmosphere the free base readily absorbs moisture, resulting in accelerated degradation. Unlike the salt forms of Ranitidine, the free base is less soluble in water than the salt forms but is readily soluble in organic solvents such as chloroform. The properties of cyclodextrins and numerous inclusion complexes are well known and have been reviewed in detail (see Szejtli, J. Cyclodextrin Technology (1988) Kluwer Academic Publishers, Dordrecht). Briefly, cyclodextrins are cyclic oligosaccharides composed of 6, 7 or 8 glucopyranose units (alpha-, beta- and gamma-cyclodextrin respectively) characterised by a cone-like molecular shape. The cavity of the cone is hydrophobic whilst the exterior is hydrophillic. The hydrophobic nature of the cavity endows the molecule with the ability to form inclusion complexes with hydrophobic guest molecules of suitable size which fit into the cavity of the host. Polar groups are less readily included than less-polar groups. The inclusion complex may be stabilised by a number of forces including van der Waals attractive forces and hydrogen bonding. Cyclodextrin inclusion complexation of a suitable guest results in a number of physicochemical changes in the properties of the guest. Firstly, the melting 5 . characteristics of the guest are modified in the cyclodextrin inclusion complex, which generally begins to decompose without melting at between 250-300°C. Secondly, the infrared spectrum and X-ray powder diffraction pattern of the complex are distinct relative to the pure guest or simple (non-complexed) mixtures of host and guest. Thirdly, a water insoluble guest may be rendered Q water soluble by cyclodextrin inclusion complexation. Fourthly, in many cases, chemically unstable guests are stabilised by inclusion complexation. The foregoing changes in the physiocochemical properties of a guest upon inclusion complexation with a cyclodextrin provide evidence that the cyclodextrin inclusion complex represents an entirely unique solid state form of the guest molecule. Depending on solvent conditions, the dissolved inclusion complex exists in equilibrium between uncomplexed host and guest, on the one hand, and complexed host/guest, on the other. Orally administered cyclodextrin-drug inclusion complexes generally result in rapid release of the drug into solution in the gastro intestinal fluids and consequent rapid absorption, facilitated by the cyclodextrin, whereas the cyclodextrin is not absorbed to any significant extent (Frϋmming, K-H & Szejtli, J. Cyclodextrins in Pharmacy (1988), Kluwer Academic Publishers). Cyclodextrins therefore possess ideal properties as true drug carriers. Cyclodextrins and their inclusion complexes possess favourable flow, binding and compaction properties which facilitate tablet compression. Cyclodextrins enhance the percutaneous absorption of certain drugs after dermal administration, and therefore may be useful in the formulation of topical drug delivery systems. The internal cavities of alpha-, beta-, and gamma-cyclodextrins have a size of about 5, 6 and 8 angstroms respectively. The upper limit of guest size for alpha-cyclodextrin inclusion is expected to be a molecule of the order of size of benzene which fits tightly in the cavity. Consequently, very stable inclusion complexes are formed between alpha-cyclodextrin and appropriately substituted five and six membered unsaturated rings. On the other hand, the large cavity of gamma-cyclodextrin generally produces stable complexes with more bulky guests such as napthalene and anthracene (see FrOmming and Szejtli, Cyclodextrins in Pharmacy). From the molecular structure and shape of Ranitidine hydrochloride, it was anticipated that stable inclusion complexes may be formed with alpha-, and perhaps beta-cyclodextrins. Theoretically, inclusion of the hydrophobic nitroketene terminal may be expected, whereas the polar ionised dimethylamino terminal would remain outside the cavity. The relatively small size of the nitroketene group indicates that it is unlikely that stable complexes would form with beta-cyclodextrin, and, very little or no complexation would take place with gamma-cyclodextrin. Also, a difficulty could arise if inclusion is incomplete due to the formation of polymorphs derived from the Ranitidine hydrochloride. South African Patent No. 94/1544 to Hexal Pharma Gmbh claims inclusion complexes of Ranitidine hydrochloride in alpha-, beta- and gamma- cyclodextrin whilst only exemplifying a beta-cyclodextrin-Ranitdine hydrochloride complex. Cyclodextrins may be covalently polymerised to form a polymer matrix of repeating cyclodextrin units capable of including suitable guest molecules. The polymers may be designed to facilitate controlled release of the heterogeneously included guest molecules. European Patent No. 446753 dated 91-09-18 to Vectorpharma Int. Spa. teaches controlled release compositions comprising a medicament loaded on crosslinked nonionic polymer and coated with polymer film. The medicament may be Ranitidine. The polymer loaded with medicament is crosslinked beta-cyclodextrin, crospovidone or a mixture of polymers. Patent GB 2207865 dated 89-02-15 to Biogal G. teaches a wound healing product containing histamine H-1 and/or H-2 blocker(s) preferably cimetidine or Ranitidine in a carrier. The carrier may be a dusting powder, polyurethane foam or cotton cloth composed of a porous hygroscopic solid, for example a hydrophobic polymer, preferably a cellulose derivative, alginate, cyclodextrin, acrylate or crosslinked polysaccharide (dextran or cyclodextrin crosslinked with epichlorohydrin). It is the object of the invention to provide a Ranitidine inclusion complex which can be easily produced; is more stable than either of the two forms of Ranitidine hydrochloride presently in production and use; is substantially tasteless; and, which possesses additional advantages over and above the presently used forms of Ranitidine. SUMMARY OF THE INVENTION In accordance with this invention there is provided an inclusion complex of Ranitidine in cyclodextrin or a pharmaceutically acceptable derivative of cyclodextrin, the complex being characterised in that the Ranitidine is in its free base form. Further features of the invention provide for the cyclodextrin to be in any one of the alpha-, beta-, or gamma-forms thereof and, in the case of a derivative, for the derivative to be either an alkyl or hydroxyalkyl derivative, preferably methyl, ethyl, hydroxyethyl or hydroxypropyl; and for the molar ratio of cyclodextrin to Ranitidine to be from 2:1 to 1 :1. The invention also provides a process for the preparation of a cyclodextrin-Ranitidine free base inclusion complex comprising the steps of: (i) forming a paste, slurry or solution containing cyclodextrin or a pharmaceutically acceptable derivative thereof; Ranitidine free base; and a solvent; (ii) treating (as may be necessary) the paste, slurry or solution to promote formation of cyclodextrin-Ranitidine free base inclusion complex; and, (iii) drying the paste, slurry or solution to remove the solvent to yield a particulate or powdered product. Further features of this aspect of the invention provide for the Ranitidine free base to be either freshly produced, or derived from a Ranitidine salt with the use of a suitable neutralising agent chosen to yield Ranitidine free base, such as the use of Ranitidine hydrochloride and a suitable alkali such as sodium or ammonium hydroxide, in which case the Ranitidine free base can be formed in situ in the paste, slurry or solution; for step (i) to be carried out by blending required amounts of cyclodextrin and Ranitidine free base and vigorous mixing with water to provide a paste followed by a step (ii) which includes kneading or vigorous mixing of the paste for a period of between 0,5 and 10 hours; or, alternatively, for step (i) to be carried out in solution in which case the cyclodextrin-Ranitidine free base complex is precipitated out by lowering the solution temperature, for example to about 4°C, followed by a liquid/solids separation step such as filtration; for step (iii) to be carried out by evaporation of the solvent under a vacuum with optional heating and also, with the optional intermittent introduction of a small quantity of gas into the mixture during at least the initial stages of the drying operation; and for the dried product to be screened to provide a product of uniform particle size. The invention still further provides a pharmaceutical preparation comprising, as at least one active ingredient thereof, an inclusion complex of Ranitidine free base in cyclodextrin as defined above. Further features of the last aspect of the invention provide for the pharmaceutical preparation to be in the form of tablets; soluble effervescent tablets; sublingual or buccal tablets; a soluble powder; coated tablets; or, a transdermal delivery system. Molecular inclusion complexes composed of Ranitidine free base and cyclodextrins are new. Stable inclusion complexes of Ranitidine free base may be readily obtained using commercially available alpha-, beta- and gamma-cyclodextrins or their derivatives, ' which derivatives are preferably methylated or hydroxypropylated. The fact that stable effective inclusion complexes of Ranitidine free base in beta-, and particularly gamma-cyclodextrins can be produced was unexpected on the basis of the size of the Ranitidine molecule. Inclusion apparently occurs, however, due to the fact that the hydrophobic Ranitidine molecule folds, up in order to become effectively received within the cyclodextrin cavity. This phenomenon results further in the fact that, again contrary to theoretical expectations, the inclusion complex with gamma-cyclodextrin is the most chemically stable, although all three cyclodextrins form satisfactory complexes. The complexes may be prepared using conventional cyclodextrin inclusion complexation techniques, for example, by crystallisation, kneading, spray drying or freeze drying. The complexes prepared according to the invention possess well characterised features as determined by high performance liquid chromatography (HPLC), proton nuclear magnetic resonance (NMR), differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR) and X-ray diffraction (XRD). The cyclodextrin-Ranitidine free base complexes possess advantageous physical and physico-chemical properties for pharmaceutical compounding, such as: (i) enhanced chemical stability relative to Ranitidine hydrochloride; (ii) little or no taste; (iii) favourable powder flow and compaction properties thereby facilitating pharmaceutical formulations including ordinary tablets, chewable tablets or sublingual or buccal tablets; (iv) potential for controlled release formulation via coated tablets or transdermal delivery systems. In order that the invention may be more fully understood a detailed description thereof follows. In this description, reference will be made to the accompanying drawings. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 illustrates FTIR spectra of Ranitidine free base (line a) and Form 2 Ranitidine hydrochloride (line b). (Arrowheads indicate characteristic group frequencies referred to in the text in this Figure and each of Figures 2 to 6). Figure 2 illustrates FTIR spectra of alpha-cyclodextrin (line a) and alpha-cyclodextrin-Ranitidine inclusion complexes from Example 1 (line b); Example 4 (line c); Example 9 (line d) and Example 11 (line e). Figure 3 illustrates FTIR spectra of beta-cyclodextrin (line a) and beta-cyclodextrin-Ranitidine inclusion complexes from Example 2 (line b); Example 5 (line c); Example 10 (line d) and Example 12 (line e). Figure 4 illustrates FTIR spectra of gamma-cyclodextrin (line a) and gamma-cyclodextrin-Ranitidine inclusion complexes from Example 3 (line b) and Example 6 (line c). Figure 5 illustrates FTIR spectra of 2-hydroxypropyl-beta-cyclodextrin DS 4 (line a) and 2-hydroxypropyl-beta-cyclodextrin-Ranitidine inclusion complex from Example 7 (line b). Figure 6 illustrates FTIR spectra of methyl-beta-cyclodextrin complex from Example 8 (line b). Figure 7 illustrates the DSC thermogram of Ranitidine hydrochloride (Form 2). Figure 8 illustrates DSC thermograms of alpha-cyclodextrin (line a) and alpha-cyclodextrin-Ranitidine inclusion complexes from Example 1 (line b); Example 4 (line c); Example 9 (line d) and Example 11 (line e). Figure 9 illustrates DSC thermograms of beta-cyclodextrin (line a) and beta-cyclodextrin-Ranitidine inclusion complexes from Example 2 (line b); Example 5 (line c); Example 10 (line d) and Example 12 (line e). Figure 10 illustrates DSC thermograms of gamma-cyclodextrin (line a) and gamma-cyclodextrin-Ranitidine inclusion complexes from Example 3 (line b) and Example 6 (line c). Figure 11 illustrates DSC thermograms of 2-hydroxypropyl-beta-cyclodextrin DS 4 (line a) and 2-hydroxypropyl-beta-cyclodextrin-Ranitidine inclusion complex from Example 7 (line b). Figure 12 illustrates DSC thermograms of methyl-beta-cyclodextrin DS 13 (line a) and methyl-beta-cyclodextrin-Ranitidine inclusion complex from Example 8 (line b). Figure 13 illustrates an X-ray diffractogram of Ranitidine hydrochloride Form 2. Figure 14 illustrates X-ray diffractograms of alpha-cyclodextrin (line a) and alpha-cyclodextrin-Ranitidine inclusion complexes from Example 1 (line b) and Example 4 (line c). Figure 15 illustrates X-ray diffractograms of beta-cyclodextrin (line a) and beta-cyclodextrin-Ranitidine inclusion complexes from Example 2 (line b) and Example 5 (line c). Figure 16 illustrates X-ray diffractograms of gamma-cyclodextrin (line a) and gamma-cyclodextrin-Ranitidine inclusion complexes from Example 3 (line b) and Example 6 (line c). Figure 17 illustrates the structure and numbering of cyclodextrins : n=6, ie alpha-cyclodextrin; n=7, ie beta-cyclodextrin; and, n=8, ie gamma-cyclodextrin. Figure 18 illustrates the chemical structure and numbering of Ranitidine. Figure 19 illustrates the chemical shift difference of cyclodextrin protons in equimolar solutions containing a 1 :1 ratio of Ranitidine hydrochloride/beta - 10 - cyclodextrin (R.HCI/BCD) and Ranitidine free base/beta-cyclodextrin (R.FB/BCD) relative to free beta-cyclodextrin. Figure 20 illustrates Ranitidine proton chemical shifts of Ranitidine hydrochloride (R.HCI), Ranitidine free base (R.FB) and cyclodextrin-Ranitidine inclusion complexes from Examples 1 , 2, 3, 11 and 12. Figure 21 illustrates the assigned ROESY spectrum of alpha-cyclodextrin -Ranitidine inclusion complex from Example 11. Figure 22 illustrates the assigned ROESY spectrum of beta-cyclodextrin-Ranitidine inclusion complex from Example 12. Figure 23 illustrates the assigned ROESY spectrum of gamma-cyclodextrin-Ranitidine inclusion complex from Example 3. Figure 24 illustrates schematic orthogonal perspective views of the molecular mechanics optimised interaction between alpha-cyclodextrin and Ranitidine based on distance constraints derived from NMR. Dotted lines represent hydrogen bonds. Figure 25 illustrates schematic orthogonal perspective views of the molecular mechanics optimised interaction between beta-cyclodextrin and Ranitidine based on distance constraints derived from NMR. Figure 26 illustrates schematic orthogonal perspective views of the molecular mechanics optimised interaction between gamma-cyclodextrin and Ranitidine based on distance constraints derived from NMR. Figure 27 illustrates the mean comparative plasma Ranitidine concentrations after single dose administration of 150mg Ranitidine in the form of the beta-cyclodextrin inclusion complex and commercial hydrochloride to 6 healthy volunteers in a single-blind randomised cross-over trial. DETAILED DESCRIPTION OF THE INVENTION Cyclodextrin inclusion complexes of Ranitidine free base may be prepared, for example, according to any of the following methods: - 11 - (a) One molar equivalent of a salt of Ranitidine, for example Ranitidine hydrochloride, and one or more molar equivalents of a cyclodextrin and alkali are allowed to react with vigorous stirring under saturating conditions in optionally heated distilled water. On standing at 4°C, the cyclodextrin inclusion complex of Ranitidine free base precipitates out of solution. The product is collected on a filter, washed with cold water and dried to give the cyclodextrin-Ranitidine free base molecular inclusion complex. (b) A saturated solution of Ranitidine free base in a suitable volatile organic solvent is added to a molar equivalent of cyclodextrin and vigorously mixed until the solvent evaporates. A small amount of water is added to the powder mixture and mixed to produce a uniform paste. The mixture is kneaded for 0.5 - 10 hours. The cyclodextrin-Ranitidine molecular inclusion complex is dried in an oven and screened. (c) A solution or slurry of a cyclodextrin-Ranitidine free base complex may be spray dried or freeze dried to give the corresponding spray dried or freeze dried cyclodextrin-Ranitidine free base molecular inclusion complex. The solution or slurry may be obtained in one case by dissolving a cyclodextrin-Ranitidine complex obtained from either method (a) or (b) in water to produce a saturated solution. In another case the solution or slurry is produced by blending equimolar amounts of Ranitidine free base and cyclodextrin and adding deionised water followed by vigorous mixing to produce a solution or slurry. (d) Equimolar amounts of Ranitidine free base and cyclodextrin are blended. A suitable quantity of purified deionised water is added with vigorous mixing to produce a paste. The paste is vigorously mixed with a kneading action for 0,5 - 10 hours. The product is dried under vacuum with optional heating and screened. The cyclodextrin may be of any of the usual forms, namely, alpha-, beta- or gamma-cyclodextrin, or a pharmaceutically acceptable derivative thereof, in which case, it is preferably alkylated, or hydroxyalkylated. The alkyl derivatives are preferably methyl or ethyl, and the hydroxyalkyl derivatives are preferably hydroxyethyl or hydroxypropyl. The alkali is preferably a hydroxide such as sodium hydroxide or ammonium hydroxide. The cyclodextrin-Ranitidine inclusion complexes obtained according to the invention contain between 12 and 22 percent by weight Ranitidine free base as determined by high performance liquid chromatography (HPLC). The equilibrium solubility of the complexes in water at 20°C corresponds to not less than 200mg Ranitidine per 100ml as determined by HPLC. The solid complexes are characterised by infrared spectra which indicate the absence of a protonated dimethylamino group and provide evidence for cyclodextrin inclusion of the o Ranitidine molecule by virtue of frequency shifts and intensity reduction of bands corresponding to included groups. Compared with the semi-solid methods (b) and (d), complexes prepared according to solution methods (a) and (c) provide more complete conversion of Ranitidine and cyclodextrin to the corresponding inclusion complex as evidenced by thermal analysis using differential scanning 5 calorimetry (DSC). Complexes prepared according to methods (a), (b) and (d) using non-derivatized cyclodextrins provide a crystalline product as evidenced by X-ray diffraction (XRD) patterns. The XRD patterns exhibit lines at different positions relative to Ranitidine hydrochloride indicating a novel crystalline form of Ranitidine. 0 Cyclodextrin complexes of Ranitidine free base prepared according to the invention possess enhanced intermolecular association between host and guest in aqueous solution relative to Ranitidine hydrochloride-beta-cyclodextrin as demonstrated by proton NMR experiments as shown in Figs. 19 and 20. The cyclodextrin-Ranitidine complexes according to the invention exhibit enhanced 5 chemical stability at elevated temperature and humidity relative to Ranitidine free . base and Form 2 Ranitidine hydrochloride. The pure cyclodextrin-Ranitidine free base inclusion complexes possess little or no taste compared with the bitter taste of Ranitidine hydrochloride. The complexes exhibit favourable powder flow, binding and compaction properties Q facilitating the formulation of solid dosage forms. In the acidic medium of the stomach, dissolution of cyclodextrin-Ranitidine tablets will be accompanied by protonation of the dimethylamino group promoting dissociation of the complex. The taste masking properties of the cyclodextrin-Ranitidine free base complex 5 permit convenient formulation of chewable or sublingual (including buccal) tablets which offer the convenience of taking the medication without the need for water. In these cases, the complex permits the formulation of a taste-masked Ranitidine tablet which may be directly compressed. The absorption enhancing properties of the cyclodextrin may facilitate rapid transmucosal absorption. A major advantage may be offered by such a sublingual or buccal dosage form since this route of administration bypasses the first pass hepatic metabolism of Ranitidine and avoids the exposure of the dose to low pH conditions which have been shown to decompose Ranitidine (Teraoka, R. et ai. Journal of Pharmaceutical Sciences 1991, 82, 601-604). The sublingual administration of Ranitidine is therefore likely to significantly increase the otherwise low (50 percent) absolute bioavailability of orally administered Ranitidine (Martindale Extra Pharmacopoeia, Ed. 29, 1105) and thus offers the highly advantageous potential to reduce the dose without affecting therapeutic efficacy. Apart from cost advantages, a reduction in the dose of Ranitidine may contribute significantly to decreased hepatic toxicity of Ranitidine. Similarly, the enhancement of dermal or mucosal penetration conferred by cyclodextrins may be employed to formulate transdermal or transmucosal controlled release drug delivery systems of the cyclodextrin-Ranitidine free base inclusion complexes with advantages comparable to those of sublingual administration. The preparation of cyclodextrin-Ranitidine free base complexes, their characterisation, and pharmaceutical compositions are further explained and exemplified in the following examples. PREPARATION EXAMPLE 1 Sodium hydroxide (0.48g) was dissolved in 20ml distilled water and alpha-cyclodextrin (11.66g) added with stirring and heating as appropriate to effect dissolution. Ranitidine hydrochloride (4.22g) was slowly added to the solution and vigorous stirring continued for 10 minutes. The solution was allowed to stand at 4°C. The precipitate was collected on filter, washed with cold water and oven dried. The pale yellow solid product (7.7g) was calculated to be a 1 :1 molecular inclusion complex of Ranitidine free base and alpha-cyclodextrin. The complex contained 20 percent by weight of Ranitidine as determined by HPLC. The complex was characterised by an infrared spectrum shown in Figure 2 (line b) as distinct from the spectra of Ranitidine (Figure 1) and alpha-cyclodextrin shown in Figure 2 (line a). The absence of a melting endotherm at 69°C in the DSC thermogram shown in Figure 8 (line b) indicates the absence of free Ranitidine and therefore provides evidence of a true inclusion complex. The X-ray powder diffraction pattern shown in Figure 14 (line b) indicates unique crystalline properties relative to pure alpha-cyclodextrin (Figure 14 (line a)) and Ranitidine hydrochloride (Figure 13). PREPARATION EXAMPLE 2 Sodium hydroxide (0.24g) was dissolved in 25ml distilled water and beta-cyclodextrin (6.81 g) was added with stirring and heating as appropriate to effect dissolution. Ranitidine hydrochloride (2.11g) was slowly added to the solution and vigorous stirring continued for 10 minutes. The solution was allowed to stand at 4°C. The precipitate was collected on a filter, washed with cold water and oven dried. The off-white solid product (3.5g) was calculated to be a 1:1 molecular inclusion complex of Ranitidine free base and beta-cyclodextrin. The complex contained 15 percent by weight Ranitidine as determined by HPLC. The complex was further characterised by an infrared spectrum, DSC thermogram, and X-ray powder diffraction pattern (see Figures 3 (line b), 9 (line b) and 15 (line b) respectively), as described in Example 1. PREPARATION EXAMPLE 3 Sodium hydroxide (0.24g) was dissolved in 25ml distilled water and gamma-cyclodextrin (7.78g) added with stirring and heating as appropriate to effect dissolution. Ranitidine hydrochloride (2.11g) was slowly added to the solution and vigorous stirring continued for 10 minutes. The solution was allowed to stand at 4°C. The precipitate was collected on a filter, washed with cold water and oven dried. The off-white solid product (6.1 g) was calculated to be a 1:1 molecular inclusion complex of Ranitidine free base and gamma-cyclodextrin. The complex contained 14 percent by weight of Ranitidine as determined by HPLC. The complex was further characterised by an infrared spectrum, DSC thermogram, and X-ray powder diffraction pattern (see Figures 4 (line b), 10 (line b) and 16 (line b) respectively) as described in Example 1. PREPARATION EXAMPLE 4 Ranitidine free base (0.73g) in chloroform (2ml) was added to alpha-cyclodextrin (2.27g) in a mortar and ground together until the solvent had evaporated. A small amount of distilled water (1-2ml) was added to the powder mixture and mixed to produce a uniform paste. The paste was kneaded for 1 hour and the product dried in an oven and screened. The pale-yellow solid product (2.8g) was calculated to be a 1 :1 molecular inclusion complex of Ranitidine free base and alpha-cyclodextrin. The complex is characterised by an infrared spectrum (see Figure 2 (line c) essentially identical to the complex obtained in Example 1 (see Figure 2 (line b). In the DSC thermogram shown in Figure 8 (line c), the broad endotherm peak at 75°C may be attributed to residual water also present in pure alpha-cyclodextrin (Figure 8 (line a)). The exotherm at 190°C may be attributed to some decomposition of the Ranitidine followed by a melting endotherm peak at 200 °C. The X-ray powder diffraction pattern shown in Figure 14 (line c) is somewhat different from the material obtained in Example 1 (Figure 14 (line b), indicating a difference in crystallne structure. PREPARATION EXAMPLE 5 Ranitidine free base (0.65g) in chloroform (2ml) was added to beta-cyclodextrin (2.3g) in a mortar and ground together until the solvent had evaporated. A small amount of distilled water (1-2ml) was added to the powder mixture and mixed to produce a uniform paste. The paste was kneaded for 1 hour and the product dried in an oven and screened. The off-white solid product (2.7g) was calculated to be a 1 :1 molecular inclusion complex of Ranitidine free base and beta-cyclodextrin. The complex was further characterised by an infrared spectrum, DSC thermogram, and X-ray powder diffraction pattern (see Figures 3 (line c) and 15 (line c) respectively) as previously described. PREPARATION EXAMPLE 6 Ranitidine free base (0.63g) in chloroform (2ml) was added to gamma-cyclodextrin (2.6g) in a mortar and ground together until the solvent had evaporated. A small amount of distilled water (1-2ml) was added to the powder mixture and mixed to produce a uniform paste. The paste was kneaded for 1 hour and the product dried in an oven and screened. The off-white solid product (2.9g) was calculated to be a 1 :1 molecular inclusion complex of Ranitidine free base and gamma-cyclodextrin. The complex contained 16 percent by weight Ranitidine as determined by HPLC. The complex was further characterised by an infrared spectrum DSC thermogram, and X-ray powder diffraction pattern (see Figures 4 (line c), 10 (line c) and 16 (line c) respectively), as previously described. PREPARATION EXAMPLE 7 Ranitidine free base (0.63g) in chloroform (2ml) was added to 2-hydroxypropylated-beta-cyclodextrin (D.S.4) (2.77g) in a mortar and ground together until the solvent had evaporated. A small amount of distilled water (1-2ml) was added to the powder mixture and mixed to produce a uniform paste. The paste was kneaded for 0.5 hour and the product dried in an oven and screened. The cream coloured solid product (3.3g) was calculated to be a 1:1 molecular inclusion complex of Ranitidine free base and 2-hydroxypropylated-beta-cyclodextrin. The complex contained 18 percent by weight Ranitidine as determined by HPLC. The amorphous complex was further characterised by an infrared spectrum and DSC thermogram (see Figures 5 (line b) and 11 (line b) respectively) as previously described. PREPARATION EXAMPLE 8 Ranitidine free base (0.63g) in chloroform (2ml) was added to methylated-beta-cyclodextrin (D.S.12-13) (2.62g) in a mortar and ground together until the solvent had evaporated. A small amount of distilled water (1 -2ml) was added to the powder mixture and mixed to produce a uniform paste. The paste was kneaded for 0.5 hour and the product dried in an oven and screened. The cream coloured solid product (3.1g) was calculated to be a 1 :1 molecular inclusion complex of Ranitidine free base and methylated-beta-cyclodextrin. The product contained 18 percent by weight Ranitidine as determined by HPLC. The amorphous complex was further characterised by an infrared spectrum and DSC thermogram (see Figures 6 (line b) and 12 (line b) respectively), as previously described. PREPARATION EXAMPLE 9 The complex obtained according to Example 1 was dissolved in distilled water at 45°C to produce a saturated solution which remained clear on cooling to room temperature. The solution was spray dried with an inlet air temperature of 120°C and air flow rate of 600 litres per minute. Solution flow rate was 10ml per minute. The pale yellow spray dried product was calculated to be a 1 :1 molecular inclusion complex of Ranitidine free base and alpha-cyclodextrin. The amorphous complex contained 21 percent by weight Ranitidine as determined by HPLC. The complex was further characterised by an infrared spectrum and DSC thermogram (see Figures 2 (line d) and 8 (line d) respectively), as previously described. PREPARATION EXAMPLE 10 The complex obtained according to Example 2 was dissolved in distilled water at 45°C to produce a saturated solution which remained clear on cooling to room temperature. The solution was spray dried according to Example 9. The off-white spray dried product was calculated to be a 1 :1 molecular inclusion complex of Ranitidine free base and beta-cyclodextrin. The amorphous complex contained 16 percent by weight Ranitidine as determined by HPLC. The complex was further characterised by an infrared spectrum and DSC thermogram (see Figures 3 (line d) and 9 (line d) respectively, as previously described. PREPARATION EXAMPLE 11 The complex obtained according to Example 4 was dissolved in distilled water at 45°C to produce a saturated solution which remained clear on cooling to room temperature. The solution was spray dried according to Example 9. The pale yellow spray dried product was calculated to be a 1 :1 molecular inclusion complex of Ranitidine free base and alpha-cyclodextrin. The amorphous complex contained 18 percent by weight Ranitidine as determined by HPLC. The amorphous complex was further characterised by an infrared spectrum and DSC thermogram (see Figures 2 (line e) and 8 (line e) respectively), as previously described. PREPARATION EXAMPLE 12 The complex obtained according to Example 5 was dissolved in distilled water at 45 °C to produce a saturated solution which remained clear on cooling to room temperature. The solution was spray dried according to Example 9. The off-white spray dried product was calculated to be a 1 :1 molecular inclusion complex of Ranitidine free base and beta-cyclodextrin. The amorphous complex contained 15 percent by weight Ranitidine was determined by HPLC. The complex was further characterised by an infrared spectrum and DSC thermogram (see Figures 3 (line e) and 9 (line e) respectively), as previously described. PREPARATION EXAMPLE 13 In a pilot scale preparation beta-cyclodextrin (12.8kg) was blended with Ranitidine free base (3.2kg) in a high intensity mixing vessel fitted with a vacuum drying facility. Purified de-ionised water (8.0/) was sprayed onto the mixture over a period of 10 minutes with vigorous mixing via a kneading action to produce a creamy paste. The paste was mixed for five hours. The vessel was evacuated and slow mixing was continued with a periodic inlet of air for the first 20 minutes and thereafter continuous vacuum was applied with slow mixing until the product contained about 7% moisture. The product was discharged and screened. The product was calculated to be a 1 :1 molecular inclusion complex and was confirmed to consist of a molecular inclusion complex of Ranitidine free base in beta-cyclodextrin by the methods referred to in Preparation Example 1. Stability The bulk stability of Ranitidine cyclodextrin complexes relative to Ranitidine hydrochloride (Form 2) are given in the following Table: Percentage Ranitidine remaining after storage at 50 °C and 70% humidity Sample Initial 10 Davs 90 Davs Ranitidine hydrochloride (form 2) 100 37.7 0 Beta-cvclodextrin-Ranitidine complex 100 93.6 92.2 Gamma-cyclodextrin-Ranitidine complex 100 100 not determined Uncomplexed Ranitidine hydrochloride was transformed into a dark syrup after 10 days at 50°C and 70% humidity with significant decomposition whereas the cyclodextrin complexes according to the invention remained solid and crystalline without significant decomposition over prolonged periods under these conditions. Characterisation The various methods used to characterise the cyclodextrin-Ranitidine free base complexes are commented upon further as follows. 1. Fourier transform infrared (FTIR) spectroscopy is particularly useful in the characterisation of cyclodextrin-Ranitidine inclusion complexes owing to the distinct enamine bands (1625 and 1575 cm "1 ) and nitroketene bands (1380 and 760 cm "1 ) which may be expected to undergo a frequency shift and/or a reduction in intensity upon inclusion complexation. The former effect is believed to be principally due to disruption of intermolecular hydrogen bonds whereas the latter effect is believed to be due to vibrational restrictions imposed on the guest molecule in the cyclodextrin cavity. Additionally, reduced intensity of bands corresponding to the unprotonated dimethylamino group (2824 and 2780 cm "1 ) and furan -C=C- stretching modes (1015 and 795 cm "1 ) may also be used as evidence for inclusion complexation. The FTIR spectra of cyclodextrin-Ranitidine free base inclusion complexes from Examples 1 - 12 (see Figures 2 - 6) show the above phenomena relative to the spectrum of pure Ranitidine (see Figure 1). The above frequency assignments are indicated at the bottom of each Figure with an arrow and are based on reported values for Ranitidine (Cholerton, TJ. ef a/. Journal of the Chemical Society, Perkin Transactions II 1984, 1761-1766). All spectra were recorded from potassium bromide discs on a Shimadzu 8100 FTIR spectrometer. Comparison of the characteristic group frequencies corresponding to the various complexes shows that a high degree of structural correlation exists between the different complexes. This finding indicates that cyclodextrin-Ranitidine free base complexes obtained according to the invention represent well characterised molecular systems independent of the method of preparation or type of cyclodextrin used. The characteristic bands corresponding to a protonated dimethylamino group (2700 - 2300 cm "1 ) in Ranitidine hydrochloride (see Figure 1) are absent in the free base and cyclodextrin-Ranitidine complexes, indicating that the complexes exclusively contain Ranitidine as the free base. 2. Differential Scanning Calorimetry (DSC) is the measurement of the rate of heat evolved or absorbed by a sample during a temperature program. The technique may be used to characterise inclusion complexation in cases where the melting point of the included molecule is below the thermal degradation range of the cyclodextrin (i.e. <250°C). Evidence for inclusion complexation may be obtained from a diminished and/or shifted thermal event corresponding to the melting point of the included guest relative to the pure substance. The DSC thermograms were recorded on a Perkin Elmer DSC 7 instrument operating at a rate of 10°C per minute. The thermal event corresponding to the melting point of Ranitidine free base (69 - 70°C) or Ranitidine hydrochloride (139 - 142°C) (see Figure 7) is absent in the DSC thermograms of the cyclodextrin-Ranitidine free base inclusion complexes obtained from Examples 1 - 12 (see Figures 7 - 12). These results indicate an absence of free Ranitidine in the cyclodextrin-Ranitidine inclusion complexes and that the Ranitidine molecule is tightly bound within the cavity, not being released at temperatures below 200°C. 3. X-ray powder diffractometry (XRD) is a technique used to characterise the crystalline nature of solids. Depending on the crystal lattice formed by successive packing of molecules during crystallisation, a unique and characteristic XRD pattern results. The XRD patterns of the crystalline cyclodextrin-Ranitidine free base inclusion complexes (Examples 1 - 6) are shown in Figures 14 - 16. The distinct difference in the two-theta values of the complexes compared with Ranitidine hydrochloride (see Figure 13) or the pure cyclodextrins indicates that the complexes are composed of a unique crystalline structure when compared with the crystal morphology of the pure cyclodextrin or Ranitidine hydrochloride. 4. Nuclear magnetic resonance (NMR) spectroscopy is a powerful tool for structure elucidation of cyclodextrin inclusion complexes in solution. From the structure of cyclodextrins (see Figure 17) it is well known that the internally oriented 3' and 5' protons undergo changes in chemical shift on inclusion complexation due to anisotropic shielding or deshielding effects of the guest molecule. Likewise, the included protons of the guest molecule may also undergo changes in chemical shift due to anisotropic interaction with the host. The structure and numbering of Ranitidine is given in Figure 18. 1 H-NMR spectra were recorded at 500 MHz on a Bruker AMX R 500 spectrometer from solutions prepared in deuterium oxide. Chemical shifts are reported downfield to external tetramethylsilane. Evidence for the preferred cyclodextrin inclusion complexation of Ranitidine free base as opposed to the protonated hydrochloride form is provided by the relative chemical shifts of 3' and 5' protons of beta-cyclodextrin from solutions containing equimolar amounts of Ranitidine (as the free base and hydrochloride respectively) and beta-cyclodextrin (see Figure 19). Relative to the 1 ', 2' and 4' cyclodextrin protons, which undergo negligible shift changes, the 3' and 5' cyclodextrin protons in the Ranitidine free base complex undergo significantly greater chemical shift differences compared with the corresponding protons in the Ranitidine hydrochloride complex (Figure 19). The result indicates that Ranitidine free base has a more intimate association with the cavity of beta-cyclodextrin than does Ranitidine hydrochloride. It may therefore be concluded that complexes of the free base are likely to be more stable owing to the higher degree of molecular association. The chemical shifts of selected Ranitidine protons measured from solutions of Ranitidine hydrochloride, Ranitidine free base and various cyclodextrin-Ranitidine free base inclusion complexes are shown in Figure 20. Large chemical shift differences exist between Ranitidine hydrochloride and the corresponding free base owing to the effect of ionisation of the dimethylamino group. The chemical shifts of the inclusion complexes however are intermediate between those of the hydrochloride and the free base, and with few exceptions (e and E), show little variance between the different complexes. The preferred three dimensional structure of cyclodextrin complexes in solution may be determined from two-dimensional Rotating frame Overhauser Enhancement Spectroscopy (ROESY) experiments. Cross peaks arising from ROESY spectra may be related to short interproton distances between correlated protons. ROESY spectra were recorded for samples obtained from Examples 4, 5 and 6 and are shown in Figures 21, 22 and 23 respectively. In all cases strong cross peaks are observed between the furan ring protons and the 3' and 5" cyclodextrin protons. Additionally, smaller cross peaks are observed between the dimethylamino methyl protons and the 3', 5' protons. Other characteristic interactions include ROE's between F and H protons and the 3', 5' or 6' protons depending on the complex. Based on the experimental interproton distances, putative structures for the different complexes were computed using molecular mechanics calculations and are shown in Figures 24 - 26. The results clearly depict the inclusion of the dimethylaminomethylfuran moiety of Ranitidine into the cavity of alpha-, beta- and gamma cyclodextrins. In the case of the beta- and gamma-cyclodextrin complexes the nitro-enamine group is also involved such that the entire Ranitidine molecule is included. This interaction is apparently made possible by folding of the Ranitidine molecule evidenced by intramolecular ROE between H and A,A' (Figure 22) and H and B (Figure 23). In the case of the alpha-cyclodextrin complex, the nitro-enamine group is situated outside the cavity with the nitro group hydrogen bonded to the 6' hydroxyl. Calculations indicate highly stabilised complexes through a network of hydrogen bonding and favourable van der Waals interactions. These findings are in good agreement with the experimental results obtained from FTIR, DSC and NMR. Pharmaceutical Compositions A number of different pharmaceutical preparations were prepared in order to test the amenability of the cyclodextrin-Ranitidine free base inclusion complexes to pharmaceutical formulation. FORMULATION EXAMPLE 1 The following formulation may be used to prepare tablets containing cyclodextrin-Ranitidine free base complex. Alpha-cyclodextrin-Ranitidine complex prepared according to Preparation Example 1 was mixed with all other components identified below for 10 minutes, screened through a 60 mesh screen and further mixed for a suitable time period. The mixture obtained was formed into oblong tablets. The unit composition of each tablet is as follows: Alpha-cyclodextrin-Ranitidine complex 750mg* Microcrystalline cellulose 277mg Cross-linked carboxymethylcellulose 20mg Macrogol 6000 powder 25mg Talc 13mg Magnesium Stearate 15mg Total 1100mg * (equivalent to 150mg Ranitidine) FORMULATION EXAMPLE 2 The following formulation may be used to prepare a readily soluble powder producing a pleasant tasting clear solution when added to 100 ml tap water. 2-hydroxypropyl-beta-cyclodextrin-Ranitidine complex prepared according to Preparation Example 7 was mixed with all other components for 10 minutes, screened through a 30 mesh screen and further mixed for a suitable time period. The mixture obtained was packed into sachets. The unit composition of each sachet was as follows: 23 - 2-hydroxypropyl-beta-cyclodextrin- Ranitidine complex 1670mg* Spray dried passion fruit flavour 150mg Sodium cyclamate 100mg Sodium saccharin 50mg Sorbitol 2030mg Total 4000mg ^equivalent to 300mg Ranitidine) FORMULATION EXAMPLE 3 The following formulation may be used to prepare a readily soluble effervescent tablet producing a pleasant tasting solution when added to 100ml tap water: monosodium fumarate was granulated with a portion of a water methanol solution containing the sucrose and dye. The granulate was oven dried and screened. The sodium bicarbonate was similarly granulated with the remaining portion of granulating medium, oven dried and screened. The macrogol was screened and blended with the beta-cyclodextrin-Ranitidine complex prepared according to Preparation Example 10, flavour, sweeteners and monosodium fumarate granulate. The mixture was screened and mixed with the sodium bicarbonate granulate. The mixture obtained was formed into tablets using a 24mm die. The unit composition of each tablet was as follows: Beta-cyclodextrin-Ranitidine complex 938mg* Sodium monofumarate 2000mg Sodium bicarbonate 950mg Sucrose 83mg Yellow dye 0.14mg Macrogol 6000 135mg Gin fizz micron 10A flavour 30mg Sodium cyclamate 50mg Sodium saccharin 50mg Total 4236.14mg ^equivalent to 150mg Ranitidine) - 24 - FORMULATION EXAMPLE 4 The following formulation may be used to prepare chewable tablets containing cyclodextrin-Ranitidine complex. The sweeteners, flavour and lubricants were screened. Gamma-cyclodextrin-Ranitidine complex prepared according to Preparation Example 6 was mixed with all other components for 10 minutes. The mixture obtained was formed into oblong tablets. The unit composition of each tablet was as follows: Gamma-cyclodextrin-Ranitidine complex 938mg* Sodium cyclanate 4mg Sodium saccharin 2mg Yellow dye 0.5mg Tabletose 284.5mg Castor sugar 236mg Passion fruit flavour 7mg Talc 13mg Magnesium Stearate 15mg Total 1500mg * (equivalent to 150mg Ranitidine) FORMULATION EXAMPLE 5 The following formulation may be used to prepare tablets containing beta-cyclodextrin-Ranitidine free base complex. Beta-cyclodextrin- Ranitidine complex prepared according to Preparation Example 13 was mixed with all other components for 10 minutes, screened through a 60 mesh screen and further mixed for a suitable time period. The mixture obtained was formed into oblong tablets with a compressional force of 200N. The tablets are optionally film coated. The unit composition of each tablet is as follows: Beta-cyclodextrin-Ranitidine complex 716mg Sodium starch glycolate 36mg Microcrystalline cellulose 36mg Magnesium stearate 12mg Total 800mg FORMULATION EXAMPLE 6 The following formulation may be used to prepare tablets containing gamma-cyclodextrin-Ranitidine free base complex. Gamma-cyclodextrin- Ranitidine complex prepared according to Preparation 6 was mixed with all other components for 10 minutes, screened through a 60 mesh screen and further mixed for a suitable time period. The mixture obtained was formed into oblong tablets with a compressional force of 200N. The tablets are optionally film coated. The unit composition of each tablet is as follows: Gamma-cyclodextrin-Ranitidine complex 763mg Sodium starch glycolate 37mg Microcrystalline cellulose 38mg Magnesium stearate 12mg Total 850mg The formulations described above are simply illustrative of the use of the inclusion complexes of this invention and are not to be interpreted as being limitative in any way. The use of the complexes of the invention extends to numerous other formulations, some of which, such as sublingual or buccal tablets, are completely new in the field of Ranitidine formulations. BIOAVAILABILITY TEST Six (6) healthy male subjects, aged between 18 and 22 years were used in a single-blind, single-dose, 2-way randomised cross-over study to compare pharmacokinetic characteristics of tablets obtained from Formulation Example 5 (test) with a commercial preparation of Ranitidine hydrochloride (reference). Both preparations contained the equivalent of 150mg Ranitidine base. The results of the Ranitidine plasma concentration versus time plots for the test and reference are given in Figure 27. The 90% confidence interval for the "test/reference" mean ratio of the pharmacokinetic variable AUDC (Area Under the Data Curve) falls within the conventional bioequivalence range of 80% to 125%. The results of the test indicate that the test product is bioequivalent to the reference product with respect to the extent of absorption of Ranitidine. It was observed that the test product gave rise to less intrasubject variation than the reference product.

Claims: CLAIMS 1. An inclusion complex of Ranitidine in cyclodextrin or a pharmaceutically acceptable derivative of cyclodextrin, the complex being characterised in that the Ranitidine is in its free base form. 2. An inclusion complex as claimed in claim 1 in which the cyclodextrin is selected from the group consisting of alpha-cyclodextrin, beta-cyclodextrin and gamma-cyclodextrin. 3. An inclusion complex as claimed in claim 2 in which the cyclodextrin is gamma-cyclodextrin. 4. An inclusion complex as claimed in claim 2 in which the cyclodextrin is beta-cyclodextrin. 5. An inclusion complex as claimed in any one of the preceeding claims in which the cyclodextrin is in the form of an alkyl or hydroxyalkyl derivative thereof. 6. An inclusion complex as claimed in claim 5 in which the cyclodextrin derivative is selected from methyl, ethyl, hydroxyethyl and hydroxypropyl. 7. An inclusion complex as claimed in any one of the preceding claims in which the molar ratio of cyclodextrin to Ranitidine free base is from 2:1 to 1 :1. 8. An inclusion complex as claimed in claim 7 in which the molar ratio of cyclodextrin to Ranitidine is 1 : 1. 9. An inclusion complex substantially as herein described and exemplified with particular reference to any one of the Preparation Examples 1 to 13. 10. A process for the preparation of a cyclodextrin-Ranitidine free base inclusion complex comprising the steps of: (i) forming a paste, slurry or solution containing cyclodextrin or a pharmaceutically acceptable derivative of cyclodextrin; Ranitidine free base; and a solvent; (ii) treating the paste, slurry or solution to promote formation of cyclodextrin-Ranitidine free base inclusion complex; and (iii) drying the paste, slurry or solution to remove the solvent to yield a particulate or powdered product. 11. A process as claimed in claim 10 in which the Ranitidine free base is formed by treating a Ranitidine salt with a suitable neutralising agent to yield o Ranitidine free base. 12. A process as claimed in claim 11 in which the Ranitidine salt is Ranitidine hydrochloride and the neutralising agent is a suitable alkali. 13. A process as claimed in claim 12 in which the alkali is sodium or ammonium hydroxide. 5 14. A process as claimed in any one of the claims 11 to 13 in which the formation of Ranitidine free base is carried out in situ in the paste, slurry or solution. 15. A process as claimed in claim 10 in which freshly produced Ranitidine free base is employed in the paste, slurry or solution. 0 16. A process as claimed in either of claims 10 or 15 in which step (i) is carried out by blending required amounts of cyclodextrin and Ranitidine free base by vigorous mixing with water to provide a paste; and step (ii) includes kneading or mixing the paste vigorously for a period of from 0,5 to 10 hours. 17. A process as claimed in claim 16 in which step (iii) is carried out by 25 evaporation of the solvent under a vacuum with optional heating. 18. A process as claimed in claim 17 in which in step (iii) a quantity of gas is introduced into the mixture periodically during the initial stages of the drying operation. 19. A process as claimed in claim 10 in which step (i) is carried out in solution and the cyclodextrin-Ranitidine free base complex is precipitated out at lowered temperature followed by a liquid/solids separation step. 20. A process as claimed in claim 17 in which step (iii) is carried out by vacuum drying, spray drying or freeze drying. 21. A process as claimed in any one of claims 10 to 20 in which the dried product is screened to provide a uniform particle size. 22. A process substantially as herein described and exemplified in any one of the Preparation Example Numbers 1 to 13. 23. An inclusion complex whenever prepared by a process as claimed in any one of claims 10 to 22. 24. A pharmaceutical preparation comprising as an active ingredient an inclusion complex as claimed in any one of claims 1 to 9 or 23. 25. A pharmaceutical preparation as claimed in claim 24 in which the preparation is in a form selected from tablets; chewable tablets; soluble effervescent tablets; sublingual or buccal tablets; a soluble powder; coated tablets or a transdermal delivery system. 26. A pharmaceutical preparation substantially as herein described and exemplified in any one of the Formulation Example Numbers 1 to 5.

Inventors: GLINTENKAMP LUETA-ANN, PENKLER LAWRENCE JOHN, GLINTENKAMP, LUETA-ANN, PENKLER, LAWRENCE, JOHN
Applicants: FARMARC NEDERLAND BV, GLINTENKAMP LUETA ANN, PENKLER LAWRENCE JOHN, FARMARC NEDERLAND B.V., GLINTENKAMP, LUETA-ANN, PENKLER, LAWRENCE, JOHN
Application year: 1995
Main classification: A61K47
IPC codes: A61K31, A61K47