HK1150766A - Pharmaceutical compositions comprising colloidal silicon dioxide - Google Patents

Description

Pharmaceutical composition comprising colloidal silicon dioxide

A divisional application of international application with the title "pharmaceutical composition comprising colloidal silica" filed on 27/9/2002 under the application number PCT/EP2002/010890, which entered the chinese national phase at 26/3/2004 under the application number 02819045.9.

Technical Field

The present invention relates to novel oral pharmaceutical compositions comprising a macrolide, such as rapamycin or a derivative thereof or an ascomycin, in a solid dispersion.

The term "macrolide" as used herein refers to a macrocyclic lactone, for example, a compound having a 12-membered or greater lactone ring. Of particular interest are "lactam macrolides", i.e., macrocyclic compounds having a lactam (amide) linkage in addition to a lactone (ester) linkage in the macrocycle, such as the lactam macrolides produced by microorganisms of the genus Streptomyces (Streptomyces) such as rapamycin, ascomycin, and FK-506, as well as numerous derivatives and analogs thereof. Such lactam macrolides have been shown to have attractive pharmaceutical properties, in particular immunosuppressive and anti-inflammatory properties.

Background

The rapamycin is prepared fromStreptomyces hygroscopicus (Streptomyces hygroscopicus)The resulting immunosuppressive lactam macrolides. The structure of rapamycin is described in Kesseler, h. et al, 1993,Helv. Chim.Acta，76: 117 are given. See, e.g., McAlpine, J.B. et al, J.antibiotics (1991)44: 688; schreiber, s.l. et al, j.am.chem.soc. (1991)113: 7433; U.S. patent No. 3929992. Rapamycin is an extremely potent immunosuppressant and has also been shown to have anti-tumor and anti-fungal activity. However, its very low and variable bioavailability limits its use as a drug. In addition, rapamycin is inAqueous media, such as water, are highly insoluble, making it difficult to formulate them into galenic compositions. Numerous derivatives of rapamycin are known. Certain 16-O-substituted rapamycin derivatives are disclosed in WO 94/02136, the contents of which are incorporated herein by reference. 40-O-substituted rapamycin derivatives are described, for example, in the following patents: US5258389 and WO 94/09010 (O-aryl and O-alkyl rapamycin derivatives), WO92/05179 (carboxylic acid esters), US 5118677 (amide esters), US 5118678 (carbamates), US 5100883 (fluorinated esters), US 5151413 (acetals), US 5120842 (silyl ethers), WO 93/11130 (methylene rapamycin and derivatives), WO 94/02136 (methoxy derivatives), WO 94/02385 and WO 95/14023 (alkenyl derivatives), all of which are incorporated herein by reference. For example, US 5256790, which is incorporated herein by reference, describes 32-O-dihydro or substituted rapamycin derivatives.

Other rapamycin derivatives are described in PCT application EP 96/02441, for example 32-deoxorapamycin in example 1 and 16-pent-2-ynyloxy-32 (S) -dihydrorapamycin in examples 2 and 3. The contents of PCT application EP 96/02441 are incorporated herein by reference.

Rapamycin and its structurally related derivatives are collectively referred to as "rapamycin and rapamycin derivatives".

Ascomycins constitute another class of lactam macrolides, many of which have potent immunosuppressive and anti-inflammatory activity, the best-known members of which are FK-506 and ascomycins. FK-506 is prepared fromTsukubaensis Streptomyces9993 to Nicotina et al. The structure of FK-506 is given in appendix A5 of Merck index 11 th edition (1989). Ascomycins are described, for example, in U.S. patent 3,244,592. Many derivatives of ascomycin and FK-506 have been synthesized, including halogenated derivatives such as 33-epi-chloro-33-desoxyascomycin as described in EP 427680. Ascomycin, FK-506 and their structurally similar analogs and derivatives are collectively referred to as "ascomycin and ascomycin derivatives".

Solid rapamycin or rapamycin derivatives are not absorbed to any significant extent into the bloodstream when administered orally to humans. PCT application WO 97/03654, the contents of which are incorporated herein by reference, describes a pharmaceutical composition in the form of a solid dispersion comprising a macrolide, such as rapamycin, an ascomycin or a derivative thereof, and a carrier medium. These compositions provide improved bioavailability of the drug substance, are convenient to administer, and are stable.

However, for certain patient populations, oral administration of drugs in solid tablet form is undesirable or not feasible. In particular, children and elderly patients may not be able to conveniently swallow such tablets. For these patients, it is often more desirable to provide tablets that can be first dispersed in an ingestible liquid and then consumed by the patient.

For administration to children and elderly patients, it is highly desirable to provide tablets that disperse rapidly in ingestible liquids such as water. Problems with prior art macrolide formulations are: since they are not necessarily rapidly dispersible in aqueous solutions, it can be inconvenient and time consuming to prepare a well-dispersed liquid formulation prior to administration to a patient. One particular difficulty in formulating macrolide solid dispersion compositions in the form of dispersible tablets is the use of a large amount of carrier as a binder in the tablet in the solid dispersion composition.

It is known that tablets which disintegrate more rapidly can be prepared by using lower compression forces during the tablet preparation process. However, this can often lead to poor mechanical properties of the tablet. In particular, an insufficiently compressed tablet exhibits insufficient hardness and is susceptible to breakage, cracking or disintegration prior to its use (i.e., during packaging, shipping, storage or at any time prior to the tablet being added to an ingestible liquid for consumption).

Disclosure of Invention

It is an object of the present invention to provide a pharmaceutical composition which ameliorates the problems of the prior art compositions. Accordingly, the present invention provides a pharmaceutical composition comprising a macrolide solid dispersion, a disintegrant and colloidal silicon dioxide, wherein the composition comprises 1% to 5% by weight of colloidal silicon dioxide.

The present invention is based on the surprising discovery that: by using colloidal silicon dioxide to facilitate disintegration, compositions comprising macrolide solid dispersions which disperse particularly rapidly can be provided. Known from the prior art are: colloidal silica is used primarily as a lubricant or flow modifier in pharmaceutical compositions. When used for this purpose, colloidal silica typically constitutes about 0.5% by weight of the composition. According to the present invention, it has been found that colloidal silicon dioxide in an amount of 1% to 5% by weight is particularly effective in promoting the disintegration of macrolide solid dispersions in aqueous solution when combined with another disintegrant.

Furthermore, the compositions of the present invention exhibit a high degree of stability and physical integrity, for example during storage, handling, packaging, etc., without limiting the disintegration properties of the compositions. The inclusion of a suitable amount of colloidal silicon dioxide is also advantageous as it allows the composition to have enhanced mechanical properties when compressed into a tablet. In particular, tablets formed from the compositions of the present invention surprisingly have both rapid disintegration in aqueous solution and mechanical stability. The inclusion of silicon dioxide may allow the tablet to have a faster disintegration rate for a given level of hardness. Alternatively, for a given disintegration rate, the tablets of the invention comprising silicon dioxide are harder than tablets without silicon dioxide.

The compositions of the present invention comprise one or more disintegrants. Examples of disintegrants include cross-linked polyvinylpyrrolidones, such as those commercially available from ISPOr("excipient Manual", pp.143-144); sodium starch glycolate available from Generichem; and croscarmellose sodium, e.g. commercially available FMCOf a driverPreferably, the disintegrant comprises crosslinked polyvinylpyrrolidone.

Preferably, no more than about 50%, e.g., 10 to 30%, more preferably about 20% by weight, is included in the compositions of the invention, all weights being based on the total weight of the composition.

In addition to the disintegrant as defined above, the composition of the invention comprises from 1% to 5% by weight of colloidal silicon dioxide. Colloidal silica may be obtained from commercially available sourcesThe colloidal silica is included in the composition of the invention in an amount of from 1% to 5% by weight of the total composition, preferably from 2% to 5% by weight of the total composition. More preferably, the composition comprises from 2% to 4%, still more preferably from 2.5% to 3.5%, of colloidal silica, based on the total weight of the composition. Most preferably, the composition comprises about 3% by weight colloidal silica.

Preferably, a mixture of colloidal silica and cross-linked polyvinylpyrrolidone in a ratio of 1: 1 (e.g., 1: 3) to 1: 50 (e.g., 1: 10) may be used.

The macrolide used in the solid dispersion of the present invention may be rapamycin OR any derivative thereof, for example, wherein the hydroxyl group on the cyclohexyl ring of rapamycin is-OR₁Substituted O-substituted derivatives, wherein R₁Is hydroxyalkyl, hydroxyalkoxyalkyl, acylaminoalkyl or aminoalkyl; for example, as described in WO 94/09010, e.g. 40-O- (2-hydroxyethyl) -rapamycin, 40-O- (3-hydroxypropyl) -rapamycin, 40-O- [2- (2-hydroxyethoxy) ethyl]-rapamycin and 40-O- (2-acetamidomethyl) -rapamycin. The rapamycin derivatives may be 26-or 28-substitutedAnd (3) derivatives. The rapamycin derivative may be an epimer of the above derivative, in particular an epimer of the derivative substituted in position 40, 28 or 26, and may optionally be further hydrogenated, for example as disclosed in WO 95/14023 and 99/15530, for example ABT578, or may be a rapamycin analogue (rapalog), for example as disclosed in WO 98/02441 and WO01/14387, for example AP 23573.

Preferred rapamycin derivatives for use in the present invention include rapamycin, 40-O- (2-hydroxy) ethyl rapamycin, 32-deoxorapamycin and 16-pent-2-ynyloxy-32 (S) -dihydrorapamycin. A more preferred compound is 40-O- (2-hydroxy) ethyl rapamycin.

The numbering of the rapamycin derivatives as used herein refers to the structure disclosed as formula a on page 4 of pctwoo 96/13273, incorporated herein by reference.

Examples of ascomycin-like compounds are those mentioned above, such as FK-506, ascomycin, and other naturally occurring compounds or synthetic analogues thereof.

A preferred class of ascomycin compounds is disclosed in EP 427680 example 66a, also known as 33-epi-chloro-33-deoxy-ascomycin. Other preferred compounds are disclosed in EP 465426 and EP 569337 (example 71). Particularly preferred is 33-epi-chloro-33-deoxy-ascomycin.

The macrolide (e.g., rapamycin or a derivative thereof such as 40-O- (2-hydroxyethyl) rapamycin or an ascomycin such as 33-epi-chloro-33-deoxo-ascomycin or FK-506) is preferably present in the composition in an amount of about 0.01% to about 30%, more preferably 0.1% to 20% by weight based on the total weight of the composition. In particular, a rapamycin derivative such as 40-O- (2-hydroxy) ethyl rapamycin may be present in the composition in an amount of 0.1% by weight.

The macrolides used in the present invention may be in crystalline or amorphous form prior to formulation into a solid dispersion. It is therefore an advantage of the present invention that the macrolide need not be crystalline. Thus, the macrolide can be used directly, for example, in combination with a solvent without prior isolation. Another advantage of the present invention is that the dissolution rate of the solid dispersion is higher than the dissolution rate of a crystalline macrolide or an amorphous macrolide in a simple mixture.

The carrier medium used to prepare the solid dispersion preferably comprises a carrier, such as a water-soluble polymer, for example one of the following polymers or mixtures thereof may be used:

-Hydroxypropylmethylcellulose (HPMC). Good results have been obtained with HPMC having a low apparent viscosity, e.g. a viscosity of less than 100cps, e.g. less than 50cps, preferably less than 20cps, e.g. HPMC 3cps, as measured in a 2% by weight aqueous solution at 20 ℃. HPMC is well known and described in, for example, "handbook of pharmaceutical excipients", published by the pharmaceutical Society of Great Britain and American pharmaceutical Association, 1994, pages 229 to 232, the contents of which are incorporated herein by reference. Commercially available HPMC, including HPMC 3cps, is available under the name Shinetsu corporation603, of the product of;

-hydroxypropylmethylcellulose phthalate (HPMCP), such as commercially available HPMCPHP50 or HPMCP HP 55;

polyvinylpyrrolidone (PVP), such as PVP K30 or PVP K12. PVP commercially available, e.g. from BASF("handbook of drug excipients", page 392-399). Superior food

Selecting a PVP having an average molecular weight of about 8,000 to about 50,000 daltons, such as PVP K30;

poly (meth) acrylates, e.g. gastric juice-resistant and intestinal juice-soluble copolymers, e.g. made of a material selected from the group consisting of

Copolymers of monomers based on acrylic acid, methacrylic acid esters, acrylic acid and acrylic acid esters, e.g. those already mentionedKnown and commercially availableOf Pharma GmbhParticularly preferred polymers are 1: 1 or 1: 2 copolymers formed from monomers selected from methacrylic acid and lower alkyl methacrylates, such as 1: 1 or 1: 2 copolymers formed from methacrylic acid and methyl methacrylate. The 1: 1 copolymer obtainable isL, 1: 2 copolymers obtainable areAnd S. A particularly preferred polymer is a 1: 1 copolymer of methacrylic acid and ethyl acrylate, commercially availableL 100-55；

-hydroxypropyl cellulose (HPC) or derivatives thereof. Examples of HPC derivatives include those having a low dynamic viscosity in an aqueous medium such as water, e.g., a viscosity of less than about 400cps, e.g., less than 150cps, as measured in a 2% aqueous solution at 25 ℃. Preferred HPC derivatives have a low degree of substitution and an average molecular weight of less than about 200,000 daltons, e.g., 50,000 to 150,000 daltons. Examples of commercially available HPCs include those available from Aqualon corporationLF、EF andJF; and available from Nippon Soda Co., LtdHPC-L。

-polyethylene glycol (PEG). Examples include PEG with an average molecular weight of 1000 to 9000 daltons, e.g.about 1800 to 7000 daltons, e.g.PEG 2000, PEG 4000 or PEG 6000 ("handbook of pharmaceutical excipients", page 355-361);

saturated polyglycolysed glycerides, obtainable for example fromE.g. of the Gattefoss é company44/14, 53/10, 50/13, 42/12, or 35/10; or

Cyclodextrins, such as beta-cyclodextrin or alpha-cyclodextrin. Examples of suitable beta-cyclodextrins include methyl

Beta-cyclodextrin, dimethyl-beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin, glucosyl-beta-cyclodextrin, maltosyl-beta-cyclodextrin, thio-alkyl ethers of beta-cyclodextrin, e.g. thio-C_1-4-alkyl ethers. Examples of α -cyclodextrins include glucosyl- α -cyclodextrin and maltosyl- α -cyclodextrin.

The content of the carrier medium of the solid dispersion is, for example, from 0.1% to 99.99%, for example from 0.1% to 99.9%, for example from 1% to 95%, for example from 5% to 95%, for example from 10% to 90% by weight, based on the total weight of the solid dispersion.

In one embodiment of the invention, the solid dispersion composition comprises 2% by weight of rapamycin or a derivative thereof, for example 40-O- (2-hydroxy) ethyl rapamycin, and 80% by weight of HPMC 3 cps.

The carrier medium used to prepare the solid dispersion may also comprise one or a group of water-soluble or water-insoluble sugars or other acceptable carriers or fillers such as sucrose, lactose, amylose, dextrose, mannitol, inositol, etc., preferably lactose;or microcrystalline cellulose, e.g. commercially available from FMCAnd("handbook of pharmaceutical excipients", pp.84-87). Preferably, lactose may be used.

If present, the filler is generally present in an amount of no more than about 50%, for example from about 0.01% to about 50%, for example from about 0.5% to about 40%, preferably from about 5% to about 35%, especially about 20% by weight, based on the total weight of the solid dispersion.

The carrier medium may also comprise one or more surfactants, for example non-ionic, ionic or amphoteric surfactants. Examples of suitable surfactants include:

-polyoxyethylene-polyoxypropylene copolymers and block copolymers, commercially availableOrE.g., as described in H.Fiedler, "Lexikon der Hilfsstuffe fur Pharmazie, Kosmetik und angenzende Gebiete", Cantor Verlag Aulendorf editor, Aulendorf, revision 4, expanded edition (1996), the contents of which are incorporated herein by reference. Preferred polyoxyethylene-polyoxypropylene block copolymers are commercially available from BASF corporation188；

Ethoxylated cholesterol, commercially available asFor example from AmercholC24；

Vitamin derivatives, for example vitamin E derivatives such as Tocopherol Polyethylene Glycol Succinate (TPGS) available from Eastman company;

-sodium lauryl sulfate or sodium lauryl sulfate;

bile acids or salts thereof, such as cholic acid, glycolic acid or salts, such as sodium cholate; or

Lecithins, e.g. soya lecithin, e.g. of commercially available LipoidS75; or lecithin (eg phospholipid), e.g. commercially available from Nattermann90。

If present, the one or more surfactants are typically present in an amount of about 0.01% to about 30%, for example 1% to 20%, for example 1% to 15% by weight, all weights being based on the weight of the solid dispersion. Good results have been obtained by the applicant with solid dispersions free of surfactants.

In another embodiment, the carrier medium used to prepare the solid dispersion may comprise other additives or ingredients, such as antioxidants and/or stabilizers, for example, in an amount of no more than about 5% by weight, such as from about 0.05% to 5%, for example from 0.05% to 1%, and especially about 0.2% by weight, all based on the total weight of the solid dispersion composition. Examples of antioxidants include Butylated Hydroxytoluene (BHT), Butylated Hydroxyanisole (BHA), DL-alpha-tocopherol, propyl gallate, ascorbyl palmitate, and fumaric acid. Preferably, butylated hydroxytoluene may be used. A suitable stabilizer may be malonic acid.

40-O- (2-hydroxy) ethyl rapamycin may be mixed with stabilizers such as butylated hydroxytoluene, for example, in a ratio of 5: 1 to 20: 1.

The carrier medium may also include antimicrobial agents, enzyme inhibitors, and preservatives.

In another aspect, the invention relates to a method of preparing a pharmaceutical composition comprising a macrolide, the method comprising preparing a macrolide solid dispersion and mixing the macrolide solid dispersion with a disintegrant and colloidal silicon dioxide to form the pharmaceutical composition.

In the above method, a macrolide solid dispersion is first prepared. The term "solid dispersion" as used herein refers to a formulation wherein the macrolide is in amorphous or substantially amorphous form and is dispersed in a carrier medium. For example, the solid dispersion may be a co-precipitate or co-evaporate of the macrolide and the carrier medium. The solid dispersion may be a composition suitable for further processing into an administrable formulation.

A. In one embodiment, the solid dispersion may be obtained by: the macrolide and, for example, a carrier medium comprising a water-soluble polymer, a filler and an antioxidant are dissolved or suspended in a solvent or solvent mixture. The solvent may be a single solvent or a mixture of solvents, and the order of dissolution and suspension of the macrolide and carrier medium in the solvent may vary. Suitable solvents for preparing the solid dispersion may be organic solvents such as alcohols, for example methanol, ethanol or isopropanol; esters, such as ethyl acetate; ethers, such as diethyl ether; ketones such as acetone; or a halogenated hydrocarbon such as dichloroethane. Preferably, a solvent mixture of ethanol/acetone in a weight ratio of ethanol to acetone of about 1: 10 to about 10: 1, for example 1: 5 to 5: 1, may be used. Typically, the weight ratio of macrolide and carrier medium to solvent is from 1: 0.1 to 1: 20. The solvent may be evaporated and the macrolide co-precipitated with the carrier medium.

B. In another embodiment, the solid dispersion may be prepared as follows: the carrier medium is melted to form a melt, and the melt and macrolide are combined, for example, with stirring, optionally in the presence of a solvent or solvent mixture as described herein. The resulting mixture may be granulated with a filler, such as lactose or mannitol.

C. In another embodiment, the solid dispersion may be prepared as follows: the macrolide and carrier medium are dissolved or suspended in the above solvent or solvent mixture and the resulting solution/suspension is granulated with a filler, e.g. lactose.

D. Solid dispersions can be prepared by spray drying techniques such as described in "theory and practice of Industrial pharmacy", Lachmann et al, 1986. The solution/suspension of macrolide and carrier medium in the above solvent or solvent mixture is dispersed through a nozzle into a container maintained at e.g. 20 to 80 ℃ and the spray pressure is e.g. 3 bar. The solvent is evaporated through a nozzle and the finely dispersed particles are collected.

E. In a further embodiment, solid dispersions may be prepared by spraying a solution/suspension of the macrolide and carrier medium in the above-mentioned solvent or solvent mixture onto a filler such as lactose or microcrystalline cellulose or a mixture thereof in a fluidized bed for granulation.

According to the invention, the above described solid dispersion comprising macrolide is further processed into a pharmaceutical composition in the form of a dispersible tablet. Preferably, the dispersible tablets have a disintegration time of 3 minutes or less.

In another aspect of the present invention, the solid dispersion composition as described above can be further processed into rapidly disintegrating powders or granules that can be filled into, for example, sachets or gelatin capsules.

The residue obtained in each of the above processes a to E may be sieved and comminuted into particles, for example particles having an average particle size of less than about 0.9mm, for example less than about 0.8mm, for example less than about 350 microns. Preferably, the particle size is at least about 5 microns, for example about 200 to 300 microns.

The (comminuted) solid dispersion may be admixed with colloidal silicon dioxide, one or more disintegrants such asAnd other excipients such as fillers, e.g. lactose, and are mixed, sieved and combined with lubricants such as magnesium stearate, mixed and, for example, compressed to obtain dispersible tablets, or filled into sachets or gelatin capsules.

The compositions of the present invention may also include one or more lubricants such as magnesium stearate. Magnesium stearate can be included in an amount of 0.5% to 2%, preferably about 0.5% by weight, all weights based on the total weight of the composition.

In a particularly preferred embodiment, the pharmaceutical composition further comprises a lubricant and a filler.

It may be advantageous for the compositions of the present invention to include, for example, about 2.5% or 5% by weight, based on the total weight of the composition, of one or more sweetening or flavoring agents.

In another embodiment of the invention, the compositions of the invention may include water soluble or water insoluble sugars or other acceptable fillers such as sucrose, lactose or microcrystalline cellulose (e.g., available from FMC corporation)). Preferably, lactose, especially anhydrous lactose, may be used, for example in an amount of not more than about 90%, for example from 20% to 80%, preferably from about 50% to about 72% by weight, all weights being based on the total weight of the composition.

The rapidly disintegrating compositions of the invention may be administered in any convenient form, for example in the form of tablets, capsules, granules or powders, for example in the form of sachets. Preferably, the formulation is in the form of a tablet. Although the compositions of the present invention are described below with particular reference to tablets, other types of dosage forms may be prepared and are included within the scope of the present invention.

Tablets may be prepared from the compositions of the invention using any suitable equipment or method. Typically, the composition is compressed using a tablet press. Different amounts of the composition can be compressed to prepare tablets of different weights. In a preferred embodiment, each tablet is compressed from 50 to 500mg of the composition. More preferably, tablets are prepared weighing about 100mg or about 250 mg.

The pressure used to compress the composition of the present invention can be varied to vary the hardness and disintegration time of the resulting tablet. The use of higher compression forces can result in a harder tablet with a longer disintegration time. For dispersible tablets, it is important that the disintegration time is sufficiently short so that the tablet can be conveniently dispersed in an aqueous solution before consumption. Therefore, a suitable compression force must be selected to achieve the desired disintegration time.

However, it is also important that the tablets have sufficient mechanical strength. The composition has the advantages that: for a given compression force, the tablets produced disintegrate more rapidly in aqueous solution than the tablets of the prior art. Even so, the tablet of the present invention can maintain sufficient hardness. Using the prior art formulation techniques, very low compression forces are required in order to obtain dispersible tablets with sufficiently short disintegration times. This leads to insufficient hardness and mechanical properties of the tablet.

It is also important to take the tablet weight into account when selecting the compression force. For smaller tablets, lower levels of hardness are required, and lower compression forces are generally used. The skilled person can select a suitable compression force in order to obtain the desired disintegration time for a tablet of a particular size.

In one aspect, the dispersible tablets of the invention have a high porosity, which is manifested by a rapid disintegration in aqueous solutions such as water. Rapid dispersion can be observed in standard examinations. Preferably, the disintegration time is determined according to the standard test of dispersible tablets as described in the european pharmacopoeia 4.1, page 2435 (2002) in combination with the european pharmacopoeia 4, page 191, 2.9.1 (2002). This examination examined the disintegration time of the tablets in water at 15 to 25 ℃.

The dispersion can be observed visually. The achievement of disintegration can be judged as follows: disintegration is considered to have been achieved when no residue remains on the screen, or if there is a residue consisting of a soft mass without a palpable unwetted hard core, or only coating fragments (tablets), or only shell fragments (capsules) remain on the screen.

The disintegration time of the tablet of the present invention is preferably 3 minutes or less, when measured according to the above examination method. More preferably the disintegration time is 2 minutes or less, still more preferably the disintegration time is 90 seconds or less, and most preferably the disintegration time is 30 to 65 seconds.

The hardness or crushing strength of the tablets of the invention can be determined by standard tests. The hardness of the tablets is preferably determined according to the standard test defined in the european pharmacopoeia 4, page 201, 2.9.8 (2002). Usable devices such as3S tablet detector. This test measures the crushing strength of a tablet as measured by the force required to break the tablet by compression.

The hardness of the tablets of the invention varies with the weight and diameter of the tablet and the compression force. For tablets of 200 to 300mg, for example 250mg, with a diameter of about 9mm, the hardness is preferably 35 to 80N. To achieve this hardness, a pressing force of 8 to 11KN is preferably applied. For tablets of 50 to 150mg, for example 100mg, with a diameter of about 7mm, the hardness is preferably from 25 to 60N and can be achieved by applying a compression force of 7 to 9 KN. For other sheet weights and diameters, the preferred hardness may vary.

Thus, the advantageous properties of the present composition can be demonstrated by the hardness and disintegration time of tablets prepared from the composition. Thus, in a preferred embodiment, the present invention relates to a pharmaceutical composition as defined above, wherein 250mg of the composition, when compressed with a 9mm die and standard flat punch at a compression force of 8 to 11KN, forms a tablet having a hardness of 35 to 80N. Preferably, a tablet press such asPT 2080 rotary tablet press compressed the composition. By the standard methods mentioned above, e.g. usingThe 3S tablet tester measures hardness. More preferred are pharmaceutical compositions: 250mg of the composition when compressed with a 9mm die and standard flat punch at a compression force of 9.5KN form tablets having a hardness of 40 to 66N. The disintegration time of a tablet formed from the composition in this way is preferably 3 minutes or less, more preferably 90 seconds or less, as determined by the test method specified above.

In an alternative embodiment, the present invention relates to a pharmaceutical composition as defined above, wherein 100mg of the composition when compressed with a 7mm die and standard punch at a compression force of 7 to 9KN results in a tablet having a hardness of 25 to 60N. More preferred are pharmaceutical compositions: 100mg of the composition when compressed with a 7mm die and standard punch at a compression force of 8.3KN, form tablets having a hardness of 29 to 53N. The disintegration time of a tablet formed from the composition in this way is preferably the disintegration time given in the preceding paragraph.

The above statements of the invention define pharmaceutical compositions in terms of the properties of the particular tablets that may be made from such compositions. It is clear, however, that the invention is in no way restricted to tablets having such a weight, diameter or hardness, or to manufacturing processes involving the use of such a compression force. As discussed above, these values may vary for different types of tablets. The above definitions are given to clarify the present inventionPharmaceutical combination Article (A)By advantageous intrinsic properties it is meant that they provide a rapid disintegration time when formulated into tablets and at the same time have a good hardness.

The shape of the tablets obtained by the above-described compression method may vary and may be, for example, circular, oval, oblong, cylindrical, flat or curved or any other suitable shape, the size of which may also vary depending on the concentration of the therapeutic agent.

In a preferred embodiment of the invention, the tablets obtained by the above-described compression process are round and flat. The edges of the tablet may be bevelled or rounded.

The compositions of the invention may be administered to a patient, such as a child, in the form of a rapidly disintegrating composition, for example a dispersible tablet, which may be co-administered with a liquid, for example an aqueous medium such as water. Upon addition of a liquid to a formulation, e.g. a unit dosage form or dose, e.g. a tablet, e.g. in a spoon, the composition disintegrates rapidly to form a dispersion, e.g. in less than 3 minutes, preferably in less than 90 seconds, more preferably in 30 to 65 seconds, allowing convenient administration. When administered to children, sweeteners or other additives may be added to the aqueous medium in which the tablets are dispersed to mask any off-tastes and make the dispersion more palatable.

If desired, the compositions of the invention in the form of rapidly disintegrating compositions are preferably formulated in unit dosage form, for example in the form of dispersible tablets, capsules, granules or powders, preferably in the form of dispersible tablets. Where the composition is in unit dosage form, each unit dosage form comprising rapamycin or a derivative thereof may suitably comprise from 0.05mg to 10mg of the drug substance, more preferably from 0.1 to 5 mg; for example 0.1 or 0.25 mg. Such tablets are suitable for administration 1 to 5 times per day, depending on the particular therapeutic purpose, treatment stage, etc.

When the composition of the invention is in a unit dosage form comprising an ascomycin, for example a dispersible tablet, each unit dosage form may suitably comprise from 1mg to 50mg of the drug substance, more preferably from 10 to 25 mg; for example 10, 15, 20 or 25 mg. Such tablets are suitably administered from 1 to 5 times per day, depending on the particular therapeutic purpose, therapeutic stage, etc.

The compositions of the invention may exhibit good stability characteristics as shown in standard stability tests, for example having a shelf life stability of up to one, two or three years and even longer.

The microparticles or granules obtained by any of the methods a to E described above may be coated, for example, with an enteric coating. Suitable coatings may comprise cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate; polymethacrylic acid polymers, e.g.L, S, respectively; or hydroxypropyl methylcellulose succinate.

Furthermore, the tablets obtained with the above-described compression method can be colored, marked to give a personalized appearance and made immediately recognizable. The use of dyes can be used to improve appearance as well as to identify the composition. Dyes suitable for use in pharmacy typically include carotenoids, iron oxides and chlorophyll. Preferably, the tablets of the invention are marked with a code.

Methods that can be used are known in the art, for example, l.lachman et al, "theory and practice of industrial pharmacy", 3 rd edition, 1986; sucker et al, Pharmazeutische technology, Thieme, 1991; hagers Handbuck der pharmazeutischen Praxis, 4 th edition (Springer Verlag, 1971) and "Remington's pharmaceutical sciences", 13 th edition (Mack publishing Co., 1970) or subsequent editions.

The pharmaceutical compositions of the invention are useful for the same indications as macrolides, such as rapamycin or ascomycin. Pharmaceutical compositions of the invention comprising rapamycin or a rapamycin derivative are particularly useful for:

a) treating or preventing allograft or xenograft rejection of cells, tissues or organs, such as heart, lung, combined heart and lung, liver, kidney, intestine, pancreas, insulin producing cells, skin or corneal transplants. The pharmaceutical composition is also suitable for preventing graft-versus-host disease which sometimes occurs after bone marrow transplantation;

b) treating or preventing autoimmune diseases and inflammatory disorders, particularly inflammatory disorders whose etiology includes an autoimmune component, such as arthritis (e.g., rheumatoid arthritis, chronic progressive arthritis, and osteoarthritis) and rheumatic diseases. Specific autoimmune diseases in which the compounds of the invention may be used include autoimmune haematological disorders (including, for example, haemolytic anaemia, aplastic anaemia, pure red cell anaemia and idiopathic thrombocytopenia), systemic lupus erythematosis, polychondritis, scleroderma (scleroderma), wegener's granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, psoriasis, sjogren's syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (including, for example, ulcerative colitis and local reopathy), endocrine ophthalmology, graves ' disease, sarcoidosis, multiple sclerosis, primary biliary cirrhosis, juvenile diabetes mellitus (type I diabetes mellitus), (pre-and post) uveitis, keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial pulmonary fibrosis, psoriatic arthritis, glomerulonephritis (with and without nephrotic syndrome, including idiopathic nephrotic syndrome or minimal change nephropathy, for example) and juvenile dermatomyositis;

c) treating or preventing asthma;

d) treating or preventing chronic graft rejection or restenosis;

e) treating cancer, hyperproliferative skin diseases, etc.;

f) treating infections, such as fungal infections;

g) treating or preventing inflammation, especially potentiating the effects of steroids.

The pharmaceutical compositions of the invention comprising an ascomycin or an ascomycin derivative are particularly useful for treating skin manifestations such as inflammatory and hyperproliferative skin diseases and immunologically mediated diseases. More particularly, the compositions of the present invention are useful as anti-inflammatory and immunosuppressive and antiproliferative agents for the prevention and treatment of inflammatory conditions and conditions requiring immunosuppression, such as

a) Prevention or treatment of

Organ or tissue transplant rejection, such as heart, kidney, liver, bone marrow and skin,

graft versus host disease, such as graft versus host disease after bone marrow transplantation,

autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, hashimoto's thyroiditis, multiple sclerosis, myasthenia gravis, type I diabetes and uveitis,

-cutaneous manifestations of immunologically mediated diseases;

b) treating inflammatory and hyperproliferative skin diseases, such as psoriasis, atopic dermatitis, contact dermatitis and also eczematous dermatitis, seborrheic dermatitis, lichen planus, pemphigus, bullous pemphigoid, epidermolysis bullosa, urticaria, angioedema, vasculitis, erythema, cutaneous eosinophilia, lupus erythematosus and acne; and

c) alopecia areata.

In a further aspect, the present invention provides the use of a composition as defined above for the preparation of a medicament for use as an immunosuppressant, e.g. in the treatment or prevention of one of the diseases or disorders described above.

Thus, in another aspect, the invention provides a method of treating a subject suffering from a disorder treatable with a macrolide, the method comprising administering to a subject in need of such treatment a therapeutically effective amount of a pharmaceutical composition of the invention.

In another aspect, the invention provides a method of administering a pharmaceutical composition of the invention to a subject in need of such treatment, the method comprising (i) contacting the composition with water, and (ii) ingesting the resulting dispersion.

The dispersible tablets of the invention may be dispersed in e.g. 20 to 50ml of water with stirring before ingestion.

The exact amount of the composition to be administered depends on several factors, such as the desired duration of treatment and the rate of release of the macrolide.

When administered orally, the compositions of the invention exhibit particularly advantageous properties, for example in terms of consistency and parallelism of bioavailability obtained in standard bioavailability tests. These tests are carried out in animals, such as rats or dogs, or healthy volunteers.

Pharmacokinetic parameters such as absorption and blood levels (blood levels) also surprisingly become more predictable, and the problem of irregular absorption during administration can be eliminated or reduced. In addition, the composition is also effective with surface active substances such as bile salts present in the gastrointestinal tract. The utility of the pharmaceutical composition can be observed in standard clinical trials in known indications such as doses of active agent that can produce blood levels of the same active agent; for example, a dose of 0.01mg to 5mg per day of rapamycin or a derivative thereof per kg body weight, for example 0.5 to 5mg per day per kg body weight, is used in mammals, for example in children (e.g. below 12 and for example at least 3 years) or elderly, and in standard animal models; or a dose of 1mg to 1000mg, such as 2.5 to 1000mg, preferably 10 to 250mg, per day of ascomycin, for example for a 75kg adult human and in standard animal models. The increased bioavailability of the drug substance provided by the present compositions is observed in standard animal tests and clinical trials.

Detailed Description

The pharmaceutical compositions of the present invention are described below by way of example only.

Example 1

Preparation of solid dispersions

A 2% Solid Dispersion (SD) composition was prepared comprising the following ingredients:

weight (g) Weight (%)

40-O- (2-hydroxyethyl) -rapamycin 0.042.0

Butylated hydroxytoluene 0.0040.2

HPMC 3cps 1.6 80.0

Lactose monohydrate (200 mesh) 0.35617.8

Total 2.0100

The composition was prepared by the following steps: (i) mixing 40-O- (2-hydroxyethyl) -rapamycin and butylated hydroxytoluene, (ii) dissolving the mixture obtained in (i) in an ethanol/acetone mixture, (iii) adding HPMC and lactose, (iv) homogeneously dispersing the mixture obtained in step (iii), and (v) removing the solvent by evaporation. The resulting residue was dried, sieved and pulverized. Preparation of pharmaceutical compositions

A pharmaceutical composition (comprising the above solid dispersion) was prepared comprising the following ingredients (in parts by weight):

40-O- (2-hydroxyethyl) -rapamycin SD 2% 5

20

3

Magnesium stearate 0.5

Anhydrous lactose 71.5

Total 100

The composition was prepared by the following steps: (i) mixing the Solid Dispersion (SD), lactose,Andmixing, (ii) sieving (0.8mm) and mixing, (iii) adding the sieved (0.8mm) magnesium stearate and mixing.

Preparation of dispersible tablet

(iv) obtaining dispersible tablets by tabletting the mixture obtained in step (iii). Using a 9mm die and a standard flat punch with a pressing force of 10.5KNPT 2080 on a rotary tablet press to compress 250mg of the pharmaceutical composition. The hardness of the resulting tablets was then estimated by measuring the force required to crush the tablets using a Kraemer 3S tablet tester. The hardness of the tablets prepared under these conditions is from 35 to 79N. The disintegration time of the tablet was 0.4 to 1.4 minutes (24 to 84 seconds).

Example 2

Pharmaceutical compositions were prepared as described above. Using a 7mm die and a standard flat punch with a press force of 7.5KN100mg of the pharmaceutical formulation was compressed on a PT 2080 rotary tablet press to prepare dispersible tablets. The hardness of the tablets prepared under these conditions is from 25 to 79N. The disintegration time of the tablet was 1.1 to 1.7 minutes (66 to 102 seconds).

The above examples illustrate compositions and tablets useful, for example, for preventing transplant rejection or for treating autoimmune diseases when administered at a dose of 0.01 to 5mg/kg body weight per day for 1 to 5 unit doses per day.

The examples are illustrated with particular reference to 40-O- (2-hydroxyethyl) -rapamycin. However, in a further example, the procedure described in examples 1 and 2 was repeated except that the 40-O- (2-hydroxyethyl) -rapamycin was replaced with an alternative macrolide. An alternative macrolide may be any of the rapamycin derivatives or ascomycin derivatives described above, for example FK-506 or 33-epi-chloro-33-deoxo-ascomycin. Tablets containing these alternative macrolides have similar hardness and disintegration time to the tablets containing 40-O- (2-hydroxyethyl) -rapamycin given above and may also be used as immunosuppressive agents.

Claims (10)

1. A pharmaceutical composition comprising a macrolide solid dispersion, a disintegrant and colloidal silicon dioxide, wherein the composition comprises 1% to 5% by weight of colloidal silicon dioxide.

2. The pharmaceutical composition of claim 1, wherein 250mg of the composition, when compressed with a 9mm die and standard flat punch at a compression force of 8 to 11KN, forms a tablet having a hardness of 35 to 80N and a disintegration time of 3 minutes or less.

3. The composition of claim 1 or claim 2, wherein the composition is in the form of a dispersible tablet.

4. The composition of claim 3, wherein the tablet has a disintegration time of 90 seconds or less.

5. A composition according to any preceding claim, wherein the macrolide is rapamycin, an ascomycin or a derivative thereof.

6. A composition according to any preceding claim, wherein the rapamycin derivative is 40-O- (2-hydroxy) ethyl-rapamycin.

7. Use of a composition according to any preceding claim in the manufacture of a medicament for use as an immunosuppressant.

8. A method of administering a pharmaceutical composition according to any of the preceding claims to a subject in need of such treatment, the method comprising (i) contacting the composition with an aqueous solution, (ii) dispersing the composition in the aqueous solution to form a dispersed mixture, and (iii) ingesting the dispersed mixture.

9. Use of colloidal silicon dioxide as an auxiliary disintegrant, wherein colloidal silicon dioxide is comprised in a pharmaceutical composition further comprising a macrolide solid dispersion and a disintegrant, and colloidal silicon dioxide is used to increase the disintegration rate of the pharmaceutical composition in an aqueous solution.

10. A method of preparing a dispersible tablet containing a macrolide, the method comprising preparing a macrolide solid dispersion, mixing the macrolide solid dispersion with a disintegrant and colloidal silicon dioxide to form a pharmaceutical composition and compressing the pharmaceutical composition to form the dispersible tablet.