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WO1996001129A1 - Complexe d'inclusion de ranitidine - Google Patents

Complexe d'inclusion de ranitidine Download PDF

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Publication number
WO1996001129A1
WO1996001129A1 PCT/EP1995/002612 EP9502612W WO9601129A1 WO 1996001129 A1 WO1996001129 A1 WO 1996001129A1 EP 9502612 W EP9502612 W EP 9502612W WO 9601129 A1 WO9601129 A1 WO 9601129A1
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WO
WIPO (PCT)
Prior art keywords
cyclodextrin
ranitidine
free base
complex
inclusion complex
Prior art date
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Ceased
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PCT/EP1995/002612
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English (en)
Inventor
Lawrence John Penkler
Lueta-Ann Glintenkamp
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Farmarc Nederland BV
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Farmarc Nederland BV
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Priority to EP95926388A priority Critical patent/EP0768897A1/fr
Priority to AU30753/95A priority patent/AU3075395A/en
Publication of WO1996001129A1 publication Critical patent/WO1996001129A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A61K47/6951—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin

Definitions

  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • 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).
  • 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.
  • 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:
  • 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)
  • 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.
  • 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 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).
  • HPLC high performance liquid chromatography
  • NMR proton nuclear magnetic resonance
  • DSC differential scanning calorimetry
  • FTIR Fourier transform infrared spectroscopy
  • XRD X-ray diffraction
  • the cyclodextrin-Ranitidine free base complexes possess advantageous physical and physico-chemical properties for pharmaceutical compounding, such as:
  • 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
  • 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
  • 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 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.
  • R.HCI Ranitidine hydrochloride
  • R.FB Ranitidine free base
  • 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.
  • Cyclodextrin inclusion complexes of Ranitidine free base may be prepared, for example, according to any of the following methods: - 11 -
  • 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.
  • 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.
  • 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.
  • 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.
  • XRD X-ray diffraction
  • 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
  • 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.
  • 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.
  • 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.
  • a reduction in the dose of Ranitidine may contribute significantly to decreased hepatic toxicity of Ranitidine.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • Beta-cvclodextrin-Ranitidine complex 100 93.6 92.2
  • FTIR Fourier transform infrared
  • Figure 1 are absent in the free base and cyclodextrin-Ranitidine complexes, indicating that the complexes exclusively contain Ranitidine as the free base.
  • DSC Differential Scanning Calorimetry
  • 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.
  • X-ray powder diffractometry 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 are shown in Figures 14 - 16.
  • 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 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.
  • ROESY Rotating frame Overhauser Enhancement Spectroscopy
  • 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:
  • Microcrystalline cellulose 277mg Cross-linked carboxymethylcellulose 20mg
  • 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 -
  • 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:
  • 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:
  • 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
  • each tablet is as follows:
  • 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:
  • 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.

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  • General Engineering & Computer Science (AREA)
  • Medical Informatics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

Complexe d'inclusion de ranitidine dans de la cyclodextrine ou l'un de ses dérivés pharmaceutiquement acceptables. Ledit composé est caractérisé par le fait que la ranitidine est sous sa forme de base libre. Des procédés de préparation dudit complexe et des préparations pharmaceutiques effectuées selon ledit procédé sont également décrits.
PCT/EP1995/002612 1994-07-06 1995-07-05 Complexe d'inclusion de ranitidine Ceased WO1996001129A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EP95926388A EP0768897A1 (fr) 1994-07-06 1995-07-05 Complexe d'inclusion de ranitidine
AU30753/95A AU3075395A (en) 1994-07-06 1995-07-05 Inclusion complexes of ranitidine

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ZA94/4875 1994-07-06
ZA944875 1994-07-06

Publications (1)

Publication Number Publication Date
WO1996001129A1 true WO1996001129A1 (fr) 1996-01-18

Family

ID=25584078

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1995/002612 Ceased WO1996001129A1 (fr) 1994-07-06 1995-07-05 Complexe d'inclusion de ranitidine

Country Status (5)

Country Link
EP (1) EP0768897A1 (fr)
AU (1) AU3075395A (fr)
IL (1) IL114464A0 (fr)
WO (1) WO1996001129A1 (fr)
ZA (1) ZA955582B (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998018827A1 (fr) * 1996-10-28 1998-05-07 Farmarc Nederland B.V. Complexes d'insertion de beta-2-adrenergiques absorbes par les muqueuses buccales
CN114839288A (zh) * 2022-04-27 2022-08-02 湖南省药品检验检测研究院 一种盐酸雷尼替丁样品的前处理方法
CN114878707A (zh) * 2022-04-27 2022-08-09 湖南省药品检验检测研究院 一种测定雷尼替丁及其固体制剂中n-亚硝基二甲胺的高效液相色谱法

Citations (5)

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Publication number Priority date Publication date Assignee Title
ZA774500B (en) * 1976-08-04 1978-05-30 Allen & Hanburys Ltd Pharmacologically active compounds
WO1982004052A1 (fr) * 1981-05-12 1982-11-25 Szejtli Jozsef Procede de preparation de complexes d'inclusion derives de n-(1-phenyle-ethyle)-3,3-diphenyle-propylamine respectivement de son chlorhydrate et de cyclodextrine
CH640846A5 (en) * 1977-07-29 1984-01-31 Allen & Hanburys Ltd Aminoalkylfuran derivative
GB2198352A (en) * 1986-12-12 1988-06-15 Glaxo Group Ltd Aqueous ethanolic compositions of ranitidine
WO1994020091A1 (fr) * 1993-03-05 1994-09-15 Hexal Pharma Gmbh Complexes cristallins d'insertion de cyclodextrine de l'hydrochlorure de ranitidine, et leur procede de preparation

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ZA774500B (en) * 1976-08-04 1978-05-30 Allen & Hanburys Ltd Pharmacologically active compounds
CH640846A5 (en) * 1977-07-29 1984-01-31 Allen & Hanburys Ltd Aminoalkylfuran derivative
WO1982004052A1 (fr) * 1981-05-12 1982-11-25 Szejtli Jozsef Procede de preparation de complexes d'inclusion derives de n-(1-phenyle-ethyle)-3,3-diphenyle-propylamine respectivement de son chlorhydrate et de cyclodextrine
GB2198352A (en) * 1986-12-12 1988-06-15 Glaxo Group Ltd Aqueous ethanolic compositions of ranitidine
WO1994020091A1 (fr) * 1993-03-05 1994-09-15 Hexal Pharma Gmbh Complexes cristallins d'insertion de cyclodextrine de l'hydrochlorure de ranitidine, et leur procede de preparation

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DARROUZET H: "PREPARING CYCLODEXTRIN INCLUSION COMPOUNDS", MANUFACTURING CHEMIST, vol. 64, no. 11, 1 November 1993 (1993-11-01), pages 33/34, XP000423501 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998018827A1 (fr) * 1996-10-28 1998-05-07 Farmarc Nederland B.V. Complexes d'insertion de beta-2-adrenergiques absorbes par les muqueuses buccales
CN114839288A (zh) * 2022-04-27 2022-08-02 湖南省药品检验检测研究院 一种盐酸雷尼替丁样品的前处理方法
CN114878707A (zh) * 2022-04-27 2022-08-09 湖南省药品检验检测研究院 一种测定雷尼替丁及其固体制剂中n-亚硝基二甲胺的高效液相色谱法
CN114839288B (zh) * 2022-04-27 2023-11-07 湖南省药品检验检测研究院 一种盐酸雷尼替丁样品的前处理方法
CN114878707B (zh) * 2022-04-27 2023-11-07 湖南省药品检验检测研究院 一种测定雷尼替丁及其固体制剂中n-亚硝基二甲胺的高效液相色谱法

Also Published As

Publication number Publication date
IL114464A0 (en) 1995-11-27
AU3075395A (en) 1996-01-25
EP0768897A1 (fr) 1997-04-23
ZA955582B (en) 1996-02-26

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