WO2002045721A1

WO2002045721A1 - Noble gas complexes

Info

Publication number: WO2002045721A1
Application number: PCT/GB2001/005356
Authority: WO
Inventors: Rodney Stewart Mason; Alexei Uriah Moozyckine; John Dingley
Original assignee: Uws Ventures Limited
Priority date: 2000-12-04
Filing date: 2001-12-04
Publication date: 2002-06-13
Also published as: AU2002220881A1

Abstract

A formulation for inducing and/or maintaining anaesthesia. The formulation includes a complex of a noble gas and a molecular encapsulating agent. The formulation may also be used as an analgesic formulation or in a neuroprotective formulation.

Description

Noble Gas Complexes

The present invention is concerned with noble gases for use in pharmaceutical applications.

All reference to the noble gas hereinafter will be to xenon; this is by way of example only and is not intended as a limitation of the application. Other suitable noble gases may be employed where appropriate instead of xenon.

Xenon is a highly polarizable, inert but hydrophobic atom which has a van der aals radius of approximately 2A. Xenon is a colourless, odourless and tasteless inert gas of atomic number 54.

Xenon has been proposed as an inhalation anaesthetic because it has both anaesthetizing and analgesic action. The use of xenon as an inhalation anaesthetic involves a high consumption of the gas unless very sophisticated breathing circuits are used. The use of xenon has previously been restricted due to the cost disadvantages which are incurred when such an expensive gas is exhausted to_t the atmosphere. In addition, treatment of a patient with such a gas requires the use of expensive technical equipment. It is for these reasons that xenon has not been widely used in anaesthesia.

Xenon, however, has a number of advantages over other inhaled anaesthetic agents which are currently favoured. One such advantage is the lack of side- effects on the cardiovascular system. A further potential advantage of xenon is that it may have brain protecting properties. The use of xenon and xenon gas mixtures for treating neurointoxications is discussed in PCT patent application EP00/02025.

The use of xenon in anaesthesia has other beneficial effects such as a short wake up time; a patient subjected to xenon induced anaesthesia wakes up from the anaesthesia quickly once the administration of xenon is stopped.

However, this advantage may not be considered a very important parameter if the xenon is being used for its lack of cardiovascular side effects rather than its short wake up time, or if the xenon is being used for another reason, for example as a protective drug for the nervous system.

PCT Patent Application EP98/01304 discloses a liquid preparation for inducing and/or maintaining anaesthesia, which contains a lipophilic inert gas (such as xenon) in a concentration effective as an anaesthetic. The inert gas is said to be dissolved or dispersed in a carrier (such as a fatty emulsion) . The liquid preparation disclosed however has a number of disadvantages. The main disadvantage is the large volume of lipid that has to be infused in order to deliver enough dissolved xenon to achieve anaesthesia. A further potential disadvantage is that xenon will diffuse out of the blood into the lungs as the blood passes through the lungs before reaching the brain; therefore a higher infused dose of xenon is required as the tendency for the xenon to diffuse out of the blood increases.

Cyclodextrins are able to form complexes with noble gases, for example, α-cyclodextrin with Kr and α- cyclodextrin with Xe. Cyclodextrin complexes of krypton are discussed in: M Sakurai, M Kitagawa, H Hoshi, Y Inoue, R Chuio, "A molecular orbital study of cyclodextrin (cyclomalto-oligasaccharide) inclusion complexes. Ill, dipole moments of clyclodextrins in various types of inclusion complex", Carbohydr. Res . , 198, 1990, 181-191.

The formation of inclusion complexes between Xe and α- cyclodextrin was acknowledged in the following publications: Y.-Q. Song, B M Goodson, R E Taylor, D D Laws, G Navon, A Pines, "Selective Enhancement of NMR signals for α-cyclodextrin with laser-polarized xenon", Angew. Chem . Int . Ed. Engl . , 36, 1997, 2368-2370; S M Rubin, M M Spence, B M Goodson, D E Wemmer, A Pines, "Evidence of nonspecific surface interactions between laser-polarised xenon and myoglobin in solution", Proc. Natl . Acad. Sci . USA, 97, 2000, 9472-9475; J A Ripmeester, C I Ratcliffe, G Enright, E Brouwer, "Thermodynamic and resonance studies of structural changes in crystals", Acta Cryst . , B51, 1995, 513-522; J A Ripmeester, C I Ratcliffe, J S Tse, " The nuclear magnetic resonance of ¹²⁹Xe trapped in clathrates and some other solids", J Chem . Soc. , Faraday Trans . 1 , 84, 1988, 3731-3745; K Bartik, M Luh er, S J Heyes, R Ottinger, J Reisse, "Probing molecular cavities in α- cyclodextrin solutions by xenon NMR", J Magn . Reson . B, 109, 1995, 164-168.

In the last work, the binding constant for Xe/α- cyclodextrin complex in water was estimated as 22+ 6 dirAnol^"1 at 298K.

Natural (parent) cyclodextrins are cyclic carbohydrates derived from starch by the action of cyclodextrin glycosyl transferase (CGTase) . The geometry of cyclodextrins can be described as toroidal frustum (or truncated cone) , which consist structurally of 6, 7 or 8 α-(l,4) linked D-glucopyranose units in a chair conformation.

It is possible to introduce different chemical moieties into the cyclodextrin molecule by reaction with the hydroxyl groups lining the upper and lower ridges of the toroid. A number of cyclodextrins which are commercially available include:

• Alkylated derivatives (methyl, ethyl, butyl, pentyl) ;

• Hydroxyalkylated derivatives (hydroxyethyl, 2- hydroxypropyl, 2-hydroxybutyl) ; • Esterified cyclodextrins (acetyl, propionyl, butyryl, succinyl, benzoyl, palmityl, toluenesulfonyl) ;

• Esterified and alkylated cyclodextrins (acetyl methyl, acetyl butyl) ; • Branched derivatives (glucosyl, maltosyl) ;

• Ionic derivatives (carboxymethyl ether, carboxymethyl ethyl, phosphate ester, sulfobutyl ester, 3-trimethylammonium-2-hydroxypropyl ether) .

Modifications in this way can be used to increase water solubility of cyclodextrins derivatives. Such modifications may also be used to optimise the attraction forces between xenon and cyclodextrin.

The property of cyclodextrins to form inclusion complexes with various types of charged and neutral guests is widely acknowledged and is summarized in multiple reviews, see for example Cyclodextrins, J Szejtli, T Osa, volume eds., in Comprehensive Supramolecular Chemistry, J L Atwood, J E D Davies, D D MacNicol, F Vδgtle, J.-M. Lehn, eds . , Elsevier Science, Oxford, 1996, vol. 3; Chem . Rev. , 98, 1998, No.5 (1941- 2076) - all issue.

Factors that make the use of cyclodextrins and their derivatives complexes for drug delivery particularly attractive include:

• Significant solubility of cyclodextrins in water {γ > a > β) ; • extremely low toxicity (especially for the oral administration) ;

• low cost;

• presence on the market as an approved pharmaceutical and cosmetic product (i.e. drug delivery agent, catalyst, etc.).

The cyclodextrin molecule therefore is capable of acting as a host to a xenon guest atom thereby forming a molecular inclusion complex. The principle structure of a parent cyclodextrin containing a xenon atom is shown by way of illustration in Figure 1.

Cyclodextrins are not simply solubilising agents, but are chemicals able to form stable molecular inclusion complexes with guest atoms such as xenon. Therefore, these inclusion complexes, represent species that are characterised by unique physico-chemical properties and usually can be separated from solution, dried and purified without decomposition.

Generally, a molecular complex is defined as a non- covalently bound species of definite substrate-to- ligand stoichiometry that is formed in a facile equilibrium process in solution (K A Connors, Binding Constants - The measurement of molecular complex stability, Wiley Interscience, New York, 1987) . Therefore, the formation of a molecular complex cannot be described simply as a solubilising process of the guest, because the nature of the inclusion complex depends very little on the nature of the solution. In the complex formation process, the changes in solubility of the guest represent one of secondary effects (this can be either positive-solubilising, negative-desolubilising, or close to zero-solubility does not change) .

It is therefore one aim of the present invention to alleviate the disadvantages highlighted above.

It is a further aim of the present invention to provide a cost effective pharmaceutically acceptable formulation for use in anaesthesia, in neuroprotection and/or for use as an analgesic.

According to a first aspect of the present invention there is provided a formulation for inducing and/or maintaining anaesthesia, the formulation including a complex of a noble gas and a molecular encapsulating agent .

^' According to a second aspect of the present invention, there is provided an analgesic formulation which includes a complex of a noble gas and a molecular encapsulating agent.

According to a third aspect of the present invention, there is provided a neuroprotective formulation which includes a complex of a noble gas and an encapsulating agent .

The noble gas may include krypton, however (as indicated above) xenon is preferred.

Typically, the encapsulating agent is a α-, β- or -γ cyclodextrin or a derivative thereof. The cyclodextrin is preferably α-cyclodextrin, β-cyclodextrin or derivatives thereof; α-cyclodextrin or a derivative thereof are particularly preferred.

The physiological effect of inhaled Xe is determined by the concentration of Xe dissolved in the blood. This concentration is proportional to the partial pressure of Xe in the gas mixture that accesses the lungs and the coefficient of solubility of Xe in blood. It is also inversely proportional to the temperature (that is about 37°C, which cannot, of course, be changed) .

Introducing cyclodextrins directly into blood of a person receiving xenon by inhalation may result in an increase of Xe uptake via a formation of soluble cyclodextrin/Xe complex. Generally, there are two ways of performing this:

1) Introducing cyclodextrin derivative into blood and maintaining the necessary concentration of it into bloodstream, while applying xenon through the respiratory system;

2) Introducing cyclodextrin/Xe soluble complex directly into bloodstream of the patient, with the possibility of applying respiratory mask only for collecting small amounts of exhaled xenon for further recovery (if desirable) .

The cyclodextrin derivative that has a highest binding constant with Xe is not necessarily the one that will show the best pharmacokinetics as the other processes involved, i.e. the transmission of Xe from the bloodstream to synapses or cell membranes might be better served by the modified cyclodextrin, where the Xe atom is correctly positioned within the host molecule cavity, thus allowing a better contact of Xe with the target site. In addition, the issues of toxicity, arising from the high affinity of cyclodextrins to lipids can be particularly important for high concentrations of intravenously administered cyclodextrin/Xe complex and must also be considered.

The redistribution coefficient for Xe between blood and alveolar air at 37°C is 0.14, (ie about 700 mL of Xe can be dissolved in 5 L of blood) (N E Burov, V N Patapov, G N Makeev, Xenon in Anaesthesiology, (Rus.), Puls, Moscow, 2000) , making the maximum concentration of Xe in blood that it possible to maintain under normal conditions [Xe] Aχ = ca 0.03 mol dm^-3. In principle, this can be easily achieved with many derivatives of cyclodextrins that have solublities in excess of 50g/100ml. This means that uptake of Xe through the complex formation with the cyclodextrin derivative dissolved in blood can be increased theoretically ca. 12 times or more, comparatively to the maximum level attainable through conventional respiratory xenon delivery methods. This also means that the entire amount of Xe can be delivered through the blood as a soluble complex with cyclodextrins, making the use of respiratory delivery system unnecessary.

Alternatively, introducing cyclodextrin derivative in the bloodstream can compliment the conventional respiratory xenon anaesthesia, making it possible to decrease the concentration of Xe in the gas mixture, whilst retaining the same therapeutic or anaesthetic effect. This would have the advantage that there will be a substantial reduction in the cost of using Xe as a routine anaesthetic.

As the Xe/cyclodextrin complex is more soluble in blood than free Xe, its application in clinical practice will increase the recovery or "wake up" times comparatively to the conventional inhaled Xe anaesthesia. (Clinical recovery or wake up from inhaled xenon anaesthesia is extremely rapid which can be advantageous in certain circumstances to the anaesthetist) .

An advantage of the present invention is that, when it is desirable, the anaesthetic effect could potentially be quickly negated via competitive binding, by introducing into the bloodstream a pharmaceutically- inert substance that forms a more stable complex with cyclodextrin than Xe. This can be used as a controlled eliminating system, forcing Xe to be released from the soluble complex into the blood and ventilated out through the lungs, maintaining the desirable rate of Xe elimination by regulating the delivery of the inert competitive binding agent.

It is preferred that the formulation is in liquid form. Further preferably the formulation is dissolved in a pharmaceutically acceptable aqueous carrier for example.

According to a further aspect of the present invention, there is provided a complex including a noble gas and an encapsulating agent, for use as a pharmaceutical substance.

According to a further aspect of the present invention, there is provided a use of a complex including a noble gas and an encapsulating agent (such as a cyclodextrin, or a derivative thereof) , as an anaesthetic.

According to yet a further aspect of the present invention, there is provided a use of a complex including a noble gas and an encapsulating agent (such as a cyclodextrin, or a derivative thereof) , as an analgesic.

According to still yet a further aspect of the present invention, there is provided a use of a complex including a noble gas and an encapsulating agent (such as a cyclodextrin, or a derivative thereof) , in a neuroprotective formulation.

The encapsulating agent and/or the noble gas are substantially as described hereinbefore.

The complex is typically soluble in blood. Preferred cyclodextrins for use in this aspect of the invention are as described above with reference to the formulation according to the invention.

A further advantage of the use of cyclodextrins in anaesthesia is that there will be a reduction (or removal) of the side effects from the deployment of gas mixtures with high Xe concentration. The density of Xe is 4.5 times higher than that of air, therefore clinical applications of Xe anaesthesia with high Xe concentrations (up to 80% Xe) often have minor negative effects, that manifest themselves in diffusive hypoxia, changes in respiratory rate (lung compliance), etc.

This means that Xe-cyclodextrin anaesthesia and therapy has yet a further advantage in that it can be used on patients with lung or breathing system problems. -li¬

lt is therefore possible to use Xe for therapeutic applications without recourse to complicated respiratory delivery systems, by introducing the soluble complex with cyclodextrin intravenously, maintaining a necessary concentration of Xe in the bloodstream through a drip.

According to a further aspect of the present invention, there is provided an infusion agent, which comprises a formulation according to the present invention.

The formulation of the invention can be used to produce anaesthesia in a patient.

Cyclodextrin -Xe complexes are discussed below, wherein the binding constant, Ku, is usually determined for simplest case of 1:1 binding in eqns. (1) to (4):

CD + Xe ^ CD~Xe (1)

[CD ~ Xe] κ„ = [CD]+[Xe] ₍₂₎

[CD] = [CD]₀ ~ [CD~Xe] (3)

[Xe] = [Xe]₀ - [CD~Xe] (4)

where [CD]₀ and [Xe]₀ are the initial concentrations of cyclodextrin and Xe, respectively.

The non-covalent interactions that contribute to the complex formation are: electrostatic (ion-ion, ion- dipole, dipole-dipole and dipole-induced dipole) , van der Waals, hydrophobic, hydrogen bonding, charge- transfer, π-π stacking interactions and steric effects. However, the most important contributions to the complexation thermodynamics of cyclodextrins are penetration of the hydrophobic guest (or its part) into cyclodextrin cavity and dehydration of the organic guest. In our instance, Xe demonstrates quite clear hydrophobic properties; on the other side, its high polarizability makes it easy to interact with cyclodextrin molecule as induced dipole-dipole type, especially taking into account quite large dipole moments of cyclodextrins ( ca 12 Debye) .

The magnitude of binding depends on several factors, e.g. charge of the guest, co-included solvent, temperature, etc. Among these factors, the size and geometry of the guest are the most important. Some characteristics of parent cyclodextrins are summarized below:

For comparison, van der Waals atomic diameters of Xe and Kr are 4.05A and 3.60A, respectively. The water solubility of parent cyclodextrins may be increased dramatically by incorporation of hydrophilic groups into exterior original cyclodextrins, the degree of substitution usually ranging from 3 to 18. For example, solubility in water of hydroxypropyl and hydroxyethyl derivatives of β-cyclodextrin (the least soluble) with degree of substitution 3 to 18 is more than 60 g/lOOmL at 25°C.

The ionic class of derivatives (anionic species like sulfobutyl ether with various possible degree of substitution) are preferred encapsulating agents for parenteral administration; examples of such compounds currently available on the market include Captisol by CyDex Inc. which has proved to be suitable for intramuscular and intravenous injections to humans (does not cause irritation and completely and rapidly eliminated unmetabolized via the kidneys) .

Some further information regarding pharmaceutical applications of various cyclodextrins' derivatives can be found in the following papers and references therein: Symposium on Pharmaceutical Applications of Cyclodextrins, University of Kansas, Lawrence, KS USA, 29 June - 2 July, 1997; T. Loftsson, Cyclodextrins in Pharmaceutical Formulations . - The effects of polymers on their complexation efficacy and drug availability, Report for Nordic Industrial Fund, 1998; US Patent 6046177, V.J. Stella, R.A. Rajewski, V.M. Rao, J.W. McGinity, G.L. Mosher, "Sulfoalkyl ether cyclodextrin based controlled release solid pharmaceutical formulations", 4 April, 2000.

The use of highly-soluble chemically-modified cyclodextrins enables the use of not only Xe but also Kr for anaesthetic or therapeutic purposes without a respiratory delivery system. Kr is not an anaesthetic at ambient (atmospheric) pressure but would be in a hyperboric chamber where the pressure is greater than atmospheric. Kr is an anaesthetic generally employed in a hyperbaric chamber. It is envisaged that if cyclodextrins allowed large quantities to be delivered to the patient's brain then possibly Kr could work at atmospheric pressure. With the same purpose of xenon delivery to the target site, apart from free cyclodextrin derivatives, it is possible that the following compounds also could be used: a) small soluble cyclodextrin polymers, or b) rotaxanes .

Rotaxanes are the compounds where several (many) cyclodextrin moieties are threaded through by a linear or branched polymer chain, with substituents on the ends to stop threaded cyclodextrin units from coming off. If the polymer chain is relatively thin, threaded cyclodextrins retain their ability to encapsulate suitable guests (e.g. Xe or Kr) . These rotaxanes might have a high enough solubility in blood and also low toxicity to make it advantageous using such formulations for Xe delivery instead of simple cyclodextrins' derivatives. (See, for example, US Patent 6037387, N Yui, M Terano, H Mori, "Blood- compatible material of a supramolecular structure", 14 March 200) .

Claims

1. A formulation for inducing and/or maintaining anaesthesia, the formulation including a complex of a noble gas and a molecular encapsulating agent.

2. An analgesic formulation which includes a complex of a noble gas and a molecular encapsulating agent.

3. A neuroprotective formulation which includes a complex of a noble gas and an encapsulating agent. -

4. A formulation according to any preceding claim wherein the noble gas is Krypton or xenon.

5. A formulation according to any preceding claim, wherein the encapsulating agent is a α-, β- or -γ cyclodextrin or a derivative thereof.

6. A formulation according to any preceding claim, wherein the formulation is dissolved in an aqueous carrier.

7. A formulation according to any preceding claim, wherein the encapsulating agent is an ionic derivative of a Cyclodextrin (such as sulfobutyl ether) .

8. A formulation according to any preceding claim, wherein the encapsulating agent is a soluble Cyclodextrin polymer or a rotaxane.

A formulation according to any preceding claim which is capable of being dissolved in blood.

10. A complex including a noble gas and an encapsulating agent, for use as a pharmaceutical substance.

5 11. A complex including a noble gas and an encapsulating agent, for use as an anaesthetic.

12. A complex including a noble gas and an encapsulating agent, for use in a neuroprotective

10 formulation.

13. A complex including a noble gas and an encapsulating agent for use as an analgesic.

15.

14. A complex according to any of claims 11 to 14 wherein the noble gas in Xenon or Krypton.

15. A complex according to any of claims 11 to 15 wherein the encapsulating agent is a Cyclodextrin 0 or a derivative thereof.

16. An infusion agent which comprises a formulation including a complex of a noble gas and a molecular encapsulating agent. 5