WO1996014057A1 - Preparation par filtration tangentielle de medicaments liposomiques et produits liposomiques obtenus - Google Patents

Preparation par filtration tangentielle de medicaments liposomiques et produits liposomiques obtenus Download PDF

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Publication number
WO1996014057A1
WO1996014057A1 PCT/EP1995/004330 EP9504330W WO9614057A1 WO 1996014057 A1 WO1996014057 A1 WO 1996014057A1 EP 9504330 W EP9504330 W EP 9504330W WO 9614057 A1 WO9614057 A1 WO 9614057A1
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detergent
solution
liposomes
tangential filtration
lipid
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PCT/EP1995/004330
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English (en)
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Rolf E. Schubert
Thomas K. Purmann
Regine Peschka
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Merz & Co Gmbh & Co
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    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes
    • A61K9/1277—Processes for preparing; Proliposomes

Definitions

  • the field of the invention is the preparation of liposomes and active-ingredient-containing, e.g., medicament- containing, liposomes.
  • the present invention provides the first and highly-advantageous method for the preparation of liposomes directly by constant volume tangential filtration and without the previously-required “dilution” or "concentration-dilution” procedures of the prior art.
  • liposomes are produced rapidly, conveniently, economically, and optionally continuously by tangential filtration of an aqueous solution of aggregates of one or more membrane-forming substances and one or more solubilizing agents forming water-soluble aggregates referred to as mixed micelles, which are in equilibrium with solubilizing agent, e.g., detergent monomers.
  • solubilizing agent e.g., detergent monomers.
  • solubilizing agent When the concentration of solubilizing agent is reduced by tangential filtration under pressure, with simultaneous introduction of an equal volume of aqueous non- solubilizing agent solution as solubilizing-agent solution is filtered off, so as not to dilute the volume of the aqueous solution of the mixed micelles or the concentration of the membrane-forming lipids in the aqueous solution, the mixed micelles are forced to grow in size due to reduction in solubilizing agent concentration and finally to form liposomes which will contain the drug or other active ingredient present in the aqueous solution of water-soluble aggregates (mixed micelles).
  • the present invention relates to a method for the preparation of liposomes and liposomal drugs, which are aqueous dispersions of artificial hollow sphere-like aggre ⁇ gates (vesicles) of suitable amphiphilic membrane-forming substances, preferably associated with drug or other active ingredients, and optionally in gel form and/or mixed with pharmaceutical auxiliaries, e.g., excipients or carriers.
  • Amphiphilic membrane-forming substances are molecules, which are poorly soluble in water and have separate hydro- philic (polar) and lipophilic (apolar) domains. Such molecules in most cases form double layer membranes, but also membrane-spanning monolayer-forming amphiphiles are known.
  • Liposomes consist of at least one membrane enclosing an aqueous compartment and have a size range of 0.02 ⁇ m up to several ⁇ m in diameter.
  • Oligolamellar large vesicles (OLVs) and multilamellar large vesicles (MLVs) are larger than 0.1 ⁇ m and have several or many, in most cases concentric, membranes.
  • Liposomes with several nonconcentric membranes, i.e., several smaller vesicles side by side in a larger vesicle, are called multivesicular vesicles ( Ws).
  • Drugs, medicaments, and cosmetics depending on their physicochemical properties, can be associated with liposomes by encapsulation into their inner aqueous compartment, by incorporation into their nonpolar membranous interior, or by adsorption to their membrane/water interfaces.
  • Such association to liposomes can result in improved solubility, enhanced stability, in well-directed biodistribution (targeting), reduced unwanted side-effects, and in controlled drug release.
  • Hydrophobic drugs, other medicaments, or cosmetics can be associated with liposomes during their preparation or by mixing with preformed liposomes.
  • Hydrophilic materials e.g., drugs
  • Methods used to date for the preparation of liposomes involve increasing the ratio between the bilayer-forming substance to solubilizing agent in the associates-containing aqueous phase in one of several ways, such as reducing the total concentration of solubilizing agent in the aqueous phase by dilution of the aqueous phase, with or without intermittent concentration removal of solubilizing agent from the associates by chemical and/or physico-chemical reactions of the solubilizing agent in the aqueous phase, reducing the total concentration of solubilizing agent by countercurrent dialysis of the aqueous phase, or increasing the total concentration of bilayer-forming substance in the aqueous phase by adding additional bilayer-forming substance.
  • total concentration of the solubilizing agent means the total content, based on the aqueous phase, of solubilizing agent in the aqueous phase and in the associates.
  • the usual ways for effecting such an inactivation is by a sudden change in temperature (temperature jump) in the aqueous phase, addition of suitable adsorbents which remove solubilizing agent present in the aqueous phase and in the associates when coming into contact therewith, a sudden change in pH value (pH jump) in the aqueous phase, and addition of a further substance to the aqueous phase to complex or precipitate solubilizing agent contained therein.
  • Detergent-mediated liposome production is based upon the solubilization of an amphiphilic bilayer-forming substance, e.g., a lipid such as lecithin, with the aid of a solubilizing agent, e.g., a detergent such as sodium cholate, octyl glucoside, or the like, followed by a controlled removal of the solubilizing agent by dialysis.
  • an amphiphilic bilayer-forming substance e.g., a lipid such as lecithin
  • a solubilizing agent e.g., a detergent such as sodium cholate, octyl glucoside, or the like
  • liposomes are formed from the initial lipid-detergent associates (mixed micelles) in direct relation to a reduction of the solubilizing agent, e.g. , detergent, concentration.
  • the solubilizing agent e.g. , detergent, concentration.
  • the method most frequently employed is the so-called flow-through dialysis (Weder's Point C) and this may be conducted in a countercurrent manner as in USP 4,731,210 or using a stationary phase micelle-containing colloidal solution as in Weder USP 4,438,052.
  • weder USP 4,731,210 provides a good starting point for the identification of problems with the most widely-accept ⁇ able methods for liposome production.
  • the aqueous phase with regard to the solubilizing agent e.g., detergent, content thereof
  • the solubilizing agent e.g., detergent
  • Column 5 and following of this patent it is stated: "— the aqueous phase — can be diluted with an additional amount of aqueous phase —", for example, in a ratio of 4:1 (line 9) and, in line 18: the composition of the "aqueous phase to be added—” is described in more detail.
  • the additional aqueous phase is simply added according to the dilution method which preferably leads to at least a two-fold increase in volume (see Claim 2 of Weder) or even a four-fold increase in volume (see Claim 3 of Weder' and, as also will be clear to one skilled in the art, it is difficult if not impossible to produce unilamellar liposomes having a minimum size when the additional amount of aqueous phase must be added instantaneously or suddenly and, of course, this requirement makes it impossible to conduct such a method on a continuous basis.
  • an equivalent volume of the filtered out amount of solubilizing- agent containing-aqueous phase is simultaneously or concurrently replaced by or made up with non-solubilizing agent-containing solution so that a constant volume is maintained continuously, and the replacement of the solubi- lizing-agent-containing aqueous phase according to the present invention can be effected or carried out constantly and continuously to maintain a constant volume as the solubilizing agent, i.e., detergent, is filtered out to decrease its concentration in the aqueous phase, in contrast to the dilution of the original volume with an additional amount of aqueous phase according to Weder.
  • solubilizing agent i.e., detergent
  • the constant volume tangential filtration (CVTF) method of the present invention in any case without dilution of the volume of the mixed micelle solution, leads to a constant increase in the molar ratio of bilayer-forming substance to solubilizing agent by filtration off of the solubilizing agent, thereby to decrease its concentration in the aqueous phase as it is replaced by non-solubilizing agent solution, especially with reference to the molar ratio of solubilizing agent to the bilayer-forming substance, e.g., lipid, which is not filtered off but which remains due to the larger structure of the aggregates in the retentate.
  • solubilizing agent to the bilayer-forming substance e.g., lipid
  • the phase to be dialyzed which contains the lipid- detergent associates (mixed micelles) will be conducted in tubes or channels made of the semipermeable membrane countercurrently along a dialyzing fluid such as water, buffer, and possibly containing the dissolved drug or other medicament.
  • a semi-permeable membrane which retains the bilayer-forming substance, e.g. , lipid, in the phase to be dialyzed but which is permeable to the solubilizing agent, e.g., detergent, solution
  • the phase to be dialyzed which contains the lipid- detergent associates mixed micelles
  • the method of the present invention involves the solubilization of an amphiphilic bilayer-forming substance, e.g., phospholipid, with the aid of a solubilizing agent, i.e., detergent, which is subsequently removed in a controlled mode but using tangential filtration under pressure.
  • a solubilizing agent i.e., detergent
  • the phase containing the lipid-detergent associates (mixed micelles) and, if desired, one or several drugs, medicaments, or cosmetics, is filtered against a suitable semipermeable membrane under pressure.
  • the flow direction of the phase is tangential to the membrane surface in contrast to the countercurrent dialysis of Weder USP 4,731,210, with simultaneous replacement of detergent solution, as it is filtered off, by non-solubilizing agent-containing solution so that no dilution occurs and so that the volume of the mixed micelle solution remains essentially constant.
  • the present method is therefore able to prevent the clogging of the membrane pores to a great extent and, in addition, such production of the liposomes by constant volume tangential filtration is a rapid and effective process, involving only a negligible loss in bilayer-forming substance, which can be conducted over extended periods and continuously, and which is accordingly much more commercially acceptable and economic.
  • the retentate thus comprises the liposome-forming micelles and formed liposomes with or without contained drug or other active ingredient in an essentially constant volume of aqueous solution, which may of course be further filtered and concentrated, whereas the off-filtered solubilizing agent, i.e., detergent or surfac ⁇ tant, can be readily and conveniently recycled in a further solubilizing process, frequently even without further concentration.
  • aqueous solution which may of course be further filtered and concentrated, whereas the off-filtered solubilizing agent, i.e., detergent or surfac ⁇ tant, can be readily and conveniently recycled in a further solubilizing process, frequently even without further concentration.
  • the liposome-formation procedure of the present invention thus involves constant volume tangential filtration and not the concentration/dilution procedure of Brown, which has certain inherent disadvantages, including excessive detergent waste and excessively long production times, along the lines of the Weder dilution procedure, as will be pointed out in greater detail hereinafter.
  • liposomes can be prepared by mechanical procedures or by using organic solvents or detergents, to capsulate:
  • Organic solvents such as ethanol or ether are used to dissolve the membrane lipids. After mixing with aqueous buffer, lipids can form lamellar structure at the arising interfaces of the two solvent systems or when the polarity of the solvent mixture increases. Upon removal or lowering the concentration of the organic solvent, liposomes are formed.
  • Suitable detergents and membrane lipids form water- soluble aggregates, so-called mixed micelles, which are in equilibrium with detergent monomers.
  • the mixed micelles Upon reducing the monomer concentration (by dilution, dialysis, gel chroma- tography, complexation, precipitation, pH jump, temperature jump, or by adsorption to added molecules), the mixed micelles are forced to grow in size and finally to form liposomes.
  • liposomes can be prepared by countercurrent dialysis, even having a unilamellar structure with a diameter of 50 nm plus or minus 2 nm or 44 nm plus or minus 2 nm with extreme homogeneity when using low lipid concentrations and high flow rates for the most rapid possible reduction of the concentration of solubilizing agenr in the solution containing the associates being dialyzed, or on the same order using simple dilution by addition of aqueous phase technique, such excellent results can only be obtained at a very low lipid concentration using a very high flow rate and with the generation of a great deal of residual waste filtrate and are accordingly not adapted to continuous, economical, or commercial production of liposomes as is the present method.
  • a procedure is therefore needed which combines the advantages of the known detergent procedures with an accelerated and efficient removal of detergent, thus strongly reducing preparation time, undesired liposome structures and aggregation at high lipid concentrations, as well as minimization of residual waste-filtrate, and which can be carried out rapidly, efficiently, commercially, economically, and if desired and preferably also continuously. Such is provided by the present invention.
  • An additional object is the provision of such a method which is carried out without dilution of the volume of the mixed micelle solution containing the bilayer-forming substance and solubilizing agent and any medicament or other active ingredient which may be present therein by the simultaneous or concurrenr introduction of water or aqueous non-solubilizing agent- containing solution in such a quantity to make up for or compensate for the volume of solubilizing agent solution lost by the tangential filtration.
  • Still another object is the provision of such a method which is carried out without dilution of the concentration of the bilayer-forming material in the starting mixed micelle solution of bilayer-forming material and solubilizing agent.
  • a further object is to provide such a method which will permit the employment of high bilayer-forming material concentrations without concur ⁇ rent production of undesirable multilamellar vesicles or inhomogeneous particle size distribution.
  • a still further object is the provision of such a method which may be carried out continuously and economically and with production of reduced amounts of waste detergent filtrate.
  • a yet addi ⁇ tional object is the provision of such a method which allows the formation of liposomes, the encapsulation, adsorbtion or incorporation of substances into the liposomes, as well as the removal of non-liposomally attached or incorporated substances and the concentration of the liposome products - all in one procedure and with the employment of a single device.
  • a method of producing liposomes from an aqueous solution comprising bilayer-forming material and detergent, in the form of a solution of mixed micelles and unbound dissolved detergent comprising the steps of eliminating aqueous detergent-containing solution by tangential filtration of the solution through a membrane adapted to pass the aqueous detergent-containing solution as a filtrate but to retain a mixed micelle- and liposome- containing fraction thereof as a retentate, while simultaneously avoiding dilution of the volume of the mixed micelle solution or of the bilayer-forming material therein, by replacing the detergent-containing solution removed by the tangential filtration by water or a non-solubilizing aqueous solution so as to maintain an essentially constant volume of the mixed micelle solution, and thereby to produce a liposome dispersion as retentate, such a method wherein the bilayer-forming material comprises a phospholipid, sphingolipid, glycolipid, sterol, archebac- terial lipid, or a non
  • the detergent is selected from the group consisting of sodium cholate, sodium deoxycholate, sodium chenodeoxycholate, sodium ursodeoxycholate, salts of these acids with other cations, n-alkylglycosides, n-alkylmethyl- glycamides, n-alkyloligooxyethylenes, and n-alkylglycosyi- amines, such a method wherein the detergent comprises at least one of sodium cholate and octyl glycoside, such a method wherein the non-solubilizing aqueous solution is a buffer-, electrolyte-, and/or active ingredient- containing aqueous solution, such a method wherein the bilayer-forming material comprises a phospholipid, such a method wherein the non-solubilizing aqueous solution is an aqueous buffer solution, such a method wherein the buffer is selected from the group consisting of MOPS, HEPES, TRIS, and
  • liposomes whenever produced by the method of tangential filtration as defined in any of the foregoing.
  • An aqueous solution of a suitable solubilizing agent, i.e., detergent, and a bilayer-forming substance, e.g., lecithin, and optionally one or more drugs, cosmetics, or medicaments is filtered under pressure through a suitable membrane.
  • a suitable solubilizing agent i.e., detergent
  • a bilayer-forming substance e.g., lecithin
  • drugs, cosmetics, or medicaments is filtered under pressure through a suitable membrane.
  • the flow direction of the solution is tangential to the membrane surface, which has the advantage that ob ⁇ struction of the membrane pores is avoided and detergent is effectively and rapidly removed without loss of bilayer- forming substance.
  • Water, buffer, salt solution, or a solution containing a drug or medicament is simultaneously substituted for the loss of fluid in the retentate without dilution of the volume of the mixed micelle solution or lipid concentration thereof.
  • detergent removal liposomes are formed continuously, whereby the drug is incorporated in the membranes, adsorbed on the membranes, or encapsulated in the inner aqueous compartment of the liposomes.
  • the method may be conducted over extended periods or continuously.
  • additional tangential filtration and substitution of wash water or other non-solubilizing agent-containing aqueous solution for the filtrate can be applied to remove residual detergent or liposome-unassociated drug.
  • the liposome dispersion optionally can be highly concentrated to a jelly consistency by an additional filtration off of the aqueous phase.
  • Liposomes prepared by this method have a narrow size distribution and are nearly exclusively unilamellar, when suitable detergents are chosen.
  • the mean size of the liposomes can be tailored by the choice of the used deter ⁇ gent, such as, e.g., sodium cholate, sodium deoxycholate, or n-alkylglycosides, the lipid/detergent ratio, the solvent system employed, i.e., the buffered or unbuffered aqueous solution, the lipid composition, e.g., phospholipids (natural, modified, or synthetic), cholesterol and/or derivatives thereof, or other membrane-forming lipids, and lipid concentration ranging from as low as one might wish up to several hundred millimolars of lipid (jelly-like consistency), and the temperature employed which may range from almost the freezing point of the solvent up to about 65°C.
  • the used deter ⁇ gent such as, e.g., sodium cholate, sodium deoxycholate, or n-alkyl
  • the tangential-flow filtration apparatus may for example be the Pellicon® (Millipore Corp., Bedford, MA) or the smaller laboratory-scale Minitan®, using a suitably-sized filter or membrane or ceramic "membrane", with a cut off preferably in the range between about 1 and ⁇ 100, preferably 10-50 kD (kiloDaltons ) .
  • the tangential flow apparatus may be a FILTRON® device such as an Ultrasette®, a Minisette®, a Centrasette®, or the like, using a tangential flow flat membrane.
  • FILTRON® screen channel cassette having a top and bottom closing membrane and ultrafiltration membranes with screens in between all membranes, thereby providing retentate channels and filtrate channels, all as is well known in the art.
  • the micelle solution flows over the membrane surface in a parallel direction in the channels, due to the dense and fine screen which is placed on the various membranes involved, especially when using a screen channel cassette, a wave-like flow of the solution over the membrane surface is effected.
  • a tangential flow is induced inasmuch as, at the bottom point or peak of a wave, the liquid current hits the particular membrane involved in a tangential direction.
  • the usual tangential filtration (TF) unit consists of a receiver or starting receptacle, a pump, the actual tangen ⁇ tial filtration instrument ("membrane"), and tubings with integrated rotary slide valve and manometer.
  • pressures can be determined in the TF unit at three sites: the feed pressure (P F ) caused by the pump; the filtrate pressure (P p ) which may be controlled by a subsequent valve; and the retentate pressure (P R ) which may also be controlled by a subsequent valve.
  • the working pressure mentioned in the Examples is the retentate pressure
  • the tangential filtration unit consists of the core piece of the entire process, i.e., one or several ultrafil- tration membranes with the associated hardware, i.e., the so-called filter holder.
  • filter holder Dependent on size and material.
  • these filter holders are as stated marketed by Filtron under the trademarks Minisette®, Centrasette®, Maxisette®, Ultrasette®, or by Millipore under the trademarks Pellicon® or Minitan®, among others.
  • the ultrafiltration membrane is available in different materials and in different molecular weight exclusion limits (pore sizes).
  • polyether sulfone ultrafiltration membranes of the Omega range with cut-offs between 1 and ⁇ 100 kD in the Minisette® filter holder were usually employed.
  • Membrane cassettes are well understood to be multiple layers of membrane assemblies comprising sheets of ultra ⁇ filtration membrane placed between waved polymeric screen retentate separators and waved screen filtrate separators. Blocked borders on the filtrate and retentate screens direct the separated fractions to defined collection areas on the bottom cassette hardware manifold.
  • the "Feed” mixed micelle solution (after vesicle formation, of course, the detergent- containing liposomal dispersion) flows over the retentate screen, thereby taking on a wave-like motion and flow. At the peak and bottom points of the wave, the "feed” flows over the ultrafiltration membrane in tangential direction. Molecules smaller than the membrane exclusion size (water, detergent, active substance) pass through the membrane, are collected as filtrate, and are discarded or recycled.
  • a tangential filtration system as employed according to the invention involves a starting receptacle for the introduction of starting materials or ingredients into the system, a pump for pumping the same onto the filter, and cooperating piping for the conveyance of the fluid starting materials to the pump and thence to the filter. From the filter, cooperating piping takes the retentate in one direction and the filtrate in another direction for recycling. The retentate is recycled back to the starting receptacle until withdrawn from the system when the detergent/lipid ratio reaches a certain predetermined minimum, e.g., less than 0.3.
  • a certain predetermined minimum e.g., less than 0.3.
  • the mixed micelle solution enters into the retentate track and moves tangentially to the membrane because of the waves imparted to the dispersion by the undulations in the screen itself, the retentate moving out of the track at the opposite side of the cassette whereas the filtrate escapes through the pore openings in the membrane at the top and bottom of the retentate track and is collected in the filtrate tracks above and below the retentate track, from which it is recovered for recycling.
  • fresh non-solubilizing solution is introduced into the system at the same rate as the filtrate is removed therefrom, so as to maintain the volume of the mixed micelle solution essentially constant.
  • Cholesterol Detergents Sodium cholate - (cholate)
  • Sodiumphosphate; monobasic Sodiumphosphate; dibasic The unit used for tangential filtration was a Filtron Minisette®. Polyethersulfone single membranes (filter surface 0.15 ft 2 ) or membrane cassettes (filter surface 0.75 ft 2 ) of the Omega range were used. Pore sizes (to be more exact: size exclusion limits) varied between 10 kD (kilo- Daltons ) and 100 kD. From the following results the general suitability of membranes ⁇ 100 kD, preferably 1-50 kD, can be derived.
  • the flow rate was between 75 and 250 ml/min. As this parameter depends on the pump used and the diameter of the tube it is not critical and, as can be taken from the following, has no influence on the resulting quality of the liposomes.
  • the liposomes by tangential filtration are usually produced at room temperature. However, production was also successful at 4°C and 65°C. The latter higher working temperature ensures the suitability of the tangential filtration process for the production of liposomes from hydrated lecithin and synthetic phospholipids such as dimyristoyl phosphatidylcholine (DMPC), dipalmitoyl phos- phatidylcholine (DPPC), and distearoyl phosphatidylcholine (DSPC).
  • DMPC dimyristoyl phosphatidylcholine
  • DPPC dipalmitoyl phos- phatidylcholine
  • DSPC distearoyl phosphatidylcholine
  • the aforementioned lipids are used in concentrations between 1 and 200 mM/100 ml (corresponding to 0.78 g/1 to 156 g/1).
  • Mixed Micelle Solution I The mixed micelle solution is usually prepared according to the classic film method: Lecithin was dissolved in 30 ml of ethanol. Cholesterol was dissolved in 10 ml of chloroform. Both solutions were mixed in a round-bottom flask, the organic solvent being removed by rotary evaporation under vacuum at 40°C. The detergent was dissolved in 100 ml 10 mM MOPS buffer (pH 7.3) and the lipid film was resuspended in this solution until a clear micelle solution occurred. (Used for Examples 8-13).
  • Mixed Micelle Solution II Much more elegant and economic is the direct dissolution of all components in 100 ml of the MOPS buffer.
  • the solution is stirred until the micelle solution is clear (used for Examples 1-7, 14, 15).
  • the detergent concentrations of the individual mixed micelle solutions were reduced until a molar ratio of detergent/lipid of ⁇ 0.3 was achieved.
  • the volume of filtered out detergent-containing filtrate was continuously substituted or replaced by an equal volume of MOPS buffer (volumetric control).
  • the same liposome quality can be obtained by the present tangential filtration metho , using the same materials and concentrations.
  • the most essential advantages are:
  • Sartorius Corp. is a tangential filtration system which is comparable to Minisette®.
  • Brown prepares a mixed micelle solution from a phospholipid mixture which generally contains phosphatidylserine PS and phosphatidylethanolamine PE (cf. Brown column 5, lines 8, 9: not less than 2.5 mol percent PE/PS) and a detergent. This mixed micelle solution is filtered through the TF unit, unbound dissolved detergent being thereby separated together with water (column 13, lines 30-32).
  • the resulting concentrated retentate (incorrectly described by Brown as dialysate) exclusively contains mixed micelles and is then made up to the original volume with a detergent-free dialysis buffer (lines 33-34; TBS containing 150 nM trehalose as dialysis buffer). This process is repeated 10 times (lines 35, 36). In total, the 10-fold amount of the initial volume of dialysis buffer passed through Brown's TF unit. Also, after the 10th cycle, a concentrated retentate results which can be made up to the initial volume as required (lines 37-39).
  • Brown's method (and also in the case of Weder), this addition of the buffer and the formation of the liposomes happens at once. Brown has to reduce the mixed micelle solution (and later the liposomal dispersion) to at most 1/10 of the initial volume to achieve a 95% removal of the detergent after 10 cycles. Similarly to Weder, Brown therefore dilutes his mixed micelle retentate in a ratio of 1:10.
  • Comparative Example D The Present Constant Volume Tan ⁇ en- tial Filtration Method (CVTF)
  • the liposomes are also produced using a Minisette®TF system equipped with a polyethersulfone membrane of the Omega type having a cut-off of 10 KD. Also in this case 780 mg soy lecithin and 860 mg Na cholate were introduced into a round-bottom flask, made up to 100.0 g with phosphate buffer pH 7 and stirred until a clear mixed micelle solution had formed. This mixed micelle solution was concentrated to a residual volume of about 8 ml per filtration cycle, and was subsequently made up to the initial volume using phosphate buffer pH 7. This process was repeated 10 times. At a flow rate of also 240 ml/min. , this process took 60 min. and produced a waste volume of 920 ml.
  • the final detergent content was 4.8%.
  • the lecithin concentration in liposome-containing pharmaceuticals or cosmetics common in the market usually ranges between 10 and 20 mMolar.
  • Two approaches for producing such formulations are possible: a) preparation of the liposome dispersion with the desired lecithin concentration, or b) preparation of a liposome concentrate with a lecithin concentration much higher than the final concentration in the formulation. This concen ⁇ trate is then incorporated into the formulation and thereby diluted to the desired lecithin concentration.
  • the liposome concentrate is 100 mMolar
  • one (1) part of this concentrate and nine (9) parts of an aqueous gel are mixed together to give a liposomal gel with a lecithin concentration of 10 mMolar.
  • the concentrate becomes diluted 1:10.
  • the production method/device is suitably adapted, it takes the same time and effort to produce one ( 1 ) kg of a 10 mMolar liposome dispersion or a 100 mMolar liposome concentrate. But in case b) one is able to produce not only one (1) kg, but rather 10 kg of a liposomal gel, because of the 1:10 dilution!
  • Brown can concentrate these solutions only to about 1/5 or even 1/2 of the starting volume before obtaining a gel-like consistency. Only 4/5 or even 1/2 of the detergent-containing buffer is filtered off during one concentration step. His concentration-dilution process therefore has to be repeated more than 10 times (in the aforementioned examples as many as 2 to even 20 cycles) to remove 95% of the detergent content.
  • composition (g) lipid— molar ratio membrane flow mean cone. lip/det (ml/min) diameter
  • composition (g) lipid— molar ratio membrane flow mean dia ⁇ cone. lip/det (ml/min) meter (nm)
  • composition (g) lipid— molar ratio membrane flow mean dia ⁇ cone. lip/det (ml/min) meter (nm)
  • Both vesicle size and quality can be controlled not only via the membrane but also above all via the qualitative and quantitative composition of the formulation. For example, with constant conditions, particle size increases in direct proportion with the lipid concentration used (cf. Examples 1-5). It is even possible to double the liposomal diameter (40.2nm -> 89.1 nm). A much stronger influence on vesicle size can be exerted through the selection of the detergent used for solubilization/mixed micelle formation. By replacing sodium cholate by octylglucoside (cf. Example 14), particle size may even be almost tripled (cf. Example 7: 55.0 nm -> 144.3 nm). In contrast, when using an admixture of octylglucoside and cholate (No. 15), only slight insignificant changes occur.
  • the vesicle size can also be controlled via the lipid/detergent ratio, i.e., via the structure/composition of the mixed micelles.
  • the effect (cf. Examples 8, 9, 12) is less pronounced as compared to the aforementioned control procedures.
  • the vesicle-increasing property of cholesterol which has often been described in the literature and which was also observed when preparing liposomes by high-pressure homogenization, such influence could not be observed in the case of the present constant volume tangential filtration (cf. Examples 2, 8). Examples 2. 5. and 8 - Constant Volume Tangential Filtration - Detailed Description
  • the time required was 12 min; the amount of detergent-containing filtrate was 300 ml which was continually substituted by MOPS buffer during the filtration procedure.
  • the resulting liposomal dispersion was filtered through a 0.22 ⁇ m cellulose acetate membrane, the mean particle diameter being determined by laser light scattering (44.8 ⁇ 8.2 nm).
  • the batch size was 100 ml. Soy lecithin was added in a quantity of 7.8 g and Na cholate in a quantity of 6.854 g. The lipid concentration was 100 mM, the lipid/detergent ratio being 1:1.6. 10 mM MOPS buffer (pH 7.3) was also used in this case.
  • the liposomes were prepared and determined under the conditions described in Example 2. As a result of the higher lipid concentration, a working pressure of 0.4 bar was achieved. The constant volume tangential filtration process lasted 75 min and 1.5 liters of filtrate were produced. The filtrate was continually substituted by MOPS buffer, thereby keeping a constant volume. The mean particle size determined was 89.1 ⁇ 20.4 nm.
  • the resulting vesicles produced in Examples 2 and 5 were extremely homogenous. They were characterized by only a single bilayer (that is, they were unilamellar) as seen from electron microscope photographs.
  • Example 16 Production of a Liposomal Dispersion Containing An Active Substance and its Further Processing into a Gel Preparation: 1.0 g of soy lecithin and 0.878 g of Na cholate were introduced into a beaker of appropriate size. The lipid concentration was 12.8 mM, the lipid/detergent ratio being 1:1.6. The beaker was made up to 100 g using a phosphate buffer (pH 6.5) containing an active substance of the following formulation: Sodium phosphate monobasic (x2 H 2 0) 8.42 g/1, sodium phosphate dibasic (x2 H 2 0) 6.26 g/1, dexpanthenol 66.7 g/1 in purified water.
  • a phosphate buffer pH 6.5
  • Constant volume tangential filtration was carried out with the aid of a 10 kD membrane cassette (Omega range) at a flow rate of 250 ml/min and a working pressure of 0.2 bar. Filtration was continued until a detergent/lipid ratio of ⁇ 0.3 was obtained. During this time (15 min) 340 ml of filtrate was obtained which was continually substituted with active substance-containing phosphate buffer of the above composition but containing 50 g/1 dexpanthenol. The resulting 100 ml of liposomal dispersion (particle size 84.2 ⁇ 15.9 nm) was reduced by further filtration without buffer substitution until a volume of 75.7 g was obtained.
  • the liposomal concentrate was diluted with a mixture of 7.0 g isopropanol and 7.8 g glycerol and jellified by adding 2 g of Na polyacrylate. Finally, 7.5 g of octyldodecyl myristate was admixed with this liposomal preparation.
  • the finished emulsion gel contained liposomes having a size of 93.2 ⁇ 18.3 nm; the dexpanthenol content was 5%.
  • Example 17 Production of a Liposomal Gel Containing a Lipophilic Active Ingredient:
  • the resulting clear mixed micelle solution was subjected to constant volume tangential filtration.
  • the Minisette® was equipped with a 10 kD membrane cassette of the Omega range (polyether sulfone membrane). The flow rate was adjusted to 450 ml/min, the resulting working pressure being 0.5 bar. The experiment was carried out at room temperature. Constant volume tangential filtration was continued until a detergent/lipid ratio of ⁇ 0.3 was obtained. Production took 45 min., the resultant waste material being 1200 ml of filtrate. From the outset, the filtrate was continually replaced by an equal volume of the above-mentioned phosphate buffer without sodium cholate. The mean liposome particle size was 32.5 ⁇ 7.7 nm.
  • Suitable bilayer-forming substances for use according to the method of the present invention may include sphingolipids, glycolipids, sterols (as for example cholesterol), archebacterial lipids, non-ionic synthetic lipids, phospholipids and in particular lecithins and the like, as is well known in the art, representatively from the disclosure of USP 4,731,210 and especially from line 35 of Column 8 through line 3 of Column 9 thereof.
  • the best-suited building elements for liposome preparations are soy or egg lecithin. (USP XXII; NFXVII; published 1989 and official from January 1, 1990). On pages 1942 and 1943 thereof, the official monograph of lecithin is clearly set forth.
  • fatty acid chain lengths of 16-20 carbon atoms representatively comprises palmitic acid, margaric acid, stearic acid, nonadecanoic acid, arachic acid, palmitoleic acid, oleic acid, linoleic acid, elaeomargaric acid, elaeostearic acid, gadoleic acid, and arachidonic acid.
  • the resulting PC esters which are in fact the phosphatidylcholines, are for example: dioleoyl-PC, dipalmitoyl-PC, but also mixed esters such as margaroyl-stearoyl-PC, palmitoyl-oleoyl-PC, and the like.
  • These well-defined phosphatidylcholines are not produced by extraction or otherwise from natural lecithins, but are synthesized de novo and are consequently referred to as synthetic lecithins.
  • the bilayer-forming material may comprise a phospholipid, sphingolipid, glycolipid, sterol (as for example cholesterol), archebacterial lipid, or a non- ionic synthetic lipid.
  • solubilizing agents usual detergents or surface active agents may be employed, such as for example bile salts such as sodium cholate, sodium deoxycholate, sodium chenodeoxycholate, sodium ursodeoxycholate, and also salts of these with other cations such as potassium, sugar derivatives such as n-alkylglycosides, n-alkylmethylglyc- amides, n-alkylglycosylamines, ionogenic substances, nonionic solubilizing agents such as n-alkyloligooxyethylenes, and mixtures thereof, as is well known in the art, and repre ⁇ sentatively from USP 4,731,210, Column 9 thereof, lines 3-37, all hereinafter referred to as "detergent", and especially those selected from the group consisting of bile salts such as sodium cholate, sodium deoxycholate, sodium chenodeoxy ⁇ cholate, sodium ursodeoxycholate, and also salts of these acids with other cations
  • bilayer-forming substances i.e., detergent
  • water which form the lipid-detergent associates or mixed micelles
  • lipophilic agents suitable for bilayer-binding are, for example, acne therapeutics such as hexachlorophene, tretinoin, or minocy- cline.
  • topical agents such as ⁇ -tocopherol nicotinate, tromantadine, croconazole, minocycline, sodium heparin, dexpanthenol, meclocycline, cyproterone, cyproterone acetate, 2-tert.-butyl-4-cyclohexylphenyl nicotinate-N-oxide, plant extracts, corticosteroids, androgens, ethinyl estradiol, non- steroid antiphlogistics, dihydropyridines, spironolactone, erythromycin esters, local anaesthetics, estradiol esters, or antihistaminics can also be incorporated.
  • the amount of active substance can be varied in dependence upon the therapeutic requirements. For example, 10 mg to 50 g of active ingredient can be used per 100 g of lecithin.
  • liposomal medicaments or cosmetics and suitable forms into which they may be converted for administration these are likewise well known in the art and such forms may be topical, parenteral, solutions, aerosols, emulsions, hydrogels, lyophilizates, and the like, all as is already known to one skilled in the art and representatively from USP 4,731,210, Column 10, lines 23-65 thereof.
  • Liposome preparations for topical application are usually mixed with polymer jellifying agents to increase viscosity and improve application.
  • polyacrylic acid and derivative 0.2 to 2.5%) gels, gel-forming cellulose and cellulose derivative (0.2 to 3%) gels, and sodium salts of acrylic acid/ acrylamide copolymerisate - 1 to 4% gels; commercially available as Hostacerin PN73®, in the concentrations indicated may be used.
  • the gel is prepared according to commonly-known procedure. Especially preferred are mixtures consisting essentially of egg or soy lecithins and the described jellifying agents and active substances.
  • common adjuvants such as, for example, an antioxidant, e.g. , vitamin E or butyl-hydroxy toluene (BHT), alcohols, and preservatives such as phenoxe- thol, sorbic acid, Kathon CG tB (Merck Index 11, No. 6677), or parabens can be added in usual amounts.
  • an antioxidant e.g. , vitamin E or butyl-hydroxy toluene (BHT)
  • BHT butyl-hydroxy toluene
  • preservatives such as phenoxe- thol, sorbic acid, Kathon CG tB (Merck Index 11, No. 6677), or parabens
  • phenoxe- thol e.g., sorbic acid
  • Kathon CG tB Merck Index 11, No. 6677
  • the method of the present invention provides a novel method for the production of liposomes by constant volume tangential filtration under pressure which permits the employment of higher lipid concentrations for the production of liposomes having extremely small particle size and a single bilayer and without the presence of multilamellar liposomes or inhomogeneous particle size distribution, which is remarkably reduced in comparison with prior art practice and results.
  • the method involves the removal of solubilizing agent solution as the filtrate and retention of the bilayer-forming material - solubilizing agent associates in the form of mixed micelles and forming and formed liposomes in the retentate, which is not diluted by the addition of aqueous phase as in prior art methods, but wherein the volume of the mixed micelle solution is maintained by simultaneous replacement with an aqueous solution of buffer, electrolyte, or drug or other active ingredient to the extent necessary to make up for the loss in volume due to filtration off of the solubi ⁇ lizing agent solution, which thereby incrementally increases the molar ratio of bilayer-forming material to solubilizing agent and incrementally and continuously induces liposome formation in the retentate.
  • the method may be practiced rapidly and conveniently and with higher lipid concentrations than according to prior art procedures and provides a novel, rapid, and convenient method for the production of liposomes and drug-, medicament-, or cosmetic-containing liposomes which may be conducted commercially.
  • the procedure of the present invention can advantageously be conducted on a continuous basis, with an unlimited scale up and minimal waste detergent filtrate, and with unprecedented uniformity of product and rapidity of production of liposomes of desired particle sizes, so that the constant volume tangential filtration method of the present invention now stands alone as the paramount process for the production of liposomes of any desired small particle size and content, including medicinal, drug, or cosmetic con ⁇ tent.
  • the process of the present invention is highly advantageous, not only from the standpoint of rapidity and convenience of large scale production, but also economics, when compared to dilution, concentration-dilution, or the usual high-pressure homogenization, ultrasound, and extrusion methods of liposome production, as will be immediately apparent to one skilled in the art.

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Abstract

On obtient des liposomes par filtration tangentielle à volume constant d'une solution de départ aqueuse d'une matière et d'une substance détergente formant une bicouche afin de réduire le rapport molaire substance détergente/matière formant une bicouche de la solution de départ contenant des micelles mixtes ou des substances associées détergentes-lipidiques tout en évitant simultanément la dilution du volume de la solution à micelles mixtes ou de la concentration de la matière formant une bicouche par substitution de la solution détergente éliminée par filtration tangentielle, au moment même de son extraction, par une solution aqueuse contenant un agent non solubilisant et qui peut contenir un tampon, un électrolyte ou un médicament ou agent cosmétique dissous, au choix. Le procédé permet la production de vésicules ou liposomes à particules de petite taille qui sont unilamellaires et de granulométrie homogène au moyen de concentrations de matière formant une bicouche relativement importante, sur une durée relativement courte et avec des volumes de filtrats résiduaires de matières détergentes relativement faibles. Ceci permet d'obtenir une plus forte production de liposomes acceptables par temps unitaire, ce qui fait de ce procédé de filtration tangentielle à volume constant un procédé extrêmement avantageux de par sa rapidité qui peut être réalisé en continu et de manière économique à l'échelle industrielle. L'invention se rapporte également aux liposomes obtenus par ce procédé de filtration tangentielle à volume constant.
PCT/EP1995/004330 1994-11-03 1995-11-03 Preparation par filtration tangentielle de medicaments liposomiques et produits liposomiques obtenus WO1996014057A1 (fr)

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