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WO1997018245A1 - Complexe de naproxene et de beta-cyclodextrine - Google Patents

Complexe de naproxene et de beta-cyclodextrine Download PDF

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Publication number
WO1997018245A1
WO1997018245A1 PCT/IB1996/001367 IB9601367W WO9718245A1 WO 1997018245 A1 WO1997018245 A1 WO 1997018245A1 IB 9601367 W IB9601367 W IB 9601367W WO 9718245 A1 WO9718245 A1 WO 9718245A1
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WO
WIPO (PCT)
Prior art keywords
naproxen
complex
mol
inclusion complex
cyclodextπn
Prior art date
Application number
PCT/IB1996/001367
Other languages
English (en)
Inventor
Lawrence John Penkler
Darryl Vanstone Whittaker
Lueta-Ann Glintenkamp
Original Assignee
Farmarc Nederland B.V.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Farmarc Nederland B.V. filed Critical Farmarc Nederland B.V.
Priority to AU76372/96A priority Critical patent/AU7637296A/en
Publication of WO1997018245A1 publication Critical patent/WO1997018245A1/fr

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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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • 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
    • 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

Definitions

  • This invention relates to an inclusion complex ot naproxen or a pharmaceutically acceptable salt thereof, a beta-cyclodext ⁇ n and a hydroxylamine, and to pharmaceutical compositions containing the inclusion complex
  • Cyclodextrins are water soluble cone-shaped cyclic oligosacchandes containing 6, 7 or 8 glucopyranose umts
  • the interior or "cavity" of the cone (hereinafter referred to as the cyclodextrin cavity) is hydrophobic.
  • cyclodextrin de ⁇ vatives such as alkyl, hydroxyalkyi and sulfoalkyl ethers have been prepared with improved solubility [see (J Szejth & K-H Fromming, Cyclodextrins in Pharmacy, Kluwer Academic Press) and (Stella, V J et al, Pharmaceutical Research 1995, 12 (9) S205)]
  • Suitably sized hydrophobic "guest” molecules may enter the "host” cavity to form a classical host-guest "inclusion compound” or "inclusion complex” with either the entire guest molecule mcluded or only a portion thereof
  • the driving mechanism for cyclodextrin inclusion complexation is the affinity of the hydrophobic guest molecule for the cavity of the cyclodextrin host molecule with displacement of cavity water molecules to a thermodynamically more stable state
  • the term 'complex stability" or stability of a given inclusion complex refers to the association
  • Cyclodextrin inclusion complexes may be prepared on the basis of liquid state, solid state or semi-solid state reaction between the components (J Szejth, Cyclodextrin Technology, Kluwer Academic Press) The first is accomplished by dissolving the cyclodextrin and guest in a suitable solvent or mixture of solvents and subsequently isolating the solid state complex by crystallization, evaporation, spray drying or freeze drying
  • the two components may be screened to uniform particle size and thoroughly mixed whereafter they are ground in a high energy mill with optional heating, screened and homogenized
  • the semi-solid state the two components are kneaded in the presence of small amounts of a suitable solvent, and the complex so-formed, is dried, screened and homogemzed
  • the liquid state reaction generally provides optimum conditions for completeness of reaction Depending on solvent conditions, the dissolved inclusion complex exists in equilibrium between uncomplexed host and guest and complexed host/guest
  • the "fit ' of a given drug into a cyclodextrin may allow for only few intermolecular interactions between host and guest leading to a low complex stability with correspondingly limited enhancement of properties such as taste masking, chemical stabilization and solubilization
  • ternary inclusion complex has been used to refer to inclusion complexes which occur when two different guest molecules, neither being water, are inco ⁇ orated into the same cyclodextrin cavity [see (J Szejth, Cyclodextrin Technology, Kluwer Academic Press, p 168-169)]
  • Such ternary complexes are more stable than the corresponding binary complexes due to occupation of greater volume of the cavity in the ternary complex with a greater number of hydrophobic/van der Waals interactions
  • organic solvents e g ethanol, ether, etc
  • the solvent may be inco ⁇ orated into the complex as a ternary component which is difficult to remove
  • ternary complex is used to define a new type of complex, comprising a drug, a cyclodextrin and a third component, wherein the third component interacts with the drug and cyclodextrin from outside the cyclodextrin cavity
  • the combination of pH modification together with cyclodextrin complexation has been used to increase the solubility of drugs through the combination of ionization and complexation [see (Loftsson, T et al, European Journal of Pharmaceutical Science 1993, (1) 95-101), (High solubility multicomponent inclusion complexes consisting of an acidic drug, a cyclodextrin and a base, Chiesi, P et al, PCT Int Appl , WO 9528965) and (Highly soluble multicomponent inclusion complexes containing a basic drug, an acid, and a cyclodextrin, Chiesi, P et al PCT Int Appl , WO 9416733)]
  • the multicomponent inclusion complexes are prepared by forming an opalescent to clear aqueous solution ot the three components, filtering and removal of the water by freeze drying or spray drying In these cases the combined effect of increasing the solubility of a drug through ionization on the
  • European Patent Application No 0538011 to Schermg Co ⁇ oration discloses a pharmaceutically acceptable composition of matter comprising a lipophilic oligosaccha ⁇ de antibiotic, at least about a stoichiometric amount of a base capable of forming a pharmaceutically acceptable salt with the lipophilic oligosaccha ⁇ de antibiotic such as tromethamme, and an amount of, for example, hydro xypropyl- ⁇ -cyclodext ⁇ n sufficient to achieve efficacious delivery of the lipophilic oligosaccha ⁇ de antibiotic to the serum of an animal, while simultaneously avoiding occurrence of adverse reaction syndrome, and optionally a pharmaceutically acceptable non-ionic surfactant It is to be noted that this composition of matter is not a ternary complex of the antibiotic, base and cyclodextrin, but rather an aggregate of the cyclodextrin and the antibiotic in the form of a salt with the base The antibiotic does not contain any readily lonisable group capable of forming an anion and thus is not readily capable
  • an inclusion complex of (a) naproxen or the pharmaceutically acceptable salt thereof, (b) an unsubstituted or substituted beta-cyclodext ⁇ n, and (c) a hydroxylamine, wherein in the complex, naproxen or the pharmaceutically acceptable salt thereof is included in the beta-cyclodext ⁇ n and the hydroxylamine interacts with both naproxen or the pharmaceutically acceptable salt thereof and the beta-cyclodext ⁇ n
  • hydroxylamine includes hydroxyalkylamines
  • (a) may be naproxen or a pharmaceutically acceptable salt of naproxen, preferably naproxen sodium
  • (b) may be an unsubstituted beta-cyclodext ⁇ n or preferably a substituted beta-cyclodext ⁇ n, more preferably 2-hydroxypropyl- ⁇ - cyclodext ⁇ n
  • (c) is a hydroxylamine preferably contaimng at least one lonisable amino group and one hydroxyl group
  • the hydroxylamine may be selected from the group consisting of ammonium hydroxide, t ⁇ s(hydroxymethyl)am ⁇ nomethane also known as tromethamme, ethanolamine, diethanolamine, triethanolamine, meglumine also known as N-mefhylglucamine, 2-am ⁇ no-2-methyl-l ,3-propaned ⁇ ol, 2-am ⁇ no-2-methyl- propanol and 2-am ⁇ no-l ,2,3-propanet ⁇ ol
  • the preferred hydroxylamines are diethanolamine, triethanolamine and tromethamme, most preferably tromethamme
  • the inclusion complex preferably has a stoichiometry of (a) (b) (c) mol/mol/mol of 1 0,5 to 100 1 to 100 , preferably 1 0,5 to 10 10 to 100 , most preferably 1 0,5 to 2 more than 10 to 100
  • a pharmaceutical composition comprising as an active ingredient a complex as set out above, and a pharmaceutically acceptable carrier
  • the pharmaceutical composition may be formulated for oral, parenteral, ophthalmic, nasal, rectal or vaginal application
  • a pharmaceutical composition in the form of a liquid formulation or in the form of a formulation for reconstitution as a liquid formulation comprising as an active ingredient a complex as set out above, which liquid formulation has a pH of from 5,5 to 8,5 inclusive, preferably from 6,5 to 7,5 inclusive
  • the formulation for reconstitution is preferably reconstituted with water at ambient temperature or less.
  • the formulation may be an effervescent formulation
  • Figure 1 illustrates the geometry optimised moleculai model of a complex formed between naproxen, methyl)aminomethane and ⁇ -cyclodextrm.
  • Figure 2 illustrates the potentiomet ⁇ c titration of an aqueous solution contaimng naproxen sodium and ⁇ -cyclodext ⁇ n as a function of pH using sodium hydroxide as titrant.
  • Figure 3 illustrates the potentiomet ⁇ c titration of a first aqueous solution containing naproxen sodium , ⁇ cy clodextrin and t ⁇ s(hydroxymethyl)am ⁇ nomethane as a function of pH using sodium hydroxide as titrant, and
  • Figure 4 illustrates the potentiomet ⁇ c titration ot a second aqueous solution contaimng naproxen sodium, ⁇ c>clodextnn and t ⁇ s(hydroxymethyl)arn ⁇ nomethane as a function of pH using sodium hydroxide as titrant
  • the crux of the invention is a complex formed between (a) naproxen or a pharmaceutically acceptable salt thereof, (b) a ⁇ -cyclodext ⁇ n, and (c) a hydroxylamine, wherein the hydroxylamine is capable of simultaneously interacting with the drug and the cyclodextrin in a manner which increases the drug/cyclodext ⁇ n stability under certain conditions ot concentration, pH and temperature
  • Electrostatic interactions occur between species of opposite formal or partial charge
  • ionic bonding is relatively strong (IO 2 kcal mol ') compared with covalent bonding (IO 6 kcal mol ') which involves the sharing of electrons between two atoms
  • Hydrogen bonding interactions arise when an acidic hydrogen atom (eg OH, NH, SH) on one molecule is attracted towards an electron greedy atom (O,N) on the same or different molecule Hydrogen bonds are fairly weak interactions (10 kcal mol * ) and form in preferred directions over distances of less than 2,5A
  • a hydrogen bond occurs between polar covalent molecules but is itself electrostatic in nature Hydrogen bonds may be disrupted by increasing temperature or large deviation of pH from neutrality
  • Van der Waals interactions also known as London dispersion forces
  • London dispersion forces are still weaker forces (1 kcal mol ') but are non directional and operate over a distance of less than 4A The latter are too weak in themselves to establish a stable molecular species If, however, a specific spatial arrangement between two molecules allows numerous van der Waals interactions to take place, the species may attain a stability which is comparable with covalent bonding This is the case with cyclodextrin inclusion complexes where there is a tight fit between host and guest The presence of
  • Hydrophilic and hydrophobic interactions are still weaker and involve groups of like polarity or apola ⁇ ty respectively in relation to the disposition of solvent molecules Hydrophilic groups will tend to assemble together with associated polar solvent molecules or polar groups, whereas hydrophobic groups will repel polar solvent molecules or groups
  • the first component ot the complex is naproxen or a pharmaceutically acceptable salt thereof such as for example naproxen sodium
  • the naproxen is preferably present in the complex as its sodium salt
  • the second component of the complex is an unsubstituted or substituted ⁇ - cyclodext ⁇ n
  • the ⁇ -cyclodext ⁇ n may be substituted with alkyl, hydroxyalkyi, ammo, maltosyl or galactosyl groups
  • the degree of substitution of the ⁇ -cyclodextrm may vary between 1 and 10 substituents per cyclodextrin molecule.
  • the ⁇ -cyclodextrm used is 2-hydroxypropyl- ⁇ -cyclodext ⁇ n having a degree of substitution of from 3 to 7 inclusive
  • the third component of the complex is a hydroxylamine
  • the hydroxylamine preferably contains at least one lonisable amino group and one hydroxyl group Suitable hydroxylamines include physiological acceptable water soluble compounds such as ammonium hydroxide, tromethamme, ethanolamine, diethanolamine, triethanolamine, meglumine, 2-am ⁇ no-2-methyl-l ,3-propaned ⁇ ol, 2-am ⁇ no-2-methyl-propanol and 2 amino- 1 ,2,3-propanet ⁇ ol
  • physiological acceptable water soluble compounds such as ammonium hydroxide, tromethamme, ethanolamine, diethanolamine, triethanolamine, meglumine, 2-am ⁇ no-2-methyl-l ,3-propaned ⁇ ol, 2-am ⁇ no-2-methyl-propanol and 2 amino- 1 ,2,3-propanet ⁇ ol
  • the preferred hydroxylamines are diethanolamine, triethanolamine and tromethamme, most preferably tromethamme
  • the complex preferably has a stoichiometry mol/mol/mol of (a) (b) (c) of from 1 0,5 to 100 1 to 100 , more preferably 1 0,5 to 10 10 to 100 , most preferably 1 0,5 to 2 more than 10 to 100
  • the complex of the invention may be prepared according to any one of the following general methodologies
  • the hydroxylamine and the drug are blended to form a solution or slurry with optional use of water
  • the mixture is added to a concentrated solution of the cyclodextrin which may be optionally buffered to around neutral pH with a pharmaceutically acceptable buffer such as phosphate buffer
  • a pharmaceutically acceptable buffer such as phosphate buffer
  • the solution may be heated to effect dissolution
  • the system is agitated for 0,5 to several hours until equilibrium is reached to obtain the liquid complex
  • Step 2 The solution obtained in Step 1 may be precipitated, sprav dried or freeze dried to obtain the solid complex
  • the hydroxylamine and the drug are blended to form a paste with optional use of water
  • the cyclodextrin is added po ⁇ ion- wise to the paste with vigorous mixing and occasional addition of water to maintain the paste consistencv
  • the mixture is kneaded for 0,5 to several hours
  • the paste may be extruded and dried in the form of pellets or directly dried in vacuo with heating and screened to uniform particle size
  • the hydroxylamine and the cyclodextrin are blended to form a paste with use of water
  • the drug is added portion-wise to the paste with vigorous mixing and occasional addition of water to maintain the paste consistency
  • the mixture is kneaded for 0,5 to several hours
  • the paste may be extruded and dried in the form of pellets or directly dried in vacuo with heating and screened to uniform particle size
  • the liquid complex obtained in step 1 may be adapted for parenteral, ophthalmic, topical, oral, vaginal or rectal application by addition of pharmaceutically acceptable excipients such as anti-oxidants (eg EDTA, N- acetylcysteine), co-solvents (eg polyethyleneglycol, propyleneglycol), viscosity modifiers (eg hydro ypropy lmethylcellulose) , osmolality modifying agents (eg sorbitol, mannitol), pH modifying agents (eg HCl, NaOH. phosphate buffers), sweeteners (eg sodium cyclamate, sodium saccharin, sucrose) or flavours
  • pharmaceutically acceptable excipients such as anti-oxidants (eg EDTA, N- acetylcysteine), co-solvents (eg polyethyleneglycol, propyleneglycol), viscosity modifiers (eg hydro ypropy lmethylcellulose) , o
  • the complexes obtained in steps 2, 3 or 4 may be adapted for use m the conventional formulation of tablets, capsules, suppositories, pessaries, nasal and pulmonary inhalations and topical applications
  • the pharmaceutical composition of the invention is preferably in the form of a liquid formulation or in the form ot a formulation tor reconstitution as a liquid formulation, which liquid formulation has a pH of from 5,5 to 8,5 inclusive, or preferably from 6,5 to 7,5 inclusive
  • naproxen forms stable inclusion complexes with beta- cyclodext ⁇ ns, and to a lesser extent, with alpha and gamma-cyclodext ⁇ ns Complexation ot naproxen or its sodium salt with beta-cyclodext ⁇ ns does not however lead to effective taste masking of naproxen.
  • the ternary complex formed between naproxen sodium/tromethamine/hydroxypropyl-beta- cyclodext ⁇ n has a bland taste when dissolved in water compared with a strong burning sensation produced by a similar bmary naproxen sodium/hydroxypropyl-beta-cyclode t ⁇ n complex at equivalent pH
  • the rationale underlying the effect ot taste masking of the ternary complex is a significantly increased association constant due to a combination of ionic, hydrogen bonding and van der Waals interactions as opposed to exclusive van der Waals interactions in the binary system
  • the increased association constant of the ternary complex retards dissociation of naproxen in the oral cavity and thereby masks its taste
  • the first important advantage of the complex of the invention is taste- masking
  • Figure 1 shows the geometry optimised molecular model of the complex formed between naproxen, t ⁇ s(hydroxymethyl)arn ⁇ nomethane and ⁇ - cyclodext ⁇ n
  • Figure 2 shows the potentiomet ⁇ c titration of an aqueous solution contaimng naproxen sodium (3 mmol) and ⁇ -cyclodext ⁇ n (15 mmol) as a function of pH using sodium hydroxide as titrant
  • the temperature and ionic strengths were controlled to 25°C ( ⁇ 0,2°C)
  • the 5 fold excess in cyclodextrin concentration was chosen to maximize complexation of naproxen
  • the percentage of naproxen (NP) species was determined as the anion NP , protonated acid (NPH), the 1.1 ⁇ -cyclodext ⁇ n inclusion complex [(CD)(NPH)] and the corresponding 2 1 complex [(CD) 2 (NPH)] by potentiometry and equilibrium simulation for titration analysis computation
  • Titrations were carried out under a stream of dinitrogen in order to exclude atmospheric carbon dioxide
  • a computer was used to control the addition of titrant from a Radiometer ABU80 burette After each incremental addition
  • Figure 3 shows the potentiomet ⁇ c titration of an aqueous solution contaimng naproxen sodium (3 mmol), ⁇ -cyclodext ⁇ n (15 mmol) and t ⁇ s(hydroxymethyl)am ⁇ nomethane (TR)(3 mmol) as a function of pH using sodium hydroxide as titrant.
  • Figure 4 shows the potentiomet ⁇ c titration of an aqueous solution contaimng naproxen sodium (0,00872 mmol), ⁇ -cyclodext ⁇ n (0,00908 mmol) and tris(hydroxymethyl)aminomethane(TR)(0,0908 mmol) as a function of pH using a sodium hydroxide as titrant.
  • FIG. 1 there is shown the geometrv optimised molecular model of the complex formed between naproxen t ⁇ s(hydroxymethyl) aminomethane and ⁇ -cyclodext ⁇ n
  • the species can be identified in solution by means of potentiomet ⁇ c titration at 25 °C using sodium hydroxide as titrant
  • the complex In the absence of the ligand, no complexation is observed between ionised naproxen and ⁇ -cyclodext ⁇ n above pH 7 (see Figure 2)
  • the complex In the presence of increasing concentrations of the ligand, the complex proportionally forms preferentially around neutral pH (see Figures 3 and 4) indicating dramatic increase in naproxen-cyclodext ⁇ n complex stability at neutral and higher pH
  • This su ⁇ smg finding indicates involvement of considerable intermolecular forces exerted by the ligand in stabilising the complex as seen in the molecular mechanics of the system shown in Figure 1
  • 2-hydroxypropyl-beta-cyclodext ⁇ n (140g) and tromethamme (13, 15 g) are triturated with a small quantity of purified distilled water to form a viscous paste Naproxen (25g) is gradually added with vigorous mixing tor 1 hour
  • the paste is dried under vacuum (2mbar) at 40 °C
  • the dried complex (1 1 1) is sieved through a 710 micron sieve
  • a unit dose of a granular formulation suitable for reconstitution in water is as follows
  • Mint flavour (spray dried) 0 120g
  • Excipients are mixed with the complex, screened through a 60 mesh screen and packed into sachets
  • n d t ⁇ s(hydroxymethyl)am ⁇ nomethane 120,0 g
  • a n d t ⁇ s(hydroxymethyl)am ⁇ nomethane 120,0 g
  • Naproxen sodium 25 g
  • the paste is dried under vacuum (2mbar) at 40°C
  • the dried complex (1 10 1 naproxen sodium tromethamme cvclodext ⁇ n) is sieved through a 710 micron sieve
  • the complex formed is void of the bitter, burning taste sensation produced by naproxen Solutions of naproxen-cyclodextrm complexes produced in the absence of the hydroxylamine produce a severe burning sensation and bitter taste
  • the complex prepared according to Example 3 may be inco ⁇ orated in a unit dose of a granular formulation suitable for reconstitution in water at room temperature as follows
  • Example 3 (equivalent to 200mg naproxen) 2 706g Saccharin 0.030g
  • Mint flavour (spray dried) 0, 120g
  • Excipients excluding tartaric acid and lubricant are mixed with the complex, and screened through a 60 mesh screen
  • the mixture is optionally granulated with the use of a water soluble binder such as polyvinylpyrollidone
  • the granulate is blended with the tartaric acid
  • the lubricant is screened into the mixture and blended
  • the product is compressed into effervescent tablets
  • the product reconstituted in water at room temperature is pleasant tasting and free from the bitter and burning taste sensation produced by naproxen

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Abstract

Cette invention concerne un composé d'inclusion, utile en tant que produit pharmaceutique, qui est constitué de naproxène ou d'un sel pharmaceutiquement acceptable de naproxène tel que du sodium de naproxène, d'une béta-cyclodextrine substituée ou non substituée telle que la 2-hydroxypropyl-béta-cyclodextrine et d'une hydroxylamine telle que la trométhamine. Dans ce complexe, le naproxène ou le sel pharmaceutiquement acceptable de naproxène est inclus dans la béta-cyclodextrine et l'hydroxylamine et le naproxène ou son sel pharmaceutiquement acceptable agissent l'un sur l'autre que même que l'hydroxylamine et la béta-cyclodextrine.
PCT/IB1996/001367 1995-11-14 1996-11-14 Complexe de naproxene et de beta-cyclodextrine WO1997018245A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU76372/96A AU7637296A (en) 1995-11-14 1996-11-14 Complex of naproxen and beta-cyclodextrin

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
ZA959658 1995-11-14
ZA95/9658 1995-11-14
ZA963815 1996-05-14
ZA96/3815 1996-05-14

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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998055148A1 (fr) * 1997-06-05 1998-12-10 Janssen Pharmaceutica N.V. Compositions pharmaceutiques comprenant des cyclodextrines
US6776164B2 (en) 1998-06-05 2004-08-17 Interag Enhanced intravaginal devices
EP1435929B1 (fr) * 2001-09-19 2008-01-16 Walcom Animal Science (I.P.) Limited Composition contenant de la cysteamine destinee a ameliorer la lactation des animaux producteurs de lait
EP1905427A1 (fr) 2006-09-28 2008-04-02 Losan Pharma GmbH Formulation solubilisée rapidement des anti-inflammatoires non stéroïdiens
EP1974751A1 (fr) * 2007-03-26 2008-10-01 The Jordanian Pharmaceutical Manufacturing Co. Formulations pour médicaments anti-inflammatoires sans stéroïdes
WO2012080718A1 (fr) * 2010-12-15 2012-06-21 Reckitt Benckiser Healthcare International Limited Nouvelle formule pharmaceutique contenant un ains et de la cyclodextrine
CN106727288A (zh) * 2016-11-10 2017-05-31 南京斯泰尔医药科技有限公司 水溶性黄体酮注射液组合物及制备方法
US9968552B2 (en) * 2003-12-19 2018-05-15 Aziende Chimiche Riunite Angelini Francesco A.C.R.A.F.S.P.A. Pharmaceutical oral dosage form comprising a non-steroidal anti-inflammatory drug, and having good palatability
WO2019105957A1 (fr) 2017-11-30 2019-06-06 Aziende Chimiche Riunite Angelini Francesco A.C.R.A.F. S.P.A. Composition liquide stable de kétoprofène, sels et énantiomères de celui-ci
US10532102B2 (en) 2016-08-19 2020-01-14 Foresee Pharmaceuticals Co., Ltd. Pharmaceutical composition and methods of uses
WO2023144692A1 (fr) * 2022-01-25 2023-08-03 Leiutis Pharmaceuticals Llp Nouvelles préparations de naproxène sodique destinées à être administrées par voie parentérale

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WO1998055148A1 (fr) * 1997-06-05 1998-12-10 Janssen Pharmaceutica N.V. Compositions pharmaceutiques comprenant des cyclodextrines
US6776164B2 (en) 1998-06-05 2004-08-17 Interag Enhanced intravaginal devices
EP1435929B1 (fr) * 2001-09-19 2008-01-16 Walcom Animal Science (I.P.) Limited Composition contenant de la cysteamine destinee a ameliorer la lactation des animaux producteurs de lait
US9968552B2 (en) * 2003-12-19 2018-05-15 Aziende Chimiche Riunite Angelini Francesco A.C.R.A.F.S.P.A. Pharmaceutical oral dosage form comprising a non-steroidal anti-inflammatory drug, and having good palatability
EP1905427A1 (fr) 2006-09-28 2008-04-02 Losan Pharma GmbH Formulation solubilisée rapidement des anti-inflammatoires non stéroïdiens
EP1974751A1 (fr) * 2007-03-26 2008-10-01 The Jordanian Pharmaceutical Manufacturing Co. Formulations pour médicaments anti-inflammatoires sans stéroïdes
US9138482B2 (en) 2010-12-15 2015-09-22 Reckitt Benckiser Healthcare International Limited Pharmaceutical formulation comprising NSAID and cyclodextrin
WO2012080718A1 (fr) * 2010-12-15 2012-06-21 Reckitt Benckiser Healthcare International Limited Nouvelle formule pharmaceutique contenant un ains et de la cyclodextrine
US10363316B2 (en) 2010-12-15 2019-07-30 Reckitt Benckiser Healthcare (Uk) Limited Pharmaceutical formulation comprising NSAID and cyclodextrin
US10532102B2 (en) 2016-08-19 2020-01-14 Foresee Pharmaceuticals Co., Ltd. Pharmaceutical composition and methods of uses
US11013810B2 (en) 2016-08-19 2021-05-25 Foresee Pharmaceuticals Co., Ltd. Pharmaceutical composition and methods of uses
US11628220B2 (en) 2016-08-19 2023-04-18 Foresee Pharmaceuticals Co., Ltd. Pharmaceutical composition and methods of uses
CN106727288A (zh) * 2016-11-10 2017-05-31 南京斯泰尔医药科技有限公司 水溶性黄体酮注射液组合物及制备方法
WO2019105957A1 (fr) 2017-11-30 2019-06-06 Aziende Chimiche Riunite Angelini Francesco A.C.R.A.F. S.P.A. Composition liquide stable de kétoprofène, sels et énantiomères de celui-ci
WO2023144692A1 (fr) * 2022-01-25 2023-08-03 Leiutis Pharmaceuticals Llp Nouvelles préparations de naproxène sodique destinées à être administrées par voie parentérale
GB2630712A (en) * 2022-01-25 2024-12-04 Leiutis Pharmaceuticals Llp Novel naproxen sodium preparations for parenteral

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