WO1996041646A2 - Pharmaceutical compositions containing lornoxicam and cyclodextrin - Google Patents

Pharmaceutical compositions containing lornoxicam and cyclodextrin Download PDF

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Publication number
WO1996041646A2
WO1996041646A2 PCT/GB1996/001236 GB9601236W WO9641646A2 WO 1996041646 A2 WO1996041646 A2 WO 1996041646A2 GB 9601236 W GB9601236 W GB 9601236W WO 9641646 A2 WO9641646 A2 WO 9641646A2
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WIPO (PCT)
Prior art keywords
cyclodextrin
lornoxicam
solution
buffer
beta
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PCT/GB1996/001236
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French (fr)
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WO1996041646A3 (en
Inventor
John Lawrence Penkler
Darryl Vanstone Whittaker
Original Assignee
Dyer, Alison, Margaret
Farmarc Nederland B.V.
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Application filed by Dyer, Alison, Margaret, Farmarc Nederland B.V. filed Critical Dyer, Alison, Margaret
Priority to AU57747/96A priority Critical patent/AU5774796A/en
Publication of WO1996041646A2 publication Critical patent/WO1996041646A2/en
Publication of WO1996041646A3 publication Critical patent/WO1996041646A3/en

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    • 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
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/40—Cyclodextrins; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A61K47/6951—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears

Definitions

  • This invention relates to a method of preparing pharmaceutical compositions comprising either lornoxicam or a pharmaceutically acceptable salt thereof and a cyclodextrin, or an inclusion complex of lornoxicam or a pharmaceutically acceptable salt thereof and a cyclodextrin, and to a composition so formed, for parenteral or ophthalmic administration.
  • Lornoxicam (6-chloro-4-hydroxy-2-methyl-N-2-pyridyl-2H-thieno- [2 , 3-e] - 1,2-thiazine carboxamide-l,l-dioxide) is a non-steroidal anti-inflammatory drug (NSAID). Lornoxicam may be utilized in the treatment of acute and difficulty in formulating the drug for parenteral or ophthalmic administration.
  • Lornoxicam is highly unstable in solution showing rapid oxidation and hydrolytic cleavage, leading to the formation of a large number of degradation products within weeks, on standing at room temperature.
  • cyclodextrins are commercially available cyclic oligosaccharides composed of 6, 7 or 8 glucopyranose units (alpha-, beta- and gamma- cyclodextrin respectively) characterized by a cone-like molecular shape.
  • the cavity of the cone is hydrophobic whilst the exterior is hydrophillic.
  • the hydropriobic nature of the cavity endows the 'm Jiecuie- with the -ability -Lu form inclusion complexes with hydrophobic guest molecules of suitable size to fit into the cavity of the host.
  • the inclusion complex may be stabilized by a number of forces including van der Waals attractive forces and hydrogen bonding.
  • Polar (ionized) groups are less readily included than less-polar (unionized) groups.
  • Cyclodextrin inclusion complexes may be prepared on the basis of liquid state, solid state or semi-solid state reaction between the components. The liquid state method 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 are 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 method the two components are kneaded in the presence of small amounts of a suitable solvent, and the complex so-formed, is dried, screened and homogenized.
  • the liquid state reaction generally provides optimum conditions for completeness of reaction. Cyclodextrin inclusion complexation of a suitable guest results in a number of physicochemical changes in the properties of the guest. The infrared spectrum of the complex is distinct relative to the pure guest or simple (non-complexed) mixtures of host and guest.
  • a water insoluble guest may be rendered water soluble by cyclodextrin inclusion complexation. In many cases chemically unstable guests are stabilized by inclusion complexation.
  • dissolved inclusion complex exists in equilibrium between uncomplexed host and guest and complexed host/guest.
  • Parenterally administered cyclodextrin-drug inclusion complexes rapidly dissociate upon dilution in the blood to release free drug and cyclodextrin. Cyclodextrins therefore possess ideal properties as true drug carriers.
  • Beta-cyclodextrin and particularly hydroxyalkyl ether derivatives have been reported to increase the aqueous solubility of NSAIDs [Solubilizationand Stabilization of Non-Steroidal Antirheumatics with Cyclodextrins and Cyclodextrin Ethers, Backensfeld, T. and Mueller, B.W. Arch. Pharm. 1990, 323, 690; Interaction of NSA with cyclodextrins and hydroxypropyl cyclodextrin derivatives, Backensfeld, T.; Mueller, B.W. and Kolter, K. Int. J. Pharm. 1991, 74, 85-93].
  • Co-precipitation methods of NSAID/cyclodextrin complex formation is described.
  • the co-precipitation method is known to generally produce low yields of complex [Inclusion Compounds of Non-Steroidal Antiinflammatory and other slightly water soluble drugs with a- and /3-Cyclodextrins in Powdered Form; Kurozumi, M. et al. Chem. Pharm. Bull. 1975,23,3062-3068].
  • PCT/GB 95/01152 South African Druggists Limited teaches a method for preparing ⁇ -cyclodextrin inclusion complexes of NSAIDs including lornoxicam, which may be formulated into pharmaceutical compositions adapted to be dissolved in water to provide a solution for oral administration.
  • South African Patent No 94/9182 (corresponding to European Patent Application No 94308690.0) to South African Druggists Limited teaches a method of preparing an injectable pharmaceutical or veterinary composition comprising either (a) diclofenac or a pharmaceutically acceptable salt thereof and 2- hydroxypropyl beta-cyclodextrin, or (b) an inclusion complex of diclofenac or a pharmaceutically acceptable salt of diclofenac and 2-hydroxypropyl beta-cyclodextrin, or a mixture of (a) and (b), which includes the step of dissolving either (a) diclofenac or a pharmaceutically salt thereof and 2-hydroxypropyl beta- cyclodextrin, or (b) an inclusion complex of diclofenac or a pharmaceutically acceptable salt of diclofenac and 2- hydroxypropyl beta-cyclodextrin, or a mixture of (a) and (b), in water to form a solution, the water having been acidified to a pH such that the pH of the solution
  • South African Patent Application No 95/9469 (corresponding to PCT/GB 95/02679) to South African Druggists Limited teaches a pharmaceutical composition for oral administration comprising an inclusion complex of a non-steroidal anti-inflammatory drug or a pharmaceutically acceptable salt thereof and a cyclodextrin, and a physiologically acceptable alkali agent selected from the group consisting of alkali and alkaline earth metal carbonates, bicarbonates, phosphates and hydroxides, and water soluble amines, in an amount equivalent to between 2 and 30 molar equivalents inclusive of the non-steroidal anti-inflammatory drug, the alkali agent being capable of forming an alkaline diffusion layer around the composition in the gastro intestinal tract.
  • the drug may be lornoxicam and the alkali agent may be tromethamine, also known as tris(hydroxymethyl)aminomethane.
  • South African Patent Application No 96/2214 (corresponding to PCT/GB 96/00737) to South African Druggists Limited teaches a method of preparing a pharmaceutical composition for administration as an injection or as a retention enema, comprising an inclusion complex of propofol and 2- hydroxypropyl-beta-cyclodextrin with approximately a 1:2 mol/mol stoichiometry, which includes the steps of dissolving in water an amount of the cyclodextrin and then adding, with mixing, an amount of propofol to provide an approximate molar ratio of propofol to the cyclodextrin of 1:2 to 1:2,5, to produce a clear colourless solution and if necessary adjusting the osmolality of the solution by adding a pharmaceutically acceptable osmolality adjustment agent.
  • a pharmaceutical composition in the form of an aqueous solution or in the form of a product for reconstitution as an aqueous solution, for parenteral administration or ophthalmic administration comprising: (i)(a) lornoxicam or a pharmaceutically acceptable salt thereof and a cyclodextrin selected from the group consisting of hydoxypropylated or sulphoalkylated derivatives of alpha, beta or gamma cyclodextrin, or (b) an inclusion complex of lornoxicam or a pharmaceutically acceptable salt of lornoxicam and a cyclodextrin selected from the group consisting of hydroxypropylated or sulphoalkylated derivatives of alpha, beta or gamma cyclodextrin, or a mixture of (a) and (b), and (ii) a pharmaceutically acceptable buffer to buffer the solution at a pH in the range of from 6,5 to 9 inclusive.
  • the buffer buffers the solution at a pH in the range of from 8 to 9 inclusive.
  • the buffer is preferably selected from the group consisting of a phosphate buffer, a tromethamine buffer, an ammonia buffer, a diethanolamine buffer and a triethanolamine buffer, or preferably a tromethamine buffer.
  • the cyclodextrin is preferably a hydroxypropylated beta-cyclodextrin.
  • the solution preferably contains from 1 to 8 mg/ml inclusive of lornoxicam.
  • SUBSTTTUTE SHEET (RULE 26)
  • the solution When the solution is intended for parenteral administration, it preferably contains from 4 to 8 mg/ml inclusive of lornoxicam.
  • the solution When the solution is intended for ophthalmic administration, it preferably contains about 1 mg/ml of lornoxicam.
  • the solution preferably contains from 15% to 40% inclusive m/v of hydroxypropyl beta-cyclodextrin, more preferably from 20% to 30% inclusive m/v of hydroxypropyl beta-cyclodextrin.
  • the preferred formulation of the invention for parenteral administration is a solution containing about 8 mg/ml lornoxicam and about 25% m/v hydroxypropyl beta-cyclodextrin.
  • a method of preparing a pharmaceutical composition for parenteral administration or ophthalmic administration comprising: (i)(a) lornoxicam or a pharmaceutically acceptable salt thereof and a cyclodextrin selected from the group consisting of hydroxypropylated or sulphoalkylated derivatives of alpha, beta or gamma-cyclodextrin, or (b) an inclusion complex of lornoxicam or a pharmaceutically acceptable salt thereof and a cyclodextrin selected from the group of hydroxypropylated or sulphoalkylated derivatives of alpha, beta or gamma-cyclodextrin, or a mixture of (a) and (b); and (ii) a pharmaceutically acceptable buffer to buffer the solution at a pH in the range of from 6,5 to 9 inclusive; which includes the step of: (1) dissolving either (a) the cyclodextrin and then lornoxicam or a pharmaceutically acceptable
  • composition suitable for administration to humans or animals, i.e. it includes veterinary compositions.
  • a “pharmaceutically acceptable” salt there is meant a salt which is acceptable for human or veterinary use.
  • Figure 1 is a phase solubility diagram of lornoxicam in solutions of alpha- cyclodextrin in phosphate buffer pH 7,4 at ambient temperature;
  • Figure 2 is a phase solubility diagram of lornoxicam in solutions of 2- hydroxypropyl-beta-cyclodextrin in phosphate buffer pH 7,4 at ambient temperature;
  • Figure 3 is a portion of the infrared spectra of alpha-cyclodextrin (top), lornoxicam (middle) and lornoxicam alpha-cyclodextrin complex
  • Figure 4 illustrates the structure and proton notation of lornoxicam, alpha-cyclodextrin and 2-hydroxypropyl-beta-cyclodextrin as used in the description of Example 3;
  • Figure 5 is a portion of the 500MHz two-dimensional ROESY spectrum of LXM/ACD (1:7) solution in D 2 O from Example 3.
  • the spectrum shows through space proton correlations between chlorothiophene/pyridyl protons of LXM and the internally oriented 3' and 5' cavity protons of ACD;
  • Figure 6 is a portion of the 500MHz two-dimensional ROESY spectrum of LXM/HPB (1:12) solution in D 2 O from Example 3.
  • the spectrum shows through space proton correlations between chlorothiophene/pyridyl protons of LXM and the internally oriented 3' and 5' cavity protons of HPB;
  • Figure 7 illustrates energy minimized molecular models of possible modes of inclusion of lornoxicam by alpha-cyclodextrin as indicated by proton magnetic resonance experiments described in Example 3.
  • the subscript n refers the number of moles of cyclodextrin;
  • Figure 8 illustrates energy minimized molecular models of possible modes of inclusion of lornoxicam by beta-cyclodextrin as indicated by proton magnetic resonance experiments described in Example 3.
  • the subscript n refers the number of moles of
  • Figure 9 is a titration curve which illustrates the effect of increasing hydroxypropyl beta-cyclodextrin (host) concentration on the chemical shift of the lornoxicam pyridyl proton H b in sodium hydroxide solution at pH 9,0 (top) and tromethamine buffer pH 9,0 (bottom).
  • the invention relates to pharmaceutical compositions comprising either (a) lornoxicam or a pharmaceutically acceptable salt thereof such as the sodium or potassium salt, and a cyclodextrin selected from the group consisting of hydroxypropylated or sulphoalkylated, such as sulphobutylated derivatives of alpha, beta or gamma-cyclodextrin, or (b) an inclusion complex of lornoxicam or a pharmaceutically acceptable salt of lornoxicam and a cyclodextrin selected from the group consisting of hydroxypropylated or sulphoalkylated, such as sulphobutylated derivatives of alpha, beta, or gamma-cyclodextrin, or a mixture of (a) and (b), the pharmaceutical composition being formulated for parenteral administration or for ophthalmic administration.
  • a lornoxicam or a pharmaceutically acceptable salt thereof such as the sodium or potassium salt
  • a cyclodextrin
  • the method of the invention is a method of preparing a pharmaceutical composition for parenteral administration or for ophthalmic administration comprising either (a) lornoxicam or a pharmaceutically acceptable salt thereof and a cyclodextrin selected from the group consisting of hydroxypropylated or sulphoalkylated, such as sulphobutylated derivatives of alpha, beta, or gamma-cyclodextrin or (b) an inclusion complex of lornoxicam or a pharmaceutically acceptable salt of lornoxicam and a cyclodextrin selected from the group consisting of hydroxypropylated or sulphoalkylated, such as sulphobutylated derivatives of alpha, beta, or gamma-cyclodextrin, or a mixture of (a) and (b) which includes the step of:
  • the inclusion complex may be prepared by any conventional method known in the art such as for example spray drying, freeze drying, kneading, or precipitation.
  • the buffer preferably buffers the solution at a pH in the range of from 8 to 9 inclusive.
  • the buffer may be any suitable pharmaceutically acceptable buffer.
  • Buffers for a variety of pH ranges are available (see Flynn, G.L. Journal of Parenteral Drug Association, 1980, 34, 139-162, Table V, page 156) which may be used to control the pH of parenteral formulations.
  • Preferred buffers include phosphate buffers (pH 6,2 to 8,2) and amine buffers such as tromethamine (pH 7,1 to 9,1) and also ammonia buffers, diethanolamine buffers and triethanolamine buffers.
  • the most preferred buffer is a tromemamine buffer. If necessary, there may be added to the solution an amount of pharmaceutically acceptable acid or base, eg HC1 or NaOH, to obtain a pH in the desired range.
  • pharmaceutically acceptable acid or base eg HC1 or NaOH
  • the cyclodextrins are hydroxypropylated or sulphoalkylated derivatives of alpha, beta, or gamma-cyclodextrin, most preferably hydroxypropyl-beta- cyclodextrin with a degree of substitution between 3,9 and 5,1, inclusive or sulphobutylated alpha or beta-cyclodextrin with a degree of substitution between 4 and 10 inclusive.
  • the solution preferably contains from 1 to 8 mg/ml inclusive of lornoxicam.
  • the solution When the solution is intended for parenteral administration, it preferably contains from 4 to 8 mg/ml inclusive of lornoxicam. When the solution is intended for ophthalmic administration, it preferably contains about 1 mg/ml of lornoxicam.
  • the solution also preferably contains from 15 % to 40% m/v inclusive of the cyclodextrin, more preferably from 20% to 30% m/v inclusive of the cyclodextrin, when the cyclodextrin is hydroxypropyl-beta-cyclodextrin.
  • 15 % m/v there is meant an amount of 15g of the hydroxypropyl beta- cyclodextrin per 100 ml of solution.
  • the preferred formulation of the invention for parenteral administration contains 8 mg/ml of lornoxicam and 25% m/v of hydroxypropyl-beta- cyclodextrin.
  • the preferred unit dose of the pharmaceutical composition of the invention for parenteral adnainistration contains 1 ml of lornoxicam solution.
  • the method may include any one or more of the following additional steps:
  • step (2) adding to the solution of step (1) a physiologically compatible compound such as potassium nitrate, sodium metabisulphite, N- acetylcysteine, thiourea, cetylpyridinium chloride, cetylpyridmium bromide, ethylenediamine tetra-acetic acid disodium salt (disodium edetate), benzalkonium chloride, chlorobutanol, xylitol, sorbitol, mannitol, dextrose or glucose;
  • a physiologically compatible compound such as potassium nitrate, sodium metabisulphite, N- acetylcysteine, thiourea, cetylpyridinium chloride, cetylpyridmium bromide, ethylenediamine tetra-acetic acid disodium salt (disodium edetate), benzalkonium chloride, chlorobutanol, xylitol, sorbito
  • step (3) after step (1) or step (2) filling the finished solution into a container such as an ampoule or vial, or an eyedrop bottle, optionally under a nitrogen atmosphere; or
  • step (1) or step (2) freeze-drying the finished solution to provide a lyophilized product for reconstitution
  • step (2) or step (3) or step (4) sterilising the finished solution or lyophilizate by conventional techniques, excluding autoclaving.
  • step (2) for a parenteral formulation there may be added to the solution an antioxidant such as N-acetyl cysteine (0,1 % m v) and disodium edetate (0,05% m/v) - to reduce oxidation of lornoxicam in solution.
  • an antioxidant such as N-acetyl cysteine (0,1 % m v) and disodium edetate (0,05% m/v) - to reduce oxidation of lornoxicam in solution.
  • step (2) for an ophthalmic formulation there may be added to the solution an antioxidant such as N-acet lcysteine (0,1 % m/v), or sodium metabisulphite (0,2% m/v), or thiourea (0,2% m v) to reduce oxidation of lornoxicam in solution.
  • an antioxidant such as N-acet lcysteine (0,1 % m/v), or sodium metabisulphite (0,2% m/v), or thiourea (0,2% m v) to reduce oxidation of lornoxicam in solution.
  • Cetylpyridinium chloride (0,01 % m/v) or cetylpyridinium bromide (0,01 % m/v) may be added as preservative agents.
  • phosphate buffers mentioned in the examples correspond to Sorenson's sodium phosphate buffer (Flynn, G.L. (1980) J. Parent. Drug Ass. 34(2), 139-162) and the European Pharmacopoeia potassium phosphate buffer.
  • phase solubility performed according to Higuchi, T. & Connors, K.A. (1965) Adv. Anal. Chem. Instr. 4,117
  • phase solubility shown in Figures 1 and 2.
  • concentrations of alpha-cyclodextrin or 2- hydroxypropyl-beta-cyclodextrin in solutions of KH 2 PO 4 at pH 7,4 were added. The mixtures were allowed to shake for 24 hours at room temperature and equilibrated for a further 24 hours.
  • Samples were filtered through a 0,22 ⁇ m filter and analyzed for lornoxicam concentration by high performance liquid chromatography.
  • the basis for the increased aqueous solubility is the formation of an inclusion complex between the host (cyclodextrin) and guest (lornoxicam).
  • a 1:7 solid complex of lornoxicam/alpha-cyclodextrin is prepared by initially dissolving 1,09 g alpha-cyclodextrin in 10 ml deionized water at 35 °C. To this solution, 60mg lornoxicam is added batchwise with vigorous stirring. The solution is stirred for a further 10 - 15 minutes and allowed to cool. The solution remains clear. Lyophilization provides an amorphous yellow solid. The complex is readily soluble in water. The solid complex is characterized by IR spectra recorded from a diffuse reflectance apparatus.
  • the spectra shown in Figure 3 reveal a decrease in the intensity of the pyridyl bands (1 and 2) and chlorothiophene bands (3 and 4)of the complex relative to spectra of lornoxicam and alpha-cyclodextrin.
  • This pattern may be attributed to intermolecular interaction between the chlorothiophene and pyridyl groups of lornoxicam with the internal cavity of the cyclodextrin as a consequence of complexation (Lin, S-Z., Wouessidjewe, D., Poelman, M- C, Duchene, D. (1991) Int. J. Pharm. 60, 211-219).
  • Alpha-cyclodextrin (3,66 g) is dissolved in 50 ml potassium phosphate buffer pH7,4 (0,05M) prepared with purified deionized water at 35 °C with mixing. Micronised lornoxicam substance (0,200g) is slowly added with vigorous mixing. Once the solution is formed the heat is removed and the solution is allowed to cool to ambient temperature with mixing. Once ambient temperature is reached the solution is stirred for a further 30 minutes. The solution is gradually brought to a volume of 90 ml with phosphate buffer pH 7,4 and pH is adjusted to 7,4 with IM NaOH. Pyrogen free sorbitol powder is added to adjust the osmolality to between 280 - 320 mOsm kg.
  • the volume is adjusted to 100 ml with phosphate buffer pH 7,4.
  • the solution is mixed for 20 minutes during which a stream of purified nitrogen gas is bubbled through the solution.
  • the solution is passed through a 1 micron prefilter followed by a 0,22 micron filter into sterile amber ampoules under nitrogen atmosphere which are filled and sealed under aseptic conditions.
  • the solution is stable for at least 10 months at 25 °C.
  • Alpha-cyclodextrin used in this example may be replaced by an equivalent quantity of sulphobutyl (D.S. 4 to 8) or hydroxypropyl (D.S. 3 to 8) alpha- cyclodextrin, with the same results.
  • 2-Hydroxypropyl-beta-cyclodextrin (22,27 g) is dissolved in 200 ml potassium phosphate buffer pH7,4 (0.05M) prepared with purified deionized water at 35 °C with mixing.
  • Micronised lornoxicam substance (0,50g) is slowly added with vigorous mixing. Once the solution is formed the heat is removed and the solution is allowed to cool to ambient temperature with mixing. Once ambient temperature is reached the solution is stirred for a further 30 minutes. The solution is gradually brought to a volume of 230 ml with phosphate buffer pH 7,4 and pH is adjusted to 7,4 with IM NaOH.
  • Pyrogen free sorbitol powder is added to adjust the osmolality to between 280 - 320 mOsm/kg.
  • the volume is adjusted to 100 ml with phosphate buffer pH 7,4.
  • the solution is mixed for 20 minutes during which a stream of purified nitrogen gas is bubbled through the solution.
  • the solution is passed through a 1 micron prefilter followed by a 0,22 micron filter into sterile amber ampoules under nitrogen atmosphere which are filled and sealed under aseptic conditions.
  • the solution is stable for at least 3 months at 25 °C and 10 months at 4 °C.
  • 2-Hydroxypropyl-beta-cyclodextrin used in this example may be replaced by an equivalent quantity of sulphobutyl-beta-cyclodextrin (D.S. 4 to 9), with the same results.
  • Alpha-cyclodextrin (3,66 g) is dissolved in 50 ml potassium phosphate buffer pH7,4 (0,05M) prepared with purified deionized water at 35 °C with mixing.
  • Micronised lornoxicam (0,200g) is slowly added with vigorous mixing. Once the solution is formed the heat is removed and the solution is allowed to cool to ambient temperature with mixing. Once ambient temperature is reached the solution is stirred for a further 30 minutes.
  • Ethylenediaminetetra-acetic acid disodium salt (50mg) and N-acetylcysteine (lOOmg) are added with stirring. The solution is gradually brought to a volume of 90 ml with phosphate buffer pH 7,4 and pH is adjusted to 7,4 with IM NaOH.
  • Pyrogen free sorbitol powder is added to adjust the osmolality to between 280 - 320 mOsm/kg.
  • the volume is adjusted to 100 ml with phosphate buffer pH 7,4.
  • the solution is mixed for 20 minutes during which a stream of purified nitrogen gas is bubbled through the solution.
  • the solution is passed through a 1 micron prefilter followed by a 0,22 micron filter into sterile amber ampoules under nitrogen atmosphere which are filled and sealed under asepetic conditions.
  • Alpha-cyclodextrin used in this example may be replaced by an equivalent quantity of sulphobutyl (D.S. 4 to 8) or hydroxypropyl (D.S. 3 to 8) alpha- cyclodextrin, with the same results.
  • 2-Hydroxypropyl-beta-cyclodextrin (10.5 g) is dissolved in 50 ml potassium phosphate buffer pH7,4 (0,05M) prepared with purified deionized water at 35 °C with mixing.
  • Micronised lornoxicam substance (0,200g) is slowly added with vigorous mixing. Once the solution is formed the heat is removed and the solution is allowed to cool to ambient temperature with mixing. Once ambient temperature is reached the solution is stirred for a further 30 minutes. Ethylenediaminetetra-acetic acid disodium salt (50mg) and N-acetylcysteine (lOOmg) are added with stirring.
  • the solution is gradually brought to a volume of 90 ml with phosphate buffer pH 7,4 and pH is adjusted to 7,4 with IM NaOH. Pyrogen free sorbitol powder is added to adjust the osmolality to between 280 - 320 mOsm/kg. The volume is adjusted to 100 ml with phosphate buffer pH 7,4. The solution is mixed for 20 minutes during which a stream of purified nitrogen gas is bubbled through the solution. The solution is passed through a 1 micron prefilter followed by a 0,22 micron filter into sterile amber ampoules under nitrogen atmosphere which are filled and sealed under aseptic conditions.
  • 2-Hydroxypropyl-beta-cyclodextrin used in this example may be replaced by an equivalent quantity of sulphobutyl-beta-cyclodextrin (D.S. 4 to 9), with the same results.
  • 2-Hydroxypropyl-beta-cyclodextrin DS 4,6 (50g) was dissolved in 180 ml of 0,06M tromethamine buffer solution prepared as a stock solution using purified deionised water. The mixture is stirred to effect dissolution in a mixing vessel under low light conditions and is sparged with dinitrogen until oxygen concentration is less than 0,1 mg/1. Micronised lornoxicam (l,72g) is added to the solution with stirring and continued sparging. A clear solution is formed, to which is added with stirring N-acetyl cysteine (0,2g) and disodium edetate (0,lg).
  • the solution is diluted to approximately 190 ml with 0.06M stock tromethamine buffer solution and stirred for 20 minutes.
  • the pH of the solution is adjusted to 8,5 by addition of either IM hydrochloric acid or IM sodium hydroxide, and brought to final volume (200 mL) with 0,06M stock tromethamine buffer solution.
  • the solution is stirred for a further 5 minutes.
  • the solution is continuously sparged with dinitrogen throughout the process.
  • the osmolarity of the solution is about 340 mOsm/kg.
  • the solution is sterilized by filtration through a 0,22 micron filter and aseptically filled into amber glass ampoules under a stream of dimtrogen.
  • the fill volume is 1,1 ml and the ampoules are flame sealed under dinitrogen.
  • Each ampoule contains at least 8,0 mg lornoxicam as determined by HPLC.
  • the solution is clear and passes a turbidity test value of less than 15 x 10 "4 cm "1 as determined by UV transmittance.
  • the solution remains clear and chemically stable when stored at 4°C for at least 1 year.
  • 2-Hydroxypropyl-beta-cyclodextrin used in this example may be replaced by an equivalent quantity of sulphobutyl-beta-cyclodextrin (D.S. 4 to 9), with the same results.
  • 2-Hydroxypropyl-beta-cyclodextrin DS 4,6 (50g) was dissolved in 180 ml of 0,06M tromethamine buffer solution prepared as a stock solution using purified deionised water. The mixture is stirred to effect dissolution in a mixing vessel under low light conditions and is sparged with dinitrogen until oxygen concentration is less than 0,1 mg/1. Micronised lornoxicam (0,2g) is added to the solution under low light with continuous dinitrogen sparging and stirring. A clear solution is formed, to which is added and dissolved, cetylpyridinium chloride (0,02g), N-acetylcysteine, (0,2g) and disodium edetate (0, lg).
  • the solution is brought to 190 ml with tromethamine buffer solution and stirred for twenty minutes under continuous dinitrogen sparging.
  • the osmolality of the solution is determined and adjusted upwards to between 280-320 mOsm kg with sorbitol if necessary.
  • the pH of the solution is adjusted to 8,0 to 8,5 by addition of either IM hydrochloric acid or IM sodium hydroxide and adjusted to the final volume with the buffer solution.
  • the solution is sparged with dinitrogen until oxygen concentration is less than 0, 1 mg/1 and is sterilised by filtration and filled directly into suitable sterile containers under aseptic conditions.
  • the headspace in the container is flushed with dinitrogen prior to sealing.
  • the resultant solution contains lornoxicam (ca. 1 mg/ml) suitable for ophthalmic instillation and is stable for at least 1 year at 4°C.
  • 2-Hydroxypropyl-beta-cyclodextrin used in this example may be replaced by an equivalent quantity of sulphobutyl-beta-cyclodextrin (D.S. 4 to 9), with the same results.
  • unsubstituted alpha-cyclodextrin and unsubstituted beta- cyclodextrin does not fall within the scope of the present invention particularly for parenteral solutions because of toxicological considerations.
  • unsubstituted gamma-cyclodextrin does not fall within the scope of the present invention as unsubstituted gamma-cyclodextrin is not sufficiently physically stable.
  • Figure 9 shows the effect of increasing hydroxypropyl beta-cyclodextrin (host) concentration on the chemical shift of the lornoxicam pyridyl proton H b in sodium hydroxide solution, pH 9,0 (top) and tromethamine buffer pH 9,0 (bottom).
  • the change in chemical shift is significantly less for the tromemamine containing solution than the sodium hydroxide solution indicating a weaker host-guest association for the tromethamine solution.
  • the buffer acts simply as a conventional buffer and does not complex with the lornoxicam or the cyclodextrin.

Abstract

A pharmaceutical composition in the form of an aqueous solution or in the form of a product for reconstitution as an aqueous solution, for parenteral or ophthalmic administration, comprises lornoxicam or a pharmaceutically acceptable salt thereof and a cyclodextrin, or an inclusion complex of lornoxicam or a pharmaceutically acceptable salt thereof and a cyclodextrin, and a pharmaceutically acceptable buffer to buffer the solution at a pH in the range of from 6,5 to 9 inclusive. A method for producing the pharmaceutical composition is also disclosed.

Description

PHARMACEUTICAL COMPOSITIONS CONTAINING LORNOXICAM AND CYCLODEXTRIN
BACKGROUND OF THE INVENTION
This invention relates to a method of preparing pharmaceutical compositions comprising either lornoxicam or a pharmaceutically acceptable salt thereof and a cyclodextrin, or an inclusion complex of lornoxicam or a pharmaceutically acceptable salt thereof and a cyclodextrin, and to a composition so formed, for parenteral or ophthalmic administration.
Lornoxicam (6-chloro-4-hydroxy-2-methyl-N-2-pyridyl-2H-thieno- [2 , 3-e] - 1,2-thiazine carboxamide-l,l-dioxide) is a non-steroidal anti-inflammatory drug (NSAID). Lornoxicam may be utilized in the treatment of acute and difficulty in formulating the drug for parenteral or ophthalmic administration.
Lornoxicam is highly unstable in solution showing rapid oxidation and hydrolytic cleavage, leading to the formation of a large number of degradation products within weeks, on standing at room temperature.
There is therefore-a need for parenteral and ophthalmic pharmaceutical compositions of lornoxicam which overcome the problems associated with low solubility and chemical instability.
The properties of cyclodextrins and numerous inclusion complexes therewith are well known and have been reviewed in detail [see Szejtli, J. Cyclodextrin Technology (1988) Kluwer Academic Publishers, Dordrecht]. Briefly, cyclodextrins are commercially available cyclic oligosaccharides composed of 6, 7 or 8 glucopyranose units (alpha-, beta- and gamma- cyclodextrin respectively) characterized by a cone-like molecular shape. The cavity of the cone is hydrophobic whilst the exterior is hydrophillic. The hydropriobic nature of the cavity endows the 'm Jiecuie- with the -ability -Lu form inclusion complexes with hydrophobic guest molecules of suitable size to fit into the cavity of the host. The inclusion complex may be stabilized by a number of forces including van der Waals attractive forces and hydrogen bonding. Polar (ionized) groups are less readily included than less-polar (unionized) groups. Cyclodextrin inclusion complexes may be prepared on the basis of liquid state, solid state or semi-solid state reaction between the components. The liquid state method 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 are 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 method, the two components are kneaded in the presence of small amounts of a suitable solvent, and the complex so-formed, is dried, screened and homogenized. The liquid state reaction generally provides optimum conditions for completeness of reaction. Cyclodextrin inclusion complexation of a suitable guest results in a number of physicochemical changes in the properties of the guest. The infrared spectrum of the complex is distinct relative to the pure guest or simple (non-complexed) mixtures of host and guest. A water insoluble guest may be rendered water soluble by cyclodextrin inclusion complexation. In many cases chemically unstable guests are stabilized by inclusion complexation.
Depending on solvent conditions, the dissolved inclusion complex exists in equilibrium between uncomplexed host and guest and complexed host/guest. Parenterally administered cyclodextrin-drug inclusion complexes rapidly dissociate upon dilution in the blood to release free drug and cyclodextrin. Cyclodextrins therefore possess ideal properties as true drug carriers.
The following further prior art is known in relation to inclusion complexes of cyclodextrins and NSAIDs.
(1) Beta-cyclodextrin and particularly hydroxyalkyl ether derivatives have been reported to increase the aqueous solubility of NSAIDs [Solubilizationand Stabilization of Non-Steroidal Antirheumatics with Cyclodextrins and Cyclodextrin Ethers, Backensfeld, T. and Mueller, B.W. Arch. Pharm. 1990, 323, 690; Interaction of NSA with cyclodextrins and hydroxypropyl cyclodextrin derivatives, Backensfeld, T.; Mueller, B.W. and Kolter, K. Int. J. Pharm. 1991, 74, 85-93].
(2) The interaction of NSAIDs with beta-cyclodextrin as a function of temperature and pH has been reported [Inclusion Complexes between Non Steroidal Antiinflammatory Drugs and β- Cyclodextrin, Orienti, I., Fini, A., Bertasi, V. and Zecchi, V. Eur. J. Pharm. Biopharm. 1991, 37, 110-112].
The above studies (1 and 2) rely on phase solubility analysis which involves the determination of the effect of increasing concentrations of cyclodextrin on the solubility of excess NSAID under a variety of conditions.
(3) The diffusibility of NSAID complexes with beta cyclodextrin has been reported [Availability of NSAIDH jS-Cyclodextrin Inclusion Complexes, Orienti, I., Cavallari, C. and Zecchi, V. Arch. Pharm (Weinheim) 1989, 322, 207-211].
(4) Co-precipitation methods of NSAID/cyclodextrin complex formation is described. The co-precipitation method is known to generally produce low yields of complex [Inclusion Compounds of Non-Steroidal Antiinflammatory and other slightly water soluble drugs with a- and /3-Cyclodextrins in Powdered Form; Kurozumi, M. et al. Chem. Pharm. Bull. 1975,23,3062-3068].
5) South African Patent Application 95/3965 (corresponding to
PCT/GB 95/01152) to South African Druggists Limited teaches a method for preparing β-cyclodextrin inclusion complexes of NSAIDs including lornoxicam, which may be formulated into pharmaceutical compositions adapted to be dissolved in water to provide a solution for oral administration.
6) South African Patent No 94/9182 (corresponding to European Patent Application No 94308690.0) to South African Druggists Limited teaches a method of preparing an injectable pharmaceutical or veterinary composition comprising either (a) diclofenac or a pharmaceutically acceptable salt thereof and 2- hydroxypropyl beta-cyclodextrin, or (b) an inclusion complex of diclofenac or a pharmaceutically acceptable salt of diclofenac and 2-hydroxypropyl beta-cyclodextrin, or a mixture of (a) and (b), which includes the step of dissolving either (a) diclofenac or a pharmaceutically salt thereof and 2-hydroxypropyl beta- cyclodextrin, or (b) an inclusion complex of diclofenac or a pharmaceutically acceptable salt of diclofenac and 2- hydroxypropyl beta-cyclodextrin, or a mixture of (a) and (b), in water to form a solution, the water having been acidified to a pH such that the pH of the solution is from 6,0 to 8,5 inclusive, in the absence of a phosphate buffer.
7) South African Patent Application No 95/9469 (corresponding to PCT/GB 95/02679) to South African Druggists Limited teaches a pharmaceutical composition for oral administration comprising an inclusion complex of a non-steroidal anti-inflammatory drug or a pharmaceutically acceptable salt thereof and a cyclodextrin, and a physiologically acceptable alkali agent selected from the group consisting of alkali and alkaline earth metal carbonates, bicarbonates, phosphates and hydroxides, and water soluble amines, in an amount equivalent to between 2 and 30 molar equivalents inclusive of the non-steroidal anti-inflammatory drug, the alkali agent being capable of forming an alkaline diffusion layer around the composition in the gastro intestinal tract. The drug may be lornoxicam and the alkali agent may be tromethamine, also known as tris(hydroxymethyl)aminomethane.
8) South African Patent Application No 96/2214 (corresponding to PCT/GB 96/00737) to South African Druggists Limited teaches a method of preparing a pharmaceutical composition for administration as an injection or as a retention enema, comprising an inclusion complex of propofol and 2- hydroxypropyl-beta-cyclodextrin with approximately a 1:2 mol/mol stoichiometry, which includes the steps of dissolving in water an amount of the cyclodextrin and then adding, with mixing, an amount of propofol to provide an approximate molar ratio of propofol to the cyclodextrin of 1:2 to 1:2,5, to produce a clear colourless solution and if necessary adjusting the osmolality of the solution by adding a pharmaceutically acceptable osmolality adjustment agent.
9) International Application WO 95/28965 to Chiesi Farmaceutici SpA teaches a multi-component inclusion complex containing an acidic drug, a base and a cyclodextrin, wherein the complex is obtained by simultaneous salt formation and complexation. The drug may be an oxicam and the base may be an amine such as diethanolamine, triethanolamine, diethylamine, memylamine, and tromethamine.
SUBSTTTUTE SHEET (RULE 26) SUMMARY OF THE INVENTION
According to a first aspect of the invention there is provided a pharmaceutical composition in the form of an aqueous solution or in the form of a product for reconstitution as an aqueous solution, for parenteral administration or ophthalmic administration, comprising: (i)(a) lornoxicam or a pharmaceutically acceptable salt thereof and a cyclodextrin selected from the group consisting of hydoxypropylated or sulphoalkylated derivatives of alpha, beta or gamma cyclodextrin, or (b) an inclusion complex of lornoxicam or a pharmaceutically acceptable salt of lornoxicam and a cyclodextrin selected from the group consisting of hydroxypropylated or sulphoalkylated derivatives of alpha, beta or gamma cyclodextrin, or a mixture of (a) and (b), and (ii) a pharmaceutically acceptable buffer to buffer the solution at a pH in the range of from 6,5 to 9 inclusive.
Preferably, the buffer buffers the solution at a pH in the range of from 8 to 9 inclusive.
The buffer is preferably selected from the group consisting of a phosphate buffer, a tromethamine buffer, an ammonia buffer, a diethanolamine buffer and a triethanolamine buffer, or preferably a tromethamine buffer.
The cyclodextrin is preferably a hydroxypropylated beta-cyclodextrin.
The solution preferably contains from 1 to 8 mg/ml inclusive of lornoxicam.
SUBSTTTUTE SHEET (RULE 26) When the solution is intended for parenteral administration, it preferably contains from 4 to 8 mg/ml inclusive of lornoxicam. When the solution is intended for ophthalmic administration, it preferably contains about 1 mg/ml of lornoxicam.
The solution preferably contains from 15% to 40% inclusive m/v of hydroxypropyl beta-cyclodextrin, more preferably from 20% to 30% inclusive m/v of hydroxypropyl beta-cyclodextrin.
The preferred formulation of the invention for parenteral administration is a solution containing about 8 mg/ml lornoxicam and about 25% m/v hydroxypropyl beta-cyclodextrin.
According to a second aspect of the invention there is provided a method of preparing a pharmaceutical composition for parenteral administration or ophthalmic administration comprising: (i)(a) lornoxicam or a pharmaceutically acceptable salt thereof and a cyclodextrin selected from the group consisting of hydroxypropylated or sulphoalkylated derivatives of alpha, beta or gamma-cyclodextrin, or (b) an inclusion complex of lornoxicam or a pharmaceutically acceptable salt thereof and a cyclodextrin selected from the group of hydroxypropylated or sulphoalkylated derivatives of alpha, beta or gamma-cyclodextrin, or a mixture of (a) and (b); and (ii) a pharmaceutically acceptable buffer to buffer the solution at a pH in the range of from 6,5 to 9 inclusive; which includes the step of: (1) dissolving either (a) the cyclodextrin and then lornoxicam or a pharmaceutically acceptable salt thereof, or (b) an inclusion complex of lornoxicam or a pharmaceutically acceptable salt thereof and the cyclodextrin, or a mixture of (a) and (b), in water to form a solution in the presence of a pharmaceutically acceptable buffer to buffer the solution at a pH in the range of from 6,5 to 9 inclusive.
If necessary there may be added to the solution an amount of a pharmaceutically acceptable acid or base to obtain a pH in the desired range.
By a pharmaceutical composition there is meant a composition suitable for administration to humans or animals, i.e. it includes veterinary compositions.
By a "pharmaceutically acceptable" salt there is meant a salt which is acceptable for human or veterinary use.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is a phase solubility diagram of lornoxicam in solutions of alpha- cyclodextrin in phosphate buffer pH 7,4 at ambient temperature;
Figure 2 is a phase solubility diagram of lornoxicam in solutions of 2- hydroxypropyl-beta-cyclodextrin in phosphate buffer pH 7,4 at ambient temperature;
Figure 3 is a portion of the infrared spectra of alpha-cyclodextrin (top), lornoxicam (middle) and lornoxicam alpha-cyclodextrin complex
SUBSTTTUTE SHEET RULE 26 (bottom) as described in Example 2. Important bands are annotated with numbers referred to in the text;
Figure 4 illustrates the structure and proton notation of lornoxicam, alpha-cyclodextrin and 2-hydroxypropyl-beta-cyclodextrin as used in the description of Example 3;
Figure 5 is a portion of the 500MHz two-dimensional ROESY spectrum of LXM/ACD (1:7) solution in D2O from Example 3. The spectrum shows through space proton correlations between chlorothiophene/pyridyl protons of LXM and the internally oriented 3' and 5' cavity protons of ACD;
Figure 6 is a portion of the 500MHz two-dimensional ROESY spectrum of LXM/HPB (1:12) solution in D2O from Example 3. The spectrum shows through space proton correlations between chlorothiophene/pyridyl protons of LXM and the internally oriented 3' and 5' cavity protons of HPB;
Figure 7 illustrates energy minimized molecular models of possible modes of inclusion of lornoxicam by alpha-cyclodextrin as indicated by proton magnetic resonance experiments described in Example 3. The subscript n refers the number of moles of cyclodextrin;
Figure 8 illustrates energy minimized molecular models of possible modes of inclusion of lornoxicam by beta-cyclodextrin as indicated by proton magnetic resonance experiments described in Example 3. The subscript n refers the number of moles of
SUBSTTTUTE SHEET (RULE 26) cyclodextrin; and
Figure 9 is a titration curve which illustrates the effect of increasing hydroxypropyl beta-cyclodextrin (host) concentration on the chemical shift of the lornoxicam pyridyl proton Hb in sodium hydroxide solution at pH 9,0 (top) and tromethamine buffer pH 9,0 (bottom).
DESCRIPTION OF EMBODIMENTS
The invention relates to pharmaceutical compositions comprising either (a) lornoxicam or a pharmaceutically acceptable salt thereof such as the sodium or potassium salt, and a cyclodextrin selected from the group consisting of hydroxypropylated or sulphoalkylated, such as sulphobutylated derivatives of alpha, beta or gamma-cyclodextrin, or (b) an inclusion complex of lornoxicam or a pharmaceutically acceptable salt of lornoxicam and a cyclodextrin selected from the group consisting of hydroxypropylated or sulphoalkylated, such as sulphobutylated derivatives of alpha, beta, or gamma-cyclodextrin, or a mixture of (a) and (b), the pharmaceutical composition being formulated for parenteral administration or for ophthalmic administration.
The method of the invention is a method of preparing a pharmaceutical composition for parenteral administration or for ophthalmic administration comprising either (a) lornoxicam or a pharmaceutically acceptable salt thereof and a cyclodextrin selected from the group consisting of hydroxypropylated or sulphoalkylated, such as sulphobutylated derivatives of alpha, beta, or gamma-cyclodextrin or (b) an inclusion complex of lornoxicam or a pharmaceutically acceptable salt of lornoxicam and a cyclodextrin selected from the group consisting of hydroxypropylated or sulphoalkylated, such as sulphobutylated derivatives of alpha, beta, or gamma-cyclodextrin, or a mixture of (a) and (b) which includes the step of:
(1) dissolving either (a) the cyclodextrin and then lornoxicam or a pharmaceutically acceptable salt of lornoxicam, or (b) an inclusion complex of lornoxicam or a pharmaceutically acceptable salt of lornoxicam and the cyclodextrin, or a mixture of (a) and (b), in water to form a solution, in the presence of a pharmaceutically acceptable buffer to buffer the solution at a pH in the range of from 6,5 to 9 inclusive.
The inclusion complex may be prepared by any conventional method known in the art such as for example spray drying, freeze drying, kneading, or precipitation.
The buffer preferably buffers the solution at a pH in the range of from 8 to 9 inclusive.
The buffer may be any suitable pharmaceutically acceptable buffer. Buffers for a variety of pH ranges are available (see Flynn, G.L. Journal of Parenteral Drug Association, 1980, 34, 139-162, Table V, page 156) which may be used to control the pH of parenteral formulations. Preferred buffers include phosphate buffers (pH 6,2 to 8,2) and amine buffers such as tromethamine (pH 7,1 to 9,1) and also ammonia buffers, diethanolamine buffers and triethanolamine buffers.
The most preferred buffer is a tromemamine buffer. If necessary, there may be added to the solution an amount of pharmaceutically acceptable acid or base, eg HC1 or NaOH, to obtain a pH in the desired range.
The cyclodextrins are hydroxypropylated or sulphoalkylated derivatives of alpha, beta, or gamma-cyclodextrin, most preferably hydroxypropyl-beta- cyclodextrin with a degree of substitution between 3,9 and 5,1, inclusive or sulphobutylated alpha or beta-cyclodextrin with a degree of substitution between 4 and 10 inclusive.
The solution preferably contains from 1 to 8 mg/ml inclusive of lornoxicam.
When the solution is intended for parenteral administration, it preferably contains from 4 to 8 mg/ml inclusive of lornoxicam. When the solution is intended for ophthalmic administration, it preferably contains about 1 mg/ml of lornoxicam.
The solution also preferably contains from 15 % to 40% m/v inclusive of the cyclodextrin, more preferably from 20% to 30% m/v inclusive of the cyclodextrin, when the cyclodextrin is hydroxypropyl-beta-cyclodextrin. By 15 % m/v there is meant an amount of 15g of the hydroxypropyl beta- cyclodextrin per 100 ml of solution.
The preferred formulation of the invention for parenteral administration contains 8 mg/ml of lornoxicam and 25% m/v of hydroxypropyl-beta- cyclodextrin.
The preferred unit dose of the pharmaceutical composition of the invention for parenteral adnainistration contains 1 ml of lornoxicam solution.
SUBSTTTUTE SHEET (RULE 26) The method may include any one or more of the following additional steps:
(2) adding to the solution of step (1) a physiologically compatible compound such as potassium nitrate, sodium metabisulphite, N- acetylcysteine, thiourea, cetylpyridinium chloride, cetylpyridmium bromide, ethylenediamine tetra-acetic acid disodium salt (disodium edetate), benzalkonium chloride, chlorobutanol, xylitol, sorbitol, mannitol, dextrose or glucose;
(3) after step (1) or step (2) filling the finished solution into a container such as an ampoule or vial, or an eyedrop bottle, optionally under a nitrogen atmosphere; or
(4) after step (1) or step (2) freeze-drying the finished solution to provide a lyophilized product for reconstitution; and
(5) after step (2) or step (3) or step (4) sterilising the finished solution or lyophilizate by conventional techniques, excluding autoclaving.
For example, in step (2) for a parenteral formulation there may be added to the solution an antioxidant such as N-acetyl cysteine (0,1 % m v) and disodium edetate (0,05% m/v) - to reduce oxidation of lornoxicam in solution.
Alternatively, for example, in step (2) for an ophthalmic formulation, there may be added to the solution an antioxidant such as N-acet lcysteine (0,1 % m/v), or sodium metabisulphite (0,2% m/v), or thiourea (0,2% m v) to reduce oxidation of lornoxicam in solution. Cetylpyridinium chloride (0,01 % m/v) or cetylpyridinium bromide (0,01 % m/v) may be added as preservative agents.
The following examples relating to the preparation of inclusion complexes between lornoxicam and alpha-cyclodextrin or 2-hydroxypropyl derivatives of alpha- or beta-cyclodextrins, their characterization, and pharmaceutical compositions containing them are described in order that the invention may be more fully understood.
The phosphate buffers mentioned in the examples correspond to Sorenson's sodium phosphate buffer (Flynn, G.L. (1980) J. Parent. Drug Ass. 34(2), 139-162) and the European Pharmacopoeia potassium phosphate buffer.
Example 1
The solubilizing effect of alpha-cyclodextrin or 2-hydroxypropyl-beta- cyclodextrin on lornoxicam may be directly demonstrated by phase solubility (performed according to Higuchi, T. & Connors, K.A. (1965) Adv. Anal. Chem. Instr. 4,117) shown in Figures 1 and 2. Briefly, to an excess of lornoxicam, varying concentrations of alpha-cyclodextrin or 2- hydroxypropyl-beta-cyclodextrin in solutions of KH2PO4 at pH 7,4 were added. The mixtures were allowed to shake for 24 hours at room temperature and equilibrated for a further 24 hours. Samples were filtered through a 0,22 μm filter and analyzed for lornoxicam concentration by high performance liquid chromatography. The basis for the increased aqueous solubility is the formation of an inclusion complex between the host (cyclodextrin) and guest (lornoxicam).
Example 2
A 1:7 solid complex of lornoxicam/alpha-cyclodextrin is prepared by initially dissolving 1,09 g alpha-cyclodextrin in 10 ml deionized water at 35 °C. To this solution, 60mg lornoxicam is added batchwise with vigorous stirring. The solution is stirred for a further 10 - 15 minutes and allowed to cool. The solution remains clear. Lyophilization provides an amorphous yellow solid. The complex is readily soluble in water. The solid complex is characterized by IR spectra recorded from a diffuse reflectance apparatus. The spectra shown in Figure 3 reveal a decrease in the intensity of the pyridyl bands (1 and 2) and chlorothiophene bands (3 and 4)of the complex relative to spectra of lornoxicam and alpha-cyclodextrin. This pattern may be attributed to intermolecular interaction between the chlorothiophene and pyridyl groups of lornoxicam with the internal cavity of the cyclodextrin as a consequence of complexation (Lin, S-Z., Wouessidjewe, D., Poelman, M- C, Duchene, D. (1991) Int. J. Pharm. 60, 211-219).
Example 3
The inclusion complex formed between lornoxicam and alpha- or 2- hydroxypropyl-beta-cyclodextrin in aqueous solution is directly demonstrable from proton magnetic resonance spectra. The structure and notation of LXM, ACD and HPB are shown in Figure 4. Proton magnetic resonance experiments were performed on a Bruker AMXR 500 spectrometer with probe temperature at 303K. Solutions of complexes of lornoxicam (LXM) and alpha-cyclodextrin (ACD) or 2-hydroxypropyl- beta-cyclodextrin (HPB) obtained according to Example 2 corresponding to LXM/ ACD (1:7) and LXM/HPB (1:12) were prepared in D2O. Two- dimensional nuclear Overhauser enhancement (NOE) spectra were recorded in the rotating frame (ROESY) for solutions of LXM/ ACD (1:7) and LXM/HPB (1:12) and are shown in Figures 5 and 6. A spin locking time of 150 ms was used.
Molecular modelling was performed using Hyperchem™ software. Molecular mechanics calculations involving rigid body docking and energy minimizations were performed using the MM+ force field. Calculations were performed on the two possible 1:1 isomeric complexes as well as on the 1:2 LXM/ ACD and LXM/HPB complexes. From one dimensional proton NMR large chemical shifts of the order of 0.1 ppm were observed for LXM protons a, b,c,d and e. From the 2D ROESY spectrum cross peaks were observed between a,b,c,d and e protons of LXM and 3 ',5' protons of ACD or HPB indicating through space couplings between spatially close ( < 4 Angstrom) protons in the cyclodextrin cavity and LXM (see Figures 4-6). The NMR results indicate complexation of the hydrophobic chlorothiophene and pyridyl rings. These findings are schematically depicted as energy minimized molecular models shown in Figures 7 and 8.
Based on the high resolution nuclear magnetic resonance studies of LXM and ACD or HPB there is direct evidence to support different modes of inclusion in aqueous solutions involving both chlorothiophene and pyridyl moieties in LXM. Therefore, during the complexation process according to the invention it is most likely that different types of inclusion compound are produced to varying extents.
Example 4
Alpha-cyclodextrin (3,66 g) is dissolved in 50 ml potassium phosphate buffer pH7,4 (0,05M) prepared with purified deionized water at 35 °C with mixing. Micronised lornoxicam substance (0,200g) is slowly added with vigorous mixing. Once the solution is formed the heat is removed and the solution is allowed to cool to ambient temperature with mixing. Once ambient temperature is reached the solution is stirred for a further 30 minutes. The solution is gradually brought to a volume of 90 ml with phosphate buffer pH 7,4 and pH is adjusted to 7,4 with IM NaOH. Pyrogen free sorbitol powder is added to adjust the osmolality to between 280 - 320 mOsm kg. The volume is adjusted to 100 ml with phosphate buffer pH 7,4. The solution is mixed for 20 minutes during which a stream of purified nitrogen gas is bubbled through the solution. The solution is passed through a 1 micron prefilter followed by a 0,22 micron filter into sterile amber ampoules under nitrogen atmosphere which are filled and sealed under aseptic conditions. The solution is stable for at least 10 months at 25 °C.
Alpha-cyclodextrin used in this example may be replaced by an equivalent quantity of sulphobutyl (D.S. 4 to 8) or hydroxypropyl (D.S. 3 to 8) alpha- cyclodextrin, with the same results.
Example 5
2-Hydroxypropyl-beta-cyclodextrin (22,27 g) is dissolved in 200 ml potassium phosphate buffer pH7,4 (0.05M) prepared with purified deionized water at 35 °C with mixing. Micronised lornoxicam substance (0,50g) is slowly added with vigorous mixing. Once the solution is formed the heat is removed and the solution is allowed to cool to ambient temperature with mixing. Once ambient temperature is reached the solution is stirred for a further 30 minutes. The solution is gradually brought to a volume of 230 ml with phosphate buffer pH 7,4 and pH is adjusted to 7,4 with IM NaOH. Pyrogen free sorbitol powder is added to adjust the osmolality to between 280 - 320 mOsm/kg. The volume is adjusted to 100 ml with phosphate buffer pH 7,4. The solution is mixed for 20 minutes during which a stream of purified nitrogen gas is bubbled through the solution. The solution is passed through a 1 micron prefilter followed by a 0,22 micron filter into sterile amber ampoules under nitrogen atmosphere which are filled and sealed under aseptic conditions. The solution is stable for at least 3 months at 25 °C and 10 months at 4 °C.
2-Hydroxypropyl-beta-cyclodextrin used in this example may be replaced by an equivalent quantity of sulphobutyl-beta-cyclodextrin (D.S. 4 to 9), with the same results.
Example 6
Alpha-cyclodextrin (3,66 g) is dissolved in 50 ml potassium phosphate buffer pH7,4 (0,05M) prepared with purified deionized water at 35 °C with mixing. Micronised lornoxicam (0,200g) is slowly added with vigorous mixing. Once the solution is formed the heat is removed and the solution is allowed to cool to ambient temperature with mixing. Once ambient temperature is reached the solution is stirred for a further 30 minutes. Ethylenediaminetetra-acetic acid disodium salt (50mg) and N-acetylcysteine (lOOmg) are added with stirring. The solution is gradually brought to a volume of 90 ml with phosphate buffer pH 7,4 and pH is adjusted to 7,4 with IM NaOH. Pyrogen free sorbitol powder is added to adjust the osmolality to between 280 - 320 mOsm/kg. The volume is adjusted to 100 ml with phosphate buffer pH 7,4. The solution is mixed for 20 minutes during which a stream of purified nitrogen gas is bubbled through the solution. The solution is passed through a 1 micron prefilter followed by a 0,22 micron filter into sterile amber ampoules under nitrogen atmosphere which are filled and sealed under asepetic conditions.
Alpha-cyclodextrin used in this example may be replaced by an equivalent quantity of sulphobutyl (D.S. 4 to 8) or hydroxypropyl (D.S. 3 to 8) alpha- cyclodextrin, with the same results.
Example 7
2-Hydroxypropyl-beta-cyclodextrin (10.5 g) is dissolved in 50 ml potassium phosphate buffer pH7,4 (0,05M) prepared with purified deionized water at 35 °C with mixing. Micronised lornoxicam substance (0,200g) is slowly added with vigorous mixing. Once the solution is formed the heat is removed and the solution is allowed to cool to ambient temperature with mixing. Once ambient temperature is reached the solution is stirred for a further 30 minutes. Ethylenediaminetetra-acetic acid disodium salt (50mg) and N-acetylcysteine (lOOmg) are added with stirring. The solution is gradually brought to a volume of 90 ml with phosphate buffer pH 7,4 and pH is adjusted to 7,4 with IM NaOH. Pyrogen free sorbitol powder is added to adjust the osmolality to between 280 - 320 mOsm/kg. The volume is adjusted to 100 ml with phosphate buffer pH 7,4. The solution is mixed for 20 minutes during which a stream of purified nitrogen gas is bubbled through the solution. The solution is passed through a 1 micron prefilter followed by a 0,22 micron filter into sterile amber ampoules under nitrogen atmosphere which are filled and sealed under aseptic conditions.
2-Hydroxypropyl-beta-cyclodextrin used in this example may be replaced by an equivalent quantity of sulphobutyl-beta-cyclodextrin (D.S. 4 to 9), with the same results.
Example 8
2-Hydroxypropyl-beta-cyclodextrin DS 4,6 (50g) was dissolved in 180 ml of 0,06M tromethamine buffer solution prepared as a stock solution using purified deionised water. The mixture is stirred to effect dissolution in a mixing vessel under low light conditions and is sparged with dinitrogen until oxygen concentration is less than 0,1 mg/1. Micronised lornoxicam (l,72g) is added to the solution with stirring and continued sparging. A clear solution is formed, to which is added with stirring N-acetyl cysteine (0,2g) and disodium edetate (0,lg). The solution is diluted to approximately 190 ml with 0.06M stock tromethamine buffer solution and stirred for 20 minutes. The pH of the solution is adjusted to 8,5 by addition of either IM hydrochloric acid or IM sodium hydroxide, and brought to final volume (200 mL) with 0,06M stock tromethamine buffer solution. The solution is stirred for a further 5 minutes. The solution is continuously sparged with dinitrogen throughout the process. The osmolarity of the solution is about 340 mOsm/kg. The solution is sterilized by filtration through a 0,22 micron filter and aseptically filled into amber glass ampoules under a stream of dimtrogen. The fill volume is 1,1 ml and the ampoules are flame sealed under dinitrogen. Each ampoule contains at least 8,0 mg lornoxicam as determined by HPLC. The solution is clear and passes a turbidity test value of less than 15 x 10"4 cm"1 as determined by UV transmittance. The solution remains clear and chemically stable when stored at 4°C for at least 1 year.
2-Hydroxypropyl-beta-cyclodextrin used in this example may be replaced by an equivalent quantity of sulphobutyl-beta-cyclodextrin (D.S. 4 to 9), with the same results.
Example 9
2-Hydroxypropyl-beta-cyclodextrin DS 4,6 (50g) was dissolved in 180 ml of 0,06M tromethamine buffer solution prepared as a stock solution using purified deionised water. The mixture is stirred to effect dissolution in a mixing vessel under low light conditions and is sparged with dinitrogen until oxygen concentration is less than 0,1 mg/1. Micronised lornoxicam (0,2g) is added to the solution under low light with continuous dinitrogen sparging and stirring. A clear solution is formed, to which is added and dissolved, cetylpyridinium chloride (0,02g), N-acetylcysteine, (0,2g) and disodium edetate (0, lg). The solution is brought to 190 ml with tromethamine buffer solution and stirred for twenty minutes under continuous dinitrogen sparging. The osmolality of the solution is determined and adjusted upwards to between 280-320 mOsm kg with sorbitol if necessary. The pH of the solution is adjusted to 8,0 to 8,5 by addition of either IM hydrochloric acid or IM sodium hydroxide and adjusted to the final volume with the buffer solution. The solution is sparged with dinitrogen until oxygen concentration is less than 0, 1 mg/1 and is sterilised by filtration and filled directly into suitable sterile containers under aseptic conditions. The headspace in the container is flushed with dinitrogen prior to sealing. The resultant solution contains lornoxicam (ca. 1 mg/ml) suitable for ophthalmic instillation and is stable for at least 1 year at 4°C.
2-Hydroxypropyl-beta-cyclodextrin used in this example may be replaced by an equivalent quantity of sulphobutyl-beta-cyclodextrin (D.S. 4 to 9), with the same results.
The use of unsubstituted alpha-cyclodextrin and unsubstituted beta- cyclodextrin does not fall within the scope of the present invention particularly for parenteral solutions because of toxicological considerations. The use of unsubstituted gamma-cyclodextrin does not fall within the scope of the present invention as unsubstituted gamma-cyclodextrin is not sufficiently physically stable.
Figure 9 shows the effect of increasing hydroxypropyl beta-cyclodextrin (host) concentration on the chemical shift of the lornoxicam pyridyl proton Hb in sodium hydroxide solution, pH 9,0 (top) and tromethamine buffer pH 9,0 (bottom). The change in chemical shift is significantly less for the tromemamine containing solution than the sodium hydroxide solution indicating a weaker host-guest association for the tromethamine solution. In the light of observations that cyclodextrin inclusion complexation leads to improved chemical stability of drugs (J.Szejtli, Cyclodextrin Technology, Kluwer Academic Press) it was surprising to find that solutions of lornoxicam and 2-hydroxypropyl-beta-cyclodextrin prepared in tromethamine buffer at pH 8,5 were significantly more chemically stable than those prepared in tromethamine or phosphate buffer at pH 7,4 despite the fact that complex stability is noticeably lower in the tromethamine buffer at pH 9,0 as evidenced by proton NMR spectroscopy. The proton NMR spectroscopy showed that the interaction between lornoxicam and hydroxypropyl-beta-cyclodextrin was noticeably reduced in the tromethamine buffer at pH 9,0 relative to the complex at the same pH in sodium hydroxide by measurement of chemical shift for protons a, b, d and e.
It is to be noted that in the pharmaceutical composition of the invention, there is no formation of a multicomponent complex between the lornoxicam, the cyclodextrin and the buffer, when the buffer is an amine such as tromethamine, diethanolamine or triethanolamme. In all circumstances, the buffer acts simply as a conventional buffer and does not complex with the lornoxicam or the cyclodextrin.

Claims

CLAIMS A pharmaceutical composition in the form of an aqueous solution or in the form of a product for reconstitution as an aqueous solution, the aqueous solution being for parenteral administration or ophthalmic administration, comprising: (i)(a) lornoxicam or a pharmaceutically acceptable salt thereof and a cyclodextrin selected from the group consisting of hydroxypropylated or sulphoalkylated derivatives of alpha, beta, or gamma-cyclodextrin, or (b) an inclusion complex of lornoxicam or a pharmaceutically acceptable salt thereof and a cyclodextrin selected from the group consisting of hydroxypropylated or sulphoalkylated derivatives of alpha, beta or gamma-cyclodextrin, or a mixture of (a) and (b), and (ii) a pharmaceutically acceptable buffer to buffer the solution at a pH in the range of from 6,5 to 9 inclusive. A pharmaceutical composition according to claim 1 wherein the buffer buffers the solution at a pH in the range of from 8 to 9 inclusive. A pharmaceutical composition according to claim 1 or claim 2 wherein the buffer is selected from the group consisting of a phosphate buffer, a tromethamine buffer, an ammonia buffer, a diethanolamine buffer and a triemanolamine buffer. 4 A pharmaceutical composition according to claim 3 wherein the buffer is a tromethamine buffer. 5 A pharmaceutical composition according to any one of claims 1 to 4 wherein the cyclodextrin is a hydroxypropylated derivative of beta-cyclodextrin. 6 A pharmaceutical composition according to any one of claims 1 to 5 wherein the aqueous solution contains from 1 to 8 mg/ml inclusive of lornoxicam. 7 A pharmaceutical composition according to any one of claims 1 to 5, for parenteral administration, wherein the aqueous solution contains from 4 to 8 mg/ml inclusive of lornoxicam 8 A pharmaceutical composition according to any one of claims 1 to 5, for ophthalmic administration, wherein the aqueous solution contains 1 mg/ml of lornoxicam. 9 A pharmaceutical composition according to claim 7 wherein the aqueous solution contains from 15% to 40% m/v inclusive of a hydroxypropylated derivative of beta-cyclodextrin. 10 A pharmaceutical composition according to claim 8 wherein the aqueous solution contains from 20% to 30% m/v of a hydroxypropylated derivative of beta-cyclodextrin. 11 A pharmaceutical composition according to claim 1 wherein the solution contains about 8 mg/ml of lornoxicam and about 25 % m/v of a hydroxypropylated derivative of beta-cyclodextrin. 12 A method of preparing a pharmaceutical composition for parenteral administration or ophthalmic administration comprising: (i)(a) lornoxicam or a pharmaceutically acceptable salt thereof and a cyclodextrin selected from the group consisting of hydroxypropylated or sulphoalkylated derivatives of alpha, beta, or gamma-cyclodextrin, or (b) an inclusion complex of lornoxicam or a pharmaceutically acceptable salt of lornoxicam and a cyclodextrin selected from the group consisting of hydroxypropylated or sulphoalkylated derivatives of alpha, beta, or gamma-cyclodextrin, or a mixture of (a) and (b), and (ii) a pharmaceutically acceptable buffer to buffer the solution at a pH in the range of from 6,5 to 9 inclusive, which includes the step of:
(1) dissolving either (a) the cyclodextrin and then lornoxicam or a pharmaceutically acceptable salt thereof, or (b) an inclusion complex of lornoxicam or a pharmaceutically acceptable salt thereof and the cyclodextrin, or a mixture of (a) and (b), in water to form a solution, in the presence of a pharmaceutically acceptable buffer to buffer the solution at a pH in the range of from 6,5 to 9 inclusive.
A method according to claim 12 wherein in step (1) there is added to the solution an amount of a pharmaceutically acceptable acid or base to obtain a pH in the desired range.
A method according to claim 12 or claim 13 wherein the method includes the step of:
(2) adding to the solution of step (1) a physiologically compatible compound.
A method according to claim 14 wherein the physiologically compatible compound is selected from the group consisting of potassium nitrate, sodium metabisulphite, N-acetylcysteine, thiourea, cetylpyridinium chloride, cetylpyridinium bromide, ethylenediamine tetra-acetic acid disodium salt, bronopol, benzalkonium chloride, chlorobutanol, xylitol, sorbitol, mannitol, dextrose and glucose.
A method according to any one of claims 12 to 15 wherein the method includes the step of:
(3) after step (1) or step (2) filling the finished solution into a container, optionally under a nitrogen atmosphere.
A method according to any one of claims 12 to 15 wherein the method includes the step of:
(4) after step (1) or step (2) freeze-drying the finished solution to provide a lyophilized product for reconstitution as an aqueous solution. 18 A method according to any one of claims 12 to 17 which includes the step of:
(5) after step (2) or step (3) or step (4) sterilising the finished solution or lyophilizate by conventional techniques excluding autoclaving.
PCT/GB1996/001236 1995-06-13 1996-05-23 Pharmaceutical compositions containing lornoxicam and cyclodextrin WO1996041646A2 (en)

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KR20080112285A (en) 2006-03-28 2008-12-24 자블린 파머슈티칼스 인코포레이티드 Formulations of low dose diclofenac and beta-cyclodextrin

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CN112912108A (en) * 2018-10-31 2021-06-04 法国施维雅药厂 Cyclodextrin-based formulations of BCL-2 inhibitors

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