SURFACTANTS

This application claims the benefit of U.S. provisional application Ser. No. 62/095,894, filed December 23, 2014, which is incorporated herein by reference in its entirety.

FIELD OF INVENTION

The present invention relates to inclusion complexes between cyclodextrin and non- ionic surfactants, especially such inclusion complexes preferably comprising one or more drug substances in the form of dry tabletable powder. Further, the present invention relates to use of such dry powder in oral dose units of drugs. The powders and tablets are new oral drug delivery systems, optionally solid self-emulsifying systems, with high stability and improved bioavailability compared to conventional tablets.

BACKGROUND

The most convenient route of administration of drugs is oral administration. However, several drug substances have to be administered as a parenteral drug formulation due to low oral bioavailability. It has been estimated that about 40% of new drug candidates might have problems related to bioavailability.

The oral bioavailability for a given drug substance is the percentage of drug substance that reach the systemic circulation compared to intravenous administration. The

bioavailability is a result of two different processes; oral absorption and first pass metabolism. Several drug substances have, due to their chemical nature, low oral absorption, while other drug substances are extensively metabolized in the liver after oral administration. First pass metabolism means that the drug is transformed to another substance during its first pass through the liver after oral administration before the drug reaches the systemic circulation. The problems related to first pass metabolism can generally not be solved for a given drug substance, however, a low oral absorption might be solved or partly solved by design of specific drug delivery formulations. The solution of this problem depends on the nature of the problem. The problem is often that the drug substance has very low solubility in water.

Drug substances can be classified into 4 different classes according to Gordon L.

Amidon et al. in Pharmaceutical Research, 12, 3, 413-420 (1995). Case 1 drugs are drugs with with high solubility and high oral permeability, Case 2 drugs are drugs with low solubility and high oral permeability, Case 3 drugs are drugs with high solubility and low oral permeability and finally case 4 drugs are drugs with low solubility and low oral permeability.

Case 2 drugs and partly case 4 drugs represent the majority of drugs with low oral bioavailability. There are several concepts in the prior art to try to improve the bioavailability of various drugs, especially case 2 drugs and case 4 drugs by design of specific formulations. Such formulations include for example micronization of the drug substance to improve solubility and specifically the solubility rate, use of solvents and/or surfactants to improve the solubility of the drug substance, formation of drug cyclodextrin complexes to improve water- solubility and thereby solubility, preparation of emulsions where the drug substance is dissolved or partly dissolved in the oil phase and use of self-emulsifying systems there the drug is dissolved or partly dissolved in an oil that is emulsified in the gastrointestinal system. The mixture in a self-emulsifying system comprises of various components like for example solvents, surfactants and co-surfactants.

Additional compositions and method for stabilizing drugs are needed.

SUMMARY

The present invention relates to inclusion complexes between cyclodextrin and non- ionic surfactants in the form of a dry tabletable powder. The invention finds use in the preparation of drugs for administration to a subject. Accordingly, the invention in some embodiments relates to inclusion complexes between cyclodextrin and non-ionic surfactants and comprising one or more drug substances. Further, the present invention relates to use of such dry powder inclusion complexes (e.g., comprising cycrodextrin and a non-ionic surfactant and a drug) to provide oral dose units of drugs. The powders and tablets are new oral drug delivery systems, optionally solid self-emulsifying systems, with high stability and improved bioavailability compared to conventional tablets.

For example, in some embodiments, the present invention provides a composition comprising: a dry composition comprising an inclusion complex of cyclodextrin and a non- ionic surfactant. In some embodiments, the present invention provides a composition comprising: a dry composition comprising an inclusion complex of cyclodextrin and a non- ionic surfactant and one or more drug substances. In some embodiments, the dry composition is crystalline, a powder, or granulate. In some embodiments, the dry composition is a tablet. In some embodiments, the composition further comprises a solvent and/or second surfactant. In some embodiments, the cyclodextrin is an unsubstituted or a substituted cyclodextrin (e.g., alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, 2-hydroxypropyl-beta- cyclodextrin, methyl-beta-cyclodextrin or 4- sulfoxybutyl-beta-cyclodextrin). In some embodiments, the first and second surfactants are selected from, for example, a

polyoxyethylene sorbitan ester, a castor oil, a Pluronic® surfactant, a polyethylene ether, a polyethylene stearate, a glyceride, a monocaprylate, a hydrophilic block polymers, an ethoxylated linear alcohol, a fatty acid ester, amine and amide derivatives, ethoxylated alkyl phenols, a sorbitan ester, carboxylic acids, perfluorocarboxylic acids, perfluorosulphonic acid, alkyl sulphate salts, sulphate ethers, quarternary ammonium compounds, dodecyl betaine, coco amphoglycinate, cocamidopropyl betaine, or oleic acid. In some embodiments, the polyoxyethylene sorbitan ester is selected from, for example, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monopalmitate, polyoxyethylene sorbitan

monostearate, polyoxyethylene sorbitan tristearate, polyoxyethylene(20)sorbitan monooleate, or polyoxyethylene sorbane trioleate. In some embodiments, the sorbitan ester is, for example, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, sorbitan tristearate, sorbitan monooleate, or sorbitan trioleate. In some embodiments, the castor oil is, for example, polyoxyethylated castor oil, hydrogenated polyoxyethylated castor oil, hydrogenated polyoxyethylated castor oil, or hydrogenated polyoxyethylated castor oil. In some

embodiments, the Pluronic® surfactant is, for example, Pluronic L-31 , Pluronic L-35, Pluronic L-61 , Pluronic L-81 , Pluronic®L-64, Pluronic®L-121 , Pluronic®P- 123, or

Pluronic®F-68. In some embodiments, the polyethylene ether is, for example,

polyoxyethylene(4) lauryl ether, polyoxyethylene (23) lauryl ether, polyoxyethylene (2) cetyl ether, polyoxyethylene ( 10) cetyl ether, polyoxyethylene (20) cetyl ether, polyoxyethylene (2) stearyl ether, polyoxyethylene (10) stearyl ether, polyoxyethylene (20) stearyl ether, polyoxyethylene (2) oleyl ether, polyoxyethylene (2) oleyl ether, polyethylene glycol oleyl ether, polyoxyethylene ( 10) oleyl ether, polyoxyethylene (20) oleyl ether, or polyoxyethylene (100) stearyl ether. In some embodiments, the polyethylene stearate is, for example, Myrj 45, Myrj 49, Myrj® 52, or Myrj® 53. In some embodiments, the glyceride is, for example, caprylocaproyl macrogol-8 glycerides, lauryl macrogol-32-glycerides, stearoyl macrogol-32 glycerides, oleoyl macrogol-6 glycerides, linoleoyl macrogol-6 glycerides, or lauroyl macrogol-6-glycerides. In some embodiments, the monocaprylate is, for example, propylene glycol monocaprylate, propylene glycol monocaprylate, propylene glycol monolaurate, polyglyceryl-3-diolate, or propylene glycol monolaurate. In some embodiments, the alkyl sulphate salt is sodium dodecyl sulphate or ammonium lauryl sulphate; the sulphate ether is sodium lauryl ether sulphate or alkyl benzene sulphonate salts; the quarternary ammonium compound is benzalkonium chloride, cetylpyridinium chloride, benzalconium chloride, cetyl trimethylammonium bromide or other trimethylalkylammonium salts. In some embodiments, the dry composition exhibits more than 20 % (50%) crystalline property. In som

embodiments, the compostion further comprises a drug (e.g., drugs are drugs with low solubility and high oral permeability or drugs with low solubility and low oral permeability or drugs with molecular weight below 1500 Da, a log P above 2 (6) an aqueous solubility below 1 mg/ml (0.1 mg/ml) and oral bioavailability of less than 20 % (1 %)). In some embodiments, the composition is formulated for oral administration. In some embodiments, the composition forms an emulsion in the gastrointestinal system.

One aspect of the invention relates to an inclusion complex of cyclodextrin and non- ionic surfactant.

Further embodiments provide the use of any of the aforementioned compositions for a drug delivery system.

Accordingly, one aspect of the present invention relates to inclusion complex of cyclodextrin and non-ionic surfactant comprising one or more drug substances.

A preferred aspect of the present invention relates to inclusion complex of

cyclodextrin and non-ionic surfactant where said inclusion complex is crystalline.

One aspect of the present invention relates to dry composition of solid material comprising inclusion complex with cyclodextrin and non-ionic surfactant comprising one or more drug substances.

One preferred aspect of the present invention relates to dry composition of solid material comprising inclusion complex with cyclodextrin and non-ionic surfactant where said dry composition comprising one or more drug substances is in the form of a powder or granulate.

Another preferred aspect of the present invention relates to dry composition of solid material comprising inclusion complex with cyclodextrin and non-ionic surfactants where said dry composition is in the form of tablets.

A more preferred aspect of this aspect of the invention relates to dry composition of solid inclusion complex of cyclodextrin and non-ionic surfactant where said dry composition is a powder or granulate and comprise a drug substance.

A more preferred aspect of this aspect of the invention relates to dry composition of solid inclusion complex of cyclodextrin and non-ionic surfactant where said dry composition is a powder or granulate and comprise an additional surfactant. A more preferred aspect of this aspect of the invention relates to dry composition of solid inclusion complex of cyclodextrin and non-ionic surfactant where said dry composition is a powder or granulate and comprise a solvent.

A more preferred aspect of this aspect of the invention relates to dry composition of solid inclusion complex of cyclodextrin and non-ionic surfactant where said dry composition is a powder or granulate and comprise a solvent.

A more preferred aspect of this aspect of the invention relates to dry composition of solid inclusion complex of cyclodextrin and non-ionic surfactant where said dry composition is a powder or granulate and comprise drug substance and an additional surfactant.

A more preferred aspect of this aspect of the invention relates to dry composition of solid inclusion complex of cyclodextrin and non-ionic surfactant where said dry composition is a powder or granulate and comprise drug substance and a solvent.

A more preferred aspect of this aspect of the invention relates to dry composition of solid inclusion complex of cyclodextrin and non-ionic surfactant where said dry composition is a powder or granulate and comprise drug substance, solvent and an additional surfactant.

A more preferred aspect of this aspect of the invention relates to dry composition of solid inclusion complex of cyclodextrin and non-ionic surfactant where said dry composition is a powder or granulate and comprise a drug substance and is for oral administration.

A more preferred aspect of this aspect of the invention relates to dry composition of solid inclusion complex of cyclodextrin and non-ionic surfactant where said dry composition is a powder or granulate and comprise an additional surfactant and is for oral administration.

A more preferred aspect of this aspect of the invention relates to dry composition of solid inclusion complex of cyclodextrin and non-ionic surfactant where said dry composition is a powder or granulate and comprise a solvent and is for oral administration.

A more preferred aspect of this aspect of the invention relates to dry composition of solid inclusion complex of cyclodextrin and non-ionic surfactant where said dry composition is a powder or granulate and comprise a solvent and is for oral administration

A more preferred aspect of this aspect of the invention relates to dry composition of solid inclusion complex of cyclodextrin and non-ionic surfactant where said dry composition is a powder or granulate and comprise drug substance and an additional surfactant and is for oral administration.

A more preferred aspect of this aspect of the invention relates to dry composition of solid inclusion complex of cyclodextrin and non-ionic surfactant where said dry composition is a powder or granulate and comprise drug substance and a solvent and is for oral administration.

A more preferred aspect of this aspect of the invention relates to dry composition of solid inclusion complex of cyclodextrin and non-ionic surfactant where said dry composition is a powder or granulate and comprise drug substance, solvent and an additional surfactant and is for oral administration.

A more preferred aspect of this aspect of the invention relates to dry composition of solid inclusion complex of cyclodextrin and non-ionic surfactant where said dry composition is a powder or granulate and comprise a drug substance and is for oral administration and the dry composition form an emulsion in the gastrointestinal system.

A more preferred aspect of this aspect of the invention relates to dry composition of solid inclusion complex of cyclodextrin and non-ionic surfactant where said dry composition is a tablet and comprise a drug substance.

A more preferred aspect of this aspect of the invention relates to dry composition of solid inclusion complex of cyclodextrin and non-ionic surfactant where said dry composition is a tablet and comprise an additional surfactant.

A more preferred aspect of this aspect of the invention relates to dry composition of solid inclusion complex of cyclodextrin and non-ionic surfactant where said dry composition is a tablet and comprise a solvent.

A more preferred aspect of this aspect of the invention relates to dry composition of solid inclusion complex of cyclodextrin and non-ionic surfactant where said dry composition is a tablet and comprise a solvent.

A more preferred aspect of this aspect of the invention relates to dry composition of solid inclusion complex of cyclodextrin and non-ionic surfactant where said dry composition is a tablet and comprise drug substance and an additional surfactant.

A more preferred aspect of this aspect of the invention relates to dry composition of solid inclusion complex of cyclodextrin and non-ionic surfactant where said dry composition is a tablet and comprise drug substance and a solvent.

A more preferred aspect of this aspect of the invention relates to dry composition of solid inclusion complex of cyclodextrin and non-ionic surfactant where said dry composition is a tablet and comprise drug substance, solvent and an additional surfactant.

A more preferred aspect of this aspect of the invention relates to dry composition of solid inclusion complex of cyclodextrin and non-ionic surfactant where said dry composition is a tablet and comprise a drug substance and is for oral administration and the dry composition form an emulsion in the gastrointestinal system.

Another aspect of the present invention relates to use of inclusion complex of cyclodextrin and non-ionic surfactant as a drug delivery system.

One preferred aspect of the present invention relates to use of crystalline inclusion complex of cyclodextrin and non-ionic surfactant as a drug delivery system.

Another aspect of the present invention relates to use of dry composition of solid material comprising inclusion complex with cyclodextrin and non-ionic surfactant as a drug delivery system.

Another aspect of the present invention relates to use of dry composition of solid material comprising cyclodextrin and non-ionic surfactant where said dry composition is in the form of a powder or granulate as a drug delivery system.

Another aspect of the present invention relates to use of dry composition of solid material comprising cyclodextrin and non-ionic surfactants where said dry composition is in the form of tablets as a drug delivery system.

Another aspect of the present invention relates to use of dry composition of solid inclusion complex of cyclodextrin and non-ionic surfactant where said dry composition is a powder or granulate and comprise a drug substance as a drug delivery system.

Another aspect of the present invention relates to use of dry composition of solid inclusion complex of cyclodextrin and non-ionic surfactant where said dry composition is a powder or granulate and comprise an additional surfactant as a drug delivery system.

Another aspect of the present invention relates to use of more preferred aspect of this aspect of the invention relates to dry composition of solid inclusion complex of cyclodextrin and non-ionic surfactant where said dry composition is a powder or granulate and comprise a solvent as a drug delivery system.

Another aspect of the present invention relates to use of dry composition of solid inclusion complex of cyclodextrin and non-ionic surfactant where said dry composition is a powder or granulate and comprise a solvent as a drug delivery system.

Another aspect of the present invention relates to use of dry composition of solid inclusion complex of cyclodextrin and non-ionic surfactant where said dry composition is a powder or granulate and comprise drug substance and an additional surfactant as a drug delivery system.

Another aspect of the present invention relates to use of a dry composition is a powder or granulate and comprise drug substance and a solvent as a drug delivery system. Another aspect of the present invention relates to use of a dry composition of solid inclusion complex of cyclodextrin and non-ionic surfactant where said dry composition is a powder or granulate and comprise drug substance, solvent and an additional surfactant as a drug delivery system.

Another aspect of the present invention relates to use of dry composition of solid inclusion complex of cyclodextrin and non-ionic surfactant where said dry composition is a powder or granulate and comprise a drug substance and is for oral administration as a drug delivery system.

Another aspect of the present invention relates to use of dry composition of solid inclusion complex of cyclodextrin and non-ionic surfactant where said dry composition is a powder or granulate and comprise an additional surfactant and is for oral administration as a drug delivery system.

Another aspect of the present invention relates to use of dry composition of solid inclusion complex of cyclodextrin and non-ionic surfactant where said dry composition is a powder or granulate and comprise a solvent and is for oral administration as a drug delivery system.

Another aspect of the present invention relates to use of dry composition of solid inclusion complex of cyclodextrin and non-ionic surfactant where said dry composition is a powder or granulate and comprise a solvent and is for oral administration as a drug delivery system.

Another aspect of the present invention relates to use of dry composition of solid inclusion complex of cyclodextrin and non-ionic surfactant where said dry composition is a powder or granulate and comprise drug substance and an additional surfactant and is for oral administration.

Another aspect of the present invention relates to use of dry composition of solid inclusion complex of cyclodextrin and non-ionic surfactant where said dry composition is a powder or granulate and comprise drug substance and a solvent and is for oral administration as a drug delivery system.

Another aspect of the present invention relates to use of dry composition of solid inclusion complex of cyclodextrin and non-ionic surfactant where said dry composition is a powder or granulate and comprise drug substance, solvent and an additional surfactant and is for oral administration as a drug delivery system

Another aspect of the present invention relates to use of dry composition of solid inclusion complex of cyclodextrin and non-ionic surfactant where said dry composition is a powder or granulate and comprise a drug substance and is for oral administration as a drug delivery system and form an emulsion in the gastrointestinal system.

Another aspect of the present invention relates to use of dry composition of solid inclusion complex of cyclodextrin and non-ionic surfactant where said dry composition is a tablet and comprise a drug substance as a drug delivery system.

Another aspect of the present invention relates to use of dry composition of solid inclusion complex of cyclodextrin and non-ionic surfactant where said dry composition is a tablet and comprise an additional surfactant as a drug delivery system.

Another aspect of the present invention relates to use of dry composition of solid inclusion complex of cyclodextrin and non-ionic surfactant where said dry composition is a tablet and comprise a solvent as a drug delivery system.

Another aspect of the present invention relates to use of dry composition of solid inclusion complex of cyclodextrin and non-ionic surfactant where said dry composition is a tablet and comprise a solvent as a drug delivery system.

Another aspect of the present invention relates to use dry composition of solid inclusion complex of cyclodextrin and non-ionic surfactant where said dry composition is a tablet and comprise drug substance as a drug delivery system.

Another aspect of the present invention relates to use of dry composition of solid inclusion complex of cyclodextrin and non-ionic surfactant where said dry composition is a tablet and comprise drug substance and a solvent as a drug delivery system.

Another aspect of the present invention relates to use of dry composition of solid inclusion complex of cyclodextrin and non-ionic surfactant where said dry composition is a tablet and comprise drug substance, solvent and an additional surfactant as a drug delivery system.

Another aspect of the present invention relates to use of dry composition of solid inclusion complex of cyclodextrin and non-ionic surfactant where said dry composition is a tablet and comprise a drug substance as a drug delivery system and form an emulsion in the gastrointestinal system.

Additional embodiments are described herein.

DETAILED DESCRIPTION

The present invention relates to inclusion complexes between cyclodextrin and non- ionic surfactants, especially such inclusion complexes in the form of dry tabletable powder. Further, the present invention relates to use of such dry powder in oral dose units of drugs. The powders and tablets are new oral drug delivery systems, optionally solid self-emulsifying systems, with high stability and improved bioavailability compared to conventional tablets.

Cyclodextrins are cyclic oligosaccharides prepared from enzymatic degradation of starch. There are three native cyclodextrins; alpha-cyclodextrin comprising six glucopuranose units, beta-cyclodextrin comprising seven glucopuranose units and gamma-cyclodextrin comprising eight glucopuranose units. The water-solubility of cyclodextrins is generally much lower than the acyclic corresponding oligosaccharides, however, the water solubility varies depending upon cyclodextrin ring size and the substitution at the cyclodextrin ring. The cyclodextrins have hydrophobic properties inside the ring system and hydrophilic properties outside the ring system. This hydrophobic property is the basis for the interaction between hydrophobic molecules, including hydrophobic drugs. The cavity size, which is directly related to the number of glucopuranose units, is an important parameter for the interaction between drug substances and cyclodextrins. In general, larger drugs need larger cyclodextrin cavities than smaller molecules to form stable inclusion compounds.

Cyclodextrins form inclusion complexes with very many drug substances. Some of these drug substances are omeprazole, irbesartan, finasteride, nimsulidine, formoterol, ibuprofen, cortisone acetate, etoricoxib, fluconazole, itraconazole, progesterone, paclitaxel, lamivudine, miconazole, ketoprofen, tenoxicam and ampicillin.

The aqueous solubility for drug substances generally increases when cyclodextrin inclusion compounds are formed. Further, the chemical stability of drug substances is often increased by formation of cyclodextrin inclusion compounds, however, there are several examples where the cyclodextrin decrease the stability of the drug substance. The rationale for preparation of preparation of drug cyclodextrin compounds are: generally to increase of oral bioavailability of drug substances and increase of chemical stability of drug substance.

Cyclodextrins with focus on medical applications are, for example described in Cyclodextrins in Pharmaceuticals, Cosmetics, and Biomedicine. Current and Future Industrial Applications. (Ed.: Erem Bilensoy) Wiley 201 1 and Rebecca L. Carrier et al. The utility of cyclodextrins for enhancing oral bioavailability in J. Controlled Release, 123, 78-99 (2007) Although the number of scientific publications and patent documents related to drug cyclodextrin compounds is huge, there are only a few pharmaceutical products on the market comprising cyclodextrins.

Cyclodextrin compounds comprising non-ionic surfactants are not known in the prior art. Further, no such compounds or materials have been isolated as dry solid powder and further no tablets comprising such materials are known. Surfactants are chemical compounds that lower the surface tension between two liquids or between a liquid and a solid. Surfactants might have several functions and may act as detergents, wetting agents, emulsifiers, foaming agents, and dispersants. Surfactant molecules comprise of a hydrophilic part and a hydrophobic part and can be grouped into 4 different groups based on the nature of the hydrophilic part of the molecule: non-ionic surfactants comprise of non-ionic hydrophilic moieties, typically ether and alcohol groups without any charge, anionic surfactants comprise of negatively charged moieties, typically carboxylic acids, phosphate groups, sulfate groups or sulfonate groups, cationic surfactants comprise of positively charged moieties, typically quaternary ammonium groups and zwitterionic surfactants comprise both cationic and anionic centers attached to the same molecule and thereby do not have a net charge.

Surfactant properties are reflected in the hydrophilic-lipophilic balance (HLB) value of the surfactant, wherein the HLB value determines the degree of hydrophilic versus lipophilic properties of a surfactant. The HLB value normally ranges from 0 to 20, where a low HLB value represents surfactants with high hydrophilic character, and a high HLB value represents surfactants with high lipophilic character. Surfactants are often used in combination with other surfactants, wherein the HLB values of the surfactant mixtures easily can be calculated. Surfactants, optionally together with other components, might improve the solubility of drug substances and might improve the oral bioavailability of drug substances. Self-Emulsifying Drug Delivery Systems (SEDDS) and Self Nano-Emulsifying Drug Delivery System

(SNEDDS) are oral drug formulation where an emulsion comprising the drug is formed in the gastrointestinal system. These SEDDS might improve the oral bioavailability of poorly water soluble drugs. The SEDDS typically comprise of surfactant, co-surfactant and a solvent. Since most surfactants and solvents used in SEDDS are liquids or semi-solids, the SEDDS are typically liquid formulations. Some recently published patent documents related to SEDDS include for example WO2014143127 (DIFFERENTIAL DRUG DEV ASSOCIATES LLC), WO20141 32134 (PRONOVA BIOPHARMA), WO2013072767 (PRONOVA BIOPHARMA) and WO2012160559 (RAPPAPORT FAMILY INST FOR RESEARCH IN HEALTHCARE),

Several surfactants and other additives used together with surfactants are liquids or semi-liquid materials. This property limits the use of surfactant for preparation of powders, especially dry powder, and tablets. However, solid formulations comprising surfactants and surfactants in mixture with other components are well known. Solid SEDDS (S-SEDDS) and solid SNEDDS (S-SNEDDS) in the form of powder are prepared by adsorbing SEDDS or SNEDDS on an inert carrier. The carriers used to prepare S-SEDDS and S-SNEDDS are microporous calcium silicate (Florite®), magnesium aluminium silicate Neusilin®) and silisium dioxide (Sylysia®, Aerosil 200). The powder can futher be filled into capsules or compressed to tablets.

Solid SEDDS including tablets are further described in: B. Tang et al. Development of solid self-emulsifying drug delivery systems: preparation techniques and dosage forms in Drug Discovery Today, 13, 13/14, July, page 606-612 (2008), A.A. Attama et al. The use of solid self-emulsifying systems in delivery of diclofenac in Int. J. Pharm., 262,23-28 (2003), M.L. Christiansen et al. Cinnarizine food-effects in beagle dogs can be avoided by

administration in a Self Nano Emulsifying Drug Delivery System (SNEDDS) in Eur. J. Pharm. Sci.,57, 164-172 (2014) and P. Carsten et al. Fed and fasted state gastro-intestinal in vitro lipolysis: In vitro in vivo relations of a conventional tablet, a SNEDDS and a solidified SNEDDS in Eur. J. Pharm. Sci.,57,232-239 (2014).

In some embodiments, the present invention provides that: Cyclodextrins form inclusion complexes with non-ionic surfactants with both low and high HLB values. The cyclodextrin/ non-ionic surfactant complex is in the form of a dry powder/dry granulate. The cyclodextrin/ non-ionic surfactant complex is in the form of a dry powder/dry granulate even when the non-ionic surfactant is a liquid or a semi-solid material. The cyclodextrin/ non-ionic surfactant complex is in the form of a dry powder/dry granulate even when the amount of non-ionic surfactant is very high (above 30% weight). The cyclodextrin/ non-ionic surfactant complex is in the form of a dry powder/dry granulate in combination with various drug substances. The cyclodextrin/ non-ionic surfactant complex is in the form of a dry

powder/dry granulate in combination with other surfactants. The cyclodextrin/ non-ionic surfactant complex is in the form of a dry powder/dry granulate in combination with solvents. The dry powder/granulate described above is tabletable per se with minimum amount of additives. The dry powder/granulate described above is tabletable even with very high loading of liquid surfactants. The tablets prepared as described above are within the specifications in Ph.Eur.with regard to physical, chemical and biological properties. The powders/granulates prepared as described above can be filled into capsules and the capsules are within the specifications in Ph. Eur. with regard to physical, chemical and biological properties. The cyclodextrin/ non-ionic surfactant complex has surfactant properties in aqueous media. The powder can be in the form of a solid self-emulsifying system where stable emulsions are formed spontaneously in the gastrointestinal system. The powder/granulates improve the oral bioavailability of drugs with poor aqueous solubility. The tablets improve the oral

bioavailability of drugs with poor aqueous solubility. The powder/granulates improve the stability of drugs with poor aqueous solubility. The tablets improve the stability of drugs with poor aqueous solubility. The present invention relates to dry powder comprising inclusion complex between cyclodextrin and non-ionic surfactant tablets comprising such powder. The powder preferably comprises a drug substance. Further, the present invention relates to a method for improving bioavailability of drug substances by administration of formulations comprising such powder or tablets.

Accordingly, in some embodiments, the present invention provides an inclusion complex of cyclodextrin and non-ionic surfactant, pharmaceutical compositions comprising such complexes, and use of such complexes as drug delivery systems.

A preferred aspect of the present invention relates to a solid inclusion complex of a drug and cyclodextrin and non-ionic surfactant, where the inclusion complex is crystalline.

In some embodiments, the composition is a dry composition of solid material comprising inclusion complex with cyclodextrin and non-ionic surfactant. In some embodiments, the dry composition is in the form of a powder or granulate or a tablet.

In some embodments, the dry composition comprises an additional surfactant and/or a solvent.

In some embodiments, the inclusion complexes described herein are formulated for oral administration.

In some embodiments, the dry composition forms an emulsion in the gastrointestinal system.

The cyclodextrin can be selected among unsubstituted and substituted cyclodextrins. The unsubstituted cyclodextrins include, but are not limited to, alpha-cyclodextrin, beta- cyclodextrin and gamma-cyclodextrin. The substituted cyclodextrins can be any

pharmaceutically acceptable cyclodextrin like, for example, including but not limited to, 2- hydroxypropyl-beta-cyclodextrin, methyl-beta-cyclodextrin and 4- sulfoxybutyl-beta- cyclodextrin.

The most preferred cyclodextrin for oral administration is, according to the present invention, beta-cyclodextrin.

The non-ionic surfactants used according the present invention include any pharmaceutically acceptable non-ionic surfactant with the whole range of HLB values. One preferred aspect is to combine two or more non-ionic surfactants to obtain a surfactant mixture with the HLB value of interest.

The HLB value of surfactant mixtures can be calculated based upon the general formula: HLB of surfactant mixture = HLB (surfactant A) x fraction of surfactant A + HLB (surfactant B) x fraction of surfactant B

Various pharmaceutically acceptable surfactants are commercially available from different suppliers under various trade names.

Tween®s (polysorbates) are nonionic surfactants which are polyoxyethylene sorbitan esters. Various Tween® products based on different polyoxyethylene sorbitan esters with different HLB vales are commercially available.

The most preferred polysorbates are according to the present invention:

polyoxyethylene sorbitan monolaurate (Tween 20) with HLB value 16.0, polyoxyethylene sorbitan monopalmitate (Tween 40) with HLB value 15.6, polyoxyethylene sorbitan monostearate (Tween 60) with HLB value 14.9, polyoxyethylene sorbitan tristearate (Tween 65) with HLB value 10.5, polyoxyethylene(20)sorbitan monooleate (Tween 80) with a HLB valuel 5.0 polyoxyethylene sorbane trioleate (Tween 85) with a HLB 1 1.0.

Span®s are nonionic surfactants which are sorbitan esters. Various Span® products based on different sorbitan esters with different HLB vales are commercially available.

The most preferred of these sorbitan esters are according to the present invention: sorbitan monolaurate (Span 20) with HLB value 8.6, sorbitan monopalmitate (Span 40) with HLB value 6.7, sorbitan monostearate (Span 60) with HLB value 4.7, sorbitan tristearate (Span 65) with HLB value 2.1 , sorbitan monooleate(Span 80) with HLB value 4.3, sorbitan trioleate (Span 85) with HLB value of 1.8.

Cremophor®s are nonionic surfactants which are derivatives of castor oil. Various Cremophor® with different HLB vales are commercially available. The most preferred of these Cremophors are: polyoxyethylated castor oil (Cremophor REL) with HLB values in the range 2- 14, hydrogenated polyoxyethylated castor oil (Cremophor RH40 ) with HLB values in the range 14- 16, hydrogenated polyoxyethylated castor oil (Cremophor RH60) with HLB values in the range 15-17, hydrogenated polyoxyethylated castor oil (Cremophor RO) with HLB value 16.

Pluronic® are nonionic copolymers composed of a central hydrophobic polymer (polyoxypropylene(poly(propylene oxide))) with a hydrophilic polymer

polyoxyethylene(poly(ethylene oxide))) on each side. Various Pluronic® products with different molecular weights and HLB vales are commercially available.

The most preferred of these Pluronics are: Pluronic L-31 with average molecular weight 1 100 Da and HLB value in the range 1.0-7, Pluronic L-35 with average molecular weight 1900 Da and HLB value in the range 18.0-23.0, Pluronic L-61 with average molecular weight 2000 Da and HLB value in the range 1.0-7.0, Pluronic L-81 with average molecular weight 2800 Da and HLB value in the range 1 .0-7.0, Pluronic®L-64 with average molecular weight 2900 Da and HLB value in the range 12.0-18.0, Pluronic®L-121 with average molecular weight 4400 Da and HLB value in the range 1.0-7.0, Pluronic®P-123 with average molecular weight 5800 Da and HLB value in the range 7-9, Pluronic®F-68 with average molecular weight 8400 Da and Pluronic®F- 108 with average molecular weight 14600 Da. The last two Pluronic products have very high HLB values.

Brij®s are nonionic surfactants comprising polyethylene ethers. Various Brij® products based on different polyethylene ethers with different HLB vales are commercially available.

The most preferred of these Brijs are: polyoxyethylene(4) lauryl ether (Brij 30) with a HLB value 9.7, polyoxyethylene (23) lauryl ether (Brij® 35) with a HLB value 16.9, polyoxyethylene (2) cetyl ether ( Brij® 52) with a HLB value 5.3, polyoxyethylene (10) cetyl ether ( Brij® 56) with a HLB value 12.9, polyoxyethylene (20) cetyl ether (Brij® 58) with a HLB value 15.7, polyoxyethylene (2) stearyl ether (Brij® 72) with a HLB value 4.9, polyoxyethylene (10) stearyl ether (Brij® 76) with a HLB value 12.4, polyoxyethylene (20) stearyl ether (Brij® 78) with a HLB value 15.3, polyoxyethylene (2) oleyl ether (Brij® 92V) with a HLB value 4.9, polyoxyethylene (2) oleyl ether (Brij® 93) with a HLB value 4, polyethylene glycol oleyl ether (Brij® 96V) with a HLB value 12.4, polyoxyethylene (10) oleyl ether (Brij® 97) with a HLB value 12, polyoxyethylene (20) oleyl ether (Brij® 98) with a HLB value 1 5.3, polyoxyethylene (100) stearyl ether (Brij® 700) with a HLB value 1 8.

Myrj® are nonionic surfactants comprising polyethylene stearates. Various Myrj® products based on different polyethylene ethers with different HLB vales are commercially available.

The most preferred of these Myrjs are: Myrj 45 with a HLB value of 1 1.1 , Myrj 49 45 with a HLB value of 1 5.0, Myrj® 52 45 with a HLB value of 16.9, Myrj® 53 with a HLB value of 17.9.

The most preferred other non-ionic surfactants to be used according to the present invention are, for example, including but not limited to, caprylocaproyl macrogol-8 glycerides (Labrasol) with a HPB value of 12, lauryl macrogol-32-glycerides (Gelucire 44/14) with a HLB value of 1 1 , stearoyl macrogol-32 glycerides (Gelucire 50/13) with a HLB value of 1 1 , oleoyl macrogol-6 glycerides (Labrafil M 1944 CS) with a HLB value of 9, linoleoyl macrogol-6 glycerides (Labrafil M 2125 CS) with a HLB value of 9, lauroyl macrogol-6- glycerides (Labrafil M 2130 CS) with a HLB value of 9, propylene glycol monocaprylate (Capryol PGMC) with a HLB value of 6, propylene glycol monocaprylate (Capryol 90) with a HLB value of 5, propylene glycol monolaurate (Lauroglycol FCC) with a HLB value of 5, polyglyceryl-3-diolate (Plurol Oleique CC 497) with a HLB value of 3 and propylene glycol monolaurate (Lauroglycol 90) with a HLB value of 3. All these products are available from Gattefosse in France.

Further non-ionic surfactants include generally hydrophilic block polymers like for example Polyoxamer 407 and Pluronic 127, ethoxylated linear alcohols, fatty acid esters, amine and amide derivatives and ethoxylated alkyl phenols.

The most preferred non-ionic surfactants are Cfemophor EL, Cremophor H 40, Cremophor RH60, Tween 20, Tween 80, Span 20, caprylocaproyl macrogol-8 glycerides, lauryl macrogol-32-glycerides, stearoyl macrogol-32 glycerides, oleoyl macrogol-6 glycerides, linoleoyl macrogol-6 glycerides, lauroyl macrogol-6-glycerides, propylene glycol

monocaprylate, propylene glycol monocaprylate, propylene glycol monolaurate, polyglyceryl- 3-diolat, Polyoxamer 407 and Pluronic 127.

The present invention is not limited to particular drug substances. The preferred drug substances, according to the present invention, are drug substances within Case 2 and Case 4 as defined by Gordon L. Amidon et al. in Pharmaceutical Research, 12, 3, 413-420 (1995). Case 2 drugs are drugs with low solubility and high oral permeability and case 4 drugs are drugs with low solubility and low oral permeability.

The most preferred drugs are drugs with molecular weight below 1500 Da and with low oral bioavailability and low aqueous solubility.

Drugs with combined low oral bioavailability and low aqueous solubility are the most preferred compounds according to the present invention.

The most preferred are drugs with molecular weight below 1500 Da, an aqueous solubility below 1 mg/ml (e.g. below 0.1 mg/ml) and oral bioavailability of less than 20 % (e.g., less than 1 5%, less than 10%, less than 5%, less than 2%, or less than 1 %).

Drug substances with low aqueous solubility have generally a high log P value. P is partition-coefficient between concentration of a drug substance in 1 -octanol and water and can be determined experimentally. If P is high, the drug substance is lipophilic. If P is 1 , the drug substance is both hydrophilic and lipophilic, and if P is below 1 , the drug substance is hydrophilic. The logarithmic figure (log P) is therefore positive for lipophilic drugs and negative for hydrophilic drugs. Drugs with combined low oral bioavailability and high log P are the most preferred compounds according to the present invention.

The most preferred are drugs with molecular weight below 1500 Da, a log P above 2 (e.g., above 2.5, above 3, above 3.5, above 4, above 5, or above 6) and oral bioavailability of less than 20 % (e.g., less than 15%, less than 10%, less than 5%, less than 2%, or less than 1 %).

Even more preferred are drug substances with high log P values without any acidic or basic functional groups. Such drug substances cannot be charged at physiological pH.

The drug substances include both well-known drugs in clinical use and new drugs in research and development.

The oral bioavailability of drug substances varies from almost 0 % to almost 100%. The absolute bioaviliability of some of the more frequently used drugs are: atorvastatin (bioavailability 12%), simvastatin (bioavailability less than 5%), losartan (bioavailability 33%), valsartan (bioavailability 25%), candesartan (bioavailability 40%), enalapril

(bioavailability 60%), atenolol (bioavailability 40-50%), propranolol (bioavailability 26%), hydrochlotiazide ( bioavailability 70%), cyclosporine (bioavailability very low), amphotericin B (bioavailability very low), dilthiazem (bioavailability 40%), phenoxymethylpenicillin (bioavailability 50%), azithromycin (bioavailability 40%), metformin ((bioavailability 50- 60%),

The list of drugs that are almost insoluble or have very low aqueous solubility is extensive. A few examples on these well-known drugs in clinical use worldwide include, but are not limited to, simvastatin, lovastatin, celecoxib, naproxen, ibuprofen, estradiol, testosterone, finasterid, glipizide, ketoconazole, methylprednisolone, mometrasone, triamcinolone, griseofulvin and amphotericin B.

Some typical examples of well-known drugs in clinical use include the following drug substances with known high log P values are: amiodarone (log P 7.81 ), amitriptyline (log P 4.41 ), amlodipine (log P 3.01 ), antazoline (log P 3.58), ariprazole (log P 3.76), atomoxetine (log P 3.36), bacampicillin (log P 3.52), benzphentamine (log P 3.84), benztropine (log P 4.04), bitolterol (log P 4. 16), bosentan (log P 4.36), bromodiphenhydramine (log P 4.03), brompheniramine (log P 3.24), bufuralol (log P 3.54), bupivacaine (log P 3.31 ), butacaine (log P 4.62), butclamol (log P 3.81 ), butorphanol (log P 3.54), carbenoxolone (log P 6.63), carvedilol (log P 4.1 1 ), chlorcyclizine (log P 3.24), chlorpromazine (log P 5.35),

chlorprothixene (log P 5.31 ), cinchonine (log P 3.69), citalopram (log P 3.47), clofibrate (log P 3.88), clopenthixol (log P3.91 ), clotrimazole 4.92), clozapine (log P 3.94), cyclazocine (log P 3.52), cyclobenzaprine (log P 6.19), cyproheptadine (log P 4.92), darifenicin (log P 3.78), deserpidine (log P 4.95), desipramine (log P 3.97), desloratadine (log P 3.50),

dextrobrompheniramine (log P 3.24), dextrofenfluramine (log P 3.55), dextromethorphan (log P 3.89), dibenzepin (log P 3.26), dibucaine (log P 4.40), diclofenac (log P 4.55), dicloxacillin (log P 3.10), dicyclomine (log P 4.64), diethazine (log P 5.55), diflunisal (log P 3.65), dihydroergocriptine (log P 6.37), dihydroergocristine (log P 6.55), dihydroergotamine (log P 5.69), dilevalol (log P 3.09), diltiazem (log P 4.73), dimethisoquin (log P 4.04), diperodon (log P 4.65), diphenhydramine (log P 3.27), diphenoxin (log P 3.97), diphenoxylate (log P 4.5 1 ), diphenylpyraline (log P 3.43), dipipanone (log P 5.10), dipyridamole (log P 3.35), donepezil (log P 3.91 ), doxepin (log P 3.85), droperidol (log P 3.10), duloxetine (log P 4.81 ), Emetine (log P 3.82), enalapril (log P 3.25), enalaprilat (log P 3.63), entacapone (log P 3.02), ergotamine (log P 7.37), estrone (log P 3.62), ethopropazine (log 4.77), etidocaine (log P 3.57), etomidate (log P 3.05), fenclofenac (log P 4.59), fenfluramine (log P 3.55), fenprofen (log P 3.72), fentanyl (log P 3.68), fesoterodine (log P 5.08), fexofenadine (log P 3.73), finasteride (log P 3.83), flurbiprofen (log P 3.66), flufenaic acid (log P 5.22), flumizole (log P 4.26), fluoxetine (log P 3.93), flupenthixol (log P 3.67), fluphenazine enanthate (log P 7.29)fluphenazine (log P 3.92), flurazepam (log P 4.84), flutamide (log P 3.52), fusidic acid (log P 5.76), fluvoxamine (log P 3.71 ), glibenclamide (log P 3.08), glyburide (log P 3.08), haloperidol (log P 3.76), hexylcaine (log P 3.65), hycanthone (log P 3.81 ), ibuprofen (log P 3.50), imipramine (log P 4.35), indacaterol (log P 3.88), indomethacin (log P 4.25), iocetamic acid (log P 4.57), iodipamide (log P 5.10), iodoquinol (log P 4.10), iopanoic acid (log P 4.65), iprindole (log P 5.02), irbesartan (log P 5.25), ketamine (log P 3.01)ketoconazole (log P 4.04), levallorphan 8Log P 3.85), leverphanol (log P 3.26), liothyronine (log P 3.91 ), Lisinopril (log P 3.47), loperamide (log P 4.15), loratadine (log P 3.90), losartan (log P 3.46), maprotiline (log P 4.36), meclizine (log P 5.28), meclofenamic acid (log P 5.44)medazepam (log P 3.89), mefenamic acid (log P 4.83), mepazine (log P 5.04), methadone (log P 3.93), methdilazine (log P 4.64), methotrimeprazine (log P 4.94), metolazone (log P 3.16), miconazole (log P 4.97), midazolam (log P 3.80), montelukast (log P 5.81 ), nabilone (log P 7.25), nebivolol (log P 4.08), nelfinavir (log P 7.28), nortriptyline (log P 3.97). novobiocin (log P 3.74)olanzapine (log P 3.08), orphenadrine (log P 3.33), oxybutynin (log P 5.05), oxyphenylbutazone (log P 3.28), pamaquine (log P 4.38), penbutolol (log P 4.02), pentazocine (log P 4.15), pergolide (log P 3.90), perphenazine (log P 3.94), perhexilene (log P 6.46), phencyclidine (log P 4.25), phenindamine (log P 3.81 ), phenindione (log P 3.19), phenothiazine (log P 4.15),

phenoxybenzamine (log P 3.69), phentolamine (log P 4.08), phenylbutazone (log P 3.38), phenyltoloxamine (log P 3.46), pimozide (log P 5.57), pipradrol (log P 3.61 ), pivampicillin (log P 3.88), Prasugel (log P 4.31 ), prazepam (log P 3.70), prochlorperazine (log P 4.65), promazine (log P 4.69), promethazine (log P 4.89), proparacine (log P 3.46), propoxyphene 8Log P 4.10), pyrathiazine (log P 4.15), Pyrrobutamine (log P 4.57), quinacrine (log P 5.59), resperidone (log P 3.04), reserpine (log P 3.65), salmeterol (log P 3.71 ), salsalate (log P 3.29), sertraline (log P 5.08), solifenacin (log P 3.70), spiperone (log P 3.25), sufentanil (log P 3.95), sulfasalazine (log P 3.05), tamoxifen (log P 5.13), tetracaine (log P 3.75)tetrahydrocannabinol (log P 6.84), thiopropazate (log P 4.76), thioridazine Log P 5.90), , thiothixene (log P 3.72), L-thyrosine (log P 4.72), tiagabine (log P 4.03), ticrynfen (log P 3.05)toloteridine (log P 5.23), trifluoperazine (log P 4.62), triflupromazine (log P 5.16), trimeprazine (log P 5.04),

Trimipramine (log P 4.71 ), triprolidine (log P 3.25), troleandomycin (log P 3.46), valdanafil (log P 3.64), valsartan (log P 4.02), verapamil (log P 4.02), vinblastine (log P 5.92), vincristine (log P 5.75)vindesine (log P 4.94), warfarin (log P 3.13) and zimeldine (log P 3.07). All log P values are calculated log P values from Foye ^' s Principles of Medicinal Chemistry. (Thomas L. Lemke, David A. Williams, Victoria F. Roche and S. William Zito), Seventh Edition, Lippincott Williams&Wilkins (201 1 ).

Some typical examples on well-known drugs in clinical use include the following drug substances with low known low bioavailability are: simvastatin and lovastatin.

The solvent can be any pharmaceutically acceptable solvent like for example, including but not limited to, glycerol, polyethyleneglycol (PEG) 300, PEG 400, propylene glycol, medium chain triglycerides like Labrafac PG from Gattefosse, glycerol esters like monolinoleate (Maisine 35- 1 from Gattefosse).

The most preferred solvents are glycerol, propylene glycol, PEG 400, Labrafac PG and Maisine 35-1 .

The additional surfactant may be any of the non-ionic surfactants listed above or an ionic surfactant. The ionic surfactants include both anionic surfactants and cationic surfactants. Typical anionic surfactants include for example salts of carboxylic acids, peril uorocarboxy lie acids and perfluorosulphonic acid, alkyl sulphate salts like sodium dodecyl sulphate and ammonium lauryl sulphate, sulphate ethers like sodium lauryl ether sulphate and alkyl benzene sulphonate salts. Cationic surfactants are typically quarternary ammonium

compounds like for example benzalkonium chloride, cetylpyridinium chloride, benzalconium chloride and cetyl trimethylammonium bromide or other trimethylalkylammonium salts.

Zwitterionic surfactants include for example dodecyl betaine, coco amphoglycinate and cocamidopropyl betaine. The most preferred additional surfactants include the most preferred non-ionic surfactants listed above and oleic acid.

The inclusion complexes can be prepared using different methods. These methods are for example described in Cyclodextrins in Pharmaceutics, cosmetics, and biomedicine.

Current and Future Industrial Applications. (Ed. Erem Bilenroy) Wiley (201 1 ). One of the preferred methods is to prepare the inclusion complex in a thick aqueous suspension at room temperature for minutes to hours followed by removal of the water. The aqueous solution comprises of cyclodextrin, non-ionic surfactant preferably drug substance(s) and optionally solvents, co-surfactants and other additives.

The drug substance(s) is preferably dissolved in the non-ionic surfactant, optionally a mixture of non-ionic surfactant and solvent and/or co-solvent, before the inclusion complex is prepared.

The water can be removed by evaporation and drying; preferably by use of vacuum drier, spray dryer, spray granulator or other standard equipment used in production of solid pharmaceuticals.

Tablets can be prepared using standard tableting presses by direct compression of the powder or granulate. The powder or granulate is dry and do not result in any technical problems during the tableting process, even when the powder or granulate comprise high amount of liquid non-ionic surfactant, optionally a liquid mixture of non-ionic surfactant and solvent and/or co-solvent.

Preferred aspects of the present invention relates therefore to tabletable dry powder, tabletable dry granulate and tablets comprising liquid non-ionic surfactants or liquid mixtures of non-surfactants and other components.

An even more preferred aspect of this part of the present invention relates to tabletable dry powder, tabletable dry granulate and tablets where the amount of liquid non-ionic surfactants or liquid mixtures of non-surfactants and other components is high or even more preferred very high.

Liquids or semi-liquids together with solid materials in powder, granulates and tablets are generally expected to form problems during tableting. The definition of the terms "liquid" and "liquid mixtures" in this context means compound or compound mixtures that are liquid or semi-liquid as pure compounds or in mixtures at temperatures during tableting. Liquids or semi-liquids are hereby defined as compounds or mixtures with melting point below 100 degrees centigrade, at least below 80 degrees centigrade, at least below 60 degrees centigrade, at least below 40 degrees centigrade and finally compounds and mixtures that are liquid at room temperature.

Most of the non-surfactants and several of the additives described in the current document are liquids. Mixtures of these compounds are therefore also liquids. For example are the polysorbates like Tween 80 and all "other the non-ionic surfactants" listed above (from Gatte fosse) liquids at room temperature.

The definitions of "high" and "very high" amount of liquid non-ionic surfactant or in liquid mixtures with other components in the dry tablet-able cyclodextrin powder or granulate are when the dry tablet-able cyclodextrin powder or granulate comprises more than 10 weight-% liquid non-ionic surfactant or in liquid mixtures with other components, preferably more than 20 weight-% liquid non-ionic surfactant or in liquid mixtures with other components, more preferably more than 30 weight-% liquid non-ionic surfactant or in liquid mixtures with other components, most preferably 40 weight-% or more of liquid non-ionic surfactant or in liquid mixtures with other components.

The crystalline property of the present inclusion complex of cyclodextrin with non- ionic surfactants is unexpected; especially when the non-ionic surfactant or non-ionic surfactant mixture according to the invention is a liquid.

As used herein, the term "crystalline property" means that a powder X-ray diffraction (powder-XRD) shows specific and characteristic patterns for a specific crystalline form. Further, crystalline property may relate to the amount (or percentage) of the compound that is in the crystalline form. One preferred aspect of the present invention relates to a powder or granulate with more than 20 % crystalline property, preferably a powder or granulate with more than 25 % crystalline property, more preferably a powder or granulate with more than 30 % crystalline property, more preferably a powder or granulate with more than 30 % crystalline property, even more preferably a powder or granulate with more than 40 % crystalline property, even more preferably a powder or granulate with more than 50 % crystalline property and most preferably a powder or granulate with more than 50 % crystalline property.

One preferred aspect of the present invention relates to capsules comprising almost entirely the powder or granulate comprising the inclusion complex.

Some tablets according to the present invention comprise one or more drug substance and are prepared from the powder or granulate comprising the inclusion complex of non-ionic surfactant and cyclodextrin. The drug substance(s) is preferably located within this powder or granulate. The amount of powder or granulate comprising the inclusion complex of non-ionic surfactant and cyclodextrin with drug substance(s) and optionally solvent and co-surfactant in a tablet varies and is dependent on drug dose and the nature of the drug.

One aspect of the present invention relates to tablets comprising a low amount (50% or less) of the powder or granulate comprising the inclusion complex of non-ionic surfactant and cyclodextrin with drug substance(s) and optionally solvent and co-surfactant in the tablets. This option might be of interest if the amount of drug substance(s) is low.

Another aspect of the present invention relates to tablets comprising a high amount (50% or more) of the powder or granulate comprising the inclusion complex of non-ionic surfactant and cyclodextrin with drug substance(s) and optionally solvent and co-surfactant in the tablets. This option might be of interest if the amount of drug substance(s) and/or the amount of non- ionic surfactants is high.

The present invention also provides tablets with very high amount of the powder or granulate; typically tablets comprising more than 90% of the present powder or granulate. The tablets, according to the present invention, comprise in addition to the present powder or granulate a lubricant like for example magnesium stearate.

One aspect of the present invention relates to tablets where the tablet core comprising no other components than the present powder or granulate and a lubricant.

Another aspect of the present invention relates to tablets that in addition to said powder or granulate and lubricant comprises other tablet excipients.

Typical tablet excipients are diluents like lactose, dicalcium phosphate,

microcrystalline cellulose, adsorbents like fumed silica, microcrystalline cellulose and magnesium carbonate, binding agents like polyvinylpyrrolidone (PVP), disintegrating substances like cross-linked polyvinylpyrrolidone, cellulose and modified starch.

Tablets preferably comprise of a coated tablet core. The coating is preferably a film coating like for example a thin film comprising hydroxypropylmethylcellulose or a functional coating to protect the tablet core from disintegrating in the acidic environment in the stomach. Typical substances used for enteric coating can be cellulose acetate phthalate.

The present invention is further illustrated by the following non-limiting examples

Examples

The invention is further illustrated by the following non-limiting examples: Reference example

Beta-cyclodextrin

Beta-cyclodextrin (20 gram) and water (1 5 ml) were mixed using a mortar and pestle. The material was dried at 40 degrees centigrade for one week.

Example 1 -7

Inclusion complex between beta-cyclodextrin and Tween 80

Beta-cyclodextrin and water (15 ml) were mixed using a mortar and pestle. Tween 80, Sigma, was added and the components were mixed in the mortar for about 5 minutes. The material was dried at 40 degrees centigrade for one week.

The amounts of beta-cyclodextrin and Polysorbate 80 in each example are shown below

Example Amount of Amount of Result

No. beta-cyclodextrin Polysorbate 80

1 1 8 gram 2 gram Dry solid powder

2 1 7 gram 3 gram Dry solid powder

3 16 gram 4 gram Dry solid powder

4 15 gram 5 gram Dry solid powder

5 14 gram 6 gram Dry solid powder

6 1 3 gram 7 gram Dry solid powder

7 12 gram 8 gram Dry solid powder

Example 8 -14

Inclusion complex between beta-cyclodextrin and Cremophor EL

Beta-cyclodextrin and water (15 ml) were mixed using a mortar and pestle. Cremophor EL was added and the components were mixed in the mortar for about 5 minutes. The material was dried at 40 degrees centigrade for one week.

The amounts of beta-cyclodextrin and Cremophor EL in each example are shown below

Example Amount of Amount of Result

No. beta-cyclodextrin Cremophor EL

8 1 8 gram 2.2 gram Dry solid powder

9 1 7 gram 3 gram Dry solid powder

10 16 gram 4.2 gram Dry solid powder

1 1 15 gram 5 gram Dry solid powder

12 14 gram 6 gram Dry solid powder 13 13 gram 7 gram Dry solid powder

14 12 gram 8 gram Dry solid powder

Example 15 -18

Inclusion complex between beta-cyclodextrin and Capryol 90

Beta-cyclodextrin and water (15 ml) were mixed using a mortar and pestle. Capryol 190 (Gattefosse, batch 134751) was added and the components were mixed in the mortar for about 5 minutes. The material was dried at 40 degrees centigrade for one week.

The amounts of beta-cyclodextrin and Capryol 190 in each example are shown below

Example Amount of Amount of Result

No. beta-cyclodextrin Capryol 190

1 5 1 8 gram 2 gram Dry solid powder

16 16 gram 4 gram Dry solid powder

17 14 gram 6 gram Dry solid powder

1 8 12 gram 8 gram Dry solid powder

Example 18 -21

Inclusion complex between beta-cyclodextrin and Labrasol

Beta-cyclodextrin and water (15 ml) were mixed using a mortar and pestle. Labrasol

(Gattefosse, batch 144789) was added and the components were mixed in the mortar for about 5 minutes. The material was dried at 40 degrees centigrade for one week.

The amounts of beta-cyclodextrin and Labrasol in each example are shown below

Example Amount of Amount of Result

No. beta-cyclodextrin Labrazol

1 8 18 gram 2 gram Dry solid powder

19 16 gram 4 gram Dry solid powder

20 14 gram 6 gram Dry solid powder

21 12 gram 8 gram Dry solid powder

Example 22 -24

Inclusion complex between beta-cyclodextrin and Labrfil Beta-cyclodextrin and water (15 ml) were mixed using a mortar and pestle. Labrafil M 1944 CS (Gattefosse, batch 133342) was added and the components were mixed in the mortar for about 5 minutes. The material was dried at 40 degrees centigrade for one week.

The amounts of beta-cyclodextrin and Labrasol in each example are shown below

Example Amount of Amount of Result

No. beta-cyclodextrin Labrafil M 1944CS

22 1 8 gram 4 gram Dry solid powder

23 16 gram 6 gram Dry solid powder

24 14 gram 8 gram Dry solid powder

Example 25 -27

Inclusion complex between beta-cyclodextrin and Lauroglycol

Beta-cyclodextrin and water (15 ml) were mixed using a mortar and pestle. Lauroglycol 90 (Gattefosse, batch 140723) was added and the components were mixed in the mortar for about 5 minutes. The material was dried at 40 degrees centigrade for one week.

The amounts of beta-cyclodextrin and Labrasol in each example are shown below

Example Amount of Amount of Result

No. beta-cyclodextrin Lauroglycol 90

25 1 8 gram 4 gram Dry solid powder

26 16 gram 6 gram Dry solid powder

27 14 gram 8 gram Dry solid powder

Example 28

Inclusion complex between beta-cyclodextrin and Capryol 90 comprising soyabean oil

Beta-cyclodextrin (20 gram) and water ( 15 ml) were mixed using a mortar and pestle. A mixture of Capryol 90 (Gattefosse, batch 134751 ) and soyabean oil (2 gram) was added and the components were mixed in the mortar for about 5 minutes. The material was dried at 40 degrees centigrade for one week. A dry powder was obtained.

Example 29 Inclusion complex between beta-cyclodextrin and Labrasol comprising soyabean oil

Beta-cyclodextrin (20 gram) and water (15 ml) were mixed using a mortar and pestle. A mixture of Labrasol (Gattefosse, batch 144789) (2 gram) and soyabean oil (2 gram) was added and the components were mixed in the mortar for about 5 minutes. The material was dried at 40 degrees centigrade for one week. A dry powder was obtained.

Example 30

Inclusion complex between beta-cyclodextrin and Labrafil comprising soyabean oil

Beta-cyclodextrin (20 gram) and water (1 5 ml) were mixed using a mortar and pestle. A mixture of Labrafil M 1944 CS (Gattefosse, batch 133342) (2 gram) and soyabean oil (2 gram) was added and the components were mixed in the mortar for about 5 minutes. The material was dried at 40 degrees centigrade for one week. A dry powder was obtained.

Example 31

Inclusion complex between beta-cyclodextrin and Lauroglycol comprising soyabean oil

Beta-cyclodextrin (20 gram) and water (15 ml) were mixed using a mortar and pestle. A mixture of Lauroglycol 90 (Gattefosse, batch 140723) (2 gram) and soyabean oil (2 gram) was added and the components were mixed in the mortar for about 5 minutes. The material was dried at 40 degrees centigrade for one week. A dry powder was obtained.

Example 32

Inclusion complex between beta-cyclodextrin and Cremophor EL comprising

amphotericin B

Amphotericin B (Alpharma, lot no.A 1960540) (100 mg) was mixed with Cremophor EL (Sigma, Lot no. 0001439553) (300 mg). Beta-cyclodextrin (3g) and water (1 ml) were mixed using a mortar and pestle. The mixture of amphotericin B and Chremophor EL was added and the components were mixed in the mortar for about 5 minutes. The material was dried. The product was a dry yellow powder.

Example 33 Inclusion complex between beta-cyclodextrin and Cremophor EL comprising soyabean oil and amphotericin B

Amphotericin B (Alpharma, lot no. A 1960540) (100 mg), Cremophor EL (Sigma, Lot no. 0001439553) (300 mg) and soyabean oil (Aldrich, batch no. 12803TB) (2 gram) was mixed. Beta-cyclodextrin (l Og) and water (10 ml) were mixed using a mortar and pestle.The mixture of amphotericin B, Chremophor EL and soya bean oil was added and the components were mixed in the mortar for about 5 minutes. The material was dried. The product was a dry yellow powder.

Example 34

Formulation comprising ciclosporin and inclusion complex between macrogolglycerol hydroxystearate/polyoxyl 40 hydrogenated castor oil

A package of Sandimmune Neoral capsules 25 mg (50 capsules) (lot no S0217) was bought at the local pharmacy. Each capsules comprised in addition to ciclosporin the following additives: alpha-tocopherol ethanol anhydrous, propylene glycol (10 mg), corn oil-mono-di- triglycerides and macrogolglycerol hydroxystearate / polyoxyl 40 hydrogenated castor oil (40.5 mg)

10 capsules were physically broken and acetone (10 ml) was added. The mixture was shaken for 2 minutes and the acetone extract was decanted of. More acetone (10 ml) was added to the broken capsules and shaked for 2 minutes. The acetone was decanted of. The grey capsules bits were visually inpected and was free from the the oily content. The combined acetone extracts was evaporated.

Beta-cyclodextrin (5 gram) and water (5 ml) were mixed using a mortar and pestle. The mixture of ciclosporin, macrogolglycerol hydroxystearate/polyoxyl 40 hydrogenated castor oil, alpha-tocopherol and propylene glycol from the evaportated extract above was added, and the components were mixed in the mortar for about 5 minutes. The material was dried. The product was a dry powder.

Example 35

Inclusion complex between beta-cyclodextrin and Cremophor EL comprising soyabean

011 and atorvastatin Atorvastatin calcium ( 2 gram) was mixed with Cremophor EL (3 gram) and soyabean oil (1 gram).

Beta-cyclodextrin (30g) and water (20 ml) were mixed using a mortar and pestle. The mixture of atorvastatin calcium, Cremophor EL and soyabean oil was added and the components were mixed in the mortar for about 5 minutes. The material was dried. The product was a dry powder.

Example 36

Tablets comprising atorvastatin and inclusion complex between beta-cyclodextrin and Cremophor EL

A tablet (6 mm diameter, 360 mg tablet weight) was prepared by direct compression of the complex of example 35. Piston pressure was 0.5 tons. The tablet had good mechanical properties. One tablet comprised 20 mg atorvastin calcium.

Example 37

Tablets comprising ciclosporin and inclusion complex between macrogolglycerol hydroxystearate/polyoxyl 40 hydrogenated castor oil

A tablet (6 mm diameter, 287 mg tablet weight) was prepared by direct compression of the complex of example 34. Piston pressure was 0.5 tons. The tablet had good mechanical ' properties. One tablet comprised 12.5 mg ciclosporin.

All publications and patents mentioned in the above specification are herein incorporated by reference in their entirety for all purposes. Various modifications and variations of the described compositions, methods, and uses of the technology will be apparent to those skilled in the art without departing from the scope and spirit of the technology as described. Although the technology has been described in connection with specific exemplary embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the described modes for carrying out the invention that are obvious to those skilled in

pharmacology, biochemistry, medical science, or related fields are intended to be within the scope of the following claims.