BRPI0614757A2 - pharmaceutical composition, microparticle and its use - Google Patents

Abstract

PHARMACEUTICAL COMPOSITION, MICROPARTICULA AND THEIR USE The present invention relates to microparticulate compositions, wherein the active agent is a topoisomerase 1 inhibitor, in particular 7-t-butoxyiminomethylcamptOteCine, which is useful for the treatment and prevention of proliferative diseases. including cancer.

Description

Patent Descriptive Report for "PHARMACEUTICAL COMPOSITION, MICROParticles and their use".

The present invention relates to microparticle compositions wherein the active agent is a topoisomerase I inhibitor and pharmaceutical compositions comprising microparticle compositions useful for the treatment and prevention of proliferative diseases, including cancer.

Background of the Invention

Camptothecin derivatives comprise a decomposed class described in US Patent 6,242,457. Campto-tecine derivatives, such as those described in US Patent 6,242,457, present highly specific difficulties with administration in general and galenic compositions in particular, including particular drug bioavailability problems, as these derivatives have poor solubility. tity.

Summary of the Invention

In accordance with the present invention, it has now surprisingly been found that stable 7-t-butoxyiminomethylcamptothecin microparticle pharmaceutical compositions have particularly interesting bioavailability characteristics. Such novel compositions have been found to substantially satisfy or reduce previously encountered difficulties, i.e. poor bioavailability observed in dry crystalline camptothecin formulations and limited drug loading observed with microemulsion preconcentrate formulations. Thus, the invention may provide effective therapy with tolerable dosage levels of 7-t-butoxyiminomethylcamptothecin, and may allow standardization and optimization closer to the daily dosage requirements for each individual.

Consequently, the occurrence of undesirable potential side effects is decreased and the overall cost of therapy may be reduced.

Detailed Description of the Drawings

Figure 1 illustrates in vitro dissolution rate profiles.

Figure 2 illustrates dog bioavailability in vivo. Figure 3 illustrates dog bioavailability in vivo.

Figure 4 illustrates in vitro dissolution rate profiles.

Detailed Description of the Invention

The present invention relates to microparticle compositions comprising a topoisomerase II inhibitor in particular 7-t-butoxyiminomethylcamptothecin as the active agent in a carrier. The present invention also relates to microparticle compositions comprising a topoisomerase I inhibitor, in particular 7-t-butoxyiminomethylcamptothecin, as the active agent, and optionally as a surface stabilizer in a vehicle. The vehicle is selected from an oily vehicle, a hydrophilic non-aqueous vehicle or a self-microemulsifying vehicle. In one embodiment, the self-microemulsifying carrier further comprises excipients. The microparticle compositions may further comprise a sedimentation inhibitor and further comprise excipients.

The present invention also relates to pharmaceutical compositions comprising the microparticle compositions of the invention and a pharmaceutically acceptable carrier, as well as any desired excipients.

Unit dose forms of the present invention are, for example, capsules, coated and uncoated tablets, ampoules, vials or bottles. Examples are capsules containing from about 0.1 g to about 5 mg of 7-t-butoxyiminomethylcamptothecin.

The present invention provides a method of treating a patient suffering from a 7-t-butoxyiminomethylcamptothecin treatable disorder comprising administering a therapeutically effective amount of a pharmaceutical composition of the invention to a patient in need of treatment.

The terms "effective amount" or "pharmaceutically effective amount" of a microparticle formulation as provided herein refer to the non-toxic but sufficient amount of the microparticle formulation to provide the desired response and the corresponding therapeutic effect. sufficient amount to treat the patient as defined below. As will be shown below, the exact amount required may vary from patient to patient, depending on the patient's species, age and general condition, the severity of the condition being treated, the mode of administration. An "effective" amount appropriated in any individual case can be determined by one with ordinary knowledge of the art using routine experimentation.

The phrase "pharmaceutically acceptable" or "pharmacologically acceptable" means a material that is not biologically or otherwise undesirable, ie the material may be administered to an individual in conjunction with the microparticle formulation without causing any undesirable biological effects or interacting with one another. detrimentally to any of the components of the composition in which it is contained.

I. Active Agent

"Active agent" as used herein means 7-t-butoxyiminomethylcamptothecin, which has the following structure known as Compound A:

<formula> formula see original document page 4 </formula>

The preferred active agent may be in a free or pharmaceutically acceptable salt form as possible enantiomers, di-astereoisomers and relative mixtures, polymorphs, amorphous, partially amorphous forms, solvates, their active metabolites and prodrugs.

According to the present invention, the active agent may be present in an amount by weight of from about 0.1% to about 30% by weight of the composition of the invention. The active agent is preferably in an amount from about 1 to 10%, but preferably in an amount from about 1% to about 5% by weight of the composition.

The term "microparticle" as used herein refers to an ingredient particle up to about 15 microns in diameter, more preferably from about 0.5 microns to about 5 microns in diameter, more preferably. noticeably from about 1 micron to about 3 microns in diameter. The size of the microparticle is readily determined by techniques well known in the art, laser diffraction and / or electron microscopy.

The term "microsuspension" as used herein refers to microparticle compositions comprising a topoisomerase I inhibitor, in particular 7-t-butoxyiminomethylcamptothecin, as the active agent, and optionally at least one stabilizer surface in a vehicle. The microparticle compositions may further comprise a dewatering inhibitor and additionally excipients.

II. Surface stabilizer

The surface stabilizer enhances the physical stability of the suspension and improves the dispersibility of suspensions in contact with aqueous, eg gastrointestinal, fluids. The surface stabilizer also assists in inhibiting the crystal growth of the active agent in the micro suspension.

Preferred surface stabilizers of the present invention include, but are not limited to, cellulose derivatives, polyvinylpyrrolidone, vinyl pyrrolidone and vinyl acetate random copolymers, sodium lauryl sulfate, dioctylsulfosuccinate, colloidal or precipitated silicas (e.g. Degussa Aerosil® or Huber Zeopharm®), polaxamers (e.g. Pluronics F68® and F108®, which are ethylene oxide and propylene oxide block copolymers); or a combination thereof. Non-limiting examples of cellulose derivatives include, but are not limited to, hydroxypropyl methylcellulose, hydroxypropylcellulose.

Other surface stabilizers which may be employed in the invention include, but are not limited to, known organic and inorganic pharmaceutical excipients. Such excipients include various polymers, low molecular weight oligomers, natural products and surfactants. Surface stabilizers also include nonionic, cationic, ionic and zwitterionic surfactants.

Additional examples of surface stabilizers include gelatin, casein, Iecithin (phosphatides), dextran, gum arabic, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glycerol monostearate, ketoestogryl emulsifying wax sorbitan esters, polyoxyethylene alkyl ethers (e.g. macrogol ethers such as ketomacrogol 1000), polyoxyethylene mammary oil derivatives, polyoxyethylene sorbitan fatty acid esters (e.g. Tween® commercially available such as, Twe-en 20® and Tween 80® (ICI Specialty Chemicals), polyethylene glycols (e.g. Carbowax 3550® and Carbowax 934® (Union Carbide)), poly (deoxyethylene stearates), phosphates, calcium carboxymethylcellulose, sodium carboxymethylcellulose, methylcellulose, hydroxyethylcellulose, hydroxypropyl methylcellulose phthalate, non-crystalline cellulose, aluminum magnesium silicate, triethanolamine, po-li (vinyl alcohol) (PVA), 4- (1,1,3,3-tetramethylbutyl) phenol polymer with ethylene oxide and formaldehyde (also known as tiloxapol, superione etriton, poloxamines (e.g. Tetronic 908®, also known as Poloxamine 908®, which is a tetrafunctional block copolymer derived from the sequential addition of propylene oxide and ethylene oxide to ethylene diamine (BASF Wyandotte Corporation, Parsippany, NJ)); Tetronic 1508® (T-508) (BASF Wyandotte Corporation), Tritons X-200® which is an alkyl aryl polyether sulfonate (Rohm and Haas): Crodestas F-100® which is a mixture of sucrose stearate and distearate of sucrose (Croda Inc.); p-isononylphenoxypoly- (glycidol), also known as Olin-IOG® or 10-G® Surfactant (OlinChemicals, Stamford, CT); Crodestas SL-40® (Croda, Inc.); and SA90HCO, which is C18 H37 CH2 (CON (CH3) -CH2 (CHOH) 4 (CH2OH) 2 (Eastman Kodak Co.); n-decanoyl-N-methylglucamide; n-decyl &-g-D-glycopyranoside; n-decyl &bgr;-D-maltopyranoside; n-dodecyl &bgr;-D-glycopyranoside; n-dodecyl &bgr;-D-maltoside;hepatnoyl-N-methylglucamide; n-hetpil &bgr;-D-glycopyranoside;thioglycoside; n-hexyl? -D-glycopyranoside; nonanoyl-N-methylglucamide; n-noyl? b-D-glycopyranoside; n-oethaneyl-N-methylglucamide; n-octyl-pD-glycopyranoside; PEG-phospholipid, PEG-cholesterol, PEG-cholesterol-derived, PEG-vitamin A, PEG-vitaminE, lysozyme, similane, random vinyl pyrrolidone and vinyl acetate copolymers.

Examples of cationic surface stabilizers are described by Cross and Singer1 Cationic Surfactants: Analytical and Biological Evaluate, Mareei Dekker (1994); Rubingh, Editor, Cationie Surfactants: Physieal Chemistry, Mareei Dekker (1991); and Richmond, Cationie Surfactants: Organic Chemistry, Mareei Dekker (1990).

Most of these surface stabilizers comprise known pharmaceutical containers and are described in detail in the Handbook of Pharmaceutical Excipients, published in association by the American Pharmaceutical Association and The Pharmaceutical Society of Great Britain (The Pharmaceutical Press (2000)), specifically incorporated by title. reference. Surface stabilizers are commercially available and / or may be prepared by techniques known in the art.

In accordance with the present invention, the surface stabilizer is present in an amount by weight of from about 0.1% to about 30% by weight of the composition of the invention. The surface stabilizer is preferably present in an amount of from about 1% to about 15% by weight of the composition.

III. Vehicle

The vehicles of the present invention may be an oily vehicle: hydrophilic non-aqueous vehicle; or self-microemulsifying vehicle.

In accordance with the present invention, the carrier is present in an amount by weight of from about 70% to about 99% by weight of the composition of the invention. The carrier is preferably present in an amount of from about 80% to about 98% by weight of the composition, more preferably in an amount of about 90-98% .A. Oily Vehicles

The oily vehicles of the present invention include alone or in combination corn oil, sesame oil, olive oil, paraffin oil, soybean oil, cottonseed oil, long-, medium- and long-chain mono-, di-, triglycerides. short chain and other suitable lipophilic components. Suitable lipophilic components include:

1) C6 -C14 mono-glyceryl fatty acid esters

These are obtained by esterification of glycerol with vegetable oil followed by molecular distillation. Suitable monoglycerides for use in the compositions of the invention include both symmetrical (i.e. β-monoglycerides) and asymmetric (α-monoglycerides) monoglycerides. They also include both uniform glycerides (in which the fatty acid constituent is composed primarily of a single fatty acid) and mixed glycerides (ie, in which the fatty acid constituent is composed of several fatty acids). The fatty acid constituent may include both saturated and unsaturated fatty acids having a chain length of, for example, C8 -C14. Particularly suitable are lauric acid and caprylic acid monoglycerides, which are commercially available, for example, under the tradename Imwitor® 308 or Imwitor® 312, respectively, of for example sasol. For example, Imwitor® 308 comprises at least 80% demonoglycerides and displays the following additional characterizing data: maximum 6% free glycerol, maximum 3 acidity index, deconification index 245-265, maximum 1 iodine index , maximum 1% water detector. It typically comprises 1% free glycerol, 90% monoglycerides, 7% diglycerides, 1% triglycerides (H. Fiedler, loc. Cit, Vol.1, p. 798). Another example is Capmul MCM C8 from Abitec Corporation.

2) C6 -C18 fatty acid mixtures of mono- and diglycerides

These include both symmetric (ie β-monoglycerides and α, α1-diglycerides) and asymmetric (ie β-monoglycerides and α, β-diglycerides) and acetylated derivatives thereof. They also include both uniform glycerides ( wherein the fatty acid constituent is composed primarily of a single fatty acid) mixed glycerides (i.e. wherein the fatty acid constituent is comprised of various fatty acids) and any derivatives thereof with lactic or citric acid. The fatty acid constituent may include both saturated and unsaturated fatty acids having a chain length of, for example, C8 -C10. Particularly they are mixed caprylic and capric acid mono- and diglycerides as commercially available, for example under the tradename Imwitor® 742 or Imwitor 928 of, for example, sasol.

For example, Imwitor® 742 comprises at least 45% monoglycerides and exhibits the following additional characterizing data: maximum 2% free glycerol, maximum 2 acid index, saponification index 250-280, maximum 1 iodine index, maximum 2% water (H. Fiedler, loc. cit., Vol 1, p. 798). Other suitable mixtures comprise caprylic acid / caprylic acid glycerol monomer / diglycerides as known and commercially available under, for example, the Capmul®MCM trade name of, for example, Abitec Corporation. Capmul® MCM displays the following additional characterizing data: maximum 2.5 acidity index, minimum 80% α-mono (as oleate), maximum 2.5% free glycerol, maximum 1 index iodine, chain length distribution: maximum 3% capric acid (C6), minimum 75% caprylic acid (C8), minimum 10% capric acid (C10), maximum 1.5% lauric acid (C12), maximum 0,5% humidity (by Karl Fisher) (manufacturer information). Suitable examples of mono- / diglycerides with additional derivatization with lactic or citric acid are those sold under the tradename Imwitor 375, 377 or 380 by sasol. In addition, the fatty acid constituent may include both saturated and unsaturated fatty acids having a chain length of, for example, C 16 -C 18 A suitable example is Tegin® O (glycerol oleate) exhibiting the Additional Characteristics: 55-65% monoglyceride content, maximum 10 peroxide content, maximum 1% water content, maximum 2 acid content, iodine index 70-76, saponification index 158 -175.2% deglycerol free, (manufacturer information).

3) Di-C6 -C18 esters of glyceryl fatty acids These include symmetrical (ie α, α-diglyceride) and asymmetric (ie α, β-diglyceride) diglycerides and acetylated derivatives thereof. They also include both uniform glycerides ( in which the fatty acid constituent is composed primarily of a single acid) and the mixed glycerides (i.e. in which the fatty acid constituent is composed of various fatty acids) and any acetylated derivatives thereof. The fatty acid constituent may include both saturated and unsaturated fatty acids having a chain length of C6 -C18, e.g. C6 -C16, e.g. C8 -C10, e.g. C8. Particularly suitable are caprylic glycerides which are commercially available, for example under the tradename Sunfat® GDC-S, for example from Taiyo Kagaku Co., Ltd. Sunfat® GDC-S has an acidity index of about 0.3, a glyceride content of about 78.8%, and a monoester content of about 8.9.

4) Medium chain fatty acid triglyceride

These include saturated fatty acid triglycerides having from 6-12, for example, 8-10 carbon atoms. Suitable medium chain fatty acid triglycerides are those known and commercially available under the trade names Acomed®, Myritol®, Captex®, Neobee® M5 F, Miglyol® 810, Miglyol® 812, Miglyol®818, Mazol®, Sefsol® 860, Sefsol®870; Miglyol® 812 being most preferred. Miglyol® 812 is a co-fractionated oil comprising caprylic-capric acid triglycerides and having a molecular weight of about 520 Daltons. Fatty acid composition = maximum about 3% C6, about 50-65% C8, about 30-45% C10, maximum 5% C12; acidity index of about 0.1. saponification index of about 330-345; maximum 1 iodine index. Migliol®818 is available from Condea. Neobee® M 5 F is a fractionated caprylic-capric acid triglyceride available from coconut oil; maximum acidity index of 0,2; saponification index of about 335-360; iodine index maximum 0.5 m, maximum 0.15% water content, D.20 0.930-0.960, nD20, 1.448-1.451 (manufacturer information). Neobee® M 5 F is available from Stepan Europe. Another example is Miglyol 829 containing additional esters with succinic acid. 5) Neo-C ie-C 18 "glyceryl fatty acid esters

These are obtained by esterification of glycerol with vegetable oil followed by molecular distillation. Suitable monoglycerides for use in the compositions of the invention include both symmetrical monoglycerides (ie β-monoglycerides) and asymmetric monoglycerides (α-monoglycerides). They also include both uniform glycerides (in which the fatty acid constituent is composed primarily of a single fatty acid) and mixed glycerides (ie in which the fatty acid constituent is composed of various fatty acids). The acid-fatty constituent may include both saturated and unsaturated fatty acids having a chain length of, for example, C 16 -C 18. Suitable examples include Eastman GMOrphic, distilled monoglycerides Rylo MG20 from Danisco Ingredients, or Monomuls 90-018 from Henkel. For example, GMOr-phic®-80 (glyceryl monooleate) displays the following additional characterizing data: minimum 94% monoglyceride content, C18: 1 minimum 75% content, maximum 2.5 peroxide index, C18: 2 + C 18: 3 15% maximum, C 16: 0 + C 18: 0 + C 20: 0 10% maximum, 3 water index maximum, 65-75 iodine index, 155-165 saponification index, 1 maximum % free deglycerin, hydroxyl number 300-330 (manufacturer information).

6) Mixed mono-, di, triglycerides

These include mono-, di-, triglycerides which are commercially available under the Gattefossé Maisine® trade name. They are transesterification products of corn oil and glycerol. Such products are predominantly comprised of mono-, di- and triglycerides of oleyolinic and oleic acid together with small amounts of mono-, di- and tri-glycerides of palmitic and stearic acid (the million oil itself comprised of about 56% by weight). weight of linoleic acid, 30% oleic acid, about 10% palmitic acid and about 3% stearic acid). Physical characteristics are: maximum 10% free glycerol, about 40% monoglycerides, about 40% diglycerides, about 10% triglycerides, and about 1% free oleic acid content. Also, the physical characteristics are: maximum of 2 acidity index, 85 to 105 iodine index, 150 to 175 saponification index, mineral acid content = 0. The fatty acid content for Maisine® is typically: about 11% palmitic acid, about 2.5% stearic acid, about 29% oleic acid, about 56% linoleic acid and about 15% others. (H. Fiedler, loc.cit., Vol.2, p. 958; manufacturer information).

Mixed mono-, di- and triglycerides preferably comprise mixtures of C8 -C10- or C12 -C20 fatty acid mono-, di- and triglycerides, especially C16 -C18 fatty acid mono-, di- and triglycerides. The fatty acid component of the mixed mono-, di- and triglycerides can comprise both saturated and unsaturated fatty acid residues. Preferably, however, they are predominantly comprised of unsaturated fatty acid residues, in particular unsaturated C18 fatty acid residues. Suitably the mixed mono-, di-, triglycerides comprise at least 60%, preferably at least 75%, more preferably at least 85% by weight of C1-8 unsaturated fatty acid mono-, di- and triglycerides (e.g. linolenic, linoleic and oleic acid). Suitably, the mixed mono-, di-, triglycerides comprise less than 20%, for example about 15% or 10% by weight or less of saturated fatty acid mono-, di- and triglycerides (e.g. palmitic and stearic acid). Mixed mono-, di-, triglycerides are preferably predominantly comprised of mono- and diglycerides; for example, mono- and diglycerides comprise at least 50%, more preferably at least 70%, based on the total weight of the lipophilic phase or component. More preferably, the mono- and diglycerides comprise at least 75% (for example, about 80% or 85% by weight of the lipophilic component. Preferably, the monoglycerides comprise from about 25% to about 50%, based on total weight). preferably from about 30% to about 40% (e.g. 35-40%) of monoglycerides are present Preferably, the diglycerides comprise from about 30% 60%, based on the total weight of the lipophilic component of the mixed mono-, di-, triglycerides More preferably from about 40% to about 55% (e.g. 48-50%) is present. Suitably the triglycerides comprise at least 5%, but less than about 25%, based on the total weight of the lipophilic component of the mixed mono-, di-, triglycerides More preferably about 7.5% About 15% (e.g., about 9-12%) triglycerides are present. Riglycerides may be prepared by mixing individual mono-, di- or triglycerides in appropriate relative proportions. However, they conveniently comprise transesterification products of vegetable oils, for example almond oil, peanut oil, olive oil, peach oil, palm oil; or preferably, corn oil, sunflower oil or turmeric oil; and, more preferably, corn oil with glycerol. Such transesterification products are generally obtained as described in GB 2 257 359 or WO 94/09211. Preferably, some of the glycerol is initially removed to give a "substantially glycerol free shell" when preparing soft gelatin capsules. Pure transesterification products of corn oil and glycerol provide particularly suitable mixed mono-, di- and triglycerides, hereinafter referred to as "refined oil" and produced according to the procedures described in Patent Specification GB 2,257. 359 or International Application Publication WO 94/09211.

7) Acetylated (C 18) monoglycerides

These include Myvacet 9-45.

8) Propylene glycol monograx acid esters

The fatty acid constituent may include both saturated and unsaturated fatty acids having a chain length and, for example, C8 -C12. Particularly suitable are caprylic and lauric acid propylene glycol monoester as commercially available, for example under the tradename Sefsol®, Capryol® 90 or Lauroglycol® 90, for example Nikko Chemicals Co., Ltd. or Gattefossé or Capmul PG -8 fromAbitec Corporation. For example, Lauroglycol® 90 displays the following additional characterizing data: maximum 8 acidity index, 200-220 saponification index, maximum 5 iodine index, maximum 5% free propylene glycol detector, minimum 90% of monoester content; Sefsol®218 exhibits the following additional characterizing data: maximum 5 acidity index, hydroxyl number 220-280 (H. Fiedler1 loc. Cit., Vol.2, p. 906, manufacturer information).

9) Propylene glycol mono- and diglycolic acid esters

These include Lauroglycol FCC and Capryol PGMC.

10) Propylene glycol diesters

Propylene glycol fatty acid esters such as propylene glycol dicaprylate (which is commercially available under the trade name Miglyol® 840 from, for example, sasol; H. Fiedler, loc. Cit., Vol. 2, p. 1008) or Captex 200 da Abitec Corporation.

11) Propylene glycol monoacetate and propylene glycol diacetate

12) Transesterified ethoxylated vegetable oils

These include transesterified ethoxylated vegetable oils, such as those obtained by reaction of various natural oils (eg corn oil, maize oil, castor oil, cereal grain oil, almond oil, peanut oil, olive oil, soybean oil, sunflower oil, turmeric oil and palm oil or mixtures thereof) with polyethylene glycols having an average molecular weight of 200 to 800 in the presence of an appropriate catalyst. These procedures are described in US Patent 3,288,824. Transesterified ethoxylated corn oil is particularly preferred.

Transesterified ethoxylated vegetable oils are known and are commercially available under the tradename Labrafil® (H. Fie-dler, loc. Cit., Vol. 2, p. 880). Examples are Labrafil® M 2125 CS (obtained from corn oil and having an acidity index of less than about 2, a saponification index of 155-175, a BHL value of 3-4, and a diode index of 90-110 ) and Labrafil® M 1944 CS (obtained from cereal grain oil having an acidity index of about 2, a saponification index of 145-175 and an iodine index of 60-90). Labrafil® M 2130 CS (which is a transesterification product of a C12-C18 glyceride and propylene glycol which has a melting point (mp) of about 35-40 ° C, an acidity index of about 2 , a saponification index of 185-200 and an iodine index of less than about 3) may also be used. The transesterified ethoxylated vegetable oil is Labrafil® M 2125 CS, which can be obtained, for example, from Gattefossé, Saint-Priest Cedex, France.

13) Fatty acid sorbitan esters

Such esters include, for example, acid-acid sorbitan esters, for example mono-C12-C18-fatty acid sorbitan esters, or tri-C1-C18-fatty acid sorbitan esters are commercially available under the tradename Span® of, for example, Uniqema. A particularly preferred product of this class of this class is, for example, Span® 20 (sorbitan mono-laurate) or Span® 80 (sorbitan monooleate) (Fiedler, loc.cit., Vol.2, p. 1430). ; Handbook of Pharmaceutical Excipients, loc. cit., p. 473).

14) Esterified fatty acid and primary alcohol compounds

These include esterified fatty acid compounds having from 8 to 20 carbon atoms and primary alcohol having from 2 to 3 carbon atoms, for example, isopropyl myristate, isopropyl palmitate, ethyl oleate, ethyl oleate, ethyl myristate, etc., with an esterified compound of linoleic acid and ethanol being particularly preferred, also isopropyl myristate and isopropyl palmitate.

15) Glycerol triacetate or (1,2,3) triacetin

This is obtained by esterification of glycerin with acetic anhydride.

Glycerol triacetate is commercially available as, for example, Priacetin® 1580 from Uniqema International, or as Eastman® Eastman® Triacetin, or fromCourtaulds Chemicals Ltd. Glycerol triacetate exhibits the following additional characteristics: molecular weight 218.03, D.20.3 1.159-1.163, Od20 of 1.430-1.243, maximum 0.2% water content, viscosity (25 °) of 17.4 mPa s, maximum 0.1 acidity index, saponification index. about 766-774, minimum of 97% triacetin content (Fiedler, loc. cit., Vol.2, p. 1580; Handbook of Pharmaceutical Excipients, loc. cit., p.534, manufacturer information).

16) Acetyl triethyl citrate

This is obtained by esterification of citric acid and ethanol, followed by acetylation with acetic anhydride, respectively. Acetyl triaceyl citrate is commercially available, for example, under the trade name Citro-flex® A-2 from, for example, Morflex Inc.

17) Tributyl citrate or Tributyl acetyl citrate

18) Polyglycerol fatty acid esters

These have, for example, 2-10, for example 6 units of glice-rol. Such a fatty acid constituent may include both saturated and unsaturated fatty acids having a chain length of, for example, C8 -C18. Particularly suitable is, for example, Platol Oleique CC497 daGattefossé, having a saponification index of 133-135. and a deconification index of 196-244, respectively. Polyglycerol fatty acid esters further include diglyceryl monooleate (DGMO) and Hexaglin-5-0 as known and commercially available from, for example, NikkoChemicals Co., Ltd.

19) PEG-fatty alcohol ether

This includes 4 Brij 30® polyoxyethylene lauryl ether.

20) Fatty alcohols and fatty acids

Fatty acids can be obtained by hydrolysis of various animal and vegetable fats and oils, such as olive oil, followed by separation of liquid acids. The acid / fatty alcohol constituent may include both saturated and mono- or di-unsaturated fatty acids / alcohols having a chain length of, for example, C6 -C20. Particularly suitable are, for example, oleic acid, oleic alcohol, linoleic acid, caprylic acid, caprylic acid, caproic acid, tetradecanol, dodecanol or decanol. Oleyl alcohol is commercially available under the tradename HD-Eutanol® V da, for example Henkel KGaA. Oleyl alcohol exhibits the following additional characterization data: maximum 0.1 acidity index, hydroxyl number about 210, iodine index about 95, maximum saponification index, D.20 about 0.869 , nD20 of 1.462, molecular weight of 268, viscosity (20 °) of about 35 mPa s (manufacturer information). Oleic acid exhibits the following additional characterizing data: molecular weight 282.47, D.20 0.0895, nD20 1.452323, acidity index 195-202, iodine index 85-95, viscosity ( 25 °) of 26 mPas [Fiedler, loc. cit., Vol.2, ρ. 1112; Handbookof Pharmaceutical Excipients, 2nd Edition, Wade and Weller, Eds. (1994), Publication in association with American Pharmaceutical Associa., Washington, USA and The PharmaceuticalPress, London, England, p. 325]).

21) Tocopherol and its derivatives, eg acetate

These include Coviox T-70, Copherol 1250, Copherol F-1300, Covitol 1360 and Covitol 1100.

22) Pharmaceutically acceptable oils

Alternatively, the lipophilic component comprises, for example, a pharmaceutically acceptable oil, preferably with an unsaturated component, such as a vegetable oil.

23) Alkylene polyol ethers or esters

These include Cs-Cs-alkylene triols, in particular glycerol, ethers or esters. C3 -C5 alkylene triol ethers or esters include mixed ethers or esters, i.e. components including other ether or ester ingredients, for example, products of transesterification of C3 -C5 alkylene triol esters with other mono-, di- or polyols . Particularly suitable mixed alkylene polyol ethers or esters are mixed C3 -C5 alkylene triol / poly (C2 -C4 alkylene) glycol fatty acid esters, especially mixed glycerol / polyethylene or polypropylene glycol fatty acid esters.

Especially suitable alkylene polyol ethers or esters include products obtainable by transesterification of glycerides, for example triglycerides, with poly (C 2 -C 4 alkylene) glycols, for example polyethylene glycols, and optionally glycerol. Such transesterification products are generally obtained by alcoholysis of glycerides, for example triglycerides, in the presence of a poly (C 2 -C 4 -alkylene) glycol, for example polyethylene glycol and optionally glycerol (i.e. for transesterification of glyceride to the polyalkylene glycol / glycerol component, ie via glycolysis / polyalkylene glycerolysis).

In general such reaction is effected by reaction of the indicated components (glyceride, polyalkylene glycol and optionally glycerol) at elevated temperature under inert atmosphere with continuous stirring. Preferred glycerides are fatty acid triglycerides, for example triglycerides. (C10-C22) fatty acids, including natural and hydrogenated oils, in particular vegetable oils. Suitable vegetable oils include, for example, olive, almond, peanut, coconut, palm, soybean and wheat germ oils, and in particular natural and hydrogenated oils rich in (C12-C28 fatty acid) ester. Preferred polyalkylene glycol materials are polyethylene glycols, in particular polyethylene glycols having a molecular weight of about 500-4,000, for example, about 1,000-2,000.

Alkylene polyol ethers or esters of alkylene polyol include mixtures of C3 -C5 alkylene glycol esters, for example, mono-, di- and triesters in varying relative amounts, and poly (C2 -C4) mono- and diesters -alkylene) glycol, along with small amounts of free C3 -C5 alkylenetriol and free poly (C2 -C5 alkylene) glycol. As set forth herein, the preferred alkylene triol moiety is glyceryl; preferred polyalkylene glycol moieties include polyethylene glycol, in particular having a molecular weight of about 500-4,000; and preferred fatty acid moieties will be C10 -C22 fatty acid ester residues, in particular, C10 -C22 saturated fatty acid ester residues.

Particularly suitable alkylene polyol ethers or esters include the transesterification products of a natural or hydrogenated oil and a polyethylene glycol and optionally glycerol; or compositions comprising or consisting of mono-, di- and tri-C10-C22-fatty acid glyceryl esters and polyethylene glycol mono- and di-C1-C22-fatty acid esters (optionally together with, for example, smaller amounts of glycerollivre and free polyethylene glycol).

Preferred vegetable oils, polyethylene glycols or polyethylene glycol fractions and fatty acid fractions with respect to the above definitions are set forth hereinbefore.

Particularly suitable ethers or esters as described above for use in the present invention include those commercially available under the trade name Gelucire® da, for example Gattefoss, in particular the products: a) Gelucire® 33/01 which has mp = about 33-37 ° C and a saponification index of about 230-255; b) Gelucire®39 / 01, mp = about 37.5-41.5 ° C, saponification index = about 225-245; and c) Gelucire® 43/01, m.p. = about 42-46 ° C, saponification index = about 22-240. The products of a) to c) above all have a maximum acidity index of 3. The compositions of the invention may include mixtures of such ethers or esters.

24) Hydrocarbons

These include, for example, squalene from, for example, NikkoChemicals Co., Ltd.

25) Ethylene glycol esters

These include Monthyle® (ethylene glycol monostearate) available from, for example, Gattefossé.

26) Pentaerythriol fatty acid esters and polyalkylene glycol ethers

These include, for example, pentaerythrite dioleate, distearate, monolaurate, polyglycol ether, and monostearate, as well as esters of pen-taeritrite fatty acid (Fiedler, loc. Cit., Vol. 2, pp. 1158-1160). , incorporated herein by reference).

Some of these, for example (1-3, 5-6, 8-9, 12-13, 19) exhibit surfactant-like behavior and may be determined to be co-active.

B. Hydrophilic Vehicle, Non-Aqueous

Hydrophilic, non-aqueous vehicles include, but are not limited to, the following excipients alone or in combination:

1) Polyethylene glycol C8 -C10 fatty acid glyceryl esters

The fatty acid ester may include mono- and / or di- and other-fatty acid. Optionally it includes both saturated and unsaturated fatty acids having a chain length of, for example, Ce-C-10. Polyethylene glycols may have, for example, from 5 to 10 units of [CH 2 -CH 2 -O], for example 7 units. A particularly suitable fatty acid ester is polyethylene glycol glyceryl monococoate (7), which is commercially available, for example under the tradename Cetiol® HE, for example from Henkel KGaA. Cetiol® has a D. (20 °) of 1.05, and an acidity index of less than 5, a saponification index of about 95, a number of hydroxyls of about 180 and an iodine index of less than 5 ( H. Fiedler, loc. Cit., Vol. 1, p. 337) or Lipestrol E-810.

2) N-Alkylpyrrolidone

Particularly suitable is, for example, N-methyl-2-pyrrolidone, for example as commercially available under the trade name Phar-masolve®, for example from Specialty Products (ISP). N-Methylpyrrolidone requires the following additional characterizing data: molecular weight 99.1, D.25 1.027-1.028, purity (as percent area per GC) (including methyl osisomers) of at least 99.85%. (H. Fiedler, loc. Cit., Vol. 2, p.1004, manufacturer information).

3) Benzyl alcohol

This is commercially available from, for example, Merck or can be obtained by distillation of benzyl chloride with potassium or sodium carbonate. Benzyl alcohol exhibits the following additional characterizing data: molecular weight 108.14, D. 1.043-1.049, nD 1.538-1.541. (H. Fiedler, loc. Cit., Vol. 1, p. 238; Handbook of Pharmaceutical Excipients, loc. Cit., P.35).

4) Triethyl citrate

This is obtained by esterification of citric acid and ethanol. Citratode triethyl is commercially available, for example, under the trade name Citroflex® 2, or in a pharmaceutical grade under the name TEC-PG / N, for example from Morflex Inc. Particularly suitable is triethyl citrate, which has a weight molecular weight 276.3, a relative density of 1,135-1,139, a refractive index of 1,439-1,441, a viscosity (25 °) of 35.2 mPa s, anhydrous base test 99.0-100.5%, 0.25% water maximum. (H. Fiedler, loc. Cit., Vol. 1, p. 371 Handbook of Pharmaceutical Excipients, loc. Cit., P.540).

Other suitable hydrophilic compounds include transcutol (C 2 H 5 - [O- (CH 2) 2] 2-OH); glycofurol (also known as tetrahydro-furfuryl alcohol polyethylene glycol ether); 1,2-propylene glycol; dimethyl isosorbide, for example, Arlasolve from Uniqema; polyethylene glycol such as 200, 300,400, 600, etc .; triethylene glycol; ethyl acetate; and ethyl lactate.

C. Self-emulsifying Vehicles

The use of self-microemulsifying media as a crushing vehicle instead of a simple oil allows to combine the advantage of a self-dispersing system with the benefit of microparticles. "Microemulsion preconcentrate" as used herein means a composition which spontaneously forms a microemulsion in an aqueous medium, for example in water, for example at a 1: 1 to 1: 300 dilution, preferably 1: 1 to 1 : 70, but especially 1: 1 to 1:10 or in the gastric juices after the application.

In some embodiments of the compositions of the invention, the self-microemulsifying carrier comprises one or more of the following lipophilic components and one or more of the following surfactants described below.

In other embodiments, the self-microemulsifying carrier comprises one or more of the following lipophilic components, one or more of the following hydrophilic components and one or more of the following surfactants described below.

(I) Surfactants

Surfactants may be complex mixtures containing by-products or unreacted starting products involved in their preparation, for example, polyoxyethylation surfactants may contain another by-product, for example polyethylene glycol. Each surfactant preferably has a hydrophilic lipophilic balance (BHL) value of 8-17, especially 10-17. The value of BHL is preferably the fear value of BHL.

Suitable surfactants include:

1) Products of the reaction of a natural or hydrogenated castor oil and ethylene oxide

The natural or hydrogenated oil may be reacted with ethylene oxide in a molar ratio of about 1:35 to about 1:60 as an optional removal of the polyethylene glycol component of the products. Several of the taistenses are commercially available. Particularly suitable surfactants include glycold-polyethylene hydrogenated castor oils available under the tradename Cremophor®; Cremophor® RH 40, which has a saponification index of about 50-60, an acidity index of less than about 1, a water content (Fischer) of less than about 2%, nD60 of about 1.435-1.546 and a BHL of about 14-16; and Cremophor® RH 60, which has a saponification index of about 40-50, an acidity index of less than about 1, an iodine index of less than about 1, a water source (Fischer) of about 4 , 5-5.5%, nd60 of about 1.453-1.457 and a BHL of about 15-17.

An especially preferred product of this class is Cremophor®RH40. Other useful products in this class are available under the trade names Nikkol® (eg Nikkol® HCO-40 and HCO-60), Mapeg® (eg Mapeg® C0-40h), Incrocas® (eg Incrocas® 40), Tagat® (eg polyoxyethylene glycerol fatty acid esters, eg Tagat® RH 40) and Simulsol OL-50 (PEG-40 castor oil, which has a saponification index of about 55 to 65 , an acid content index of max. mo 2, an iodine content of 25-35, a water content of up to 8%, and a BBH of about 13, available from Seppic). These surfactants are still described by H. Fiedler, loc. cit.

Other suitable surfactants of this class include polyethylene glycol mother oils, such as that available under the tradename Cremophor® EL, which has a molecular weight (by steam osmometry) of about 1630, a saponification index of about 65-70, an acidity index of about 2, an iodine index of about 28-32 and an nD25 of about 1.471.

2) Polyoxyethylene sorbitan fatty acid esters

These include mono- and trilauryl esters, palmityl, oleyl stearyl and oleyl esters of the known type and commercially available under the tradename Tween® (H, Fiedler, loc. Cit., P.1615 et seq.) Including the products:

• Tween® 20 [polyoxyethylene (20) sorbitan monolaurate], • Tween® 21 [polyoxyethylene (4) sorbitan monolaurate],

• Tween® 40 [polyoxyethylene (20) sorbitan monopalmitate],

• Tween® 60 [polyoxyethylene (20) sorbitan monostearate]

• Tween® 65 [polyoxyethylene (20) sorbitan stearate],

• Tween® 80 [polyoxyethylene (20) sorbitan sorbitan monooleate],

• Tween® 81 [polyoxyethylene (5) sorbitan monooleate],

• Tween® 85 [polyoxyethylene (20) sorbitan trioleate],

Especially preferred products of this class are Tween® 20e Tween® 80.

3) Polyoxyethylene fatty acid esters

These include polyoxyethylene stearic acid esters of known and commercially available form under the trade name Myrj® da Uniqema (H. Fiedler, loc. Cit., Vol 2, p.1042). An especially preferred product of this class is Myrj® 52 having D25 of about 1.1, mp of about 40-44 ° C, BHL index of about 16.9, acidity index of about 0 to 1e. saponification index of about 25 to 35.

4) Polyoxyethylene-polyoxypropylene block copolymers and copolymers or poloxamers

These include the type known and commercially available under the trade names Pluronic® and Emkalyx® (H. Fiedler, loc. Cit., Vol. 2, p.1203). An especially preferred product of this class is BASF's Pluronic® F68 (poloxamer), having a m.p. of about 52 ° C and a molecular weight of about 6,800-8,975. Also a preferred product of this class is Syni-peronic® PE I44 (polymer 124) from Uniqema.

5) Saturated C10-C22 Polyoxyethylene Monoesters

These include substituted C18, for example hydroxy fatty acid, for example, PEG 12 stearic hydroxy acid ester, for example PEG, of about 600 to 900 Daltons PM, e.g. 660 Daltons, e.g. Solutol® HS 15 from BASF, Ludwigshafen, Germany. According to BASF datasheet, MEF 151E (1986) comprises about 70% by weight polyethoxylated 12-hydroxystearate and about 30% by weight of unesterified polyethylene glycol component. Solutol HS 15 has a hydrogenation index of 90-110, a saponification index of 53-63, a maximum acidity index of 1, and a maximum water content of 0.5% by weight.

6) Polyoxyethylene alkyl ethers

These include polyoxyethylene glycol ethers of C 12 -C 18 alcohols, for example Polyoxy 2-, 10- or 20- cetyl ether or Polyoxyethyl 23-lauryl ether, or polyoxyethyl 20-oleyl ether, or Polyoxyethyl 2-, 10-, 20 - or stearyl 100-ether as are known and commercially available, for example under the tradename Brij® 35 (Polyoxyl 23 lauryl ether) or Brij® 98 (Polyoxyl 20 oleyl ether) (H. Fiedler, loc. cit., Vol. 1, pp. 259; Handbook of Pharmaceutical Excipients, loc. cit., p. 367). Similarly, suitable products include polyoxyethylene polyoxypropylene alkyl esters, for example polyoxyethylene polyoxypropylene ethers of C 12 -C 18 alcohols, for example polyoxyethylene-20-polyoxypropylene-4-cetyl ether, which is known and commercially available under the name Nikkol PBC® 34, for example, Nikko Chemicals Co., Ltd. (H. Fiedler, loc. cit., Vol. 2, p. 1239). Polyoxypropylene fatty acid ethers, for example Acconon® E are also suitable.

7) Sodium alkyl sulfate and sulfonate, and sodium alkyl aryl sulfonates

These include sodium lauryl sulfate, which is also known as sodium dodecyl sulfate and is commercially available, for example under the tradename Henkel KGaA Texapon K12®.

8) Water-soluble tocopheryl polyoxyethylene glycol succinic acid esters (TPGS)

These include those with, for example, polymerization numbers of about 1,000 or, for example, available from Eastman FineChemicals Kingsport, TX, USA.

9) Polyglycerol fatty acid esters

These include those with, for example, 10-20, for example 10 units of glycerol. The fatty acid constituent may include both saturated and unsaturated fatty acids having a chain length of, for example, C8 -C18. Particularly suitable is, for example, decaglyceryl monolaurate or decaglyceryl monomyristate as known and commercially available under Trademark Decaglyn® 1-L or Decaglyn®1-Μ or Decaglyn 1-0, respectively, from, for example, Nikko Chemicals Co., Ltd (H. Fiedler, loc. cit., Vol. 2, p. 1228).

10) Alkylene polyol ethers or esters

These include C3 -C5 alkylene triols, in particular glycerol, ethers or esters. Suitable C3 -C5 alkylene triol ethers or esters include mixed ethers or esters, i.e. components that include other ether or ester ingredients, for example, C3 -C5 alkylene triol esters transesterification products with other mono-, di- or polyols. Particularly suitable polyalkylene ethers or esters are mixed C 3 -C 5 alkylene triol / poly (C 2 -C 4 alkylene) glycol fatty acid esters, especially glycerol / polyoxyethylene or polypropylene glycol fatty acid esters, mixed.

Especially suitable alkylene polyol ethers or esters include products obtainable by transesterification of glycerides, for example triglycerides, with poly (C 2 -C 4 alkylene) glycols, for example polyethylene glycols and optionally glycerol.

Such transesterification products are generally obtained by alkolysis of glycerides, for example triglycerides, in the presence of a poly (C2 -C4 -alkylene) glycol, for example polyethylene glycol and optionally glycerol (i.e., to effect the glyceride transesterification to the polyalkylene glycol / glycerol component, i.e. via glycolysis / polyalkylene glycerolysis). In general such reaction is effected by reaction of the indicated components (glyceride, polyalkylene glycol and optionally glycerol) at elevated temperature under inert atmosphere with continuous stirring.

Preferred glycerides are fatty acid triglycerides, for example, C10 -C22 fatty acid triglycerides, including natural and hydrogenated oils, in particular vegetable oils. Suitable vegetable oils include, for example, olive, almond, peanut, coconut, palm, soybean and corn germ oils, and in particular natural or hydrogenated oils rich in C12 -C18 fatty acid ester residues.

Preferred polyalkylene glycol materials are polyethylene glycols, in particular polyethylene glycols having a molecular weight of from about 500 to about 4,000, for example from about 1,000 to 2,000. Suitable alkylene polyol esters or esters include mixtures of polyethylene glycol esters. C3-C5-alkylene glycol, for example mono-, di- and tri-esters in varying relative amounts, and poly (C2-C4-alkylene) glycol mono- and diesters, together with small amounts of C3-C5-alkylene triol free epoly (C 2 -C 5 alkylene) glycol. As set forth herein, the preferred alkylenethriol moiety is glyceryl; Preferred polyalkylene glycol moieties include polyethylene glycol, in particular, having a molecular weight of about 500-4000; and preferred fatty acid fractions will be C10 -C22 fatty acid ester residues, in particular C10 -C22 fatty acid ester residues.

Particularly suitable alkylene polyol ethers or esters include transesterification products of a natural or hydrogenated vegetable oil and a polyethylene glycol and optionally glycerol; or compositions which comprise or consist of glyceryl mono-, di- and tri-C10 -C22-fatty acid esters and polyethylene glycol mono- and di-C10-C22-fatty acid esters (optionally together with, for example, , small amounts of free glycerol and free polyethylene glycol).

Preferred vegetable oils, polyethylene glycols or polyethylene glycol fractions and fatty acid fractions over the above definitions are as set forth hereinbefore.

11) Glycerylpolyethylene glycol fatty acid esters

The fatty acid ester may include mono- and / or di- and / or trigram fatty acid ester. The fatty acid constituent may include both unsaturated and fatty acids having a chain length of, for example, C 12 -C 18. Polyethylene glycols may have, for example, from 10 to 40 units of [CH 2 -CH 2 -O], for example 15 or 30 units. Particularly suitable is polyethylene glycol (15) glyceryl monostearate, which is commercially available, for example, under the tradename TGMS®-15, for example from Nikko Chemicals Co. Ltd. Other glyceride fatty acid esters These include polyethylene glycol (30) glyceryl monooleate, which is commercially available, for example, under the trade name Tagat® O, for example, from Goldschmidt (H. Fiedler, loc. cit., Vol. 2, 1502-1503), and Tagat 02 (polyethylene glycol (20) glycerol monooleate, as well as Tagat L (polyethylene glycol (30) glycerol monolau) and Tagat L2 (polyethylene glycol (3) glycerol monolaurate) and Tagat L2 (polyethylene glycol (20) glycerol monolaurate), all, for example, from Goldschmidt (H. Fiedler, loc. Cit., Vol. 2, pp. 1502-1503) Another glyceryl polyethylene glycol fatty acid ester , suitable, is Tagat TO.

12) Sterols and derivatives thereof

These include cholesterols and derivatives thereof, in particular phytosterols, for example, products comprising sitosterol, peasanterol or stigmasterol, and ethylene oxide adducts thereof, for example, soy sterols and derivatives thereof, for example polyethylene glycol sterols, for example polyethylene glycol phytosterols or polyethylene glycol sterols. Polyethylene glycols may have, for example, 10-40 units of [CH2-GH2-O], for example 25 or 30 units. Particularly suitable is polyethylene glycol phytosterol (30), which is commercially available, for example under the tradename Nikkol BPS®-30, for example from Nikko Chemicals Co. Ltd. Still suitable is soybean sterol polyethylene glycol (25), which is commercially available, for example under the trade name Generol® 122 E 25, for example from Henkel (H. Fiedler, loc. cit, Vol. 1, p. 680).

13) Transesterified polyoxyethylated caprylic-capric acid glycerides.

These include those that are commercially available under the trade name Labrasol® from, for example, Gatterfossé. Labrasol® has an acidity index of at most 1, a saponification index of 90-110, and an iodine index of at most 1 (H. Fiedler, loc. Cit., Vol. 2, p. 880).

14) Sugar-fatty acid esters

These include those of C12-Cie-fatty acids, for example sucrose monolaurate, for example Ryoto L-1695®, which is commercially available from, for example, Mitsubishi-Kasei Food Corp., Tokyo, Japan.

15) PEG Sterol Ethers

These include those having, for example, from 5 to 35 units of [CH2-CH2-O], for example, 20 to 30 units, for example Solulan® C24, which is commercially available from, for example, Amerchol.

16) Sodium dioctyl sulfosuccinate

This is commercially available under the tradename AerosolOT® from, for example, American Cyanamid Co. (H. Fiedler, loc. Cit., Vol. 1, p. 118).

17) Phospholipids

These include, in particular, Iecithins (H. Fiedler, loc. Cit., Vol.2, p. 910, 1184). Suitable lecithins include in particular dasoja lecithins.

18) Fatty acid salts, sulphates and fatty acid sulphonates

These include those of, for example, C 6 -C 18 fatty acids, esulfates and C 6 -C 18 fatty acid sulfonates as known and commercially available from, for example, Fluka.

19) Acylated amino acid salts

These include those of acetylated C6 -C18 amino acids, for example, sodium lauroyl sarcosinate, which is commercially available, for example, from Fluka.

20) Medium or long chain alkyl salts, for example Ce-C-ie-ammonium salts

These include C6 -C6 acylated amino acids, for example, cetyl trimethyl ammonium bromate, which is commercially available from, for example, E. Merck AG.

(II) Lipophilic components are described above.

(III) Hydrophilic Components

Examples of hydrophilic components of the present invention include, but are not limited to:

1) C6 -C10 glyceryl polyethylene glycol fatty acid esters

The fatty acid ester may include esters of mono- and / or di- and / or trigrams. It optionally includes both saturated and unsaturated fatty acids having a chain length of, for example, C8 -C10.

Polyethylene glycols may have, for example, from 5 to 10 units of [CH 2 -CH 2 -O], for example 7 units. A particularly suitable fatty acid ester is glyceryl polyethylene glycol monocoate (7), which is commercially available under the tradename Cetiol® HE, for example from HenkelKGaA. Cetiol® HE has a D. (20 °) of 1.05, an acidity index of less than 5, a saponification index of about 95, a hydroxyl index of about 180 and an iodine index of less than 5 ( H. Fiedler (loc. Cit., Vol. 1, p. 337) or Lipestrol E-810.

2) N-Alkylpyrrolidone

Particularly suitable is, for example, N-methyl-2-pyrrolidone, for example as commercially available under the trade name Pharmasolv® from, for example, International Specialty Products (ISP). N-Methylpyrrolidone exhibits the following additional characterizing data: 99.1 pesomolecular D. 25 from 1.027 to 1.028, minimum purity (as percent area by GC) (including methyl isomers) of 99.95%. ((H. Fie-dler, loc. Cit., Vol. 2, p. 1004, manufacturer's information).

3) Benzyl alcohol

This is commercially available from, for example, Merck or can be obtained by distillation of benzyl chloride with potassium or sodium carbonate. Benzyl alcohol exhibits the following additional characterizing data: molecular weight 108.14, D. 1.043 to 1.049, nD 1.538 to 1.541 (H. Fiedler, loc. Cit., Vol. 1, p. 238; Handbook of Pharmaceutical Exci -patients, loc. cit., p. 35).

4) Triethyl citrate

It is obtained by esterification of citric acid and ethanol. Triethyl citrate is commercially available, for example under the trade name Citroflex®, or in a pharmaceutical grade under the trade name TEC-PG / N da, for example, Morflex Inc. Particularly suitable is triethyl citrate, which has a molecular weight of 276.3, a relative density of 1,135 to 1,139, a refractive index of 1,439 to 1,441, a viscosity (25 °) of 35,2 mPa s, a test (on anhydrous basis) of 99,0 to 100,5%, a maximum of 0.25% water (H. Fiedler, loc. cit., Vol. 1, p. 371; Handbook of Pharmaceutical Excipients, loc. cit., p.540).

Other suitable hydrophilic compounds include transcutol (CH 2 H 5 - [O- (CH 2) 2] 2-0H); glycofurol (also known as tetrahydro-furfuryl alcohol polyethylene glycol ether); 1,2-propylene glycol, dimethyl isosorbide, e.g. Arlasolve from Uniqema; polyethylene glycol, such as 200,300, 400, 600, etc .; triethylene glycol; ethyl acetate; and ethyl lactate.

An example of self-microemulsifying media includes polyoxyl hydrogenated mamma oil, corn oil, mono-, di-, triglycerides, propylene glycol 1,2 and ethanol.

An example of the self-microemulsifying media includes polyoxyl hydrogenated mamma oil, corn oil, mono-, di-, triglycerides, and propylene glycol 1,2.

Another example of self-microemulsifying media includes polyoxyl hydrogenated castor oil, corn oil, mono-, di- and triglycerides, polyethylene glycol 400 and ethanol.

Another example of self-microemulsifying media includes polyoxyl hydrogenated castor oil, corn oil, mono-, di- and triglycerides and polyethylene glycol 400.

Another example of the self microemulsifying media includes vi-tamine E TPGS, dimethyl isosorbide, triethyl citrate and ethanol.

Another example of the self microemulsifying media includes vi-tamine E TPGS, dimethyl isosorbide and triethyl citrate.

Another example of the self microemulsifying media includes polyoxyl hydrogenated castor oil, C8 / C10-mono- / diglyceride, detryl citrate and ethanol.

Another example of the self-microemulsifying media includes polyoxyl hydrogenated castor oil, C8 / C10 mono-diglyceride, and detryl citrate.

Another example of the self-microemulsifying media includes polyoxyl hydrogenated castor oil, yineoyl macrogol-6 glycerides, propylene glycol and ethanol.

Another example of the self-microemulsifying media includes polyoxyl hydrogenated castor oil, yineoyl macrogol-6 glycerides and propylene glycol.IV. Sedimentation Inhibitor

The microparticle compositions of the present invention may further comprise a sedimentation inhibitor that significantly enhances viscosity. Examples of the sedimentation inhibitor are oleogel formers which include, but are not limited to, precipitated silica or colloidal silica (e.g. Aerosil 200® or 300®), bentonite, zinc-aluminum stearate and certain copolymers such as ethylene / propylene / styrene copolymer, butylene / ethylene / styrene copolymer (e.g. Versagel® MP), hydrogenated styrene / isoprene copolymer and hydrogenated styrene / butadiene copolymer.

Another example of sedimentation inhibitors are solid waxes and excipients, for example surfactants, lipophilic or hydrophilic excipients, for example, higher molecular weight polyethylene glycol (2,000,4,000, etc.) or alkylene polyol ethers or esters. e.g. Gelucire 44/14.

The sedimentation inhibitor may be added either during grinding or after the grinding procedure.

V. Pharmaceutical Compositions and Treatment Methods

The pharmaceutical compositions of the present invention comprising the microparticle compositions of the present invention may be administered as oral suspensions in single or multi-finger containers or filled in hard or soft gelatin capsules. The microparticles of the present invention may also be absorbed into a vehicle and pressed into hard tablets. Examples of suitable carriers are precipitated and colloidal silicas (eg, Huber Corp. Zeopharm 80®, 600® or 5170®, Aerosil 200® or 300®, Aeropert 300® from Degus-sa) as well as sugar or cellulose derivative beads (eg Asahi-Kasei's Celphere® or Syntapharm's Cellets®).

Certain embodiments of the pharmaceutical compositions of the present invention include additives, for example, antioxidants, antimicrobial agents, enzyme inhibitors, stabilizers, preservatives, flavorings, sweeteners, and other components, such as those described by H. Fieder. Ioc. cit.

Preferred antioxidants include ascorbyl palmitate, butyl hydroxy anisole (BHA), butyl hydroxy toluene (BHT), alpha-tocopherol.

Preferred stabilizers include an organic acid, for example, citric acid, fumaric acid, maleic acid, tartaric acid, ascorbic acid and phosphoric acid.

The dose of active agent in the compositions of the invention is about the same as or in half that of known active agent compositions. The compositions of the invention show activity at concentrations of from about 0.1 mg to about 40 mg / day of the active agent, preferably from about 0.1 mg to about 20 mg / day, for example, more preferably from about 0.1%. 1 to about 5 mg / day of the active agent.

A typical dose for the active agent is 0.1 to 5 mg / day to treat proliferative diseases or diseases that are associated with or triggered by persistent angiogenesis.

A proliferative disease is mainly triggered by tumor disease (s) (or cancer) (and / or any metastases). Inventive compositions are particularly useful for treating a tumor which is breast cancer, lung cancer, gastrointestinal cancer, including esophageal, gastric, small intestine, large intestine and colorectal cancer, glioma, sarcoma, such as those involving bone, cartilage, smooth tissue, muscle, blood and lymphatic vessels, ovarian cancer, myeloma, female cancer, endometrial cancer, head and neck cancer, mesothelioma, kidney cancer, ureter, bladder and urethral cancers, prostate cancer, skin cancers and melanoma. In particular, the inventive compositions are particularly useful for treating:

(i) breast tumor, lung tumor, for example, non-small cell and small cell lung cancer; a gastrointestinal tumor, for example, a colorectal tumor; or a genitourinary tumor, for example, a prostate tumor;

(ii) a proliferative disease that is refractory to treatment with other chemotherapeutic substances; or (iii) a tumor that is refractory to treatment with other substances

chemotherapeutic agents due to multidrug resistance. In a broader sense of the invention, a proliferative disease may furthermore be a proliferative condition, such as leukemia, lymphoma and multiple myeloma.

Such additives or ingredients may comprise about 0.05-5% by weight of the total weight of the composition. Antioxidants, antimicrobial agents, enzyme inhibitors, stabilizers, or preservatives typically provide up to about 0.05-2% by weight based on the total weight of the composition. Sweetening or flavoring agents typically provide up to about 0.5% or 1% by weight based on the total weight of the composition.

The microparticle compositions of the present invention may be prepared by milling techniques including, but not limited to, wet milling including ball milling, high pressure homogenization, microfluidization or precipitation techniques.

Below are examples of specific embodiments for carrying out the present invention. The examples are offered by way of illustration only, and are not intended to limit the scope of the present invention at all.

Efforts have been made to ensure accuracy with respect to the numbers used (eg, quantities, temperatures, etc.), but some perimental error and deviation should naturally be allowed.

Example 1 Microparticle Compositions

Wet co-grinding was performed in a ball mill using glass beads (3 mm in diameter). Seven (7) hours of trituration time at 3,200 rpm was employed; Alternatively, microsuspensions may be prepared using other mills and / or grinding conditions (rotational speed, ingredient concentration, time, material counts and size). Table 1: Illustration of Microparticle Compositions of the present invention. vention

<table> table see original document page 34 </column> </row> <table>

"Composition (w / w,%)

Self-microemulsifying system 1: 36% and mono-, di- and triglycerides, 45% hydrogenated polyethylene glycol castor oil 40 (Cremo-phor RH-40), 9% propylene glycol, 10% abs ethanol .

Self-microemulsifying system 2: 40% mono-, di- and triglycerides, 49% hydrogenated polyethylene glycol castor oil 40 (Cre-mophor RH40), 10% propylene glycol.

The particle size distribution of 7-t-butoxyiminomethylcamptothecin after grinding was measured using laser light scattering or light microscopy. Results are given in Table 2.

Table 2: Particle Size Distribution after Grinding

<table> table see original document page 35 </column> </row> <table>

* Particle size distribution determined by light microscopy.

** Larger irregularly shaped particles can be identified as excipient particles, although the small particles are particles of drug substances.

Example 2 Dissolution Rate / Bioavailability

The results of the technical experiments and the in vivo study with chorro clearly demonstrated:

1) Increased bioavailability compared to powdered mixtures of crystalline 7-t-butoxyiminomethylcamptothecin.

2) Required lower doses of 7-t-butoxyiminomethylcamptothecin to achieve the same bioavailability as compared to conventional forms of 7-t-butoxyiminomethylcamptothecin.

3) Good redispersibility of the 7-t-butoxyiminomethylcamptothecin microparticles present in the compositions following oral administration.

4) Increased dissolution rate compared to conventional crystalline forms of 7-t-butoxyiminomethylcamptothecin.

5) Improved performance characteristics for oral administration, such as higher dose loading, and thus smaller formulation volumes, i.e. smaller capsules.

Figure 1 of the present invention depicts in vitro dissolution rate profiles (USP2, 1,000 mL, 0.3% SDS, 50 rpm, 37 ° C). It may therefore be that all microparticle formulations showed improved dissolution and resuspension behavior compared to the crystalline substance of the drug. Especially significant increase in dissolution rate was observed in Experiments 4 and 5 containing corn oil and Pluronic F68® as surface stabilizer and Experiments 8, 9, 11 and 13 using self-microemulsifying vehicles as crushing media. .

The bioavailability of 7-t-butoxyiminomethylcamptothecin is compared as determinable after administration of the ground-up drug substance in a dry powder (hard capsule) formulation and a composition according to the present invention.

Form administered: 0.5 mg of 7-t-butoxyiminomethylcamptothecin by capsule and dog.

The composition according to the present invention corresponds to Experiments 4 and 8 in Example 1.

Six (6) dogs completed the study. Each dog receives all three formulations. Blood samples for plasma 7-t-butoxyiminomethylcamptothecin determination were taken prior to dosing, then 10 minutes, 30 minutes, 45 minutes, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours. , 4 hours, 6 hours, 10 hours and 24 hours after drug ingestion. Individual concentrations of 7-t-butoxyiminomethylcamptothecin in heparinized plasma were determined for each sample by liquid chromatography / tandem mass spectroscopy in electrospray positive ionization (ESI positive / MS-MS) mode. Heparinized plasma samples were prepared for analysis by liquid-liquid extraction and evaporation of the supernatant to dryness prior to reconstitution in the injection medium. The limit of quantitation was 0.1 ng / mL.

Figures 2 and 3 of the present invention describe the bioavailability in dogs (0.5 mg of 7-t-butoxyiminomethylcamptothecin / dog, Beagle dogs, 6 dogs). A significant increase in bioavailability was observed for the two microparticle formulations (Figure 2) compared to that observed for a dry mixture containing crystalline compound A (Figure 3). The microparticle suspension compositions tested corresponded to Experiments 4 and 8 in Table 1.

Example 3 Scalable Production

To demonstrate the scalable production capacity of the wet co-grinding process, a 2 L batch was processed into a ball mill using glass beads (1 mm in diameter). In continuous mode, the processing time was 72 hours / batch, while the suspension remained 7 hours in the grinding chamber at 3,200 rpm. Alternatively, the microparticle formulation may be prepared using other mills and / or grinding conditions (speed of rotation, concentration of ingredients, time, beads - material and size).

Table 3: Illustration of Compositions of Microparticle CompositionsDuring Scalable Production

<table> table see original document page 37 </column> </row> <table>

"Composition (w / w,%):

Auto-microemulsifying system 1: 36% corn oil mono-, di- and triglycerides, 45% polyethylene glycol 40 hydrogenated castor oil (Cremophor RH40), 9% propylene glycol, 10% abs ethanol .

Self-microemulsifying system 2: 40% corn oil mono-, di- and triglycerides, 49% polyethylene glycol 40 hydrogenated castor oil (Cremophor RH40), 10% propylene glycol.

The particle size distribution of the compound was measured using laser light scattering. Results are given in Table 4. Small-scale production particle size and 2L scale batches were in the same range.

<table> table see original document page 38 </column> </row> <table>

Figure 4 of the present invention depicts in vitro dissolution rate profiles (USP2, 1,000 mL, 0.3% SDS1 50 rpm, 37 ° C) from the batch production batch in Experiment 15 to the batch. -small scale 14. Rate profiles were comparable.

Example 4 Final Dosage Form

Microparticle formulations 16 and 17 were diluted with the self-microemulsifying system also used to prepare the tri-turbulent product. In some cases, Aerosil 200 has been added. The resulting diluted microparticle formulation was filled into soft gelatin capsules (18, 19) or hard gelatin capsules (20, 21). The composition of these dosage forms is summarized in Table 5.

<table> table see original document page 38 </column> </row> <table> <table> table see original document page 39 </column> </row> <table>

*Composition

Auto-microemulsifying system 1: 36% corn oil mono-, di- and triglycerides, 45% polyethylene glycol 40 hydrogenated castor oil (Cremophor RH40), 9% propylene glycol, 10% abs ethanol.

Auto-microemulsifying system 2: 40% corn oil mono-, di- and triglycerides, 49% polyethylene glycol hydrogenated castor oil 40 (Cremophor RH40), 10% propylene glycol.

Claims (13)

Pharmaceutical composition, characterized in that it comprises 7-t-butoxyiminomethylcamptothecin microparticles in one vehicle and, optionally, at least one surface stabilizer, in which the microparticles are up to about 15 microns. Pharmaceutical composition according to Claim 1, characterized in that the carrier is selected from an oil carrier, a hydrophilic non-aqueous carrier or a self-emulsifying carrier. Pharmaceutical composition according to Claim 1, characterized in that at least one surface stabilizer is selected from hydroxymethyl propyl cellulose, polyvinylpyrrolidone, PluronicF68®, sodium dodecyl sulfate or colloidal silica. Pharmaceutical composition according to Claim 2, characterized in that the oily vehicle is selected from one or more corn oil, sesame oil, olive oil, paraffin oil, deoiling oil, cottonseed oil, mono- di-, long-, medium- and short-chain triglycerides and other suitable lipophilic components. Pharmaceutical composition according to Claim 2, characterized in that the hydrophilic non-aqueous vehicle comprises one or more of the following excipients: glyceryl polyethylene glycol C6-Cio-fatty acid esters, N-alkylpyrrolidone, benzyl alcohol or triethyl citrate. Pharmaceutical composition according to Claim 2, characterized in that the self-microemulsifying carrier comprises one or more lipophilic components, one or more surfactants, and optionally one or more hydrophilic components. Pharmaceutical composition according to claim 6, characterized in that the self-microemulsifying vehicle comprises corn oil mono-, di-, triglycerides, polyethylene glycol hydrogenated castor oil, polyoxyl 40, propylene glycol and optionally , ethanol. Pharmaceutical composition according to claim 1, characterized in that it comprises a sedimentation inhibitor. Pharmaceutical composition according to claim 7, characterized in that the sedimentation inhibitor is colloidal silica. 10. Microparticle, characterized in that it is a 7-t-butoxyiminomethylcamptothecin microparticle of about 1 micron to about 5 microns. Microparticle according to Claim 10, characterized in that it is produced by grinding, homogenizing under high pressure or precipitation techniques. Use of a microparticle as defined in claim 10 or 11, characterized in that it is in the preparation of a pharmaceutical composition for use in treating a proliferative disease in a patient in need of such treatment. Use according to claim 12, characterized in that said proliferative disease is selected from breast cancer, lung cancer, gastrointestinal cancer, large bowel cancer and colorectal cancer, glioma, sarcoma, ovarian cancer, myeloma, cervical cancer, endometrial cancer, head and neck cancer, mesothelioma, kidney cancer, prostate cancer, uterus cancer, bladder and urethral cancer, skin cancer and melanoma.