WO1997010814A1

WO1997010814A1 - Propofol nanodispersions

Info

Publication number: WO1997010814A1
Application number: PCT/IB1996/000868
Authority: WO
Inventors: Hans Georg Weder
Original assignee: Vesifact Ag
Priority date: 1995-09-18
Filing date: 1996-08-29
Publication date: 1997-03-27
Also published as: AU6708096A

Abstract

The invention relates to nanodispersions for the intravenous administration of the anaesthetic agent propofolum having lipophilic properties. The nanodispersion is prepared by adding propofolum to an aqueous solution of a partial fatty acid ester of polyoxyethylene sorbitan at low concentrations followed by moderate stirring at room temperature or under moderate heating.

Description

PROPOFOL NANODISPERSIONS

The following invention relates to nanodispersions for the intravenous administration of an anaesthetic agent having lipophilic properties, a process for the preparation of these nano¬ dispersions and its use in therapeutic methods

Propofol (propofolum), cf Merck Index Tenth Edition (1989), entry No. 7847, page 1245, chemical name 2,6-diisopropylphenol, is an intravenous sedative hypnotic agent for use in the induction and maintenance of anaesthesia or sedation Intravenous injection of a therapeutic dose of propofol produces hypnosis rapidly and smoothly with minimal excitation, usually within 40 seconds from the start of an injection, cf Physicians ' Desk Reference, 49th Edition 1995, Medical Economics (USA), page 2436. In various countries the active agent propofol is commercially available only in a single pharmaceutical dosage form, e g which is an injectable emulsion marketed under the trade mark Disoprivan^® (Stuart, Zeneca) This formulation is an emulsion consisting of soy bean oil, egg lecithin, and glycerol

Emulsions of this type used as injectables have serious drawbacks M Tressler et al report in Can. J. Anaesth. 1992, 39 (5 Pt 1), 509-511 of undesirable growth of bacteria in emulsions containing propofol C Pirttikangas et al report in Intensive Care Med. 1993, 19(5), 209-302 of undesirable immunesuppressive effects resulting from bolus administrations or rapid infusion treatment M Lindholm reports in Minerva Anaesthesiol 1992, 58 (10), pages 875-879 that the maximal lipid clearance is exceeded Physician 's Desk Reference, loc. cit., mention serious adverse reactions, such as bradycardia, apnea, hypotension, and others A detailed section is dedicated to Warnings, Precautions, and Drug Interactions

The act of administering the dosage form intravenously is also painful This may be explained by the lipophilic character ofthe ingredients ofthe dosage form For this reason, the simul¬ taneous administration with analgetics is also recommended Strict aseptic technique must always be maintained during handling The detailed restrictions and instructions according to Physicia 's Desk Reference, loc. cit. , are self-explanatory and indicate the need for an improved formulation

A suitable intravenous dosage form has not yet been available for the important anaesthetic agent propofol The object ofthe present invention, therefore, is to make available a suitable intravenous dosage form for the lipophilic active agent propofol

The number of approaches for solving the problem according to the present invention by developing suitable alternative dosage form is severely limited, since propofol has to be administered in the course of intensive care to unconscious patients or temporarily handi¬ capped patients This excludes the use of oral dosage forms, e g capsules which appear suitable for formulating lipophilic therapeutic agents. However, the use of such dosage forms requires improved health status ofthe patient. In a narrower sense, the object ofthe present invention is the preparation of an improved new intravenous dosage form

The drawbacks ofthe known injectable emulsion are explicable by its insufficient homogeneity caused by the lipophilic properties ofthe additives and the therapeutic agent propofol Its pronounced lipophilicity especially explains the insufficient suitability for intravenous dosage forms which require the solubilization ofthe therapeutic agent in the carrier liquid In order to effect solubilization successfully, the lipophilicity ofthe active agent also necessitates the addition of larger amounts of pharmaceutical carrier materials. U.S. Patent Specification No. 4 452 817 discloses a microemulsion containing 1 % propofol, which also contains 10 % ofthe additive Tween^® (ICI) 80 Such a high amount of surfactants in an intravenous dosage form is physiologically inacceptable

In a narrower sense, the object ofthe present invention is the preparation of a new, improved intravenous dosage form for the lipophilic agent propofol which contains physiologically acceptable amounts of carrier materials In the event that the addition of one ofthe few solubilizers permitted in national pharmacopoeias still fails to promote the solubility ofthe active agent, the incoφoration in finely dispersed systems based on lipid mixtures is suggested in the prior art In such systems, the sparingly soluble therapeutic agent is encapsulated in lipid particles ofa particle size of less than 1 μm The "loaded" lipid particles then form with the aqueous carrier liquid an aqueous phase of colloidally dispersed or, preferably, finely dispersed character, which differs from the true homogeneous distribution of solutes at molecularly dispersed level but is, nevertheless, sufficiently homogeneous for the preparation of intravenous and oral dosage forms Numerous publications suggest the incorporation of therapeutic agents of low solubility in micelles, mixed micelles, reversed micelles, unilamellar or multilamellar liposomes, nanocapsules or nanoparticles

It has suφrisingly been found that the addition of specified amounts of a partial fatty acid ester of polyoxyethylene sorbitan in low concentrations is especially suitable for the preparation ofa homogeneous dispersion of small particles in the form of a nanodispersion ofthe active agent propofol

The present invention, therefore, relates to a nanodispersion for the intravenous administration of an anaesthetic agent having lipophilic properties, which comprises a) 1 0 - 2 0 weight % ofthe therapeutic agent 2,6-diisopropylphenol (propofolum), b) 1 0 - 3 0 weight % ofa partial fatty acid ester of polyoxyethylene sorbitan, c) the carrier liquid water, in the degree of purity necessary for intravenous administration, wherein the weight ratios of component a) to component b) are in the range of 0 33 - 1 2

The nanodispersion defined above is distinguished by useful phase properties ofthe solubilized therapeutic agent For example, where opalescence and transparency occur in incident light, only an extremely slight milky turbidity reveals that the dispersion formed still has physical differences vis-a-vis the ideal state ofa true molecular solution Electron microscope images show that a population of more than 95 % ofthe sparingly soluble propofol is present in the form ofa dispersion of nanoparticles having a particle size of less then 30 nm ("nano¬ dispersion") However, these differences vis-a-vis a true solution are acceptable in view of some remarkable homogeneity properties ofthe nanodispersion These properties can be made apparent in a high storage stability, for example there is no separation after storage for several months at 2-8°C (by extrapolation the expected stability is more than two years) A comparison with the conventional injectable emulsion formulation Disoprivan^® reveals the following: A sample of Disoprivan^® of 1 0 ml contains a mean of about 3.2 x IO⁶ particles having a size of > 1 0 μm and still about 10 to 30 particles having a size of > 25 0 μm, whereas in a sample of 1 ml ofthe nanodispersion according to the present invention only a small population of up to some thousends particles having a particle size of more than 1 μm is present. Practically no particles having a particle size of more than 25 μm are present Such particle distribution of extremely few particles of undesirably large sizes is particularly useful and is far below the limits which are acceptable according to the regulations of national regulatory authorities, such as the Food and Drug Administration (FDA) in the U S

A preferred embodiment ofthe present invention relates to a nanodispersion comprising a) 1 0 - 2 0 weight % ofthe therapeutic agent 2,6-diisopropylphenol (propofolum), b) 1 0 - 3 0 weight % of polyoxyethylene(20)sorbitan monooleate, c) the carrier liquid water, in the degree of purity necessary for intravenous administration, wherein the weight ratios of component a) to component b) are in the range of 0 33 - 1 0

The therapeutic agent propofol - component a) - is present in the nanodispersions defined above in the dose which is approved for injection formulations According to Physicia 's Desk Reference, loc. cit., an injectable formulation of 1 ml contains a dose of 10 mg

The partial fatty acid ester of polyoxyethylene sorbitan - component b) consists preferably of a substantially pure ester of sorbitan or a mixture of different esters of sorbitan in which the structure ofthe fatty acid groups and the length ofthe polyoxyethylene chains may vary The hydrophilic sorbitan is preferably etherified by three hydrophilic polyoxyethylene chains and esterified by a hydrophobic fatty acid group The sorbitan may, however, alternatively be etherified by only one or two polyoxyethylene chains and correspondingly esterified by two or three fatty acid groups The basic sorbitan structure is altogether substituted by a minimum of two and a maximum of three hydrophilic groups, the term "hydrophilic group" embracing the polyoxyethylene chains, whereas the fatty acid groups are hydrophobic The polyoxyethylene chain is linear and has preferably from 4 to 10, especially from 4 to 8, ethylene oxide units The ester groups on the basic sorbitan structure are derived from a satu¬ rated or unsaturated, straight-chain carboxylic acid having an even number of from 8 to 20 carbon atoms The ester group derived from that carboxylic acid is preferably straight-chained having 12, 14, 16 or 18 carbon atoms, for example n-dodecanoyl, n-tetradecanoyl, n- hexadecanoyl or n-octadecanoyl The ester group derived from an unsaturated carboxylic acid having an even number of from 8 to 20 carbon atoms is preferably straight-chained having 12, 14, 16 or 18 carbon atoms, for example oleoyl The mentioned esters of sorbitan are in conformity with the data given in the British Pharmacopoeia (specialised monograph) or Ph Helv VII In particular, the product specifications published by the mentioned manufac¬ turers with the information on data sheets for the relevant product, especially specifications such as shape, colour, HLB value, viscosity, ascending melting point and solubility, apply

Suitable partial fatty acid esters of polyoxyethylene sorbitan are commercially obtainable under the trademark Tween^® of ICI Coφ and known by the chemical names polyoxyethylene (20 or 4)sorbitan monolaurate (TWEEN 20 and 21), polyoxyethylene(20)sorbitan mono- palmitate or monostearate (TWEEN 40 and 60), polyoxyethylene(4 or 20)sorbitan mono¬ stearate or tristearate (TWEEN 61 and 65), polyoxyethylene(20 or 5)sorbιtan monooleate (TWEEN 80 or 81) and polyoxyethylene(20)sorbitan trioleate (TWEEN 85) In an especially preferred embodiment ofthe invention, polyoxyethylene(20)sorbitan monooleate (TWEEN 80) is used as component b)

Component c), the carrier liquid water having the degree of purity necessary for intravenous administration is, in accordance with the regulations of national pharmacopoeias, germ- and pyrogen-free

Excipients suitable for injection puφoses are present in the nanodispersion if desired Suitable excipients are approved by Regulatory Authorities for injection purposes, e g glycerol, benzyl alcohol in the degree of purity prescribed for injection purposes, and also excipients suitable for the production of isotonic conditions, for example ionic excipients, e.g. sodium chloride, or other water-soluble excipients, e.g. sorbitan, mannitol, glucose, lactose or fructose

The present invention also relates to a process for the preparation ofthe nanodispersions defined above, which is known per-se and which process comprises.

First dissolving component b) - partial fatty acid ester of polyoxyethylene sorbitan - in component c) - water - and thereafter adding to this solution component a) - active agent propofol - in the specified amounts and weight ratios defind above, and subjecting the nanodispersion obtainable to the following subsequent operations addition ofa further amount of water as carrier liquid and optionally further water-soluble excipients that are suitable for injection puφoses; sterile filtration ofthe clear nanodispersion, or sterile filtration and subsequent conversion ofthe nanodispersion obtainable into a dry preparation, optionally with the addition of water-soluble excipients, and reconstitution ofthe dry preparation to form an injectable nanodispersion.

According to this method, an especially homogeneous, intravenously administrable nano¬ dispersion ofthe therapeutic agent propofol is prepared

The nanodispersion is prepared by adding the oily phase of pure propofol - component a) - to the aqueous phase containing the component b) This mixture is stirred during 2 to 3 houres using a magnetic stirrer or static mixer. Mixing preferably is effected at room temperature or under moderate heating up to 45°C.

The dispersion obtainable can be defined as a dispersion of colloidal nanoparticles ofthe sparingly soluble lipophilic active agent propofol, or, more simply, as a nanodispersion By means of measurements from laser light scattering and electron micrographs, the colloidal nanoparticles present in the nanodispersion can be distinguished from other particles such as liquid crystals, micelles, inverse micelles or liposomes. For the statistical plurality of more than 95 %, especially more than 99 %, an average particle size of less than 25 nm is typical.

For the identification ofthe nanodispersions obtainable, methods known per se are suitable, for example optical examination: Transparence with slight to intense opalescence ofthe preparation is easily identifiable (indicates average particle size of less than 50 nm); laser light scattering (determination ofthe particle size and homogeneity); or electron microscopy (freeze fracture and negative contrast technique).

The necessary amount of water, which must be ofthe purity prescribed for injectables, can be added to the nanodispersion. This nanodispersion can be directly administered after selecting the filtration method suitable for such types of dispersions, preferably sterile filtration (0.2 μm), for example with a PAL filter (Gelman), and optionally after adding further water-soluble excipients that can be used for intravenous dosage forms. Especially sterile filtration is applicable to separate off all relatively large particles in the nanodispersion having a diameter greater than about 200 nm, as well as floating and solid substances. This yields a nano¬ dispersion having a high proportion of hydrophilic particles of extremely uniform size.

As an alternative to the preparation of a directly administrable nanodispersion, the nano¬ dispersion may be converted into a dry preparation, especially into a lyophilisate, which is reconstituted prior to administration by the addition of water. An administrable nanodispersion is obtained again after reconstitution ofthe lyophilisate. For the preparation of lyophilisates, the addition of so-called builders, such as lactose or mannitol, is customary. These excipients are added in such amounts that after reconstitution ofthe lyophilisate the nanodispersion to be administered has isotonic properties.

Measured amounts of nanodispersion are introduced, optionally in the form of a concentrate, into containers suitable for a unit dose, for example glass ampoules (vials). The filled containers can be cooled, if desired, to about -40° to -50°C, especially to about -45°C, and then lyophilised at a pressure of about 0 2 to 0 6 mbar by slowly heating to a final temperature of about 25° to 35°C

The nanodispersion according to the present invention is particularly useful as injection formulation for intravenous administration for the induction and maintenance of anaesthesia or sedation

The following examples illustrate the invention, the relevant physico-chemical parameters, such as size and distribution ofthe nanoparticles (laser light scattering methods in the nm range), number of particles per ml (particle counter according to USP in the μm range), viscosity, and concentrations ofthe active agent in the formulation are shown in the TABLE attached to the Examples

Example 1 Formulation for an injectable formulation 10 mg/ml Percentages are given in weight percent

1 4 % polysorbatum 60 92 8 % aqua ad inj

1 0 % propofolum (active substance)

0 5 % benzyl alcohol

4 3 % mannitolum Polysorbatum 60 is dissolved in water, and the mixture is stirred at 45°C with a magnetic stirrer To this solution the active substance propofol and benzyl alcohol is given The mixture is stirred for two to three hours at room temperature with a magnetic stirrer (200-300 φm) until the mixture appears transparent and weakly opalescent The clear mixture is then sterile filtered (0 2 μm) and filled into vials under sterile conditions The vials may be stored at temperatures up to 25°C Example 2 Formulation for an injectable formulation 10 mg/ml Percentages are given in weight percent

1 4 % polysorbatum 60 92.9 % aqua ad inj

1 0 % propofolum (active substance)

4 7 % mannitolum The formulation is prepared in a manner analogous to Example 1 at room temperature Benzyl alcohol is omitted

Example 3 Formulation for an injectable formulation 10 mg/ml Percentages are given in weight percent

1 4 % polysorbatum 80 92 8 % aqua ad inj

1 0 % propofolum (active substance) 4 8 % mannitolum

The formulation is prepared in a manner analogous to Example 2 at room temperature

Example 4 Formulation for an injectable formulation 20 mg/ml Percentages are given in weight percent

2 8 % polysorbatum 80 90 4 % aqua ad inj

2 0 % propofolum (active substance) 4 8 % mannitolum The formulation is prepared in a manner analogous to Example 3 at room temperature Physico-chemical data of injectable formulations according to the Examples compared with the commercial formulation Disoprivan^®

TABLE

Example Batch Laser-Light- Number of Viscosity Concentr

No / Scattering" [nm] Particles/ml²⁾ [mPas] Propofol¹'

Size [mg/ml]

[kg]

1 040 AVG⁴⁾ 208 ± 70 > 1 μm 12175 11 98

> 10 μm 213 >20μm 26 10 > 30 μm 11

2 045 AVG⁴⁾ 178+ 57 > 1 μm 6394 11 99

> 10 μm 45 >20μm 4 10 > 30 μm 1

3 002 AVG⁴⁾ 179+ 50 > 1 μm 4154 13 96

> 10 μm 12 >20μm 0 500 > 25 μm 0

4 063 AVG⁴⁾ 115142 > 1 μm 6899 15 198

> 10 μm 55 >20μm 0 10 > 30 μm 0

Diso- MP21 AVG⁴⁾ 1238 + 379 > 1 μm 3163978 16 100 pπvan ® Exp > 10 μm 1308 0997 >20μm 24

> 30 μm 10 ¹⁾ Nicomp 370 Submicron Particle Sizer;

²⁾ A3 Particle Counter VS, USP conform/ Examples 1 and 2: mean from 6, Examples 3 and 4: mean from 3, Disoprivan^® : mean from 18 measurements;

³⁾ HPLC; ⁴⁾ AVG = Gauss- Analysis number weighting particle distribution;

Claims

1. A nanodispersion for the intravenous administration of an anaesthetic agent having lipophilic properties, which comprises: a) 1 0 - 2.0 weight % ofthe therapeutic agent 2,6-diisopropylphenol (propofolum), b) 1.0 - 3.0 weight % ofa partial fatty acid ester of polyoxyethylene sorbitan, c) the carrier liquid water, in the degree of purity necessary for intravenous administration, wherein the weight ratios of component a) to component b) are in th range of 0.33 - 1.2

2 A nanodispersion for the intravenous administration of an anaesthetic agent having lipophilic properties, which comprises: a) 1.0 - 2 0 weight % ofthe therapeutic agent 2,6-diisopropylphenol (propofolum), b) 1.0 - 3 0 weight % of polyoxyethylene(20)sorbitan monooleate; c) the carrier liquid water, in the degree of purity necessary for intravenous administration, wherein the weight ratios of component a) to component b) are in th range of 0.33 - 1 0

3 A process for the preparation ofa nanodispersion according to claim 1, which comprises First dissolving component b) - partial fatty acid ester of polyoxyethylene sorbitan - in component c) - water - and thereafter adding to this solution component a) - active agent propofolum - in the specified amounts and weight ratios according to claim 1 or claim 2 and stirring this mixture using a magnetic stirrer or static mixer preferably at room temperature or under heating up to 45°C

4 Nanodispersions ofthe therapeutic agent 2,6-diisopropylphenol (propofolum) according to claim 1 or claim 2 for use in a therapeutic method by intravenous administration

5. Nanodispersions according to claim 4 for the induction and maintenance of anaesthesia or sedation by intravenous administration