HK1159493B - Solution of lipophilic substances, especially medicinal solutions - Google Patents

Description

Solution of lipophilic substances, in particular pharmaceutical solutions

The subject of the invention is in particular pharmaceutical preparations for lipophilic, poorly water-soluble substances, preferably drugs which can be used topically or systemically on or in the surface of the human or animal body. Here, parenteral and oral use is possible. The system is particularly suitable for topical application, particularly in the eye.

Highly effective active ingredients already exist for many diseases. However, these substances are generally very lipophilic and therefore poorly water-soluble. This property of low solubility can be defined in accordance with the european pharmacopoeia by the parts by weight of solvent required in the preparation of a solution of one part by weight of a substance (european pharmacopoeia 5.0/1.04.00.00). The relevant areas are:

difficult to dissolve

100 to 1000 parts of solvent per part of material are required

Difficult to dissolve

1000 to 10000 parts of solvent per part of material are required

-substantially insoluble

More than 10000 parts of solvent are required per part of material.

There are a number of proposals for the solubilization and administration of poorly soluble, lipophilic pharmaceutically active ingredients.

There are therefore proposals for the preparation of stable solutions of relevant active ingredients for oral administration, wherein the active substance should remain stable in solution by the application of a selected solvent system and by the addition of a solvent. Examples of this are DE 4003844A1, EP 0488181A1, EP 0650730A1, WO 95/29677A1 and WO 99/08684A 2.

DE 4003844a1 relates in particular to the avoidance of ethanol for the preparation of liquid pharmaceutical compositions comprising cyclosporin as an active ingredient.

EP 0488181a1, EP 0650730a1 and WO 95/29677a1 relate to solvent systems tailored specifically for certain active ingredients such as nifedipine, rapamycin or camptothecin. The stable solution obtained according to WO 95/29677a1 may also be injected parenterally.

The solvent systems described herein may include, inter alia, polyethylene glycol as a co-solvent or co-solvent. The aim is to maintain the stability of the active ingredient in solution, the precipitation of the active ingredient at the site of application is not to be expected.

Stabilized pharmaceutical solutions of active ingredients for parenteral administration, which undergo degradation catalyzed by carboxylation, are described in DE 69402022T 2. For solubilization, it is advisable to use a mixture consisting of a solvent and a non-ionic solubilizer, wherein polyethylene glycol can be used as solvent. By means of which a stable solution will be ensured, precipitation of the active ingredient is undesirable.

US 4,000,263 describes a storable liquid medicament for the treatment of acne in which erythromycin is present as active ingredient in a mixed solvent consisting of propylene glycol, ethanol and ethoxylated ether of lauryl alcohol. Applying the solution to a treatment area, wherein the active ingredient remains in the area after evaporation of the volatile component.

WO 2006/133510a1 relates to formulations of docetaxel, or a pharmaceutically active salt thereof, for parenteral administration. The solvent mixture used and its additives are likewise selected here in such a way that the active ingredient remains stable in solution. Precipitation is undesirable.

WO 2008/101344a1 relates to a composition comprising a solubilized lipophilic bioactive compound, such as coenzyme Q10 in particular. The composition may be applied in pharmaceutical, cosmetic or food applications. The active ingredient is mixed with the non-ionic emulsifier and melted, and the melt is stirred into water to form a clear solution. Polyethylene glycol is used herein as a stabilizer for lyophilization, rather than as a solvent.

The problem of lipophilicity is the low availability of the active substance in dissolved form at the site of application in the therapeutic field of poorly to substantially insoluble substances. This is of outstanding importance, since usually only dissolved substances in an aqueous biological environment are able to reach their target structures, for example receptors on the cell surface.

Furthermore, problems arise with regard to the transport of poorly soluble substances across biological barriers, such as the intestinal wall after oral administration or the cornea during ocular administration, since usually only dissolved substances are able to diffuse through cells and tissues and form small gradients of low concentration and thus attract the production of a micro-substance flow.

A basic prerequisite for avoiding the above-mentioned problems is that the substance is applied to the application site in a suitable pharmaceutical form such that it is present in the site as homogeneously as possible, i.e. uniformly distributed. This ensures that the highest possible concentration is achieved quickly and permanently in the range of solubility.

To achieve this, a large number of methods are known to the expert. The simplest strategy is to dissolve the active ingredient in an oil, such as a liquid triglyceride found in many vegetable oils or well known as a neutral oil under the trade name Miglyol. Although such solutions can be used both parenterally (i.e. for example by injection) in the eye, they have the disadvantage that they release only a small amount of the drug into the aqueous environment. Furthermore, compatibility problems with tissues may arise at the site of application. The administration of the oily solution is usually accompanied by an inflammatory response. In the field of ophthalmic applications, visual impairment is caused in part by mucus formation, which is attributed to the fact that the oil cannot mix with the tear fluid. Furthermore, the residence time in the eye is not sufficient.

In order to improve the availability of the drug, ointments are provided which are specifically applied to the eye, using a pharmacopoeia sense (european pharmacopoeia 5.0, semisolid formulation for skin use 5.0/0123 and semisolid formulation for eye use 5.0/1163). Although their residence time in the eye is extended, their sterile preparation requires a large-scale sterile production process, which adds significantly to the cost of a solution that can be sterile-filtered. Moreover, such formulations are accompanied by poor patient compliance, as patients must tolerate foreign body sensation and substantial temporary visual impairment through mucus formation. Furthermore, parenteral administration of such systems often fails due to the viscosity of the system, which is prevented by the cannula.

"solubilizers" attempt to avoid the use of lipophilic carriers such as oils or also ointments partially used for lipophilic substances by surrounding the substance by a solubilizer. The hydrophilic surface created by such aggregates improves the solubility of the poorly soluble substance in water. Cyclodextrins and surface-active substances, so-called surfactants (Tenside), offer the possibility of, for example, improving solubility. However, this ultimately results in a solution with a very short residence time in the eye and thus a low absorption rate.

Colloidal carrier systems are another attempt to achieve useful levels of active ingredient. However, micellar formulations have too low storage stability and durability, and formulation of liposomes is very expensive to develop and prepare. Both variants, if only aseptic filtration can be conditionally possible, would place a high burden on the drug if other sterilization methods such as autoclaving or radiation sterilization would be used, which here also makes expensive aseptic preparation unavoidable.

The "fine" and homogeneous distribution of the drug at the site of administration, by which the suspension or nanosuspension of the lipophilic drug is brought about, offers the possibility of complying with the above-mentioned administration requirements. However, this is in contrast an extremely complicated preparation. In particular in the case of suspensions, the low storage stability is attributed to agglomeration or precipitation, which has to be suppressed as long as possible with a great deal of effort.

The most promising possibility for packaging and application of lipophilic drugs to date is emulsions.Are eye drop formulations that have been marketed in the united states for a long time and provide effective levels of active ingredient at multiple daily applications. There are, however, also high production and development costs and problems with insufficient durability and stability of the system in the presence of water. A further disadvantage is that the patient must be self-administered (e.g.as a preparation)In the case of (a) and redispersing the emulsion, so that the therapeutic effect is dependent on the correct preparation and use of the patient.

What is therefore desirable is a formulation which dissolves lipophilic substances, but is not attributable to oily solvents, nor is it miscible with water. After administration the system should be miscible with water at the site of administration, which releases the drug completely and homogeneously in the area. Furthermore, the system should be inexpensive to produce, and it may be sterile, for example, by filtration as a solution. Such a system can ensure a better comfort of use in the treatment, since it is not only simple to administer parenterally by injection or by instillation without mucus formation in the eye but is also well tolerated by the body.

With regard to a homogeneous distribution of the drug at the site of administration, nanoparticle suspensions of lipophilic substances having a size of less than 10 μm can meet the requirements mentioned above. By their large surface area, nanoparticles lead to a higher dissolution rate and thus improve the bioavailability of the administered substance.

Besides, nanosuspensions have serious disadvantages. Which is too costly in preparation, makes the development and production of such systems rather expensive, and stability is limited due to, for example, aggregation tendency and particle size growth.

It is therefore an object of the present invention to provide an improved system which meets the above-mentioned requirements, with which the bioavailability of lipophilic substances on or in the surface of the human or animal body can be increased and made easier, and which is obtained in a simple and economical manner, for example by means of sterile filtration.

This object is achieved according to the invention by a solution comprising at least one water-miscible, biocompatible solvent and at least one lipophilic substance dissolved therein, wherein the solution forms a nanosuspension on contact with aqueous body fluids on or in the body surface of a human or animal, in which nanosuspension at least one lipophilic substance suspended in the form of nanoparticles is present.

The present invention is due to the advantage of nanosuspensions, i.e. very finely dispersed particles, but this is not associated with the aforementioned disadvantages, which nanosuspensions are inherently present. The solutions according to the invention are therefore extremely suitable for the administration of lipophilic substances to humans or animals. The administration may be oral, parenteral or topical. In particular, the solutions according to the invention are particularly suitable for parenteral administration and for administration of lipophilic substances to the eye.

The invention is based on the principle that a solution with lipophilic substances, when brought into contact with water, releases the dissolved substance while forming defined nanostructures which, by virtue of their large surface area and uniform distribution, provide improved formulation conditions for poorly water-soluble active ingredients.

For this purpose, lipophilic substances having solvents miscible with water are processed to a typical, i.e. in particular molecularly dispersed, stable solution. The suspension of the lipophilic substance is formed spontaneously at the site of application only on application of this solution, by the water-absorbing mixture (also so-called desolvens) acting as a so-called anti-solvent. The solution according to the invention can be applied anywhere, those locations where an aqueous liquid is present. This relates to the human or animal body containing sufficient water. For example, for application to the eye, in situ precipitation of the active ingredient will be initiated by contact with the tear fluid.

With the present invention it is thus possible to administer lipophilic substances as solutions without using "oily" solvents or other lipophilic solvents such as triglycerides or cholesterol. These oily or lipophilic solvents are those solvents which, in contrast to the solvents used according to the invention, are immiscible with water and form emulsions when mixed with water, i.e. a two-phase system.

According to the invention, a solvent which is miscible with water and in particular forms a homogeneous system with water is used.

Solvents suitable for use in the present invention may dissolve lipophilic materials completely so that a typical solution is formed. Preferably, the solvent should be physiologically compatible and non-toxic. It should be particularly preferred that it be transparent. It should be liquid and preferably have a melting point near or below body temperature of about 37 c.

Examples of suitable solvents are, for example, polyethylene glycol (PEG) and derivatives thereof, such as alkyl ethers, and also glycerol, propylene glycol, dimethyl sulfoxide (DMSO), N-vinylpyrrolidone and solvents for preparing liquid polymer solutions for delayed release of active ingredients, as described, for example, in WO 95/27481A 1.

It is also possible to use mixtures of two or more of these solvents.

Particularly preferred are polyethylene glycol, propylene glycol and N-vinylpyrrolidone.

Polyethylene glycols or derivatives thereof suitable as solvents in particular have a molar mass in the range from 50 to 100.000 dalton, preferably from 100 to 1.000 dalton and particularly preferably from 200 to 600 dalton. Particularly preferred is polyethylene glycol having a molar mass, wherein the polyethylene glycol is present in liquid form at a body temperature in the range of about 37 ℃. Examples of polyethylene glycol derivatives are the monoethyl and diethyl ethers thereof.

The higher molecular weight solid polyethylene glycols can be used, for example, in mixtures with liquid polyethylene glycols or other liquid solvents.

The invention is suitable in principle for all lipophilic substances, such as, in particular, lipophilic pharmaceutically active ingredients, such as pharmaceuticals. It can thus be successfully administered with lipophilic, poorly water soluble to substantially water insoluble substances. The invention is also particularly suitable for active ingredients that are poorly water soluble to substantially water insoluble. Examples of this are substances such as cyclosporin A, budesonide, beclomethasone, triamcinolone acetonide, dexamethasone, fluticasone dipropionate.

The solution containing the dissolved substance according to the invention interacts upon contact with water, wherein the solvent is mixed with water and thereby causes a decrease in solubility for the substance, resulting in the precipitation of solid particles of the lipophilic substance at a minimum.

The solid particles, i.e. nanoparticles, generally have a size in the range of up to 10 μm. Preferably the particles have a size in the range to 1 μm and particularly preferably the particles have a size of less than 1 μm. Particles having a particle size as small as possible are particularly suitable for the use according to the invention. Thus, for example, particles having a size of a few nanometers, for example to 1nm, can be used.

The obtained particles may have irregular surfaces and shapes. The size thus referred to refers to the major axis of the particle, i.e. the axis having the greatest extension.

The presence of the nanoparticles in suspension and their determination can be carried out by known methods, for example by means of laser diffraction and photon correlation spectroscopy.

The properties of the solutions and nanoparticles according to the invention can be varied or adjusted in a number of ways depending on the different requirements of the actual application. The principles and measures known to the formulator for liquid pharmaceutical formulations can be used here.

The precipitation of the nanoparticles from solution can thus be controlled by the introduction of one or more surfactants (surface-active substances). Physiologically compatible surfactants are preferably used in the present invention. Examples of this are cetyl alcohol, stearyl alcohol, sodium cetearyl sulfate (natriumcetyl sulfate), glycerol monostearate and sorbitan fatty acid esters. Particularly preferably used surfactants, such as are present in the physiological environment of the human and animal body, for example lecithin, cholesterol, phosphatidylcholine, phosphatidylserine, phosphatidylinositol and phosphatidylethanolamine.

For this reason, the solution properties of the solvent can also be varied by adding cosolvents, wherein varying the particle size can be achieved with different combinations.

An amphiphilic phospholipid such as diheptanoyl glycerophosphocholine (DHGPC), a phosphatidylcholine species that is not physiologically present and can also act as a cosolvent, can also be used.

One possibility for controlling the particle size is that the growth of the particles is influenced by the physicochemical properties of the solution according to the invention containing the dissolved substance dissolved therein. One such property is viscosity. Diffusion-limiting particle agglomeration can be achieved by increasing the viscosity of the system. At the same time, fractal structures, i.e. particles with a high degree of surface irregularities, are produced, which thus have the advantage of a particularly large surface area.

To increase the viscosity, the solutions according to the invention can be used, for example, with viscosity-increasing agents, which are well known to formulators for parenteral administration. Examples here are viscosity-increasing polymers and also polyethylene glycols, cellulose ethers, polyvinylpyrrolidone and polyvinyl alcohol.

Some substances may form a coating complex with the nanoparticles, by which the nanoparticles are surrounded. The particle size can also be adjusted by forming such a coating compound, since the growth and aggregation of the particles will thereby be prevented. An example of such a substance is polyvinylpyrrolidone, which at the same time also acts as a viscosity-increasing agent.

Depending on the application or the solution system, respectively, it may be advantageous if the generated nanoparticles are maintained at the release site for as long as possible to increase the uptake rate. This may be achieved, for example, by avoiding the mobility of the nanoparticles.

The mobility of the nanoparticles can be caused, for example, by the addition of adhesion promoters or by optimizing the electrostatic attraction forces.

For increasing the viscosity, the above-mentioned tackifiers can be used, for example.

To reduce the mobility of the nanoparticles, the electrostatic interaction of the nanoparticles with the tissue at the site of application can be exploited.

For example, the zeta potential of the nanoparticles can be adjusted to be opposite to the potential of the tissue. The opposite potential may be a material property of the nanoparticle itself. Additives for adjusting the zeta potential, such as phosphates or citric acid, may be added. Such additives for adjusting the zeta potential are well known to the expert, for example as deflocculants.

The most diverse compositions of the solvent system according to the invention can be obtained on the basis of the above-mentioned principles.

Examples of various embodiments are exemplified below, upon which it will be illustrated how the properties of the solvent system or nanoparticles according to the invention can be modified by a combination of one or more additives and adjuvants.

1. The simplest variant is a binary formulation of a solvent with a lipophilic substance suitable according to the invention. The properties of the solution can be varied by the incorporation of cosolvents, wherein the desired particle size can be achieved depending on the respective combination.

2. Further approaches for influencing and controlling the generation, size and function of nanoparticles are available from ternary systems, comprising, in addition to the solvent or solvent mixture and the lipophilic substance, further additives and auxiliaries.

a) The growth process of the nanoparticles can be influenced by the addition of surfactants or other amphiphiles.

b) The diffusion of the nanoparticles that grow and precipitate out of the particles can be slowed by the addition of a viscosifier.

Substances which gel in situ can also be used in order to increase the viscosity. Substances that gel "in situ" only at the site of application by a change in environmental conditions, such as pH, temperature, shear stress or other external influences.

c) The nanoparticles can be slowed down by the change of the Zeta potential. For this purpose, it is preferable to use a medium which can be used for adjusting the Zeta potential, which can adjust the Zeta potential of the nanoparticles to be positive.

d) Functionalization of the nanoparticles or of the entire system of formulations described in the preceding 2a) to c) can be achieved by selecting suitable amphiphilicity or viscosity-increasing media.

i) Thus, upon addition of a charged surfactant, the nanoparticles encapsulated thereby can be immobilized on an oppositely charged surface for a longer period of time in relation to the charge.

ii) the entire system can be kept on an oppositely charged surface for a specific period by adding a charged adhesion promoter or an in situ gelling substance.

3. Proceeding from the embodiments 1. and 2 described above, further changes can be introduced into the system by the quaternary formulation, and thus increased specificity and efficiency are achieved.

a) It is thus possible to add two different amphiphiles to the solution according to 1). The efficiency described for the surfactant according to 2a) can be enhanced or optimized according to different combinations and characteristics of such amphiphiles, such as charge, lipophilic particle size, etc.

b) The presence of the surfactant in the embodiment according to 2a) allows a smaller portion of the formulation to be added to the water, thereby promoting a spontaneous precipitation reaction upon contact with water at the site of application.

c) High efficiency can be achieved by adding a combination of a tackifier and a surfactant to the embodiment according to 1. Here, the nanoparticles may be charged or uncharged, uniformly distributed in a gel-like state, bound to stay on the surface for a longer time, and more effectively release the active ingredient. In order to increase the viscosity, tackifiers or substances which gel in situ can be added.

The embodiments illustrated above are only examples to illustrate the possibilities of providing a variety of variants of the solution according to the invention.

Of course, the above-mentioned additives, as well as other additives customary in formulators, can be used in any combination according to the different needs, according to the basic embodiment of 1.

The solutions according to the invention, when used according to the invention, produce a precipitate in the form of nanoparticles of the previously dissolved active ingredient on contact with the aqueous solution, since the solubility of the active ingredient will decrease when the solvent is homogeneously mixed with water. The particle size can either be kept as small as possible and aggregation suppressed by the amphiphilic additive, by the tackifying additive or by a combination thereof, which is "activated" at the same time.

The present invention thus relates to an in situ generated nanosuspension, wherein the generated nanoparticles have a variety of tunable functionalities and combine the advantages of typical solutions with those of nanosuspensions without introducing the disadvantages of both. The present invention is therefore a low-cost, sterile filterable product with improved administration and absorption rates, whereby higher bioavailability will be achieved.

The solutions according to the invention are particularly suitable for the preparation of pharmaceutical compositions of pharmaceutically active ingredients for topical, oral or parenteral administration.

Preferably, the solutions according to the invention are used for topical or parenteral administration of pharmaceutically active ingredients. It is particularly preferred that the solution according to the invention is a pharmaceutical composition of a pharmaceutically active ingredient for administration to the eye.

It will be understood that, where it is desired to prepare a pharmaceutical composition based on a solution according to the invention, further auxiliaries may additionally be present, as are customary for the formulator in his or her respective use.

The principle of the invention and the preparation of the solutions according to the invention are further illustrated below with the aid of examples.

Examples

Example 1: miscibility of solvent with water

Mixing a clear liquid solvent polyethylene glycol 400 at a ratio of 1: 10 to 1: 1 (H)₂PEG400) were mixed with water in various ratios and the characteristics of the resulting solution were described. The homogeneous mixing of the solutions was carried out on a room temperature (21 ℃) Vortex mixer (Vortex Mischer). All ratios tested gave a clear, homogeneous mixture.

Example 2: solutions of active substances and solvents

Polyethylene glycol 400 was used as a solvent. 20mg of cyclosporin A (CsA concentration 20mg/ml) were dissolved in 1ml of this clear, already slightly viscous liquid. The dissolution process was carried out under the shaking of a room temperature (21 ℃) vortex mixer. The resulting solution was clear and free of suspended particles. This can be confirmed under a microscope. When 100. mu.l of water was added to 500. mu.l of this solution, turbidity spontaneously formed. The coarse precipitates with marked crystallinity are visible under microscope observation.

Example 3: solutions of active ingredients, conditioning agents and solvents

20mg of phospholipid (diheptanoyl glycerophosphocholine (DHGPC)) was dissolved in 1ml of polyethylene glycol 400 on a vortex mixer. A clear solution was obtained at room temperature (21 ℃). Then 20mg of cyclosporin A was dissolved therein under the same conditions. The resulting mixture was clear and free of suspended particles. The recording of the microscope confirmed this. 100 μ l of water was dropped into 500 μ l of this solution to cause spontaneous precipitation. The finely distributed structure did not form recognizable, larger crystals, as observed under a microscope.

Example 4: absorption capacity for water

A solution of 10mg of phospholipid and 2mg of cyclosporin A in 1ml of polyethylene glycol 400 was prepared. The dissolution of the material was carried out on a room temperature (21 ℃) vortex mixer. In this solution, water is added in a ratio of 1: 10 to 3.5: 10 (H)₂O: solution) were added dropwise and mixed. The system started to be cloudy. Until all ratios are reduced to 3: 10 (H)₂O: solution) and a clear solution is formed without suspended particles. Very finely dispersed particles, apparently shielded by a phospholipid layer, were visible under the microscope. The mixture with higher water content does not settle and forms a permanent precipitate.

Claims (5)

1. A pharmaceutical composition for ophthalmic administration comprising a solution containing at least one water-miscible biocompatible solvent and dissolved therein a lipophilic substance selected from at least one pharmaceutically active ingredient, said lipophilic substance forming a nanosuspension on the surface or the interior of the human or animal body upon contact with aqueous body fluids, wherein said lipophilic substance is present in suspension in the form of nanoparticles, wherein said nanoparticles are smaller than 10 μm, and wherein said at least one water-miscible biocompatible solvent is at least one selected from the group consisting of polyethylene glycol and derivatives thereof and glycerol, propylene glycol, dimethyl sulfoxide, N-vinyl pyrrolidone.

2. The pharmaceutical composition according to claim 1, wherein the solution additionally comprises at least one additive selected from the group consisting of surface-active substances, viscosity-increasing agents and agents for adjusting the Zeta potential of the nanoparticles.

3. The pharmaceutical composition according to claim 1 or 2, wherein the solution comprises two or more lipophilic substances.

4. A pharmaceutical composition according to any one of the preceding claims, wherein the nanoparticles have a size of 1nm or greater.

5. Use of a pharmaceutical composition according to one of claims 1 to 4 for the preparation of a medicament for the administration of one or more lipophilic substances to the eye of a human or animal.