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US20030113367A1 - Alprazolam inclusion complexes and pharmaceutical compositions thereof - Google Patents

Alprazolam inclusion complexes and pharmaceutical compositions thereof Download PDF

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Publication number
US20030113367A1
US20030113367A1 US10/220,563 US22056302A US2003113367A1 US 20030113367 A1 US20030113367 A1 US 20030113367A1 US 22056302 A US22056302 A US 22056302A US 2003113367 A1 US2003113367 A1 US 2003113367A1
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Prior art keywords
cyclodextrin
beta
mol
inclusion complex
alprazolam
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US10/220,563
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English (en)
Inventor
Lawrence Penkler
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Farmarc Nederland BV
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Farmarc Nederland BV
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Assigned to FARMARC NEDERLAND BV reassignment FARMARC NEDERLAND BV ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: PENKLER, LAWRENCE JOHN
Publication of US20030113367A1 publication Critical patent/US20030113367A1/en
Priority to US11/144,965 priority Critical patent/US7202233B2/en
Abandoned legal-status Critical Current

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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
    • A61K47/50—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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics

Definitions

  • This invention relates to an inclusion complex of alprazolam and an unsubstituted or substituted beta- or gamma-cyclbdextrin, and to pharmaceutical compositions containing such a complex, particularly for oral, nasal or rectal mucosal delivery, for the treatment of anxiety and panic attack.
  • Alprazolam is also known as 8-chloro-1-methyl-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine.
  • Alprazolam is indicated for the short term treatment of Generalised Anxiety Disorder (GAD) and has particular utility as an agent for the management of panic disorders (with or without agoraphobia)
  • alprazolam is well absorbed from a tablet formulation after conventional orogastric administration, maximum plasma levels occur between 0,7 to 1,8 hours post-dose. The onset of anxiolysis correlates with attainment of maximum plasma levels. The absorption rate is therefore often not sufficiently rapid to provide immediate symptomatic relief in an anxiety crisis. Absorption of alprazolam from the stomach is further adversely affected by the presence of food and antacids, the use of the latter being frequently associated with stress related syndromes. Rapid absorption of alprazolam in a manner which would avoid these complications and avoid the need for administration of the dosage form with a liquid would have distinct advantages.
  • the mucosal route of drug delivery offers a useful alternative to parenteral delivery where a rapid therapeutic effect is desired.
  • Sublingual use of the commercially available oral tablet dosage forms of alprazolam offers no significant benefit over conventional orogastric administration in terms of speed of onset [see J. M. Scavone et al, J. Clin. Psychopharmacol., 1987, 7, 332-335].
  • Formulation of alprazolam in a manner which permits rapid uptake from the sublingual, nasal or rectal mucosa would have distinct utility in the emergency relief of anxiety symptoms.
  • the oral, nasal and rectal cavities have several advantages as sites for systemic drug delivery, particularly avoidance of pre-systemic metabolism.
  • the low permeability of the membranes that line the oral and nasal cavities result in a low flux of drug.
  • the absorption of drugs from mucosal membranes may be enhanced by (i) increasing drug solubility, (ii) pH modification to favour the unionised form of the drug, (iii) addition of mucoadhesive agents to improve contact between the delivery system and the membrane and (iv) incorporation of so-called penetration enhancers.
  • Cyclodextrins and their derivatives have found extensive application as solubilizers and stabilizers due to their ability to form inclusion complexes with a wide variety of compounds (see J. Szejtli, Cyclodextrin Technology, Kluwer Academic Press) and (J. Szejtli & K-H Fromming, Cyclodextrins in Pharmacy, Kluwer Academic Press). Cyclodextrins have been used to enhance intenstinal absorption of drugs primarily through increasing solubility. Recently, cyclodextrins have been shown to have positive and negative effects on transdermal penetration of drugs (see Loftsson, T. et al International Journal of Pharmaceutics 1995, 115, 255-258), (Vollmer, U.
  • Cyclodextrins may improve nasal absorption of drugs (see Merkus, F. W. et al. Pharmaceutical Research 1992, 9, 1157-1163) and enhance absorption from sublingual administration of drug/cyclodextrin complexes. Cyclodextrins also protect nasal mucosal damage by penetration enhancers (see Jabbal. Gill, I. et al. European Journal of Pharmaceutical Sciences 1994, 1 (5), 229-236).
  • Cyclodextrins are water soluble cone-shaped cyclic oligosaccharides containing 6, 7 or 8 glucopyranose units.
  • the interior or “cavity” of the cone is hydrophobic whilst the exterior is hydrophilic.
  • the size of the cavity increases with increasing number of glucose units.
  • cyclodextrin derivatives such as alkyl, hydroxyalkyl and sulfoalkyl ethers have been prepared with improved solubility (see J. Szejtli & 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 included 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.
  • 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 stabilising inclusion complexes (Bergeron, R.
  • Cyclodextrin inclusion complexes may be prepared on the basis of liquid state, solid state or semi-solid state reaction between the components (J. Szejtli, 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 crystallisation, 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 homogenised.
  • 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 homogenised.
  • 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.
  • Loftsson et al [see Int. J. Pharm, 1998, 162(2), 115-121] have also reported an enhancement in the solubility and have demonstrated improved complexing ability for ⁇ -cyclodextrin in solutions of drugs containing water soluble polymers, including the drug alprazolam. No solid complex is described.
  • a pharmaceutical composition for transmucosal delivery comprising an inclusion complex of (a) alprazolam and (b) a water soluble unsubstituted or substituted beta- or gamma-cyclodextrin, and a pharmaceutically acceptable carrier therefor.
  • the pharmaceutically acceptable carrier must be suitable for transmucosal delivery of the alprazolam inclusion complex.
  • the cyclodextrin is preferably a water soluble unsubstituted or substituted beta-cyclodextrin, more preferably an alkylated beta-cyclodextrin, a hydroxyalkylated beta-cyclodextrin, or a sulfoalkylated beta-cyclodextrin.
  • the inclusion complex is preferably an inclusion complex of alprazolam and 2-hydroxypropyl-beta-cycodextrin, of alprazolam and a randomly methylated-beta-cyclodextrin, or of alprazolam and sulfobutyl ether beta-cyclodextrin.
  • the inclusion complex preferably has a stoichiometry of (a) to (b) from 1:1 mol/mol to 1:10 mol/mol inclusive and more preferably 1:7 mol/mol inclusive.
  • an inclusion complex of (a) alprazolam and (b) a water soluble unsubstituted or substituted beta- or gamma- cyclodextrin.
  • the pharmaceutical composition is preferably for use in the treatment of Generalised Anxiety Disorder (GAD) and has particular utility as an agent for the management of panic disorders.
  • GAD Generalised Anxiety Disorder
  • the pharmaceutical composition is preferably adapted for oral, nasal or rectal mucosal delivery.
  • FIG. 1 represents the effect of varying concentrations of beta-cyclodextrin (BCD) on the aqueous solubility of alprazolam at 25° C.
  • BCD beta-cyclodextrin
  • FIG. 2 represents the effect of methyl-beta cyclodextrin (squares) and 2-hydroxypropyl-beta-cyclodextrin (triangles) on the aqueous solubility of alprazolam at 25° C.
  • FIG. 3 represents the dissolution rate of alprazolam from a physical mixture (solid squares) of alprazolam and 2-hydroxypropyl-beta-cyclodextrin and the corresponding complex (open diamonds) obtained from Example 3 and performed according to Example 5.
  • FIG. 4 represents the dissolution rate of alprazolam from a physical mixture (solid squares) of alprazolam and methyl-beta-cyclodextrin and the corresponding complex (open diamonds) obtained from Example 4 and performed according to Example 5.
  • the powder samples were compressed into disks using a single punch and die.
  • the crux of the invention is an inclusion complex of (a) alprazolam and (b) an unsubstituted or substituted beta- or gamma-cyclodextrin, and pharmaceutical compositions containing the inclusion complex for transmucosal delivery.
  • the second component of the inclusion complex is an unsubstituted or substituted beta- or gamma-cyclodextrin.
  • cyclodextrins such as 2-hydroxypropylated or randomly methylated or sulfoalkylated derivatives of beta-cyclodextrin are the preferred cyclodextrins of the invention.
  • Gamma-cyclodextrin or 2-hydroxypropylated or randomly methylated or sulfoalkylated derivatives of gamma-cyclodextrin may also be used in the same manner as the corresponding preferred beta-cyclodextrin derivatives.
  • the degree of substitution of the cyclodextrin derivatives may vary between 1 to 20 substituents per cyclodextrin molecule, but more preferably between 3 to 15 substituents per cyclodextrin molecule.
  • the preferred degree of substitution is between 3,9 and 5,1 hydroxypropyl groups per cyclodextrin molecule.
  • the preferred degree of substitution is between 1,8 and 2 methyl groups per glucose unit.
  • the preferred degree of substitution is between 1 and 7 sulfobutyl ether groups per cyclodextrin molecule.
  • the inclusion complex of the invention may be prepared from aqueous solutions, slurries or pastes of alprazolam and cyclodextrin according to conventional methods.
  • the molar ratio of alprazolam to cyclodextrin may vary between 1:1 to 1:10 inclusive, but more preferably between 1:1 to 1:7 inclusive.
  • Solutions are prepared by dissolving the cyclodextrin in a sufficient quantity of purified deionised water. Alprazolam is added to the solution with stirring until dissolved.
  • the solution may be used in the preparation of liquid delivery systems such as drops, sprays or aerosols. Where a solid inclusion complex is desired, the solution or slurry may be dried by spray drying or freeze drying.
  • alprazolam and cyclodextrin are mixed.
  • the powder mixture is wetted with water while mixing vigorously until a paste is formed.
  • the paste is mixed for 0,25 to 2 hours and dried in an oven or in vacuo at elevated temperature. The dried complex is crushed and sieved to the desired particle size.
  • the particle size of the complex is preferably 95% less than 100 microns and most preferably 95% less than 50 microns, to facilitate wetting of a solid formulation.
  • the second aspect of the invention is a pharmaceutical composition which comprises as an active ingredient an inclusion complex as described above.
  • composition of the invention is of particular application in the treatment of GAD and for the management of panic disorders.
  • the pharmaceutical composition of the invention is preferably adapted for oral, nasal, or rectal mucosal delivery.
  • anxiolytic drug through the mucosal tissue of the nose, mouth or rectum avoids the problems associated with oral administration of alprazolam (i.e. slow onset of action, low bio-availability and associated poor compliance).
  • the unpleasant taste and irritant properties of the active principle are reduced by presenting the drug to the nasal or rectal oral mucosal membranes in the form of a cyclodextrin inclusion complex.
  • the present invention achieves these advantages by molecular encapsulation of the drug in a cyclodextrin, so forming a molecular inclusion complex which may be used in the solid form for the preparation of sublingual or buccal tablets, buccal patches, nasal inhalation powders (insufflations), suppositories, or powder aerosols for nasal or pulmonary application.
  • the inclusion complex may be used in the liquid state for the preparation of metered dose sprays, drops or pressurised aerosols for nasal or oral administration.
  • the complex according to the invention may be incorporated into a shearform matrix designed for immediate release as described in Fuisz Technolgies Ltd. patents (Eur. Pat. Appl. EP 95-650038 and PCT Int. Appl. WO 95/34293).
  • the water soluble complexes of alprazolam according to the invention may be incorporated into controlled release matrices for sustained release following oral administration of a matrix tablet.
  • the matrix may be composed of any suitable erodible matrix such as substituted celluloses and the like.
  • the complexes may be applied to non-pareil spheres by coating methods known in the art.
  • the coated spheres may be optionally coated with controlled release polymers such as polyacrylates and the like.
  • alprazolam has been found to be included in the cavity of beta- and gamma-cyclodextrins to form molecular inclusion complexes.
  • Inclusion complexes of alprazolam may therefore be prepared according to methods known in the art such as spray drying, freeze drying and kneading, as described above.
  • the complexes according to the invention may also be incorporated into microspheres by methods appreciated in the art.
  • the complexes according to the invention are stable and highly water soluble.
  • Penetration enhancers may be used to promote the passage of alprazolam across the mucosal membranes.
  • Typical permeation enhancers include fatty acids and their salts such as sodium caprate, sodium caprylate and sodium oleate, sodium laurate, and bile salts such as sodium glycodeoxycholate, sodium glycocholate, sodium cholate and sodium laurodeoxycholate.
  • Other penetration enhancers may include tensides, ionic surfactants such as sodium lauryl sulphate, or non-ionic surfactants such as polyethylene glycol 660 hydroxystearate or polyoxyethylene lauryl ethers, fusidates such as sodium taurodihydrofusidate.
  • Typical concentrations of permeation enhancers are between 0,1% to 5%, more preferably between 0,25% to 3% by weight of the composition.
  • Liquid compositions suitable for nasal or oral administration may contain a suitable quantity of viscosity modifying agents such as hypromellose or carbopol 934P and preservative agents such as benzalkonium chloride, chlorhexidine gluconate or thiomersat.
  • viscosity modifying agents such as hypromellose or carbopol 934P
  • preservative agents such as benzalkonium chloride, chlorhexidine gluconate or thiomersat.
  • Oral compositions may contain suitable flavouring and sweetening agents such as cherry, mint, spearmint, vanilla, aspartame, sucrose, xylitol, saccharin and the like.
  • Typical sublingual or buccal tablets may include lubricants such as magnesium stearate, calcium stearate and sodium stearyl fumarate to facilitate tablet compression, diluents such as lactose, microcrystalline cellulose, maize starch and the like and mucoadhesive agents such as chitosan, carbopol 934P, and hydroxypropylcellulose and the like.
  • lubricants such as magnesium stearate, calcium stearate and sodium stearyl fumarate to facilitate tablet compression
  • diluents such as lactose, microcrystalline cellulose, maize starch and the like
  • mucoadhesive agents such as chitosan, carbopol 934P, and hydroxypropylcellulose and the like.
  • Typical disintegrants to enhance sublingual tablet disintegration may include sodium carboxymethylcellulose, sodium starch glycolate, polyplasdone XL, and dried starch.
  • Typical suppositories may be formulated according to methods known in the art described in the Pharmaceutical Codex 12 th Edition, the Pharmaceutical Press, pp 170-176 or Remington's Pharmaceutical Sciences 18 th Edition, Mack Publishing Company, pp 1609-1614.
  • alprazolam is added to aqueous solutions of varying concentrations of beta-cyclodextrin. The mixtures are shaken for 24 hours and filtered. The filtrate is analysed by Ultraviolet spectrophotometry for alprazolam concentration. The concentration of alprazolam is plotted as a function of beta-cyclodextrin concentration in FIG. 1.
  • alprazolam is added to aqueous solutions of varying concentrations of methyl-beta-cyclodextrin and 2-hydroxypropyl-beta-cyclodextrin. The mixtures are shaken for 24 hours and filtered. The filtrate is analysed by Ultraviolet spectrophotometry for alprazolam concentration. The concentration of alprazolam is plotted as a function of cyclodextrin concentration in FIG. 2.
  • Alprazolam (6,53 g) and 2-hydroxypropyl-beta-cyclodextrin (200,4 g) are mixed.
  • Purified deionised water 70 ml is added with vigorous kneading to form a uniform paste with optional heating. Kneading is continued for 5 hours and the paste is dried in vacuo at 80° C. The dried complex is crushed and passed through a 250 micron sieve.
  • Alprazolam (6,0 g) and methyl-beta-cyclodextrin (198 g) are mixed.
  • Purified deionised water 70 ml is added with vigorous kneading to form a uniform paste with optional heating. Kneading is continued for 5 hours and the paste is dried in vacuo at 80° C. The dried complex is crushed and passed through a 250 micron sieve.
  • the unit composition of a sublingual tablet containing the equivalent of 1,0 mg alprazolam is as follows: Alprazolam/2-hydroxypropyl-beta-cyclodextrin complex 32.7 mg (from Example 3) Lactose NF 19 mg Sodium stearyl fumarate 0.6 mg
  • the complex is blended with lactose and the lubricant.
  • the mixture is formed into sublingual tablets by compression at 10-30 N.
  • Methylated beta-cyclodextrin D.S.1.8 (200 g) is dissolved in 90 ml purified deionised water.
  • Alprazolam (2.5 g) is added to the solution with stirring until a clear solution is obtained.
  • Benzalkonium chloride (0.01%) is added as a preservative.
  • the volume is adjusted to 1000 ml by addition of purified deionised water.
  • the tonicity of the final solution is adjusted by addition of sodium chloride.
  • the solution is filtered through a 0.45 ⁇ m filter. Each 0.1 milliliter of solution contains 0.25 mg alprazolam. The solution is well tolerated after intranasal administration by drops or spray.
  • Example 8 The solution obtained from Example 8 is packaged in a suitable metered dose aerosol dispenser adapted for intranasal application.
  • the concentration of the solution provides convenient dispensing of 0.25 mg alprazolam per 0.1 ml.

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US20070020298A1 (en) * 2003-12-31 2007-01-25 Pipkin James D Inhalant formulation containing sulfoalkyl ether gamma-cyclodextrin and corticosteroid
US20070232566A1 (en) * 2006-03-28 2007-10-04 Curtis Wright Formulations Of Low Dose Diclofenac And Beta-Cyclodextrin
US20090312724A1 (en) * 2007-06-28 2009-12-17 Cydex Pharmaceuticals, Inc. Nasal and Ophthalmic Delivery of Aqueous Corticosteroid Solutions
US9827324B2 (en) 2003-12-31 2017-11-28 Cydex Pharmaceuticals, Inc. Inhalant formulation containing sulfoalkyl ether cyclodextrin and corticosteroid
US10709662B1 (en) 2020-01-29 2020-07-14 King Abdulaziz University Mucoadhesive buccal film having a dual release carrier system
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US12370352B2 (en) 2007-06-28 2025-07-29 Cydex Pharmaceuticals, Inc. Nasal and ophthalmic delivery of aqueous corticosteroid solutions

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DE60115217T2 (de) 2006-07-20
AU4866001A (en) 2001-10-08
EP1267941B1 (fr) 2005-11-23
DE60115217D1 (de) 2005-12-29
US20050222086A1 (en) 2005-10-06
US7202233B2 (en) 2007-04-10
EP1267941A1 (fr) 2003-01-02

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