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WO1997018245A1 - Complex of naproxen and beta-cyclodextrin - Google Patents

Complex of naproxen and beta-cyclodextrin 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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WIPO (PCT)
Prior art keywords
naproxen
complex
mol
inclusion complex
cyclodextπn
Prior art date
Application number
PCT/IB1996/001367
Other languages
French (fr)
Inventor
Lawrence John Penkler
Darryl Vanstone Whittaker
Lueta-Ann Glintenkamp
Original Assignee
Farmarc Nederland B.V.
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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/en

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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

An inclusion complex of naproxen or a pharmaceutically salt thereof such as naproxen sodium, an unsubstituted or substituted beta-cyclodextrin such as 2-hydroxypropyl-beta-cyclodextrin, and a hydroxylamine such as tromethamine, wherein in the complex, naproxen or the pharmaceutically acceptable salt thereof is included in the beta-cyclodextrin and the hydroxylamine interacts with both naproxen or the pharmaceutically acceptable salt thereof and the beta-cyclodextrin, is useful as a pharmaceutical product.

Description

COMPLEX OF NAPROXEN AND BETA-CYCLODEXTRIN
BACKGROUND OF THE INVENTION
This invention relates to an inclusion complex ot naproxen or a pharmaceutically acceptable salt thereof, a beta-cyclodextπn and a hydroxylamine, and to pharmaceutical compositions containing the inclusion complex
The solubility and chemical stability of drugs strongly influences successful pharmaceutical formulation Many drugs from virtually all therapeutic categories suffer from solubility and/or chemical stability problems
Poorh soluble (hydrophobic) drugs, when orally administered as sohd dosage forms, are slow to dissolve thereby retarding the absoφtion process which in some cases may lead to incomplete absoφtion Slowly dissolving drugs may also exacerbate local side effects produced by the drug (e g gastric imtancy) Furthermore it is often difficult, it not impossible, to formulate insoluble drugs for liquid drug
Figure imgf000004_0001
ιa oral, parenteral, ophthalmic, vaginal, nasal or rectal administration without effective drug solubilization Chemically labile drugs are susceptible to degradation in the solid state, and more frequently in solution, due to hydrolysis, photolysis or oxidation
Among the variety of techniques available to improve drug solubility (e g pH modification, co-solvents, surfactants and the like), cyclodextrins and their derivatives have found extensive application as solubilizers and stabilizers due to their ability to form inclusion complexes with a wide vaπety of compounds [see (J Szejth, Cyclodextrin Technology, Kluwer Academic Press) and (J Szejth & K-H Frommmg Cyclodextrins in Pharmacy, Kluwer Academic Press)]
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. whilst the exterior is hydrophilic The size of the cavity increases with increasing number of glucose units Several cyclodextrin deπvatives 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/dissociation equilibrium of host and guest in solution Complex stability depends on the number of intermolecular bonding interactions between the host and guest Van der Waals forces and hydrophobic interactions are the main interactions stabilizing inclusion complexes (Bergeron R J et al, Journal of the American Chemical Socien 1977,99,5146) Depending on the nature and position of hydrogen bonding functionalities on a given guest, there may be hydrogen bonding between the guest and hydroxyl groups of the cyclodextrin or other hydrogen bonding groups in the case of cyclodextrin derivatives Ionic interactions between the host and guest are also possible in the case of ionic cyclodextrins such as sulphobutyl ethers (Stella, V J et al Pharmaceutical Research 1995, 12(9)S205)
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 In the solid state method, 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 In 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
In many cases, 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
In the past in the hterature, the term ternary inclusion complex has been used to refer to inclusion complexes which occur when two different guest molecules, neither being water, are incoφorated 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 In cases where organic solvents are used (e g ethanol, ether, etc) to prepare inclusion complexes, the solvent may be incoφorated into the complex as a ternary component which is difficult to remove
However, in this application the term 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 one hand and cyclodextrin complexation on the other hand leads to a greater total solubility of the drug than either ionization or complexation alone However, ionized guests exhibit up to an order of magnitude lower complex stability than complexes of the corresponding unionized form due to the increased polarity of the ionized form [see (Connors, K A, Journal of Pharmaceuticdl Sciences 1982,71 ,217- 222), (Oπenti, I , et al, European Journal of Pharmacy and Biopharmaceutics 1991 ,37, 110-112) and (Hendrickson, K et al, Australian Journal of Chemistry 1995, 48(6) 1125-1132)] Thus simple drug ionization with the addition of cyclodextrin ieads to an increase in drug solubility, but because the complex stability constant is decreased by ionization, a greater fraction of "free" uncomplexed drug is present which defeats the object of inclusion complexation where chemical stability or taste masking effects (which are dependant on inclusion complexation) are desired
Large water soluble polymers such as polyvinylpyrrolidone and hydroxypropylmethylcellulose have been used to enhance drug/cyclodextπn complexation and improve drug solubility [see (Loftsson, T, US Pat 5,324,718) and (Loftsson, T et al, International Journal of Pharmaceutics 1995, 126, 73-78)]. Such complexes are prepared by heating aqueous solutions of the three components and then removal of the water by freeze drying or spray drying if required The dramatic effect of the polymer and cyclodextrin on increasing the solubility of the drug in a concentration dependant manner was related to an increase in the complex stability of hydrocortisone from solubility isotherm calculation However in more recent work the same polymers were shown to enhance drug solubility in the absence ot cyclodextrin (Loftsson, T et al International Journal ot Pharmaceutics 1996, 127, 193-196) The calculation of complex stability from the initial section of the solubility isotherm (the solubility of guest as a function ot cyclodextrin concentration after attaining equilibrium) assumes a l l host/guest stoichiometry and that the increase m guest solubility is proportionally related to host concentration [see (J Szejth, Cyclodextrin Technology, Kluwer Academic Press, p 143 154)] If a third component is added to the system which increases guest solubility, the relationship is no longer valid There is no direct correlation between complex stability and solubility Other techniques such as potentiometry have been used successfully to determine complex stability constant for different complex species present in solution [see (Connors, K A & Rosanske, T W, Journal of Pharmaceutical Sciences 1980, 69, 173) and (Connors, K A et al, Journal of Pharmaceutical Sciences 1982,71 ,217-222)]
European Patent Application No 0538011 to Schermg Coφoration discloses a pharmaceutically acceptable composition of matter comprising a lipophilic oligosacchaπde antibiotic, at least about a stoichiometric amount of a base capable of forming a pharmaceutically acceptable salt with the lipophilic oligosacchaπde antibiotic such as tromethamme, and an amount of, for example, hydro xypropyl-β-cyclodextπn sufficient to achieve efficacious delivery of the lipophilic oligosacchaπde 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 of ionic association with the base
SUMMARY OF THE INVENTION
According to a first aspect of the invention there is provided an inclusion complex of (a) naproxen or the pharmaceutically acceptable salt thereof, (b) an unsubstituted or substituted beta-cyclodextπn, and (c) a hydroxylamine, wherein in the complex, naproxen or the pharmaceutically acceptable salt thereof is included in the beta-cyclodextπn and the hydroxylamine interacts with both naproxen or the pharmaceutically acceptable salt thereof and the beta-cyclodextπn
The term "hydroxylamine" includes hydroxyalkylamines
In the complex, (a) may be naproxen or a pharmaceutically acceptable salt of naproxen, preferably naproxen sodium
In the complex, (b) may be an unsubstituted beta-cyclodextπn or preferably a substituted beta-cyclodextπn, more preferably 2-hydroxypropyl-β- cyclodextπn
In the complex, (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, tπs(hydroxymethyl)amιnomethane also known as tromethamme, ethanolamine, diethanolamine, triethanolamine, meglumine also known as N-mefhylglucamine, 2-amιno-2-methyl-l ,3-propanedιol, 2-amιno-2-methyl- propanol and 2-amιno-l ,2,3-propanetπol
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
According to a second aspect of the invention there is provided 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
According to a third aspect of the invention there is provided 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
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 illustrates the geometry optimised moleculai model of a complex formed between naproxen,
Figure imgf000011_0001
methyl)aminomethane and β-cyclodextrm.
Figure 2 illustrates the potentiometπc titration of an aqueous solution contaimng naproxen sodium and β-cyclodextπn as a function of pH using sodium hydroxide as titrant.
Figure 3 illustrates the potentiometπc titration of a first aqueous solution containing naproxen sodium , β cy clodextrin and tπs(hydroxymethyl)amιnomethane as a function of pH using sodium hydroxide as titrant, and
Figure 4 illustrates the potentiometπc titration ot a second aqueous solution contaimng naproxen sodium, β c>clodextnn and tπs(hydroxymethyl)arnιnomethane as a function of pH using sodium hydroxide as titrant
DESCRIPTION OF EMBODIMENTS
The crux of the invention is a complex formed between (a) naproxen or a pharmaceutically acceptable salt thereof, (b) a β-cyclodextπn, 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/cyclodextπn stability under certain conditions ot concentration, pH and temperature
In the complex, there is ionic interaction between a basic group on the hydroxylamine and the acidic group of naproxen, and there is hydrophobic or van der Waals interactions between the included portion ot the drug and the cyclodextrin cavity Optionally there mav also be electrostatic, hydrophilic and/or hydrogen bonding interactions between the hydroxy groups of the hydroxylamine and the
Figure imgf000012_0001
groups and anv other complementary substituents on the cyclodextrin
Brief definitions of the various terms used in the specification are given below
Electrostatic interactions occur between species of opposite formal or partial charge For example, ionic bonding, is relatively strong (IO2 kcal mol ') compared with covalent bonding (IO6 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) 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 electron donating substituents in a guest (eg halogens) enhances van der Waals interactions
Hydrophilic and hydrophobic interactions are still weaker and involve groups of like polarity or apolaπty 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 β- cyclodextπn For example, the β-cyclodextπn may be substituted with alkyl, hydroxyalkyi, ammo, maltosyl or galactosyl groups The degree of substitution of the β-cyclodextrm may vary between 1 and 10 substituents per cyclodextrin molecule.
Preferably, the β-cyclodextrm used is 2-hydroxypropyl-β-cyclodextπn 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-amιno-2-methyl-l ,3-propanedιol, 2-amιno-2-methyl-propanol and 2 amino- 1 ,2,3-propanetπol
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
It has to be noted that the use of higher levels of the hydroxylamine increases the taste masking effects of the complex and thus leads to a complex which gives a more palatable pharmaceutical formulation Taste masking is one of the particular advantages of the complex of the invention as will be detailed below
The complex of the invention may be prepared according to any one of the following general methodologies
1 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 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
2 The solution obtained in Step 1 may be precipitated, sprav dried or freeze dried to obtain the solid complex
3 The hydroxylamine and the drug are blended to form a paste with optional use of water The cyclodextrin is added poπion- 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
4 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
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
The advantages of the complex of the invention will now be discussed
It is known that naproxen forms stable inclusion complexes with beta- cyclodextπns, and to a lesser extent, with alpha and gamma-cyclodextπns Complexation ot naproxen or its sodium salt with beta-cyclodextπns does not however lead to effective taste masking of naproxen. presumably due to the relatively low association constant of the naproxen/beta-cyclodextπn complex (KASS < 500M ') at neutral or physiological pH which leads to rapid dissociation of the complex in the oral cavity The ternary complex formed between naproxen sodium/tromethamine/hydroxypropyl-beta- cyclodextπn, for example, has a bland taste when dissolved in water compared with a strong burning sensation produced by a similar bmary naproxen sodium/hydroxypropyl-beta-cyclode tπn 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
Thus, the first important advantage of the complex of the invention is taste- masking
Other advantages of the complex are
increase in water solubility of the drug, increased stabilisation of the drug molecule to chemical or photodegradation, decreased irritant effects, for example gastric irritation, burning of parenteral or ophthalmic solutions, rectal or vaginal intolerance, and improved rate and extent of drug absorbtion
Figure 1 shows the geometry optimised molecular model of the complex formed between naproxen, tπs(hydroxymethyl)arnιnomethane and β- cyclodextπn
Figure 2 shows the potentiometπc titration of an aqueous solution contaimng naproxen sodium (3 mmol) and β-cyclodextπn (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 β-cyclodextπn 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 of titrant, the computer recorded the emf measured by a Radiometer research pH meter between Metrohm electrodes immersed m the titrant solution The results clearly indicate that naproxen does not participate in inclusion complexation with β-cyclodextπn to an significant extent at pH values above 6,5 at which naproxen exists exclusively as the tree anion (NP ) Below pH 6,5 the protonated acid (NPH), the 1 1 β- cyclodextπn inclusion complex [(CD)(NPH)] and the corresponding 2 1 complex [(CD)2 (NPH)] are detected in varying proportions
Figure 3 shows the potentiometπc titration of an aqueous solution contaimng naproxen sodium (3 mmol), β-cyclodextπn (15 mmol) and tπs(hydroxymethyl)amιnomethane (TR)(3 mmol) as a function of pH using sodium hydroxide as titrant. Experimental conditions were as described above for Figure 2 Under these conditions it was found that an equimolar proportion of TR relative to NP produced complexes according to the invention as follows pH 2,3 - 6,5 (CD)(TR)(NP )H+)2 with maximum concentration of 50% occurring around pH 3,3, pH 3,0 - pH 9,8 (CD)(TR)(NP")(H+) with maximum concentration of 30% occurring around pH 7,0
Figure 4 shows the potentiometπc titration of an aqueous solution contaimng naproxen sodium (0,00872 mmol), β-cyclodextπn (0,00908 mmol) and tris(hydroxymethyl)aminomethane(TR)(0,0908 mmol) as a function of pH using a sodium hydroxide as titrant. Experimental conditions were as described above for Figure 2 Under these conditions it was found that a ten fold molar excess of TR relative to equimolar NP and CD produced complexes according to the invention as follows pH 2,3 - 7,2 (CD)(TR)(NP )(H+)2 with maximum concentration of 85 % occurring around pH 3,3, pH 3,0 pH 9,8 (CD)(TR)(NP )(H + ) with maximum concentration of 60% occurring around pH 7,0
Referring to Figure 1 there is shown the geometrv optimised molecular model of the complex formed between naproxen tπs(hydroxymethyl) aminomethane and β-cyclodextπn The species can be identified in solution by means of potentiometπc titration at 25 °C using sodium hydroxide as titrant In the absence of the ligand, no complexation is observed between ionised naproxen and β-cyclodextπn above pH 7 (see Figure 2) 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-cyclodextπn complex stability at neutral and higher pH This suφπsmg 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
It is important to note that from the expeπment represented in Figure 4, complexation at neutral pH was doubled using ten times the amount of trιs(hydroxymethyl)amιnomethane and decreasing the amount of cyclodextrin three times, relative to the experiment represented by Figure 3 This is suφπsing since one would expect decreased complexation when reducmg the concentration of cyclodextrin This unexpected observation clearly shows the concentration dependant effect of tπs(hydroxymethyl)amιnomethane in enhancing complexation of lomsed naproxen
It is further important to note that tπs(hydroxymethyl)amιnomethane promotes complex formation near pH 7 A comparison of Figures 2 and 3 shows that, in the absence of tns(hydrox meth> l)amιnomethane, no significant β-cyclodextπn naproxen complexation is detectable at pH 7
Vaπous examples of the invention will now be giv en
Example 1
2-hydroxypropyl-beta-cyclodextπn (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
Example 2
A unit dose of a granular formulation suitable for reconstitution in water is as follows
Complex of Example 1 (eq to 200mg naproxen) 1 ,429g Saccharin 0,030g
Mint flavour (spray dried) 0 120g
Excipients are mixed with the complex, screened through a 60 mesh screen and packed into sachets
The contents of the sachet are added to 100ml tap water to provide a clear, pleasant tasting solution Example 3
2 - H y d r o x y p r o p y 1 - b e t - c y c 1 o d e x t r l n ( 1 4 0 g ) a n d tπs(hydroxymethyl)amιnomethane (120,0 g) are triturated with a small quantity of purified distilled water to form a viscous paste Naproxen sodium (25 g) is gradually added with vigorous mixing for 1 hour The paste is dried under vacuum (2mbar) at 40°C The dried complex (1 10 1 naproxen sodium tromethamme cvclodextπn) 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
Example 4
The complex prepared according to Example 3 may be incoφorated in a unit dose of a granular formulation suitable for reconstitution in water at room temperature as follows
Complex of Example 3 (equivalent to 200mg naproxen) 2 706g Saccharin 0.030g
Mint flavour (spray dried) 0, 120g
Excipients are mixed with the complex, screened through a 60 mesh screen and packed into sachets On reconstitution with tap water the product is palatable and free from the bitter and burning taste sensation produced by naproxen
Example 5
Complex of Example 3 (equivalent to 200mg naproxen) 2,706g
Saccharin 0,030g Mint flavour (spray dried) 0, 1 OOg
Sodium carbonate 0,600g
Tartaric acid l ,000g
Magnesium stearate 0.375g
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

Claims

An inclusion complex of (a) naproxen or a pharmaceutically acceptable salt thereof, (b) an unsubstituted or substituted beta- cyclodextπn, and (c) a hydroxylamine, wherein in the complex, naproxen or the pharmaceutically salt thereof is included in the beta- cyclodextπn and the hydroxylamine interacts w ith both naproxen or the pharmaceutically acceptable salt thereof and the beta-cyclodextπn
An inclusion complex according to claim 1 wherein (a) is naproxen sodium.
An inclusion complex according to claim 1 or claim 2 wherein (b) is 2-hydroxypropyl-beta-cyclodextπn.
An inclusion complex according to any one of claims 1 to 3 wherein (c) is selected from the group consisting of ammonium hydroxide, tπs(hydroxymethyl)amιnomethane, ethanolamine, diethanolamine, triethanolamine, meglumine, 2-ammo-2-methyl-l ,3-propanedιol, 2- amino-2-methyl-propanol and 2-amιno-1.2,3-propanetπol
An inclusion complex according to claim 4 wherein (c) is selected from the group consisting of diethanolamine, triethanolamine and tromethamme.
An inclusion complex according to claim 5 wherein (c) is tromethamine.
An inclusion complex according to any one of claims 1 to 6 wherein the inclusion complex has a stoichiometry of (a) (b) (c) mol/mol/mol of 1 0,5 to 100 1 to 100
An inclusion complex according to claim 7 wherein the inclusion complex has a stoichiometry ot (a) (b) (c) mol/mol/mol of 1 0,5 to 10 10 to 100
An inclusion complex according to claim 8 wherein the inclusion complex has a stoichiometry of (a) (b) (c) mol/mol/mol of 1 0 5 to 2 more than 10 to 100
An inclusion complex of (a) naproxen sodium, (b) 2-hydroxypropyl- beta-cyclodextπn, and (c) tromethamme, wherein in the complex, naproxen sodium is included m2-hydroxypropyl-beta-cyclodextπn and tromethamme interacts with both naproxen sodium and 2- hydroxypropyl-beta-cyclodextπn, the complex having a stoichiometry of (a) (b) (c) mol/mol/mol of 1 0,5 to 100 10 to 100
A pharmaceutical composition compπsing as an active ingredient an inclusion complex according to any one of claims 1 to 10 and a pharmaceutically acceptable carrier
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 an inclusion complex according to any one of claims 1 to 10, which liquid formulation has a pH of from 5,5 to 8,5 inclusive
A pharmaceutical composition according to claim 12 wherem the liquid formulation has a pH of from 6.5 to 7,5 inclusive
A pharmaceutical composition according to claim 12 or claim 13 wherein the formulation for reconstitution is reconstituted with water at ambient temperamre or less
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