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WO2008040799A2 - Procédé servant à préparer des formes instantanées de solutions micellaires aqueuses mélangées servant de systèmes de tampon physiologique destinés à être utilisés dans l'analyse de la libération in vitro - Google Patents

Procédé servant à préparer des formes instantanées de solutions micellaires aqueuses mélangées servant de systèmes de tampon physiologique destinés à être utilisés dans l'analyse de la libération in vitro Download PDF

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Publication number
WO2008040799A2
WO2008040799A2 PCT/EP2007/060592 EP2007060592W WO2008040799A2 WO 2008040799 A2 WO2008040799 A2 WO 2008040799A2 EP 2007060592 W EP2007060592 W EP 2007060592W WO 2008040799 A2 WO2008040799 A2 WO 2008040799A2
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WIPO (PCT)
Prior art keywords
phospholipid
mixed micellar
acid
molar ratio
components
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Ceased
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PCT/EP2007/060592
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English (en)
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WO2008040799A3 (fr
Inventor
Julia Boni
Jennifer Dressman
Martin Wunderlich
Rolf-Stefan Brickl
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Boehringer Ingelheim International GmbH
Boehringer Ingelheim Pharma GmbH and Co KG
Boehringer Ingelheim Pharmaceuticals Inc
Original Assignee
Boehringer Ingelheim International GmbH
Boehringer Ingelheim Pharma GmbH and Co KG
Boehringer Ingelheim Pharmaceuticals Inc
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Publication of WO2008040799A2 publication Critical patent/WO2008040799A2/fr
Publication of WO2008040799A3 publication Critical patent/WO2008040799A3/fr
Anticipated expiration legal-status Critical
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    • 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
    • A61K9/08—Solutions
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • 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
    • A61K9/10—Dispersions; Emulsions
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers

Definitions

  • the invention relates to a process for preparing instant forms of aqueous mixed micellar solutions which are stable enough for storage, wherein the mixed micelles comprise
  • (C) optionally one or more non-phospholipid substances selected from among triacylglycerides and the breakdown products thereof,
  • the molar ratio of the components (A) : (B) is from 0.1 :1 to 1 :1 and optionally the molar ratio of the components (C) : (B) is from 0.1 :1 to 6:1 ,
  • micellar solutions are generally physically dispersions or emulsions.
  • the invention relates to the instant forms of aqueous mixed micellar solutions that are stable enough for storage and to a process for preparing ready-to- use aqueous mixed micellar solutions, characterised by the addition of water or aqueous buffer to the instant form according to the invention.
  • the process according to the invention is thus suitable for preparing a storable mixed micellar formulation for the rapid and reproducible preparation of aqueous mixed micellar solutions for use as release media.
  • Aqueous mixed micellar solutions of this kind are required particularly for use in the analysis of in vitro release as physiological buffer systems for predicting the in vivo resorption of pharmaceutical active substances.
  • the present invention therefore relates to the use of the ready-to-use mixed micellar solution redispersed from an instant form, as a biorelevant medium or as a physiological buffer system in the analysis of the in vitro release of pharmaceutical active substances.
  • Liposomal systems which constitute pure lipid dispersions, and dispersed mixed micelles which are formed by the addition of bile salts to liposomal systems and their use in pharmaceutical formulations have long been known.
  • (1 ) ' (2) ' (3) ' (4) phospholipid mixed micellar systems are used in all kinds of applications, e.g. for the manufacture and analysis of drugs.
  • the systems are characterised in that they form mixed micelles (Ref: Shankland W 1970. The equilibrium and structure of lecithin-cholate mixed micelles. Chemistry and Physics of Lipids 4:109-130) which may contain an active substance in dissolved, dispersed, suspended or emulsified form depending on the end use envisaged.
  • Examples of such systems are pharmaceutical formulations such as Konakion ® MM and Valium ® MM.
  • Further examples are the mixed micellar solutions FaSSIF and FeSSIF (1) ' (2) ' (3) known from the literature and used in pharmaceutical analysis.
  • aqueous mixed micellar solutions are used to improve the formulation qualities and resorption of substances, and on the other hand they may be used as media in the analysis of the release of different formulations in vitro, e.g. for the investigation of food effects.
  • In vitro diagnosis is a tool for improving formulations under development and should be the best possible predictor of in vivo releases. Therefore it makes sense to simulate physiological in vivo conditions using a simplified media model as effectively as possible.
  • Known models such as the above-mentioned biorelevant media FaSSIF and FeSSIF (1) (2) (3) , simulate the physiological state with regard to the pH, the osmolality, the buffer capacity and the concentrations of lecithin and bile salts.
  • Lecithin and bile salts form mixed micelles and may thus act as solubilisers to improve the release of substances (Ref: Alkan- Onyuksel H, Ramakrishnan S, Chai HB, Pezzuto JM 1994. A mixed micellar formulation suitable for the parenteral administration of taxol. Pharmaceutical Research 11 :206-212).
  • FaSSIF is a model for the pre-prandial small intestine or for the conditions prevailing therein. Because of the major fluctuations between individuals, the composition is given in ranges (Ref.: Kalantzi L, Goumas K, Kalioras V, Abrahamsson B, Dressman JB, Reppas C 2006. Characterization of the human upper gastrointestinal contents under conditions simulating bioavailability/bioequivalence studies. Pharmaceutical Research 23: 165-176):
  • PH 5 - 7 (preferably 6 - 7) osmolality 100 - 300 mosmol/kg (preferably 200 - 300 mosmol/kg)
  • the contents of bile salts and lecithin are small, the buffer capacity relatively poor.
  • the osmolality is adjusted using NaCI, KCI or CaCI 2 .
  • FaSSIF has the following preferred composition:
  • FaSSIF contains a phosphate buffer (pH 6.5, buffer capacity 10 mEq per litre and pH unit) instead of the natural bicarbonate buffer, to avoid pH instabilities.
  • the content of bile salts and lecithin is typical of the pre- prandial state.
  • the medium is made isoosmolar with NaCI; instead of NaCI it is also possible to use equimolar amounts of KCI or CaCI 2 .
  • FeSSIF constitutes a model of the postprandial small intestine or the conditions prevailing therein. Because of the major fluctuations between individuals the composition is given in ranges (time of measurements: approx. 120 min after taking food; Ref.: Kalantzi L, Goumas K, Kalioras V, Abrahamsson B, Dressman JB, Reppas C 2006. Characterization of the human upper gastrointestinal contents under conditions simulating bioavailability/bioequivalence studies. Pharmaceutical Research 23:165-176):
  • the contents of bile salts and lecithin are increased by the emptying of the gall bladder, while the buffer capacity is greatly increased.
  • the osmolality is adjusted using NaCI, KCI or CaCI 2 .
  • FeSSIF has the following preferred composition:
  • the preferred composition of FeSSIF contains an acetate buffer (pH 5.0, buffer capacity 75 mEq per litre and pH unit).
  • the content of bile salts and lecithin as well as the buffer capacity are significantly increased compared with FaSSIF and reflect the contributions of the food eaten and the secretions.
  • the osmolarity may be adjusted using NaCI or an equimolar amount of KCI or CaC ⁇ ; this is somewhat higher, compared with FaSSIF.
  • FeSSIFplus dietary fats (triacylglycerides) and the breakdown products thereof may also be added to FeSSIF, which is hereinafter referred to as FeSSIFplus:
  • FeSSIFplus has the following preferred composition:
  • the preferred composition of FeSSIFplus contains a citrate buffer (pH 5.8, buffer capacity 25 mEq per litre and pH unit).
  • the content of bile salts and lecithin as well as the buffer capacity are lower compared with FeSSIF, as the medium simulates the postprandial state approx. 2 - 3 hours after eating and at this stage some of the food eaten and electrolytes have already been resorbed.
  • the osmolarity may be adjusted using NaCI or an equimolar amount of KCI or CaC ⁇ ; this is somewhat higher, compared with FaSSIF, and somewhat lower compared with FeSSIF.
  • the preparation of the biorelevant media e.g. FaSSIF, FeSSIF and FeSSIFplus, using the methods described in the prior art is time-consuming and not always reproducible.
  • To prepare the biorelevant media FaSSIF, FeSSIF and FeSSIFplus first of all the non-phospholipid substance (B), here usually the sodium salt of taurocholic acid, is dissolved in aqueous buffer.
  • the phospholipid substance here usually egg lecithin
  • dichloromethane the organic solvent is eliminated in the rotary evaporator
  • the non-phospholipid substances (C) here usually glycerolmonooleate and the sodium salt of oleic acid, which have also been dissolved in dichloromethane, are added and the organic solvent is again eliminated in the rotary evaporator.
  • the mixed micellar solution is then diluted to the desired final concentration using aqueous buffer.
  • the aim of the present invention was therefore to prepare a storage-stable precursor of aqueous mixed micellar solutions as an "instant form", particularly FaSSIF Instant, FeSSIF Instant and FeSSIFplus Instant, from which the ready-to-use aqueous mixed micellar solutions, such as the biorelevant release media, e.g. FaSSIF, FeSSIF and FeSSIFplus, can be produced as necessary within a few minutes by the addition of water or aqueous buffer solution.
  • the invention relates to a process for preparing a storable instant form of an aqueous mixed micellar solution or mixed micellar dispersion comprising the steps of
  • (C) optionally one or more non-phospholipid substances selected from among triacylglycerides and the breakdown products thereof, wherein
  • the molar ratio of the components (A) : (B) is from 0.1 :1 to 1 :1 and the molar ratio of the components (C) : (B) is from 0.1 :1 to 6:1 ,
  • the invention relates to a process for preparing ready-to-use aqueous mixed micellar solutions, characterised in that in another step
  • the invention relates to an instant form of an aqueous mixed micellar solution free from organic solvents and substantially anhydrous, which is sufficiently stable for storage, comprising
  • (C) optionally one or more non-phospholipid substances selected from among triacylglycerides and the breakdown products thereof, wherein
  • the molar ratio of the components (A) : (B) is from 0.1 :1 to 1 :1 and the molar ratio of the components (C) : (B) is from 0.1 :1 to 6:1 ,
  • the present invention relates to the use of the ready-to-use mixed micellar solution redispersed from an instant form according to the invention, as a biorelevant medium or as a physiological buffer system in the analysis of the in vitro release of pharmaceutical active substances.
  • the non-phospholipid component (B) selected from among bile acid, bile acid salts, bile acid derivatives and salts of a bile acid derivative is dissolved or suspended in water or an optionally buffered aqueous solution, at a temperature between 0 and 50 0 C, preferably between 20 and 40 0 C, the phospholipid component (A) and optionally the non-phospholipid component (C) is either added directly to the solution or suspension containing the component (B) and dispersed therein, at a temperature between 0 and 50 0 C, preferably between 20 and 40 0 C, or however dispersed separately in water or an optionally buffered aqueous solution and the aqueous systems thus obtained containing component (A), (B) and optionally (C) are combined,
  • the resulting suspension is homogenised, for example by ultrasound and/or high pressure filtration, while if both methods of homogenisation are used the high pressure filtration is preferably carried out after the ultrasound treatment.
  • a pore size of between 0.2 and 0.5 ⁇ m is expediently chosen. A particle size distribution in the nm range is obtained with a high degree of reproducibility.
  • Step (i) is preferably carried out at a temperature of for example 10 to 40°C, e.g. at 15 to 25°C, but particularly without any external introduction of heat.
  • the non-phospholipid component (B) is first of all dissolved or suspended in water or aqueous buffer solution in a concentration of 1 - 95 % (m/V) and particularly in a concentration of 10 - 60 % (m/V).
  • the phospholipid component (A) and optionally the non-phospholipid component (C) is then preferably added to the solution or suspension containing component (B) and emulsified with stirring, for example in a concentration of 0.5 - 35 % (m/V) and particularly in a concentration of 5 - 20 %.
  • the molar ratio of components (A) : (B) with regard to all aspects of the invention is 0.1 :1 to 1 :1 , preferably 0.2:1 to 0.4:1 , but particularly preferably about 0.25:1.
  • the molar ratio of the optionally added component (C) : (B) is 0.1 :1 to 6:1 , preferably 1 :1 to 5:1 , but particularly preferably about 4:1 , with regard to all aspects of the invention.
  • the solvents used may be aqueous buffer solutions with added salt, but pure water is preferably used.
  • the buffer substances used are for example the following acids and their associated salts as well as mixtures thereof: phosphoric acid, acetic acid, citric acid, malic acid, oxalic acid, succinic acid, fumaric acid, tartaric acid, phthalic acid, boric acid, malonic acid, glutaric acid, glutamic acid and aspartic acid.
  • the salts used to adjust the osmolality are NaCI, KCI or CaC ⁇ .
  • the pH values of the solvents are between 4-8, preferably between 5-7. If aqueous buffer and salt solutions are used, both buffer substance and also salt are dissolved before the addition of the non-phospholipid substance.
  • step (i) a clear solution or dispersion is formed within a few hours with stirring at ambient temperature.
  • time taken for clarification can be shortened to about 30 min and in addition a high reproducibility can be achieved in terms of the particle size.
  • Further improvement to the reproducibility is achieved by subsequent filtration, e.g. high pressure filtration through a 0.45 ⁇ m or 0.2 ⁇ m filter.
  • step (ii) is carried out by lyophilisation or spray drying, particularly preferably by lyophilisation, thus rendering the mixed micelles suitable for storage.
  • the dispersion obtained in step (i) of the process according to the invention may then be lyophilised gently in the freeze-dryer without the addition of further excipients.
  • the freeze-drying may for example be carried out by freezing the dispersion to -40 0 C (1 K/min), subsequent main drying at 0 - 20 0 C and 0.28 mbar and after-drying at 30°C and 0.01 mbar.
  • the dispersion is placed in metered amounts for example in dishes as a bulk material or in vials or blisters for later use, frozen and the water is eliminated in vacuo.
  • the advantage of this process is the low stress to which the mixed micelles are subjected during drying.
  • the lyophilisate may be sealed directly under a nitrogen gas current and this results in an instant form which is stable (particularly with regard to the hydrolysis of the phospholipid components) and storable as the precursor of an aqueous mixed micellar solution.
  • Another possible method of eliminating the solvent is spray drying, in which the solvent water is removed by spray drying from the dispersion obtained according to step (i). Both the pure aqueous mixed micellar solution and also the solution after the addition of buffer can be dried by the spray-drying method.
  • the spray drying may for example be carried out at an entry temperature of 60 to 130 0 C, preferably 70 to 110 0 C, particularly preferably about 80°C, and an exit temperature of 40 to 90 0 C, preferably 50 to 80°C, particularly preferably about 70°C.
  • Suitable phospholipid components (A) for the purposes of the invention are
  • a mixture of phospholipids of natural origin for example egg lecithin or soya lecithin with a high concentration of phosphatidylcholine, preferably at least 80%, but particularly preferably at least 96% based on the dry mass, or
  • R 1 and R 2 which may be identical or different, represent saturated and mono- or polyunsaturated straight-chain fatty acid groups with 14 to 18 C atoms, preferably with 16 to 18 C atoms.
  • R 1 and R 2 are the myristoyl, palmitoyl, stearoyl, oleoyl and elaidoyl group.
  • Suitable non-phospholipid components (B) for the purposes of the invention are derivatives of 5 ⁇ -cholanic-24-acid of general formula
  • R 3 and R 4 each independently of one another denote a hydroxy group or a hydrogen atom and R 5 denotes a hydroxy group, the taurine or glycine group, including the salts thereof, particularly the sodium and potassium salts thereof.
  • non-phospholipid components (B) are preferably cholic acid, glycocholic acid, taurocholic acid, deoxycholic acid, glycodeoxycholic acid, taurodeoxycholic acid, chenodeoxycholic acid, glycochenodeoxycholic acid, taurochenodeoxycholic acid, ursodeoxycholic acid, lithocholic acid, hyocholic acid, hyodesoxycholic acid, sodium taurocholate, sodium taurodesoxycholate, sodium glycocholate, sodium taurochenodesoxycholate, potassium taurocholate, potassium taurodesoxycholate, potassium glycocholate and potassium taurochenodesoxycholate, but particularly sodium taurocholate, sodium taurodesoxycholate, sodium glycocholate, sodium taurochenodesoxycholate, potassium taurocholate.
  • Suitable non-phospholipid components (C) for the purposes of the invention are selected from among saturated, mono- or polyunsaturated straight-chain fatty acids with 8 to 18 C atoms, the salts and compounds thereof of general formula
  • R 6 to R 8 each independently of one another denote a hydrogen atom or a saturated, mono- or polyunsaturated straight-chain fatty acid group (acyl group) with 8 to 18 C atoms.
  • the breakdown products that occur in the gastrointestinal tract are predominantly free fatty acids R 6 -OH and monoacylglycerides of formula (III), wherein R 6 and R 8 denote hydrogen atoms and R 7 denotes one of the above-mentioned fatty acid groups, wherein the free fatty acids are usually saturated or monounsaturated and the esterified fatty acid group is usually mono- or polyunsaturated.
  • Preferred non-phospholipid components (C) are 2-glycerolmonooleate, lauric acid, myristic acid, myhstoleic acid, palmitic acid, palmitoleic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, arachidonic acid and behenic acid, the salts, particularly the sodium salts thereof, of which the sodium salt of oleic acid is particularly preferred, including the mixtures thereof.
  • the process for preparing ready-to-use aqueous mixed micellar solutions according to the second aspect of the invention consists in the fact that after steps (i) and (ii) have been carried out the instant form obtained, which is present as a powdered mixed micellar system, is redispersed in another step (iii) in water or an aqueous buffer directly before use.
  • the redispersing may be carried out in a few seconds and leads to mixed micellar solutions that can be used directly, which have reproducible micelle sizes and a high batch homogeneity in terms of their particle size, viscosity, surface tension, osmolality and density.
  • the third aspect of the invention comprises an instant form free from organic solvents and sufficiently stable for storage, as the precursor of an aqueous mixed micellar solution comprising
  • the molar ratio of the components (A) : (B) is from 0.1 :1 to 1 :1 , preferably between 2:10 to 4:10, but particularly preferably about 1 :4 and the molar ratio of the optionally added component (C) : (B) with regard to all aspects of the invention is from 0.1 :1 to 6:1 , preferably between 1 :1 to 5:1 , but particularly preferably about 4:1 ,
  • the phospholipid component (A) consists of a pure phosphatidylcholine, such as dipalmitoylphosphatidylcholine or palmitoyloleoylphosphatidylcholine, or of a mixture of phospholipids of natural origin such as egg lecithin or soya lecithin with a high concentration of phosphatidylcholine, preferably at least 80%, particularly preferably at least 96% based on the dry mass, wherein the phosphatidylcholine has the following fatty acid composition, for example: in each case about 33% palmitic acid, 27% oleic acid, 17% linoleic acid, 14% stearic acid and 9% other fatty acids,
  • the non-phospholipid component (B) consists of cholic acid, glycocholic acid, taurocholic acid, deoxycholic acid, glycodeoxycholic acid, taurodeoxycholic acid, chenodeoxycholic acid, glycochenodeoxycholic acid, taurochenodeoxycholic acid, ursodeoxycholic acid, lithocholic acid, hyocholic acid, hyodesoxycholic acid, sodium taurocholate, sodium taurodesoxycholate, sodium glycocholate or sodium taurochenodesoxycholate, but particularly of sodium taurocholate, sodium taurodesoxycholate, sodium glycocholate or sodium taurochenodesoxycholate, of which sodium taurocholate is particularly preferred,
  • the molar ratio of the components (A) : (B) is for example 1 :3 to 1 :5, but particularly preferably about 1 :4 and the molar ratio of the optional component (C) : (B) is 0.1 :1 to 6:1 , preferably 1 :1 to 5:1 , but particularly preferably about 4:1.
  • FaSSIF Instant, FeSSIF Instant and FeSSIFplus Instant as instant forms of the biorelevant media FaSSIF, FeSSIF and FeSSIFplus which are free from organic solvents, substantially anhydrous, and sufficiently stable for storage, comprising
  • FaSSIF Instant, FeSSIF Instant and FeSSIFplus Instant are prepared according to the invention without the addition of buffer and salts.
  • the fourth aspect of the present invention comprises using the ready-to-use mixed micellar solution obtained from the instant form produced by the process according to the invention and redispersed after the addition of water, as a biorelevant medium or as a physiological buffer system in release tests, for example on pharmaceutical forms (analysis of in vitro release of pharmaceutical active substances).
  • a biorelevant medium or as a physiological buffer system in release tests
  • pharmaceutical forms analysis of in vitro release of pharmaceutical active substances.
  • the high reproducibility of the media produced also results in a high reproducibility of the releases.
  • releases are generally carried out in defined volumes (usually 200 to 1000 ml) it is possible to prepare or decant the freeze-dhed mixed micelles in batches for the preparation of the aqueous mixed micellar solution.
  • Suitable methods include for example freeze-drying in vials or blisters or the decanting of the bulk-dried mixed micelles into special containers with the addition of desiccants, for example calcium chloride, calcium oxide, 3 ⁇ molecular sieve, 4 ⁇ molecular sieve or silica gel.
  • desiccants for example calcium chloride, calcium oxide, 3 ⁇ molecular sieve, 4 ⁇ molecular sieve or silica gel.
  • the concentrated mixed micellar solution is decanted to suit the final concentration and lyophilised in the freeze-dryer.
  • the subsequent sealing should take place in the drying chamber or under a nitrogen gas current.
  • the portion packs thus obtained may be redispersed with water or with aqueous buffer directly in the release vessel. No further treatment is required.
  • the reproducibility of the aqueous mixed micellar solutions prepared is evaluated according to the parameters of particle size, particle size distribution, surface tension, density, osmolality and viscosity. With regard to all the parameters higher reproducibility can be achieved with the method of preparation according to the invention than with the processes described in the prior art. For example, using the process according to the invention, after redispersion of the instant forms aqueous mixed micellar solutions are readily obtained which reproducibly conform to the following parameters:
  • FeSSIFplus particle size distribution: PdI value between 0.2-0.3 (FaSSIF), 0.12-0.17 (FeSSIF) and 0.1-0.15 (FeSSIFplus) surface tension: 53-58 mN/m (FaSSIF), 46-49 mN/m (FeSSIF) and 48-50 mN/m (FeSSIFplus) density: 1.0055-1.0065 g/cm 3 (FaSSIF), 1.0125-1.0135 g/cm 3 (FeSSIF) and 1.0115-
  • D90 value 90% of the particles have a particle size less than or equal to the value specified
  • PdI value polydispersity index
  • cP centi-Poise.
  • step (i) For the process for preparing the aqueous mixed micellar solutions for lyophilisation, which is described hereinbefore as step (i), the compositions listed below and designated Examples 1.1 -1.8 in Table 1 were used. All the phospholipid substances contained lecithins with at least 80% phosphatidylcholine and all the non- phospholipid substances had a purity of at least 98%.
  • freeze-drying parameters in the preparation of the Examples were as follows: Freezing the aqueous mixed micellar solutions from ambient temperature to -40 0 C at a rate of 1 K/min and maintaining this temperature for 3 hours. Lowering the pressure during the main drying to 0.28 mbar and heating to 0 0 C over 10 hours and to 20 0 C over 5 hours. Increasing the vacuum during the after-drying to 0.001 mbar and increasing the temperature to 30°C for 3 hours. Then the drying chamber was ventilated to a pressure of 800 mbar with nitrogen and the vials were sealed. The mixed micelles dried in dishes were individually metered into containers with desiccant (calcium chloride) under a drying air current or decanted in bulk. The blisters were sealed under a drying air current.
  • desiccant calcium chloride
  • the dried storage form consists of a phospholipid and a non-phospholipid substance in the proportions described in Table 1 under 1.1 -1.6, optionally with the addition of the amounts of buffer and salt specified in Table 1 under 1.7-1.8, while after dissolving and dispersing in water the water content was reduced to less than 1 % by lyophilisation and the powders obtained were sealed in airtight manner so as to be impervious to water vapour. In this way, storable powders are obtained for preparing mixed micellar solutions or dispersions and above all biorelevant media.
  • the powders may be produced for preparing ready-to-use mixed micellar solutions and dispersions in the solvents described in Table 1 under 1.1 -1.8.
  • amounts of lyophilisate corresponding to the final volume were weighed out or the pre-metered amounts were redispersed in the appropriate dispersing agent (water or buffer) and used directly.
  • the appropriate dispersing agent water or buffer
  • FaSSIF 2.2 g of the powder prepared according to Table 1 under 1.1 were redispersed in 1 litre of 29 mM phosphate buffer, pH 6.5, with the addition of
  • the lyophilisates according to Table 1 1.1-1.8 may be redispersed with solvent and used as the release medium.
  • Table 1 under 1.3 is redispersed in 5.4 litres of 35 mM acetate buffer, pH 6.0, and used directly as media.
  • PC phosphatidylcholine
  • NPh-type description of the type of non-phospholipid substance NaTC: sodium taurocholate; NaTDC: sodium taurodesoxycholate; NaGC: sodium glycocholate; NaTCDC: sodium taurochenodesoxycholate; GMO: glycerolmonooleate; NaO: sodium oleate) NPh-M.

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Abstract

L'invention concerne un procédé servant à préparer des formes instantanées de solutions micellaires aqueuses mélangées contenant des composants phospholipides et non-phospholipides, en particulier un instantané du fluide intestinal simulé FaSSIF, un instantané du fluide intestinal simulé FeSSIF et un instantané du fluide intestinal simulé FeSSIFplus, lesdites formes étant suffisamment stables pour être stockées, consistant à préparer une solution micellaire aqueuse mélangée concentrée et à la suite de cela à éliminer le solvant sous pression réduite, par lyophilisation ou séchage par pulvérisation, sans utiliser aucun solvant organique dans l'une quelconque des étapes de procédé. Les solutions micellaires aqueuses mélangées redispersées sont en particulier destinées à être utilisées dans l'analyse de la libération in vitro en tant que systèmes de tampon physiologique servant à prédire la résorption in vivo de substances pharmaceutiques actives.
PCT/EP2007/060592 2006-10-06 2007-10-05 Procédé servant à préparer des formes instantanées de solutions micellaires aqueuses mélangées servant de systèmes de tampon physiologique destinés à être utilisés dans l'analyse de la libération in vitro Ceased WO2008040799A2 (fr)

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EP06121890.5 2006-10-06
EP06121890 2006-10-06
EP07105055 2007-03-27
EP07105055.3 2007-03-27

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WO2008040799A2 true WO2008040799A2 (fr) 2008-04-10
WO2008040799A3 WO2008040799A3 (fr) 2008-06-12

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EP2645099A1 (fr) 2012-03-30 2013-10-02 Phares Pharmaceutical Research N.V. Compositions biopertinentes
EP2857043A4 (fr) * 2012-05-31 2015-11-04 Terumo Corp SUPPORT SENSIBLE AU pH ET PROCÉDÉ POUR LE PRODUIRE, MÉDICAMENT SENSIBLE AU pH ET COMPOSITION PHARMACEUTIQUE SENSIBLE AU pH CONTENANT CHACUN LEDIT SUPPORT, ET PROCÉDÉ DE CULTURE EMPLOYANT LEDIT MÉDICAMENT SENSIBLE AU pH OU LADITE COMPOSITION PHARMACEUTIQUE SENSIBLE AU pH
WO2021165386A1 (fr) 2020-02-19 2021-08-26 Bayer Aktiengesellschaft Prédiction de propriétés de formulation

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2645099A1 (fr) 2012-03-30 2013-10-02 Phares Pharmaceutical Research N.V. Compositions biopertinentes
WO2013144374A1 (fr) 2012-03-30 2013-10-03 Phares Pharmaceutical Research N.V. Compositions biologiquement pertinentes
EP2857043A4 (fr) * 2012-05-31 2015-11-04 Terumo Corp SUPPORT SENSIBLE AU pH ET PROCÉDÉ POUR LE PRODUIRE, MÉDICAMENT SENSIBLE AU pH ET COMPOSITION PHARMACEUTIQUE SENSIBLE AU pH CONTENANT CHACUN LEDIT SUPPORT, ET PROCÉDÉ DE CULTURE EMPLOYANT LEDIT MÉDICAMENT SENSIBLE AU pH OU LADITE COMPOSITION PHARMACEUTIQUE SENSIBLE AU pH
JPWO2013180253A1 (ja) * 2012-05-31 2016-01-21 テルモ株式会社 ｐＨ感受性担体およびその製造方法、並びに該担体を含むｐＨ感受性医薬、ｐＨ感受性医薬組成物およびこれを用いた培養方法
US9248192B2 (en) 2012-05-31 2016-02-02 Terumo Kabushiki Kaisha pH sensitive carrier and preparation method thereof, and pH sensitive drug and pH sensitive drug composition each containing the carrier, and method for treating or preventing diseases using the same
US10765751B2 (en) 2012-05-31 2020-09-08 Terumo Kabushiki Kaisha pH sensitive carrier and preparation method thereof, and pH sensitive drug and pH sensitive drug composition each containing the carrier, and method for treating or preventing diseases using the same
WO2021165386A1 (fr) 2020-02-19 2021-08-26 Bayer Aktiengesellschaft Prédiction de propriétés de formulation

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