Classifications

• • 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
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
  • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
• • 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
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
  • A61K31/716—Glucans
  • A61K31/724—Cyclodextrins
• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants

Definitions

• the present invention relates to an inclusion complex, particularly, but not exclusively to an inclusion complex of S-omeprazole, and to a method of making it.
• omeprazole (5-methoxy-2-[[(4-methoxy-3,5-dimethyl- 2-pyridinyl)methyl]sulfinyl]-lH-benzimidazole) and therapeutically acceptable salts thereof are well known as effective gastric acid secretion inhibitors, and are useful as anti-ulcer agents.
• Omeprazole has two enantiomeric forms, the R and S- enantiomers, otherwise known as R-omeprazole and S-omeprazole, and normally exists as a racemic mixture. Certain optically pure salts of R and S omeprazole are described for example in US 5714504.
• the magnesium salt of S-omeprazole trihydrate is described in WO 98/54171, and S-omeprazole in a neutral, solid form (which can be in a partly or substantially crystalline state) is described in WO 98/28294.
• the optical isomers of omeprazole (in particular the S-enantiomer) are believed to possess certain advantages over the racemic form - for example, the optically pure salts of omeprazole disclosed in WO 94/27988 are said to have improved pharmacokinetic properties which give an improved therapeutic profile such as a lower degree of inter-individual variation.
• one particular problem with S-omeprazole, as with other similar benzimidazole compounds is that it is not stable in its free form.
• the compound is readily degraded by moisture and under neutral and acidic conditions.
• Previous approaches to providing a stable form of S-omeprazole have concentrated on the provision of alkali metal or alkaline earth metal salts of S- omeprazole (see WO 94/27988 and WO 98/54171), but these approaches are not entirely satisfactory since the salts per se are still liable to degradation.
• Another problem with S-omeprazole in its free form is that it is difficult to isolate. It can be isolated as a trihydrate having about 13 to 15% moisture content, although this form has to be stored under refrigerated conditions to provide even limited stability.
• S-omeprazole and related benzimidazoles can be provided in a form which is both stable and easily isolated and processed with minimal risk of degradation.
• an inclusion complex comprising a substantially pure optical isomer of a benzimidazole compound such as omeprazole, lansoprazole, pantoprazole or rabeprazole, and cyclodextrin.
• the optically pure isomer is the S isomer and most preferably it is S- omeprazole.
• the cyclodextrin is preferably ⁇ -cyclodextrin.
• substantially pure optical isomer in the context of the present invention means the S isomer when substantially free of the R isomer (or vice versa), preferably with an enantiomeric excess (e.e.) of 90% and more preferably 95% e.e.
• the invention provides a process for preparing an inclusion complex comprising a substantially pure optical isomer of a benzimidazole compound and cyclodextrin, which process comprises adding a cyclodextrin to an aqueous solution of a substantially pure optical isomer of a benzimidazole compound or a pharmaceutically acceptable salt thereof, and isolating the inclusion complex so formed from the solution. It is preferred to keep the solution at an alkaline pH throughout the process (i.e. a pH of above 7) so as to avoid any degradation of the active compound.
• the process is preferably used to prepare a ⁇ -cyclodextrin complex of S-omeprazole, but it can also be applied to other substituted benzimidazoles such as S-lansoprazole, S-pantoprazole and S-rabeprazole.
• the present method enables S-omeprazole and the S isomers of other benzimidazole compounds to be prepared in a stable form, which form has much greater resistance to degradation than either the S isomers in their free form or as salts.
• the inclusion complex of the invention can be easily isolated in the form of a stable white powder by the present process, and this powder in turn has the advantage of excellent handleability. It can, for example, be processed easily and conveniently into final dosage forms without the need to take special precautions to stabilise the active material during processing.
• US 5399700 discloses a method for stabilising a racemic mixture of an acid-unstable compound such as omeprazole by forming an inclusion complex of racemic omeprazole with cyclodextrin.
• EP 1018340 A teaches a method of stabilising a racemic mixture of a benzimidazole compound by forming an inclusion compound comprising a racemic benzimidazole derivative with one or more amino acids and one or more cyclodextrins.
• both of these disclosures relate to racemic benzimidazoles and there is no teaching about either the S or R isomers.
• racemic omeprazole is a free powder having a high melting point, which can be purified by normal solvent crystallisation techniques, dried free of solvents and can be handled easily at room temperature and formulated into dosage forms.
• S-omeprazole is a low melting point solid which cannot be easily purified using solvent crystallisation methods since it has a tendency to hold the solvent molecule (as a solvate), thus drying the product becomes extremely difficult.
• S-omeprazole can be isolated from water only as a trihydrate (as noted above). Any attempt to further dry the product so that it is free of water results in decomposition of the product.
• S-omeprazole can be prepared by procedures well known in the art, such as those described and referred to in WO 94/27988. In forming the inclusion complex, the S-omeprazole can be used either in its free form or in the form of a pharmaceutically acceptable salt, such as the potassium salt.
• the proportion of S-omeprazole and cyclodextrin used is important in order to form a stable complex.
• a molar ratio of S-omeprazole to ⁇ - cyclodextrin in the range 1:1.5 to 1:5, with a ratio of 1:2 being particularly preferred. Reducing the amount of cyclodextrin much below these levels causes unwanted discoloration of the product to arise.
• the process is preferably carried out under alkaline conditions by using an aqueous alkaline solution containing, for example, sodium hydroxide, to which the S-omeprazole is added.
• an aqueous alkaline solution containing, for example, sodium hydroxide, to which the S-omeprazole is added.
• any alkaline substance can be employed so long as it does not interfere with the formation of the inclusion complex.
• Alkali metal hydroxides such as sodium hydroxide are particularly suitable.
• the S-omeprazole can be added to the alkaline solution either in solid form (such as a powder) or in the form of an aqueous solution.
• the temperature of the solution is above at least 30°C, more preferably above 40°C. A temperature of around 45°C is ideal.
• cyclodextrin preferably as ⁇ -cyclodextrin
• cyclodextrin is added to the alkaline solution of S-omeprazole. It is preferred to add the cyclodextrin in small quantities over a period of about one hour.
• the mixture is preferably stirred thoroughly throughout the addition.
• the mixture is then preferably further diluted by the addition of water in order to provide a clear solution.
• the dilution ensures that the cyclodextrin is completely dissolved and is entirely available for complex formation.
• the dilution is at least 1 in 4 by volume of the initial solution.
• the pH of the mixture is then checked and preferably adjusted to between 8 to 9. For example, this can be carried out using a 5% aqueous solution of boric acid, although other equivalent means can be used.
• the mixture is then cooled, most preferably to around 5°C. Cooling enables maximum recovery of the product.
• the inclusion complex is then isolated. This can be done, for example, by filtering the complex from the cooled solution. The inclusion complex is thus isolated in the form of a white powder.
• the inclusion complex can be formulated into final dosage forms such as tablets, capsules and the like using standard excipients. A particularly preferred dosage formulation is that described in our publication WO 98/52564.
• an aqueous solution of sodium hydroxide (5.5 g NaOH in 1 litre) maintained at about 45°C is added an aqueous solution of potassium S-omeprazole (54 g in 200 ml).
• ⁇ -cyclodextrin (495 g) in small quantities over a period of about 1 hour.
• the mass is then further diluted with 3.5 litres of water to obtain an almost clear solution.
• the pH of the mass is then adjusted to between 8 to 9 using a 5% aqueous solution of boric acid.
• the contents are cooled to 5°C and filtered to obtain 420 g of an inclusion complex of S-omeprazole with ⁇ - cyclodextrin.
• the complex contains about 10 to 14% of the active ingredient and is in the form of a white powder.

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• Health & Medical Sciences (AREA)
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• Life Sciences & Earth Sciences (AREA)
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• Animal Behavior & Ethology (AREA)
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• Bioinformatics & Cheminformatics (AREA)
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• Molecular Biology (AREA)
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• Crystallography & Structural Chemistry (AREA)
• General Engineering & Computer Science (AREA)
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• Medical Informatics (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Organic Chemistry (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Plural Heterocyclic Compounds (AREA)
• Polysaccharides And Polysaccharide Derivatives (AREA)
• Medicinal Preparation (AREA)

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Cited By (6)

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Citations (9)

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• 2001
  • 2001-06-06 GB GB0113792A patent/GB2376231A/en not_active Withdrawn
• 2002
  • 2002-06-06 NZ NZ529956A patent/NZ529956A/en unknown
  • 2002-06-06 US US10/479,658 patent/US20040147481A1/en not_active Abandoned
  • 2002-06-06 ES ES02776528T patent/ES2232780T3/es not_active Expired - Lifetime
  • 2002-06-06 DE DE60201995T patent/DE60201995T2/de not_active Expired - Lifetime
  • 2002-06-06 WO PCT/GB2002/002542 patent/WO2002098423A1/en not_active Ceased
  • 2002-06-06 PT PT02776528T patent/PT1401442E/pt unknown
  • 2002-06-06 JP JP2003501462A patent/JP2004536810A/ja active Pending
  • 2002-06-06 CA CA2449769A patent/CA2449769C/en not_active Expired - Fee Related
  • 2002-06-06 EP EP02776528A patent/EP1401442B1/en not_active Expired - Lifetime
  • 2002-06-06 RU RU2003137221/15A patent/RU2313343C2/ru not_active IP Right Cessation
  • 2002-06-06 PL PL02366940A patent/PL366940A1/xx not_active Application Discontinuation
  • 2002-06-06 AT AT02776528T patent/ATE282412T1/de not_active IP Right Cessation
  • 2002-06-06 AU AU2002344386A patent/AU2002344386B2/en not_active Ceased
• 2003
  • 2003-12-03 LT LT2003100A patent/LT5182B/lt not_active IP Right Cessation
  • 2003-12-19 ZA ZA200309841A patent/ZA200309841B/en unknown
• 2004
  • 2004-01-06 LV LVP-04-01A patent/LV13154B/en unknown

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