Classifications

• • C—CHEMISTRY; METALLURGY
  • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
  • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
  • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
  • C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
  • C08B37/0009—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid alpha-D-Glucans, e.g. polydextrose, alternan, glycogen; (alpha-1,4)(alpha-1,6)-D-Glucans; (alpha-1,3)(alpha-1,4)-D-Glucans, e.g. isolichenan or nigeran; (alpha-1,4)-D-Glucans; (alpha-1,3)-D-Glucans, e.g. pseudonigeran; Derivatives thereof
  • C08B37/0012—Cyclodextrin [CD], e.g. cycle with 6 units (alpha), with 7 units (beta) and with 8 units (gamma), large-ring cyclodextrin or cycloamylose with 9 units or more; Derivatives thereof
  • C08B37/0015—Inclusion compounds, i.e. host-guest compounds, e.g. polyrotaxanes
• • 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
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/04—Centrally acting analgesics, e.g. opioids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • 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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
  • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
  • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D215/18—Halogen atoms or nitro radicals
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
  • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems

Definitions

• Tomoxiprole 2-(4-methoxyphenyl)-3-(1 -methylethyl)-3/-/-naphth[1 ,2-d ⁇ imidazole (formerly indicated as MDL 035) is a compound belonging to the class of the cycloxygenase 2 inhibitors, with analgesic, antinflammatoriry, antiarthritis activity
• MDL 035 cycloxygenase 2 inhibitors
• analgesic, antinflammatoriry, antiarthritis activity The efficacy of tomoxiprole against said disorders has been demonstrated in animal studies.
• active doses of the compound are devoid of ulcerogenic activity (P. Schiatti et al. Arzneim - Forsch / Drug Res 1986, 36, 102-109; See also EP 0 012 866 A1 )
• tomoxiprole The main predicted use of tomoxiprole is as analgesic, for the management of diseases as dental pain, post traumatic pain, headache and dysmenorrhoea. A rapid onset of the therapeutical action with consequent relieve of the pain is an important aspect of the medical treatment of said diseases.
• the present invention relates to different approaches to obtain a faster solution rate of the molecule in conditions mimicking gastric juice, and hence a more rapid absorption of the drug.
• tomoxiprole Form I crystals (illustrated in Fig.2) is due to their physical characteristics: low surface wettability (water contact angle 81 ° at any pH) and a high crystal lattice stability, as demonstrated by the melting point (165 °C). Attempts at obtaining different crystal forms consisting in dissolving the sample in a solvent and inducing precipitation by cooling or concentrating the solution failed. Several solvents were used, such as acetone, anhydrous ethanol, methylene chloride. In all the cases the crystal Form I, melting point 165 °C, (determined by DSC, see graph reported in Fig. 5) was observed.
• Form II a solid mainly consisting of a new form (Form II) was obtained. Pure crystals of the new form were prepared by dissolving the sample in methanol, adding water to precipitate the compound and removing methanol under vacuum. Form II in DSC is characterized by a melting point 155 °C, followed by recrystallization into Form I and subsequent melting at 165 °C. As predicted by the DSC results, Form II is unstable and even at room temperature slowly transforms into Form I.
• the total content of active ingredients of a tablet or capsule preferably, should not exceed the weight of one gram.
• Another reported property of drug/cyclodextrin complexes is stabilization of the active product crystalline or amorphous solid state forms.
• tomoxiprole is mentioned among an extremely large group of compounds which may be bound to a NO-releasing radical and then combined with cyclodextrin, this document does not contain any disclosure of a complex and a method for the preparation thereof where the molar ratio between the active substance and cyclodextrin has a predetermined value and does not provide any indication or hint or suggestion to preparing a stable complex where tomoxiprole is contained in a molar ratio near 1 :1 with 2-hydroxypropyl-beta-cyclodextrin.
• This invention relates to the preparation of a stable amorphous tomoxiprole- cyclodextrin complex with molar ratio near 1 :1 , presenting a fast dissolution rate at acidic pH.
• this invention concerns the preparation and use of a complex in which amorphous tomoxiprole is stabilized by forming a complex with an about equimolecular amount of 2-hydroxypropyl-beta-cyclodextrin, suitable for preparing devices for oral administration, such as tablet or capsules, and presenting a dissolution rate in an aqueous solution buffered at acidic pH which is remarkably faster than that of tomoxiprole crystalline Form I.
• a common practice for the preparation of complexes substance/cyclodestrin consists of dissolving the two components in a suitable solvent or mixture of solvents and then concentrating the solution by evaporation at reduced pressure.
• An explanation of the failures of the attempts above mentioned could be that tomoxiprole is generally less soluble than 2-hydroxypropy-beta-cyclodestrin in polar solvents. Concentration at reduced pressure substantially lowers the temperature of the solution causing the partial precipitation of tomoxiprole. Therefore, a method has been devised to rapidly evaporate the solvents without cooling the solution.
• tomoxiprole and 2-hydroxypropyl-beta- cyclodextrin (HPBCD) in molar ratios ranging from 1 :1 to 1 :1 ,5 are added to ethanol and the mixture is heated at 30-40 °C to obtain a clear solution which is then rapidly evaporated at atmospheric pressure under a warm air stream (40-50 °C), till an amorphous solid is formed.
• the products of the different preparations are collected and dried under vacuum.
• the content of tomoxiprole in the samples, as determined by the UV light extinction at 328 nm is in the range of 17% to 17,5% by weight.
• the calculated content of tomoxiprole is 18.6% by weight. Therefore, the samples appear to be constituted by the said complex with a purity degree in the range from 90 to 93% (by weight). Further washing of the obtained product with a solvent capable of removing unreacted cyclodextrin yields a complex wherein the ratio is near 1 :1 as shown in Example 1 .
• the complex shows a remarkably faster dissolution rate in comparison with tomoxiprole crystals Form 1 .
• the saturation concentration at the conditions reported in Example 2 is about 5 mg/ml.
• the concentration observed with the complex at 0.5 min. is 2.5 mg/mL, or 50% of the total soluble amount.
• concentration determined at the same time with tomoxipole crystals is 1 mg/mL or 20% of the soluble amount.
• the saturation concentration is reached after 4 min with the complex and over 8 min with tomoxiprole crystals.
• TMX tomoxiprole
• HPBCD tomoxiprole-2-hydroxypropyl-beta-cyclodextrin complex
• the complex of amorphous tomoxiprole with 2-hydroxypropyl-beta-cyclodextrin, according to this invention is very stable: after six months of storage at room temperature no signs of formation of tomoxiprole crystals were detected.
• the complex is particularly suitable for the preparation according to methods known in the art of pharmaceutical oral dosage forms, such as tablets and capsules, especially for use in the treatment of patients needing rapid absorption of tomoxiprole and onset of the therapeutical action.
• oral dosage units such as tablets and capsules, each of which having a content of the complex of amorphous tomoxiprole with 2-hydroxypropyl-beta-cyclodextrin herein described which corresponds to from 50 to 150 milligrams of tomoxiprole.
• Example 1 tomoxiprole-2-hydroxypropyl-beta-cvclodextrin complex
• the infrared spectrum of the product (Fig. 4B) is in agreement with the assumption that the product is essentially an equimolecular inclusion complex of tomoxiprole and 2-hydroxypropyl-beta-cyclodextrin, mixed with some unreacted cyclodextrin.
• the content of tomoxiprole in the sample is about 17% by weight.
• the content calculated for an equimolecular complex is 18,8%. This indicates that the product is by 90% (by weight) composed of the equimolecular complex and by about 10% of unreacted cyclodextrin.
• HPBCD 2-hydroxypropyl-beta-cyclodextrin
• TMX/HPBCP tomoxiprole-2-hydrozypropyl-beta-cyclodextrin complex attribution TMX TMX/HPBCD
• Example 2 tomoxiprole-2-hydroxypropyl-beta-cvclodextrin complex dissolution rate.
• the dissolution rate of the complex tomoxiprole-2-hydroxypropyl-beta-cyclodextrin obtained in Example 1 is determined by the following method.
• tomoxiprole-2-hydroxypropyl-beta- cyclodextrin complex (corresponding to 100 mg of tomoxiprole) are added to 10 ml of a buffer solution HCI-KCI pH 1 ,5. Samples of the suspension are collected at intervals of time, clarified by centrifugation and the tomoxiprole concentration in the clear supernatant is determined by UV absorption at 328 nm.
• the dissolution rate of tomoxiprole crystals was measured for comparison purpose .
• Fig.1 XRPD pattern of tomoxiprole crystals Form I.
• the X-rays powder diffraction (XRPD) test was carried out with MINI FLEX (Rigaku) instrument; the tube has a Copper target, with a current intensity of 15 mA and a voltage of 30 kV: the radiation was constituted by K a (1 .540562 A) and K a2 (1 .544398 A); Nickel filter was used for the suppression of Kp radiation (1 .392218 A).
• Fig. 2 Dissolution rate of tomoxiprole in buffer pH 1 ,5;
• FIG. 1 Vertical axis: concentration of tomoxiprole (mg/mL); horizontal axis: time (minutes).
• Fig 3 XRPD pattern of the complex tomoxiprole-2-hydroxypropyl-beta-cyclodextrin;
• the X-rays powder diffraction (XRPD) test was carried out with MINI FLEX (Rigaku) instrument; the tube has a Copper target, with a current intensity of 15 mA and a voltage of 30 kV: the radiation was constituted by K a (1 .540562 A) and K a2 (1 .544398 A); Nickel filter was used for the suppression of Kp radiation (1 .392218 A).
• Vertical axis Intensity (cps); horizontal axis: 2-theta in degrees.
• Fig. 4A and 4B Infrared spectrum of tomoxiprole and complex tomoxiprole-2- hydroxypropyl-beta-cyclodextrin;.
• Fig. 5 Differential Scanning Calorimetry plot of tomoxiprole, 2-hydroxypropyl-beta- cyclodextrin and complex tomoxiprole-2-hydroxypropyl-beta-cyclodextrin.
• the Differential Scanning Calorimetry ⁇ DSC was carried out with DSC 821 (Mettler- Toledo) lying the samples in an open, covered, aluminum pan.
• the heating rate was set at 10 °C/min, under nitrogen flow at 30 ml/min.
• Fig. 5A thermal behaviour of tomoxiprole. A sharp absorption of energy is observed at 165.-167 °C, due to the melting of tomoxiprole crystals
• Fig. 5B thermal behaviour of 2-hydroxypropy-beta- cyclodextrin. A gradual energy absorption is observed from room temperature until 120 °C corresponding to a desolvation endotherm
• Fig. 5C thermal behaviour of the complex tomoxiprole-2-hydroxypropy-beta- cyclodextrin. A desolvation endotherm is observed from room temperature until 130°C. No peak related to tomoxiprole is detected demonstrating that this substance is linked in amorphous form to the matrix
• Fig. 6 Dissolution rate of the complex tomoxiprole-2-hydroxypropyl-beta-cyclodextrin.
• Vertical axis concentration of tomoxiprole (mg/mL); horizontal axis:time (min)

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• 2012
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