Patent 6,682,747

The present invention relates to orally administered suspensions of pharmaceutical active substances of the NSAID type, particularly the antirheumatic agent Meloxicam, which are stabilized by the addition of small amounts of highly dispersed silicon dioxide using high shear forces and adding small amounts of hydrophilic polymers to form a three-dimensional siloid structure, and a process for the preparation thereof.

BRIEF SUMMARY OF THE INVENTION

Surprisingly, the suspension of a pharmaceutically active substance of the NSAID type can be stabilised by the addition of small amounts of highly dispersed silicon dioxide in the presence of small amounts of hydrophilic polymers. Because of the low concentration of highly dispersed silicon dioxide and hydrophilic polymer in the dispersion medium, the viscosity is low; unwanted increased in viscosity, which will prevent reconstitution of the suspension, caused by gel-like thickening of the dispersion medium does not occur if at the same time small amounts of hydrophilic polymer which are soluble in the dispersion medium are added to the medium and the silicon dioxide is added to the suspension with the aid of high shear forces. Suitably high shear forces can be produced with a suitable shear-intensive homogenising mixer, e.g., with mixers of the series "Becomix" made by Messrs. A. Berents GmbH & Co. KG, Henleinstr. 19, D-28816 Stuhr, which comprise rapidly rotating homogenizers working on the rotor-stator principle. A circumferential rotor speed of about 25 to 27 m/s is particularly suitable for generating sufficiently high shear forces and is used to introduce the highly dispersed silicon dioxide into the dispersing agent for about 10-15 minutes, e.g., using the mixers Becomix RW 15/RW 60/RW 1000. This produces a special siloid structure which consists of a spongy three-dimensional structure of hydratised highly dispersed silicon dioxide shot through with cavities, the active substance being adsorbed onto said structure.

Suitable highly dispersed silicon dioxide has a specific surface area of at least 50 m² /g, preferably 100 to 400 m² /g, for example, whilst a specific surface area of about 200 m² /g is particularly preferred (e.g. Aerosil.RTM. 200).

DETAILED DESCRIPTION OF THE INVENTION

The invention relates to a suspension of a pharmaceutically active substance of the NSAID type with a suspendable particle size spectrum in a physiologically inert dispersion medium in which the active substance has very little solubility, so that the suspension has no perceptible taste of its own, for oral administration, characterised in that the suspension contains a small amount of highly dispersed silicon dioxide for stabilisation by forming a three-dimensional siloid structure, the three-dimensional siloid structure being produced by adding the silicon dioxide to the dispersion medium under the action of high shear forces, and the suspension additionally contains a small amount of hydrophilic polymer which is soluble in the dispersion medium.

The above-mentioned three-dimensional siloid structure consists of crosslinked, swollen and coherent strands of SiO₂ between which can be found fairly large cavities filled with dispersion medium. The suspended solid particles of the active substance, e.g. meloxicam, are adsorbed almost exclusively onto the SiO₂ strands. In this way, the suspended particles are rapidly and fully wetted and agglomeration of the particles of pharmaceutical substance can be prevented entirely. This results in a suspension of the active substance of exceptional homogeneity and dosing precision. The siloid structure described does not lead to any gel-like thickening of the dispersion medium but rather produces a low viscosity pourable suspension.

At the same time, the three-dimensional siloid structure acts as a sedimentation stabiliser. The structure described is very bulky and is compressed only slightly and very slowly even by sedimentation. Thus, even after months of storage, the volume of the siloid structure decreases by only about 20%. The reduction in volume caused by sedimentation does not result in undesirable caking; the sediment can be easily and quickly redispersed by the use of extremely slight mechanical forces (e.g. very gentle shaking of an oral suspension of meloxicam packaged in standard commercial glass bottles). The slowness of sedimentation ensures that the user has sufficient time to take homogeneous single doses of the oral suspension of a pharmaceutically active substance according to the invention out of its primary packaging, thus ensuring accuracy of dosing.

For example, an active substance suspension according to the invention contains 0.1-5 wt. % of highly dispersed silicon dioxide (e.g. Aerosil.RTM. 200), preferably 0.5-2 wt. %, more particularly 0.5-1.5 wt. %.

Suitable soluble hydrophilic polymers are pharmaceutical grade cellulose ethers such as hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC) and hydroxypropylmethyl cellulose (HPMC). Hydroxyethyl cellulose is preferred. For example, a suspension of active substance according to the invention contains 0.05-2 wt. % of water soluble cellulose ether, preferably 0.05-0.5 wt. %, but more particularly 0.05-0.1 wt. %.

Most preferably the active substance suspension according to the invention contains 0.5-1.5 wt. % of highly dispersed silicon dioxide and 0.05-0.1 wt. % of hydroxyethyl cellulose.

The properties of a liquid oral suspension of active substance according to the invention are greatly influenced by the particle size of the suspended active substance. To achieve the rapid onset of activity which is desirable when the preparation is taken once, a small particle size is essential, ensuring the fastest possible dissolution of the active substance in gastrointestinal tract. In the particle size spectrum of the active substance which is suitable for a suspension according to the invention, therefore, at least 90% of the particles are smaller than 50 .mu.m, preferably at least 50% of the particles are smaller than 10 .mu.m, and most preferably about 90% of the particles are smaller than 10 .mu.m (determined for example by laser diffractometry). A correspondingly finely dispersed grade of pharmaceutical can easily be achieved by suitably grinding a coarser grade. Suitable mills for grinding operations of this kind are the standard commercial jet mills, for example.

The small particle size of the active substance in a suspension according to the invention as described also have the advantage of a slow rate of sedimentation of the suspended particles, which favorably affects the homogeneity of the liquid oral formulation of the active substance described and correspondingly ensures a high degree of accuracy in measuring the dose.

The solubility of the active substance in suitable physiologically acceptable dispersion media should be less than 500 .mu.g/ml. Preferably, the solubility is not more than 50 .mu.g/ml, most preferably the solubility is not more than 5 .mu.g/ml, but more particularly not more than 0.5 .mu.g/ml.

It is readily possible for the skilled person to find, for any given active substance of the NSAID type, a suitable physiologically acceptable dispersion medium in which the active substance has the solubility characteristics mentioned above. For meloxicam, the physiologically acceptable dispersion medium preferably consists of an aqueous buffer system with a pH in the range from 2-4.

An orally administered suspension according to the invention may contain one or more NSAID's as pharmaceutically active substance. The classic active substance acetylsalicylic acid and the active substances of the following categories are mentioned as examples of NSAID's:

(1) propionic acid derivatives,

(2) acetic acid derivatives,

(3) fenamic acid derivatives,

(4) biphenylcarboxylic acid derivatives,

(5) acid enolcarboxamides,

(6) diaryl heterocycles with methylsulphonyl or aminosulphonyl substituents and

(7) acid sulphonamides.

The following active substances are mentioned as examples of propionic acid derivatives, although this list should not be regarded as limiting this category of active substance:

ibuprofen, naproxen, flurbiprofen, fenoprofen, fenbufen, ketoprofen, indoprofen, pirprofen, carprofen, oxaprozin, pranoprofen, miroprofen, tioxaprofen, suprofen, alminoprofen, tiaprofenic acid and fluprofen or the pharmaceutically acceptable salts thereof.

Examples of acetic acid derivatives include the following active substances, although the list does not constitute any restriction of this category of active substance:

indomethacin, sulindac, tolmetin, zomepirac, nabumetone, diclofenac, fenclofenac, alclofenac, bromfenac, ibufenac, aceclofenac, acemetacin, fentiazac, clidanac, etodolac and oxpinac or the pharmaceutically acceptable salts thereof.

The following active substances are mentioned as examples of fenamic acid derivatives, although the list does not constitute a limitation to this category of active substance:

mefenamic acid, meclofenamic acid, flufenamic acid, nifluminic acid and tolfenamic acid or the pharmaceutically acceptable salts thereof.

Examples of biphenylcarboxylic acid derivatives include the following active substances, although the list does not constitute a limitation of this category of active substance:

diflunisal and flufenisal or the pharmaceutically acceptable salts thereof.

The following are examples of acid enolcarboxamides (oxicams), although the list does not constitute a restriction to this category of active substance:

piroxicam, tenoxicam, lornoxicam and meloxicam or the pharmaceutically acceptable salts thereof.

Nimesulide is mentioned by way of example of an acid sulphonamide, but should not constitute a restriction to this category of active substances.

Chemical structures, pharmacological activity, side effects and information regarding the usual dosage ranges for the above-mentioned NSAID's are given for example in Physician's Desk Reference, 35^th Edition, 1981; The Merck Index, 12^th Edition, Merck and Company, Rahway, N.J. (1996); Cutting's Handbook of Pharmacology, 6^th Edition, Ed. T. Z. Czacky, M. D., Appleton-Century-Crofts, New York, 1979, Chapter 49:538-550.

A dosage unit for the following NSAID's may be, for example:

100 mg to 500 mg diflunisal, 25 mg to 100 mg zomepirac sodium, 50 mg to 400 mg ibuprofen, 125 mg to 500 mg naproxen, 25 mg to 100 mg flurbiprofen, 50 mg to 100 mg fenoprofen, 10 mg to 20 mg piroxicam, 5 mg to 20 mg meloxicam, 125 mg to 250 mg mefenamic acid, 100 mg to 400 mg fenbufen, and 25 mg to 50 mg ketoprofen.

Particularly preferred oral administered suspensions according to the invention are those which contain as active substance an acid enolcarboxamide, especially meloxicam.

Meloxicam is an NSAID with the structural type of an enolic acid and exhibits a distinctly pH-dependent solubility. The minimum solubility in buffered aqueous systems is found at pH values from 2-4. The solubility in this pH range is less than 0.5 .mu.g/ml (Luger P., Daneck K., Engel W., Trummlitz G., Wagner K., Structure and physicochemical properties of meloxicam, a new NSAID, Eur. J. Pharm. Sci. 4 (1996), 175-187).

Suitable dispersion media for a liquid oral suspension of meloxicam according to the invention are therefore physiologically acceptable aqueous buffer systems with a pH in the range from 2-4, mixtures thereof or mixtures thereof with other physiologically acceptable liquids which are additionally suitable for improving specific properties of the meloxicam suspension, especially

for adjusting the viscosity of the dispersion medium in order to reduce the rate of sedimentation of the suspended particles of pharmaceutical,

to ensure that the liquid oral preparation has a pleasant flavor and

to improve the wetting qualities of the suspended pharmaceutical particles.

other physiologically acceptable liquids in the sense of the invention described are preferably glycerol and optionally aqfueous solutions of sugar alcohols such as sorbitol, mannitol and xylitol, and mixtures thereof. In a suspension according to the invention these substances have the advantage

of increasing the viscosity of the dispersion medium and hence reducing the rate of sedimentation of the suspended pharmaceutical particles and making it easier to handle when the liquid formulation is transferred into metering aids (e.g. standard measuring spoons or special metering systems such as metering syringes) and when the liquid formulation is measured out in drops (e.g. standard dropper inserts),

of their slightly sweet inherent flavor which gives the liquid oral formulation a pleasant taste,

of their suitability for diabetic patients and animals which can be treated with antirheumatic drugs and

of improving the wetting properties of the suspended pharmaceutical particles.

Suitable physiologically acceptable aqueous buffer systems with a pH in the range from 2-4 include, for example, sodium dihydrogen-phosphate dihydrate/citric acid monohydrate buffer, glycine/HCl (S. P. Sorensen, Biochem. Z., 21, 131 (1909); Biochem. Z., 22, 352 (1909)), Na-citrate/HCl (S. P. Sorensen, Biochem. Z., 21, 131 (1909); Biochem. Z., 22, 352 (1909)), K-hydrogen phthalate/HCl (Clark and Lubs, J. Bact., 2, 1 (1917)), citric acid/phosphate (T. C. McIlvaine, J. Biol. Chem., 49, 183 (1921)), citrate-phosphate-borate/HCl (Teorell and Stenhagen, Biochem. Z., 299, 416 (1938)) and Britton-Robinson-Buffer (Britton and Welford, J. Chem. Soc., 1, 1848 (1937)).

Preferably, a dispersion medium for a liquid oral suspension of meloxicam according to the invention is based on an aqueous buffer system with a pH in the range from 2-4 mixed with one or more of the physiologically acceptable liquids glycerol and aqueous solutions of the sugar alcohols mannitol, sorbitol and xylitol.

For example, the dispersion medium of a liquid oral suspension of meloxicam according to the invention consists of mixtures of about 30-50% aqueous buffer system, pH 2-4, preferably aqueous sodium dihydrogen phosphate dihydrate/citric acid monohydrate buffer, about 10-20% glycerol, about 10-20% xylitol and about 20-30% sorbitol or mannitol solution (70% sorbitol or mannitol in water). Glycerol and the above-mentioned sugar alcohols may be present either individually or in admixture with one another in the dispersion medium.

The suspension ready for use may contain varying amounts of the active substance meloxicam, e.g. 0.050 to 3.000 g/118 g, preferably 0.050 to 2.000 g/118 g, but particularly 0.050 to 1.5 g/118 g, based on the mass of the preparation ready for use.

To improve the flavor still further, one or more flavorings and/or one or more sweeteners may be added to a liquid oral suspension according to the invention.

Suitable flavorings include, for example, liquid and powdered, water soluble natural and nature-identical flavorings. Particularly preferred are liquid flavorings, particularly raspberry, strawberry and honey.

Suitable sweeteners include, for example, saccharin sodium, saccharin, cyclamate, acesulfame potassium and taumatin.

Moreover, conventional excipients and/or preservatives effective in the pH range, i.e. preferably sodium benzoate in the case of the active substance meloxicam, may be added to a liquid oral suspension according to the invention.

Because of the three-dimensional siloid structure and the adhesion of the suspended solid particles, there is no need to add any surfactants to improve the wetting qualities. Surfactants may have a negative effect in suspensions since the solubility of the solid in the dispersion medium may be increased in some cases, leading to an unwanted growth in particle size. Moreover, surfactants, particularly ionic surfactants, are frequently allergenic and/or irritant to the mucous membranes.

The invention further relates to a process for producing an orally administered liquid preparation of a pharmaceutically active substance of the NSAID type in the form of a stabilised suspension, characterised in that

(i) the solid active substance is ground in order to produce a particle size spectrum in which at least 90% of the particles are smaller than 50 .mu.m, preferably at least 50% of the particles are smaller than 10 .mu.m, but in particular about 90% of the particles are smaller than 10 .mu.m,

(ii) the ground active substance is suspended in a physiologically inert dispersion medium in which the solubility of the active substance is very low,

(iii) small amounts of highly dispersed silicon dioxide are added to the dispersion medium with the application of high shear forces,

(iv) small amounts of hydrophilic polymer soluble in the dispersion medium are added to the dispersion medium and

(v) optionally, one or more flavorings, one or more sweeteners, conventional excipients or one or more preservatives may, independently of one another, be added to the dispersion medium, the flavorings preferably being added during the final stage of manufacture owing to their foam breaking properties.

A preferred embodiment of the process according to the invention is characterised in that

(i) a particle size spectrum is produced in which about 90% of the particles are smaller than 10 .mu.m,

(ii) the ground active substance is suspended in a physiologically acceptable, aqueous buffer system at a pH in the range from 2-4, for example sodium dihydrogen phosphate dihydrate/citric acid monohydrate buffer, glycine/HCl, K-hydrogen phthalate/HCl, citric acid/phosphate, citrate-phosphate-borate/HCl or Britton-Robinson buffer, mixtures thereof with one another or mixtures thereof with other physiologically acceptable liquids such as glycerol or optionally aqueous solutions of sugar alcohols such as sorbitol, mannitol and xylitol,

(iii) with the aid of a mixer by the application of high shear forces, characterised for example by a circumferential rotor speed of 15-35 m/s, preferably 20-30 m/s, 0.1-5.0 wt.-% of highly dispersed silicon dioxide, based on the weight of the suspension ready for use, are added to the dispersion medium,

(iv) water soluble cellulose ethers of pharmaceutical grade are added to the dispersion medium as hydrophilic polymers in an amount of from 0.05-2 wt.-%, based on the weight of the suspension ready for use, and

(v) one or more flavorings, one or more sweeteners, conventional excipients or one or more preservatives may optionally be added independently of one another to the dispersion medium.

A particularly preferred embodiment of the process according to the invention is characterised in that

(i) a particle size spectrum is produced in which about 90% of the particles are smaller than 10 .mu.m,

(ii) the ground active substance is suspended in a dispersion medium consisting of mixtures of 30-50% aqueous buffer systems with a pH in the range from 2-4, aqueous sodium dihydrogen phosphate dihydrate/citric acid monohydrate buffer being preferred, 10-20% glycerol, 10-20% xylitol and 20-30% sorbitol or mannitol solution (70% sorbitol or mannitol in water), whilst glycerol and the above-mentioned sugar alcohols may be present in the dispersion medium either individually or in admixture with one another,

(iii) 0.5-2.0 wt.-% of highly dispersed silicon dioxide, based on the weight of the suspension ready for use, are added to the dispersion medium with the aid of a mixer by applying high shear forces, characterised for example by a circumferential rotor speed of 20 to 30 m/s, preferably about 25 to 27 m/s,

(iv) pharmaceutical grade water-soluble cellulose ethers, preferably hydroxyethyl cellulose, are added to the dispersion medium as hydrophilic polymers, in an amount of from 0.05-0.5 wt.-%, based on the weight of the suspension ready for use, and

(v) one or more flavorings, one or more sweeteners, conventional excipients or one or more preservatives may optionally be added to the dispersion medium independently of one another.

In all the above-mentioned embodiments of the process, steps (ii) to (v) are preferably carried out in vacuo since the entry of air affects the density of the suspension to be produced, as a result of floating effects or air absorption on the siloid structure, and inhomogeneities may be produced.

A particularly preferred embodiment of the process according to the invention is characterised in that the active substance is an acid enolcarboxamide, particularly meloxicam.

A third object of the invention is the use of an active substance of the NSAID type, preferably an acid enolcarboxamide, but particularly meloxicam, for preparing a liquid preparation of the active substance in the form of a stabilised suspension with a particle size spectrum wherein at least 90% of the particles are smaller than 50 .mu.m, in a physiologically inert dispersion medium in which the active substance has very low solubility, so that the suspension does not have any noticeable taste, for oral administration, characterised in that the suspension contains a small amount of highly dispersed silicon dioxide for stabilising it by forming a three-dimensional siloid structure, the three-dimensional siloid structure being produced by adding the silicon dioxide to the dispersion medium with the action of high shear forces, and the suspension additionally contains a small amount of hydrophilic polymer soluble in the dispersion medium.

Claim 1 of 20 Claims

What is claimed is:

1. A process for preparing a pharmaceutical composition of matter which is an orally administered suspension of active substance particles of an acid enolcarboxamide which comprises the steps of:

(a) grinding the active substance particles to produce ground active substance particles having a particle size spectrum in which at least about 90% of the particles are smaller than about 50 .mu.m;

(b) suspending the ground active substance particles in a physiologically inert dispersion medium in which the solubility of the active substance is less than 500 .mu.g/ml to produce a suspended ground active substance;

(c) adding highly dispersed silicon dioxide to the suspended ground active substance with the aid of a mixer having shear forces characterized by a circumferential rotor speed of about 15 m/s to 35 m/s to produce a ground active substance and highly dispersed silicon dioxide mixture; and

(d) adding about 0.05% to about 2% by weight of a hydrophilic polymer soluble in the dispersion medium to the ground active substance and highly dispersed silicon dioxide mixture to produce the pharmaceutical composition of matter.

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