WO2017216584A1

WO2017216584A1 - New compositions

Info

Publication number: WO2017216584A1
Application number: PCT/GB2017/051782
Authority: WO
Inventors: Albert Mihranyan
Original assignee: Albert Mihranyan
Priority date: 2016-06-17
Filing date: 2017-06-19
Publication date: 2017-12-21
Also published as: GB201610628D0

Abstract

There is provided a pharmaceutical composition comprising a modified microcrystalline cellulose excipient and an active pharmaceutical ingredient (e.g. from the Type 2 or 4 BCS class), wherein the modified microcrystalline cellulose excipient has a relatively high5 surface area. Compositions of the invention find particularly utility as formulations comprising BCS Type 2 and 4 drugs, including NSAIDs or other drugs, that may be employed in the treatment of migraine and dysmenorrhea, as well as formulations comprising other poorly soluble active ingredients where rapid release in vivo is advantageous.

Description

New Compositions

Field of the Invention This invention relates to new cellulose-based pharmaceutical compositions that provide for enhanced solubility of active ingredients, such as Type 2 and 4 BCS drugs, featured with low solubility in the gastrointestinal tract. The invention also relates to methods of manufacturing such pharmaceutical compositions. Background

The drug needs to dissolve first before it can be absorbed. According to Biopharmaceutics Classification System (BCS) all drugs are divided in 4 general groups based on their solubility and permeability (Amidon, G.L. et al. 1995. Pharm. Res. 12(3):413-420).

According to FDA BCS guidelines, the following boundaries are currently valid:

• A drug substance is considered HIGHLY SOLUBLE when the highest dose strength is soluble in < 250 ml water over a pH range of 1 to 7.5.

• A drug substance is considered HIGHLY PERMEABLE when the extent of absorption in humans is determined to be > 90% of an administered dose, based on mass-balance or in comparison to an intravenous reference dose.

• A drug product is considered to be RAPIDLY DISSOLVING when > 85% of the labeled amount of drug substance dissolves within 30 minutes using USP apparatus I or II in a volume of < 900 ml buffer solutions.

Further, a dose number Do may also be useful as a solubility indicator:

M

D = o.

V 0 xS app

(1) wherein Mo is the maximum dose, Vo is the volume available for dissolution, normally 250 ml, and S_app is the apparent solubility of the drug in the medium. Thus, Do<1 in a range of pH between 1 and 7.5 indicates good solubility, whereas if Do>1 at any pH the solubility of a drug is poor.

The present invention pertains to enhancing the solubility and bioavailability of Type 2 and 4 BCS drugs. Various APIs which are classified as Type 2 or 4 BCS drugs are disclosed in Takagi et al. Mol. Pharm. 2006; 3(6): 631-643; Lindenberg et al., Eur. J. Pharm. Biopharm. 2004; 58: 265-278; and Pham T. et al., Mol. Pharm. 2013; 10: 2445-2461. These references mainly deal with APIs on the WHO essential drugs list. However, the invention is useful also for developmental substances since it is known that at least more than half and as much as 90% of drug candidates are poorly soluble substances. In the context of the drug substances useful in the present invention, the molecular descriptors for typical BCS Type 2 and 4 substances can be used as summarized by Pham T. et al. Mol. Pharm. 2013; 10: 2445-2461 , provided that they contain at least one aromatic ring or polycondensed cyclic structure.

Table 1 - Typical molecular descriptors of various classes BCS drugs. Table adapted from Pham T. et al. Mol. Pharm. 2013; 10: 2445-2461.

Type 1 BCS Type 2 BCS Type 3 BCS Type 4 BCS logD pH6 0.71/0.65 1.81/1.9 -0.88/- 1.11 1.37/1.28 mean/median

logD pH7.5 -1.72 to 5.18 -8.24 to 5.07 -7.69 to 5.18 -8.11 to 6.6 range

logD pH7.5 1.34/1.18 1.63/1.67 -0.56/-0.73 1.40/1.00 mean/median

nHA+B range 1 -15 1-40 2-27 1 -28 nHA+B 4.97/4 6.24/6 8.81/8 10.81/10 mean/median

RBN, range 0-13 0-19 0-16 1 -20

RBN, mean 4.12/4 4.34/4 5.07/4 7.56/7 /median

RBN, rotating bonds number; nHA+B total number of hydrogen bond acceptors and donors; Papp apparent permeability; logD pH dependent distribution coefficient in octanol-water; logP partition coefficient in octanol-water; Mw molecular weight Most of NSAIDs are normally Type 2 or 4 BCS substances with low solubility although some of them, such as salicylic acid derivatives e.g. ASA, salicylic acid, ethenzamide, etc., or acetaminophen, are classed as Type 1 (or Type 3) substances. NSAIDs are a practical model of poorly soluble drugs because they are affordable and have relatively low toxicity as compared to other pharmacological classes of drugs and therefore are less hazardous for research personnel and environment.

NSAIDs mimic arachidonic acid (AA) to be able to inhibit COX, i.e. (i) they contain a centre of acidity or a free carboxylic group and (ii) are largely lipophilic and feature at least one aromatic ring. Normally, NSAIDs have a centre of acidity, typically represented by a carboxylic acid group or alternatively by enolic group, hydroxamic acid, sulfonamide, or a tetrazole ring. The acidic group of NSAIDs is important for H-bonding with the polar region at Arg120 and oppositely located Tyr355 of COX (Hawkey 1999. Lancet 353:307- 314). All NSAIDs possess at least one aromatic ring, which renders NSAIDs lipophilic, which is essential for inhibiting COX enzymes and ensures unhindered passive diffusion across biological membranes. The overall lipophilic character of NSAIDs results in poor solubility-limited bioavailability, i.e. Type 2 and 4 BCS drugs. Another important parameter is rate of absorption. Because most NSAIDs have poor solubility, their rate of absorption is limited and this results in poor bioavailability. To enhance the bioavailability and achieve a therapeutic effect, NSAIDs are typically administered in high doses and the peak plasma concentration is reached usually in 2 hours.

The administration of high doses of NSAIDs is partly the reason for the side effects, such as peptic ulcers and ultimately bleeding or perforation of the stomach, associated with these drugs. Some 10% to 50% of patients are unable to tolerate treatment with NSAIDs because of side effects, including abdominal pain, diarrhoea, and upset stomach. There is therefore a need to provide formulations containing NSAIDs, which are able to produce a therapeutic effect as rapidly as possible while minimising the risk of side effects for the patient. Oral route of drug administration is the most frequently used and convenient route for administration of many drugs. Microcrystalline cellulose is an important tableting excipient for oral administration. European Pharmacopoiea defines microcrystalline cellulose (MCC) as purified, partially depolymerized cellulose, prepared by treating a- cellulose, obtained as a pulp from fibrous plant material, with mineral acids. Although the primary aim of treating a-cellulose with mineral acid to a so-called level-off degree of polymerization (DP 100-350) is to remove amorphous regions of cellulose, the overall degree of crystallinity of MCC does not exceed 80% as measured by XRD (Mihranyan et al. Int. J. Pharm. 2004; 269 (2), 433-442). Normally MCC is an essentially non-porous powder featuring a surface area around 0.5-1 m²/g as measured by nitrogen gas adsorption (ibid). MCC is normally produced by spray-drying of the cellulose slurry that is obtained following the acidic hydrolysis.

Oguchi T. et al., Yakuzaigaku, Vol. 57, No. 3 (1997) 168 discusses the use of a porous form of microcrystalline cellulose, referred to as "porous crystalline cellulose" PCC, as a drug carrier in a composition with naproxen. However, the manner in which the drug carrier is prepared is not disclosed. Here and throughout the text the term PCC refers solely to an undisclosed material supplied by Asahi Kasei, Japan. In the disclosed document, PCC is a material featured with pores, which are predominantly 4 nm (40 A) in size.

Matsumoto K. et al. , Chem. Pharm. Bull. 46(2) 314-318 (1998) and Matsumoto K. et ai, Int. J. Pharm. 1994: 108: 167 discloses the use of PCC in mixtures with ethenzamide, i.e. a type 1 (3) BCS substance. No details regarding the preparation of the excipient are provided and PCC is used having pores, which are predominantly below 10 nm and centred around 4 nm in size. The material described therein displays poor stability in the presence of moisture as it progressively loses its specific surface area when exposed to various relative humidities.

Tozuka Y., et al. Bull. Chem. Soc. Jpn., 73, 1567-1572 (2000) discloses a composition of PCC with 2-naphthoic acid, a non-pharmaceutical ingredient. However, very little information concerning the origin of the PCC is provided.

Nakai Y. et al., Chem. Pharm. Bull. 26(10) 2983-2989 (1978) discloses compositions of MCC with naphthalene (non-pharmaceutical ingredient), camphor and o-cresol, non- pharmaceutical ingredient. Nakai Y., Drug Dev. Ind. Pharm. 1986; 12(7): 1017-1039. discloses formulations containing ground MCC mixtures having enhanced solubility. It is clear from Nakai (1986) that the drugs are not stable in the formulations disclosed therein. Furthermore, it is evident from the XRD data that the structure of the MCC gradually changes resulting in the MCC becoming progressively more amorphous over time. The literature also discusses the effect of pore size on amorphization inside the pores of various adsorbent materials. Oguchi T. et al., Yakuzaigaku, Vol. 57, No. 3 (1997) 168; Matsumoto et al. Int. J. Pharm. 1994: 108: 167; Yonemochi and Yamamoto in Encyclopedia of Surface and Colloid Science, Ed. P. Somasundaran, 2^nd ed., 2006, vol. 6, pp. 5068-5077 discuss in great detail the importance of pore size in controlled pore glasses on amorphisation behaviour in porous matrices. In particular, amorphisation behaviour is strongest when the size of the pores is less than 30 nm, and more preferably less than 10 nm. It is believed that in sufficiently small pores the reorientation and crystallisation is effectively hindered. Further, Yonemochi et al. Chem Pharm Bull 1991 ; 39: 1027 report higher chemical instability of aspirin was associated mainly with pores below 30 nm because in these pores aspirin was essentially amorphous, while above 30 nm more of the aspirin was crystalline and therefore more stable.

The listing or discussion of an apparently prior-published document in this specification should not necessarily be taken as an acknowledgement that the document is part of the state of the art or is common general knowledge. Disclosure of the Invention

According to a first aspect of the invention, there is provided a pharmaceutical composition comprising a modified microcrystalline cellulose excipient and an active pharmaceutical ingredient, wherein the modified microcrystalline cellulose excipient has a surface area of from about 2 to about 60 m²/g. Compositions comprising such features are hereinafter referred to together as "the compositions of the invention".

The inventor has advantageously found that compositions of the invention provide for rapid release of active pharmaceutical ingredients, particularly Type 2 and 4 BCS active ingredients, and also provide for an enhancement of their bioavailability in the gastrointestinal tract (GIT) following peroral administration of the composition. In one embodiment, substantially all (e.g. at least about 85%) of the drug is released from the formulation in the first hour following administration of the formulation. The release may also be such that amount of drug released from the composition reaches a plateau within a short time (e.g. within about 1 hour, such as within about 15 minutes). That is, substantially all (e.g. at least about 90%) of the total amount of drug that is released during the first 24 hours may be released during the first two hours (e.g. during the first 60 minutes). In the present application, the terms "rapid release" and "immediate release" are used interchangeably. The compositions of the invention are not limited to oral administration, and can be delivered by other routes, as is discussed elsewhere herein.

The term "rapid release" will be understood by the skilled person to refer to compositions that provide for, and/or are adapted to provide for, a "quick" and/or an "immediate" release of drug (in which drug is released at a sufficiently high rate for a sufficient period of time to produce a therapeutic response in a very short time) from the formulation. Release from the formulation refers to release of the drug from the network structure of the modified microcrystalline cellulose excipient.

The compositions of the invention are also advantageous as they exhibit an increased physical stability of the active pharmaceutical ingredient (e.g. an increased stability of its physical form) within the formulation. In the compositions of the invention, the active pharmaceutical ingredient, which is typically a Type 2 or 4 BCS substance, is preferably present in a predominantly amorphous form. The compositions allow the active pharmaceutical ingredient to remain in such a predominantly amorphous form for an extended period of time (e.g. up to at least 1 month, such as up to at least six months). Upon release from the cellulose carrier, the active pharmaceutical ingredient is provided in a form having a high degree of amorphicity compared to other formulations. This in turn enhances the rate of dissolution of the active pharmaceutical ingredient in surrounding media, and accelerates uptake by the body.

As is mentioned elsewhere herein, the compositions of the invention may contain a plurality of active pharmaceutical ingredients, provided that at least one of said active pharmaceutical ingredients, which is typically a Type 2 or 4 BCS substance, is present in a predominantly amorphous form.

Enhanced dissolution is particularly important for Type 2 and 4 BCS active ingredients as these substances have a low solubility profile. By enhancing the dissolution rate of the active pharmaceutical ingredient following administration, the overall dose of drug that is provided to the subject may be reduced while still achieving the intended therapeutic benefits.

Microcrystalline cellulose (MCC) is a well-defined and thoroughly studied natural polymer that is profoundly important in the pharmaceutical industry, especially in oral tablet formulations. MCC is particularly useful as a pharmaceutical tableting aid. A complete description of MCC is provided in European Pharmacopoeia.

Microcrystalline cellulose is produced by mineral acid hydrolysis of refined cellulose to a level-off degree of polymerisation (DP 100-350). Under controlled conditions, the acid induces hydrolytic cleavage of glycosidic bonds in the amorphous regions of cellulose in the fibres leaving crystalline regions intact. The free crystallites flocculate and form compact structures of the cellulose fibre aggregates in the dispersion. The produced slurry is then washed and spray-dried to finally produce dry solid powder. The surface area of such conventional MCC is typically about 0.5-1 m²/g, measured by N2 gas adsorption.

The compositions of the invention comprise a modified microcrystalline cellulose excipient, which is obtainable from microcrystalline cellulose. The modified microcrystalline cellulose excipient has a surface area of from about 2 to about 60 m²/g which is significantly higher than that associated with conventional microcrystalline cellulose (which typically has a surface area in the region of 0.5-1 m²/g, measured by N2 gas adsorption), and significantly lower than that associated with "porous crystalline cellulose", PCC (which typically has a surface area in excess of 90 m²/g). It is surprisingly observed that the modified microcrystalline cellulose excipient disclosed herein (also referred to herein as P-MCC) can inhibit recrystallization of amorphous drug even if it features pores predominantly of about 50 nm in size (diameter), while previously it was suggested that pores smaller than 30 nm, and more preferably smaller than 10 nm, are needed to observe such effect. For instance, in PCC the active pores are predominantly in the region around 4 nm in size, see Oguchi et al. Yakuzaigaku, Vol. 57, No. 3 (1997) 168. Thus in one embodiment, the modified microcrystalline cellulose excipient comprises pores having a median pore size of greater than or about 40 nm (e.g. from about 40 nm to about 60 nm), or particularly greater than or about 50 nm.

It is believed that the surface area is also an important feature in this respect. In one embodiment, the modified microcrystalline cellulose excipient has a surface area of from about 2.5 to about 50 m²/g, for example from about 5 to about 50 m²/g. In a further embodiment, the modified microcrystalline cellulose excipient has a surface area of from about 5 to about 40 m²/g, e.g. from about 5 to about 30 m²/g, such from about 5 to about 20 m²/g. References herein to the surface area of the modified microcrystalline cellulose excipient are to the surface area of that excipient in the absence of any active pharmaceutical ingredient, i.e. prior to the introduction of an active pharmaceutical ingredient. When an active pharmaceutical ingredient is brought into association with a modified microcrystalline cellulose excipient as defined herein and subjected to processing conditions that are suitable for allowing these two ingredients to become thoroughly mixed, a portion the active pharmaceutical ingredient is expected to become incorporated into the pores in the modified microcrystalline cellulose excipient with the result that the apparent surface area of the modified microcrystalline cellulose excipient will be measurably lower than the surface area prior to introduction of the API.

Surface area values mentioned herein refer to values determined through measuring adsorption and desorption of a gas (typically nitrogen gas, at 77 K), and calculating the specific surface area according to the BET method during adsorption. One skilled in the art will attest that different gases for measuring the surface area may yield different values. Further, different non-gas adsorption methods may also yield different values due to the different accessibility of the measuring analyte to the pores. The modified microcrystalline cellulose excipients used in the compositions of the invention may also have total pore volumes that are particularly suited to the uses disclosed herein. Suitable pore volumes that may be mentioned in this respect include pore volumes of at least about 0.005 cm³/g (e.g. ranging from about 0.005 to about 0.2 cm³/g). The pore volumes are obtained from condensation of gas at relative pressures approaching 1. Other methods may yield different volumes. Thus, in one embodiment, the modified microcrystalline cellulose excipient has a total pore volume of at least about 0.005 cm³/g. In a further embodiment, the modified microcrystalline cellulose excipient has a total pore volume of from about 0.005 to about 0.2 cm³/g, such as from about 0.01 to about 0.1 cm³/g, preferably from about 0.01 to about 0.05 cm³/g. The pore size distribution may be determined using any standard techniques known to those skilled in the art. One such suitable method includes calculation via the DFT method based on N2 adsorption data.

The pore volume of the modified microcrystalline cellulose excipients disclosed herein may also vary in a characteristic manner with the size of said pores. Compared to ordinary MCC, which is essentially non-porous, the modified microcrystalline cellulose excipient disclosed here shows specific surface area and total pore volume values which are about an order of magnitude larger. Furthermore, the pore size distribution is broad and predominantly centred at around 50 nm. It has been unexpectedly found that an excipient having such larges pores is capable of being used to enhance the solubility of the BCS Class 2 and 4 drugs mentioned herein. PCC on the other hand typically has very much smaller pore sizes (with a median value in the region around 4 to 5 nm) and so there would be a greatly reduced contribution to the total pore volume from pores having a diameter in the region of 50 nm.

The chemical structure of said cellulose may be provided either in the form in which it is naturally produced, or as a derivative of such a form. Derivatives that may be mentioned in this respect are produced by surface limited modification of cellulose without its dissolution. The chemical routes of modification may include any of the known surface limited reactions involving primary and secondary alcohols such as but not limited to TEMPO-mediated oxidation, acylation, esterification, etherification, epoxylation, sulfonation, phosphorylation, and halogenation, e.g. chlorination, bromination, or iodination. Such derivatives are typically only present at the 2^nd, 3^rd and 6^th carbon atoms of the D-glucose units. It is also preferred that, when the cellulose is provided in the form of a derivative, it is a surface modified cellulose without dissolution. By this we mean that the cellulose has been modified primarily at only the exposed surfaces of the network structure rather than at every modifiable position on every D-glucose unit within the cellulose network. By limiting the modifications to only the surface regions, the large scale structure of the cellulose that is present prior to chemical modification can be preserved during and after chemical modification. For the avoidance of doubt, the surface- and bulk-modified celluloses can be discerned by their degree of crystallinity, i.e. the degree of crystallinity of surface modified cellulose will be essentially unaltered following chemical modification, whereas that of bulk modified cellulose will be significantly reduced, compared to the unmodified cellulose.

The modified microcrystalline cellulose excipients that are useful in the compositions of the invention may be prepared by way of a variety of techniques, using standard equipment, such as by spray-drying a low surface area microcrystalline cellulose (i.e. MCC having a surface area of from about 0.5 to about 1 m²/g).

Processes for the formation of compositions of the invention typically involve spray- drying a dispersion comprising microcrystalline cellulose precursor (e.g. a low surface area microcrystalline cellulose) in a suitable solvent. Such a process requires the formation of a dispersion comprising microcrystalline cellulose precursor and a suitable solvent system. Solvent systems that may be used in this respect include aqueous solvents, e.g. mixtures of water with one or more additional water-miscible solvents (preferably one or more additional volatile water-miscible solvents). Thus, according to a second aspect of the invention, there is provided a process for preparing a modified microcrystalline cellulose excipient as hereinbefore defined, which process comprises:

(i) forming a dispersion comprising a microcrystalline cellulose precursor and a solvent system, wherein the solvent system comprises a mixture of water and one or more volatile water-miscible solvents; and

(ii) spray-drying said dispersion.

Particular solvent systems that are useful in the formation of modified microcrystalline cellulose excipients having the desired surface area include mixtures of water with one or more additional water-miscible solvents. Water-miscible solvents that may be used in this context are non-aqueous solvents with a relatively high volatility. Without wishing to be bound by theory, it is believed that the evaporation of the water-miscible solvent during the spray drying process accelerates the removal of the water from the dispersion, which in turn reduces the extent to which the porous structure of the spray-dried microcrystalline cellulose excipient collapses during the drying process. This allows the relatively high porosity in the final modified microcrystalline cellulose excipient to be attained. Suitable solvents for use in this respect include water-miscible solvents having a vapour pressure of at least about 1 kPa, e.g. at least about 5 kPa, at 25°C. Examples of such solvents include alcohols (such as methanol, ethanol and propanol (e.g. n- propanol and isopropanol)), ketones (such as acetone and methyl ethyl ketone), ethers (such as tetrahydrofuran), acetonitrile and mixtures thereof.

Further particular solvent systems that may be mentioned include solvent systems in which the one or more volatile water-miscible solvents are present in an amount ranging from about 10 to about 70% by volume of the solvent system. In one embodiment, the one or more volatile water-miscible solvents are present in an amount ranging from about 30 to about 60% by volume of the solvent system. The precursor of microcrystalline cellulose that may be used in such dispersions may be a particulate material, preferably one which has a D50 value (prior to the spray drying step) of up to 1 μηι, e.g. up to 500 nm.

Other forms of microcrystalline cellulose precursor that may be suitable for incorporation into a dispersion in order to form the modified microcrystalline cellulose excipient include so-called dispersible-grade microcrystalline celluloses. Dispersible-grade microcrystalline celluloses typically comprise a mixture of microcrystalline cellulose and one or more hydrocolloids in which the microcrystalline cellulose and one or more hydrocolloids have been co-spray dried. The hydrocolloids used in dispersible-grade microcrystalline celluloses are typically carbohydrates. Examples of hydrocolloids that are suitable in this respect include carboxymethylcellulose (e.g. sodium carboxymethylcellulose), carrageenan, guar gum, sodium alginate (as well as mixtures thereof). Thus, in one embodiment of the second aspect of the invention, the microcrystalline cellulose in the dispersion is a dispersible-grade microcrystalline cellulose comprising microcrystalline cellulose and a hydrocolloid selected from the group consisting of carboxymethylcellulose (e.g. sodium carboxymethylcellulose), carrageenan, guar gum, sodium alginate, and mixtures thereof. Examples of commercially available dispersible grades of microcrystalline cellulose include Avicel RC or CL grades, Vivapur MCG, Neocel, and the like.

If a conventional low surface area microcrystalline cellulose is used as the starting material it can be re-hydrolysed with a strong mineral acid, such as hydrochloric acid, sulphuric acid, nitric acid or phosphoric acid prior to the step of forming a dispersion for spray-drying, as required by the second aspect of the invention. The use of the phrase "re-hydrolysed with a strong mineral acid" in this context, refers to an acid hydrolysis step that is additional to any acid hydrolysis step that was conducted during the production of the microcrystalline cellulose from refined cellulose. Thus, in one embodiment of the second aspect of the invention, the process further comprises acid hydrolysis of the microcrystalline cellulose precursor prior to the formation of the dispersion (i.e. the dispersion with a solvent system comprising a mixture of water and one or more water- miscible solvents). The product obtained by such an acid hydrolysis step may be further processed prior to its incorporation into the dispersion for the spray-drying step. Such further processing steps include neutralisation, sonication and/or high-shear homogenisation (e.g. using a fluidiser). Homogenisation is particularly useful as it enables the formation of a homogeneous dispersion, which in turn enables greater control of the relative porosity of the final modified microcrystalline cellulose excipient.

The use of dispersible-grade microcrystalline celluloses, as discussed above, in the formation of the modified microcrystalline cellulose excipient may be particularly advantageous as it should not be necessary to subject such materials to an additional acid hydrolysis step prior to dispersion and generally require lower energy input for dispersion prior to spray-drying.

Spray-drying may be performed by way of a variety of routine techniques, and using standard equipment, known to the skilled person. The spray-drying is typically performed in inert atmosphere, i.e. in the substantial absence of oxygen gas. While the inlet temperature, which is invariably higher than that of the outlet, can vary depending on the composition of the solvent mixture, the outlet temperature is set to that corresponding to the evaporation temperature of the solvent featured with the highest boiling point. For instance, if water is one of the components and has the highest boiling temperature among the solvents, the outlet temperature is set at about 95-105 °C. A suspension of the microcrystalline cellulose precursor in a solvent system (e.g. as defined above) is typically fed into a spray-dryer. The suspension is then released in the form of a spray at a suitable flow rate, e.g. from 0.1 to 1000 L/h, in a nitrogen atmosphere. The feed rate of the liquid is adjusted so that the outlet temperature range is maintained as discussed above, as known by someone skilled in the art.

As is stated above, the compositions of the invention comprise a microcrystalline cellulose excipient having a surface area of from about 2 to about 60 m²/g, and such microcrystalline cellulose excipients may be obtained by the processed described herein. Such celluloses may be referred to as "modified microcrystalline cellulose excipients". Thus, in one embodiment, the modified microcrystalline cellulose excipient in the composition of the invention is obtainable by a process as defined in the second aspect of the invention. The ability of the modified microcrystalline cellulose excipients disclosed herein to form stable amorphous mixtures with an active pharmaceutical ingredient is an important property of these materials. The data in Example 6 show that test material exhibits excellent stability following storage for at least 2 months at room temperature and 75% relative humidity, as followed by X-ray diffraction analysis.

The compositions of the invention have good physical stability. Physical stability refers to stability to undesired solid-state transformations of the drug, the modified microcrystalline cellulose excipient, or both. Examples of solid-state transformations include collapse of the cellulose porous structure, amorphous-crystalline transformations, and the formation of polymorphs. A stable amorphous composition is one in which the drug in the composition remains present in a predominantly amorphous state, e.g.≥90% amorphous following long term storage (e.g. storage for at least 2 months under ambient conditions). Changes in amorphicity may be quantified using melting enthalpy data obtained in differential scanning calorimetry (DSC). Alternatively, this may be qualitatively verified by the absence of sharp peak in XRD which would otherwise be indicative of crystalline drug and/or its polymorph. The WHO essential drugs list includes the following Type 2 and 4 BCS drug categories: antihelminthic, anticonvulsant, antiepileptic, antibacterial, antiulcerative, antihyperlipidemic, anticholelithogenic, antimanic, antimigraine, antiamebic, antiviral, diuretic, antihypertensive, antipsychotic, analgesic, antipyretic, anti-inflammatory, antihistaminic, gastroprokinetic, antidiabetic, antiasthmatic, antianginal, immunosuppressant, antiobesity, antiosteoporotic, antihyperlididemicm, antiandrogen, contraceptive, antidysmenoreic, antiparkinsonian, anticoagulant, anticancer, anti- cirrhosis (biliary), anxyolithic, sedative, antifungal. The compositions of the invention are particularly suited for use with these drugs. In one embodiment, the composition of the invention contains an active pharmaceutical ingredient that is considered to have low solubility according to FDA BCS guidelines.

Active ingredients that may be employed in compositions of the invention preferably include Type 2 or 4 BCS active pharmaceutical ingredients, including among others non- steroidal anti-inflammatory drugs (NSAIDs) as normally described in pharmacological literature. NSAIDs are particularly suited to the compositions of the present invention due to the enhanced bioavailability, rapid release characteristics and reduced administered dose that can be achieved when used in these compositions. Apart from their several pharmacological effects, NSAIDs are useful in the treatment of dysmenorrhea and migraine, and in both cases rapid delivery of the drug aids in alleviating symptoms quickly. NSAIDs are also frequently suited for the compositions of the present invention given the presence of one or more aromatic rings or polycondensed cyclic structures (fully or partially saturated) and one or more hydrogen bond donors/acceptors in the drug molecule structures.

In one embodiment of the invention, the composition contains one or more additional active pharmaceutical ingredients (i.e. in addition to the active pharmaceutical ingredient that is required by the first aspect of the invention), thus providing a combination medication which is useful in treating any of the diseases mentioned herein. For example, compositions of the invention which contain an NSAID (which is preferably present in a predominantly amorphous form) may further contain a non-NSAID active pharmaceutical ingredient, which latter ingredient may be present in any degree of crystallinity. Examples of non-NSAID active pharmaceutical ingredients which may be mentioned in this respect include non-NSAID analgesics, such as paracetamol and codeine, and stimulants, such as caffeine. One or more of said additional active pharmaceutical ingredients may be present in a predominantly amorphous form (i.e. similar to the active pharmaceutical ingredient required by the first aspect of the invention), particularly where said one or more additional active pharmaceutical ingredients includes a Type 2 or 4 BCS active ingredient. Amorphisation of each of said one or more additional active pharmaceutical ingredients may be achieved by way of any of the methods mentioned herein, including heat-assisted intensive mixing (e.g. melt extrusion), static heat sealing, and the like. Such compositions may enable rapid release of a plurality of active pharmaceutical ingredients thus facilitating accelerated treatment of a broader range of symptoms in the patient.

In a further such embodiment, one or more of said additional active pharmaceutical ingredients may be present in a predominantly crystalline form, provided that each of the active pharmaceutical ingredients that is present in a predominantly crystalline form is different from the active pharmaceutical ingredient that is required by the first aspect of the invention (which is preferably provided in a predominantly amorphous form). To illustrate the inventive concept, compositions of the invention in which the active pharmaceutical ingredient is an NSAID are described in the examples. However, the invention is not limited to such drug compounds. For the avoidance of doubt, the compositions of the invention may contain any active pharmaceutical ingredient, and preferably contain at least one active pharmaceutical ingredient that is a Type 2 or 4 BCS active pharmaceutical ingredient, which has the molecular features discussed above.

Other particular active ingredients that may be employed in compositions of the invention include antibiotics, steroids and cholates. Steroids, in particular corticosteroids, are mainly used to reduce inflammation and suppress the immune system. They are used to treat conditions such as asthma, allergic rhinitis and hay fever, urticarial (hives), atopic eczema, chronic obstructive pulmonary disease (COPD), painful and inflamed joints, muscles and tendons, lupus, inflammatory bowel disease (IBD) (including Crohn's disease and ulcerative colitis), giant cell arteritis, polymyalgia rheumatica, and multiple sclerosis (MS). Progesterone, a natural steroid sex hormone, and its analogues, such as estradiol (e.g. ethynyl estradiol), progestin or estrogen, are used in treatment of primary dysmenorrhea. Cholates (in particular cholic acid, deoxycholic acic, ursodeoxycholic acid) may be used in the treatment of bile acid synthesis disorders due to single enzyme defects and peroxisomal disorders (such as Zellweger syndrome). Ursodeoxycholic acid is used for treatment of primary biliary cirrhosis.

In embodiments of the invention in which the active pharmaceutical ingredient may be an NSAID, particularly preferred NSAIDs include propionic acid derivatives (such as alminoprofenb, benoxaprofen, carprofen, dexibuprofen, dexketoprofen, fenbufen, fenoprofen, flunoxaprofen, flurbiprofen, ibuprofen, ibuproxam, indoprofen, ketoprofen, loxoprofen, miroprofen, naproxen, oxaprozin, pirprofen, suprofen, tarenflurbil, tepoxalin, tiaprofenic acid, vedaprofen, and naproxcinod), acetic acid derivatives (such as aceclofenac, acemetacin, alclofenac, amfenac, bendazac, bromfenac, bumadizone, bufexamac, diclofenac, difenpiramide, etodolac, felbinac, fentiazac, indomethacin, indomethacin farnesil, ketorolac, lonazolac, oxametacin, proglumetacin, sulindac, tolmetin, zomepirac, and nabumetone), oxicams (also referred to as "enolic acid derivatives"; such as ampiroxicam, droxicam, isoxicam , lornoxicam, meloxicam, piroxicam, tenoxicam, and phenylbutazone (bute)), anthranilic acid derivatives (so-called "fenamates"; such as azapropazone, etofenamate, flufenamic acid, flunixin, meclofenamic acid, mefenamic acid, morniflumate, niflumic acid, and tolfenamic acid), selective COX-2 inhibitors (such as apricoxib, celecoxib, cimicoxib, deracoxib, etoricoxib, firocoxib, lumiracoxib, mavacoxib, parecoxib, robenacoxib, rofecoxib, and valdecoxib), pyrazolones and pyrazolidines (such as aminophenazone, ampyrone, azapropazone, clofezone, famprofazone, feprazone, kebuzone, metamizole, mofebutazone, morazone, nifenazone, oxyphenbutazone, phenazone, phenylbutazone, propyphenazone, sulfinpyrazone and suxibuzone), and sulfonamides (such as nimesulide).

Particularly preferred NSAIDS include anthranilic acid derivatives (so-called "fenamates"; such as azapropazone, etofenamate, flufenamic acid, flunixin, meclofenamic acid, mefenamic acid, morniflumate, niflumic acid, and tolfenamic acid). It has been surprisingly found that these active ingredients are capable of being incorporated into the modified microcrystalline cellulose excipient described herein (e.g. using the heat- assisted methods disclosed herein) in spite of the relatively high melting points and relatively low vapour pressures associated with these substances. The reference to heat-assisted methods above includes heat-assisted intensive mixing (e.g. melt extrusion), static heat sealing, and the like.

Still further active ingredients that may be employed in compositions of the invention include antineoplastic agents. Antineoplastic agents are mainly used to treat or prevent cancer. Particularly preferred antineoplastic agents include those which contain at least one aromatic ring (preferably at least two aromatic rings), and at least one hydrogen bond donor or hydrogen bond acceptor. Examples of suitable antineoplastic agents include protein-kinase inhibitor substances, for example Afatinib, Alectinib, Axitinib, Binimetinib, Bosutinib, Brigatinib, Cabozantinib, Cediranib, Ceritinib, Cobimetinib, Crizotinib, Dasatinib, Entrectinib, Erlotinib, Fostamatinib, Gefitinib, Ibrutinib, Imatinib, Lapatinib, Lenvatinib, Lestaurtinib, Masitinib, Momelotinib, Mubritinib, Neratinib, Nilotinib, Nintedanib, Olmutinib, Osimertinib, Pacritinib, Pazopanib, Ponatinib, Radotinib, Regorafenib, Rociletinib, Ruxolitinib, Selumetinib, Semaxanib, Sorafenib, Sunitinib, Tivozanib, Toceranib, Trametinib, Vandetanib and Vemurafenib. Pharmacologically, protein kinase inhibitors are drug substances that inhibit the action of one or several kinases by phosphorylation of liable aminoacids, e.g. tyrosine, threonine, serine. Selective phosphorylation can be used to regulate biological hyperactivity of various mutant or overexpressed protein kinases in cancer.

Protein kinase inhibitors, which are considered to be BCS Type 2 substances, exhibit dramatic structure-activity relationships. Many non-specific kinase inhibitors have dyelike structures, i.e. flat, highly conjugated polyaromatic systems. (Knight and Shokat Features of selective kinase inhibitors, Chemistry & Biology, 2005; 12: 621-637.) Further, selective kinase inhibitors almost always contain heterocycles. They are also typically entropically constrained, with four or fewer freely rotatable bonds connecting any two-ring systems. These compounds tend to be hydrophobic, bind to proteins non- specifically, and aggregate at high concentrations, which suggests high propensity to ττ- π interactions.

Table 2 summarises some of the typical solid-state properties for selected substances.

Table 2 - solid-state properties

Substance Mw Tm, C pK logP solubility, mg/ml dasatinib 488 280 8.5 2.8 0.0128 sorafenib 464 205 11.5 4.1 0.0017 nilotinib 529 230 11.9 4.5 0.0020 erlotinib 393 230 16.1 3.1 0.0089 imatinib 493 226 12.4 3.5 0.0146

Particularly preferred NSAIDS include arylpropionic acid derivatives (e.g. ibuprofen, ketoprofen, flurbiprofen, and naproxen) anthranilic acid derivatives (e.g. flufenamic acid, mefenamic acid, and tolfenamic acid), acetic acid derivatives (e.g. indomethacin, and sulindac), and enolic acid derivatives (e.g. pyroxicam).

In embodiments of the invention in which the active pharmaceutical ingredient is a steroid or a cholate, particularly preferred active pharmaceutical ingredients include a contraceptive such as progesterone, estradiol (e.g. ethynyl estradiol), progestin, estrogen, cholic acid, deoxycholic acic or ursodeoxycholic acid.

Active pharmaceutical ingredients that are particularly useful in the compositions of the invention include compounds, which contain at least one aromatic ring or a polycondensed (fully or partially saturated) cyclic structure, optionally wherein the molecule also contains at least one hydrogen bond donor or hydrogen bond acceptor. Hydrogen bond donors include at least one XH moiety wherein X = C, N, O, or S (preferably wherein X = N or O). Hydrogen bond acceptors include oxygen and nitrogen atoms. Other active pharmaceutical ingredients that are particularly useful in the compositions of the invention include compounds which contain at least one aromatic ring or a polycondensed cyclic structure, and at least one hydrogen bond donor or hydrogen bond acceptor. Without wishing to be bound by theory, it is believed that such compounds are able to participate in hydrophobic interactions (ττ-ΧΗ interactions wherein X = C, N, O, S; and ττ-π interactions) with large surface area hydroxyl-rich portions of the cellulose.

Results obtained from molecular modelling studies suggest that the rapid-release characteristics observed for the compositions containing flufenamic acid in the Examples will similarly be observed for compositions of the invention containing other drug molecules which have at least one aromatic ring or a polycondensed (fully or partially saturated) cyclic structure, particularly where the drug molecule also contains at least one hydrogen bond donor or hydrogen bond acceptor.

The molecular modelling studies are summarised here. Interaction energies between aromatic organic molecules (AOM) and cellulose were probed using density functional theory (DFT) with respect to weak intermolecular interactions such as H-bonding, ττ-π stacking, and ττ-ΟΗ bonds.

Three model AOMs, viz. benzene, benzamide and benzoic acid, were used for ab initio simulations with cellulose using cellobiose as the structural monomer. No consideration to different cellulose allomorphs or cellulose crystal planes was taken. All pre-relaxation molecular coordinates were acquired from the PubChem Compounds Database. The Van der Waals exchange-correlation functional vdW-DF by Dion et al (Dion M. et al. (2004), Phys. Rev. Lett. 92, 246401) as implemented by Roman-Perez and Soler (Soler JM et al (2002) J. Phys. Condens. Matter 14, 2745-2779; Roman-Perez et al (2009) Phys. Rev. Lett. 103, 096102) was used. The basis set was DZP and the energy cut-off was set at 300 Ry. The molecular systems were structurally relaxed using the iterative Conjugate Gradient (CG) method.

Results

Table 3 - interaction energies of AOM dimers

It was found that the studied aromatic organic molecules are in general more likely to interact with cellulose than to form a dimer. Although H-bonding was particularly strong, the contribution of ττ-ΟΗ interactions was still significant. The results predict that there is a high affinity between cellulose and AOM and this affinity will be further amplified over the large surface area that cellulose may provide, wherein the interactions at a monolayer or close to a monolayer will be the strongest. Particularly preferred BCS Type 2 and 4 APIs that may be mentioned in this respect include compounds which contain at least one aromatic ring (preferably at least two aromatic rings), and at least one hydrogen bond donor or hydrogen bond acceptor. Thus, a further embodiment relates to compositions of the invention containing at least one active pharmaceutical ingredient (e.g. an NSAID) having such structural features (i.e. at least one (e.g. at least two) aromatic ring, and at least one hydrogen bond donor or hydrogen bond acceptor). Particular NSAIDs that may be mentioned in this respect include arylpropionic acid derivatives (e.g. ibuprofen, ketoprofen, flurbiprofen, naproxen), anthranilic acid derivatives (e.g. flufenamic acid, mefenamic acid), acetic acid derivatives (e.g. indomethacin, sulindac), and enolic acid derivatives e.g. pyroxicam. Particular NSAIDs having at least two aromatic rings that may be mentioned in this respect include arylpropionic acid derivatives (e.g. ketoprofen, flurbiprofen, naproxen); anthranilic acid derivatives (e.g. flufenamic acid, mefenamic acid), acetic acid derivatives (e.g. indomethacin, sulindac), and enolic acid derivatives (e.g. pyroxicam).

Further particularly preferred BCS Type 2 and 4 APIs that may be mentioned in this respect include compounds which contain at least two aromatic rings, and at least one hydrogen bond donor or hydrogen bond acceptor. Thus, a further embodiment relates to compositions of the invention containing at least one active pharmaceutical ingredient (e.g. an NSAID or an antineoplastic agent) having at least two aromatic rings, and at least one hydrogen bond donor or hydrogen bond acceptor. It has been surprisingly found that these active ingredients are capable of being incorporated into the modified microcrystalline cellulose excipient described herein (e.g. using the heat-assisted methods disclosed herein) in spite of the relatively high melting points and relatively low vapour pressures associated with these substances. The reference to heat-assisted methods above includes heat-assisted intensive mixing (e.g. melt extrusion), static heat sealing, and the like.

In a further embodiment, including embodiments in which the compositions of the invention containing at least one active pharmaceutical ingredient (e.g. an NSAID or an antineoplastic agent) having at least two aromatic rings and at least one hydrogen bond donor or hydrogen bond acceptor, said active pharmaceutical ingredient may have a molecular weight of at least 200 g/mol, preferably at least 210 g/mol. In still further embodiments, the molecular weight may be at least 220, at least 230, at least 240, at least 250, at least 260, at least 270, at least 280, at least 290 or at least 300 g/mol. Active pharmaceutical ingredients having a melting point (or glass transition temperature) not greater than the temperature at which cellulose degrades are also preferred as this ensures that incorporation of the active pharmaceutical ingredient into the cellulose excipient can be more easily achieved. Typically, therefore, the active pharmaceutical ingredient will have a melting point (or glass transition temperature) of up to about 350°C, preferably up to about 300°C.

The active pharmaceutical ingredients mentioned herein, in particular the NSAIDs and antineoplastic agents mentioned above as well as compounds having at least two aromatic rings and at least one hydrogen bond donor or hydrogen bond acceptor, are particularly suited for use in the compositions of the present invention. Such compositions may stably contain the active pharmaceutical ingredient in an amorphous form such that the composition is capable of rapidly releasing the active pharmaceutical ingredient in vivo. This in turn provides a significant clinical benefit to the patient, particularly where relief from painful discomfort is desired. Other classes of compounds that may be particularly suited to be formulated with the modified microcrystalline cellulose excipients described herein include those which contain a free carboxylic acid group (typically together with the one (or preferably two) aromatic ring), or an amide. The compositions of the present invention are particularly suited to the delivery of active pharmaceutical ingredients that are poorly soluble.

It should be noted that the advantages that have been identified for the compounds of the present invention are not limited to the compositions containing NSAIDs. The advantages may be realised for any drug which has a relatively low solubility, i.e. Type 2 and 4 BCS drugs, and which is typically administered orally to patients and has desirable structural features which enable ττ-π and ττ-ΟΗ interactions. For the avoidance of doubt, the compositions of the invention may be administered by other routes, in particular transmucosally (such as via sublingual or buccal administration), or via rectal or vaginal administration.

Active ingredients may further be employed in salt form or any other suitable form, such as e.g. a complex, solvate or prodrug thereof, or, if relevant, in any stereoisomeric form including any enantiomeric, diastereomeric or racemic form, or a combination of any of the above. Pharmaceutically-acceptable salts of active ingredients that may be mentioned include acid addition salts and base addition salts. Such salts may be formed by conventional means, for example by reaction of a free acid or a free base form of an active ingredient with one or more equivalents of an appropriate acid or base, optionally in a solvent, or in a medium in which the salt is insoluble, followed by removal of said solvent, or said medium, using standard techniques (e.g. in vacuo, by freeze-drying or by filtration). Salts may also be prepared by exchanging a counter-ion of active ingredient in the form of a salt with another counter-ion, for example using a suitable ion exchange resin. Examples of pharmaceutically acceptable addition salts include those derived from mineral acids, such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric and sulphuric acids; from organic acids, such as tartaric, acetic, citric, malic, lactic, fumaric, benzoic, glycolic, gluconic, succinic, arylsulphonic acids; and from metals such as sodium, magnesium, or preferably, potassium and calcium.

In the compositions of the invention, the active pharmaceutical ingredient is present in a predominantly amorphous form. In one embodiment, at least 80% of the active pharmaceutical ingredient in the composition is in an amorphous form. For example, the active pharmaceutical ingredient may be essentially amorphous (i.e. at least about 90% amorphous, that is at least about 90% by weight of the active pharmaceutical ingredient is present in an amorphous form). Preferably, the active pharmaceutical ingredient is at least about 95% amorphous, at least about 98% amorphous or most preferably at least about 99% amorphous. The degree of amorphicity in the active pharmaceutical ingredient may be determined by e.g. DSC. Additionally, the XRD profile for a product which is in a predominantly amorphous form would be one in which sharp peaks associated with the crystalline product (i.e. the drug or its polymorphs in the compositions of the invention) are substantially absent. For example, for a composition in which the active pharmaceutical ingredient is present in a predominantly amorphous form, the degree of crystallinity of the active pharmaceutical ingredient may be found to be less than about 10%, when determined using DSC. Compositions in which the active pharmaceutical ingredient is present in a predominantly amorphous form may be qualitatively identified via their XRD profiles by virtue of the absence of sharp characteristic diffraction peaks typical for crystalline substances. Infra-red absorption spectroscopy (e.g. FT-IR) can also show shifts in absorption frequencies indicating molecular rearrangement and interactions between API and excipient. Where the drug is a substance that contains an aromatic group and a carbonyl group (such groups are typically present in NSAIDs) the changes in the frequencies of the aromatic vibrations (between around 1000 and 800 cm^-1) and C=0 vibrations (between around 1500 and 1800 cm^-1) will be indicative of significant molecular rearrangement. One skilled in the art will understand that shifts of other characteristic peaks for H-bond donors/acceptor groups may also be indicative of molecular rearrangement.

Prior to introduction to the composition, the active pharmaceutical ingredient may be provided in any form, including a form that is crystalline or substantially crystalline.

In a further embodiment, the weight ratio of the active pharmaceutical ingredient to the modified microcrystalline cellulose excipient described herein in the composition of the invention is at most about 1 :3. For example, the weight ratio may be at most about 1 :5. In a preferred embodiment, the weight ratio of the active pharmaceutical ingredient to the modified microcrystalline cellulose excipient in the composition is not more than about 1 :9.

In further preferred embodiment, the pharmaceutical composition comprises the active pharmaceutical ingredient at an amount of between 5 and 30% by weight of the composition.

Particularly preferred compositions of the invention include those in which the weight ratio of the active pharmaceutical ingredient to the modified microcrystalline cellulose excipient in the composition is not more than about 1 :3 (e.g. not more than about 1 :5), and the surface area of the modified microcrystalline cellulose excipient (prior to the introduction of the active pharmaceutical ingredient) is from about 5 to about 50 m²/g (e.g. from about 10 to about 40 m²/g) as measured by N2 gas adsorption technique according to the Brunauer Emmett Teller (BET) method. Further preferred compositions of the invention include those in which the weight ratio of the active pharmaceutical ingredient to the modified microcrystalline cellulose excipient in the composition is not more than about 1 :3 (e.g. not more than about 1 :5), and the active pharmaceutical ingredient is at least about 90% amorphous. Still further preferred compositions of the invention include those in which the weight ratio of the active pharmaceutical ingredient to the modified microcrystalline cellulose excipient in the composition is not more than 1 :5 (e.g. not more than 1 :9), and the active pharmaceutical ingredient is at least about 95% amorphous.

Still further preferred compositions of the invention include those in which the modified microcrystalline cellulose excipient has a degree of crystallinity of from about 70% to about 90%, the surface area of the modified microcrystalline cellulose excipient (prior to the introduction of the active pharmaceutical ingredient) is from about 5 to about 50 m²/g (e.g. from about 10 to about 40 m²/g), and the active pharmaceutical ingredient is at least about 90% amorphous.

Compositions of the invention may be prepared by way of a variety of routine techniques, and using standard equipment, known to the skilled person, including mixing together the active pharmaceutical ingredient and a modified microcrystalline cellulose excipient having the desired surface area.

Typically the active pharmaceutical ingredient will be initially provided in a crystalline form. Amorphisation of the active pharmaceutical ingredient may be achieved through any technique which is capable of reducing the level of crystallinity of the active pharmaceutical ingredient in the composition without substantially degrading the cellulose component or adversely altering its physical structure. Suitable techniques include heat-assisted intensive mixing (e.g. melt extrusion), static heat sealing, intensive mixing, reduced pressure mixing, moderate heating, combined grinding and heating, and co-spray drying with a solvent. Heat-assisted intensive mixing, for example melt extrusion, is particularly useful. During the heat-assisted mixing the components are heated while being mixed, while the heating temperature may be at or below the melting point of the active ingredient. An extruder equipped with heated compartments, e.g. similar to those used for melt extrusion, is particularly useful. For the compositions of the invention, the process involves the processing of a mixture containing the active pharmaceutical ingredient (optionally initially in a substantially crystalline form) and the modified microcrystalline cellulose excipient having the desired surface area. A classical melt extrusion process is a process during which at least one component in the blend is melted (or at least heated to close to its melting point or above its glass transition temperature) and the mixture is formed into products of different shapes and sizes by forcing the components and active substances through an orifice or die under controlled temperature, pressure, feeding rate, and screw speed. Suitable melt extrusion techniques that will be known to the skilled person include those described in Shah S., et ai, Int. J. Pharm., 453 (2013) 233. Conventional melt extrusion techniques are typically used with thermoplastic polymers, i.e. polymers that melt before they degrade. In contrast, native cellulose, such as MCC, is a non-thermoplastic polymer, which degrades by pyrolysis before it melts. Nonetheless, melt extruders and other heat-assisted intensive mixers are particularly useful in the context of the present invention. Thus, these techniques can also be used with the non-thermoplastic cellulose-based systems of the present invention, e.g. using single- or twin-screw extruders, preferably with a heating unit as long as the temperature inside the mixture does not exceed that at which the cellulose degrades by pyrolysis. Thus, the temperature inside the mixture should not exceed about 350°C, and preferably should not exceed about 300°C.

It may also be possible to form compositions of the invention without extrusion by statically heating blends of pre-mixed active ingredient and the modified microcrystalline cellulose excipient described herein. The mixture is then heated to a temperature above the glass transition temperature of the active ingredient for a sufficient period of time but below the degradation temperature of the cellulose such that the active pharmaceutical ingredient is substantially present in an amorphous form. In practice, the blends are heated in the range between 50 and 300 °C.

Compositions of the invention may also be prepared by static heat sealing. In this process, mixtures of drug and cellulose are placed in a sealed vessel. The mixture is then heated to a temperature above the glass transition temperature of the active pharmaceutical ingredient for a sufficient period of time (the exact period to be determined empirically depending on the quantities of the used ingredients, e.g. between 5 min and 72 hours) such that the active pharmaceutical ingredient is substantially present in an amorphous form.

Thus a further aspect of the invention relates to a pharmaceutical composition comprising a modified microcrystalline cellulose excipient as defined herein and an active pharmaceutical ingredient, wherein the composition is obtained by a process involving heating a mixture of the active pharmaceutical ingredient and the modified microcrystalline cellulose excipient to a temperature close to or above the glass transition temperature of the active pharmaceutical ingredient. In practice, we mean that the mixture is heated to a temperature above about 50 °C. The temperature should not exceed that at which degradation of the cellulose component would occur. Thus, typically in processes in which the cellulose component is heated in the presence of the active pharmaceutical ingredient, the temperature used should not exceed about 300 °C.

Heat-assisted extrusion, including melt extrusion, is a particularly preferred technique for use in the context of the present invention. Thus, in one embodiment, the invention relates to a composition which is formed by a process involving heat-assisted extrusion of a mixture of the cellulose or cellulose derivative and the active pharmaceutical ingredient. The mixing time period is likely to vary according to the equipment used, and the skilled person will have no difficulty in determining by routine experimentation a suitable mixing time for a given combination of ingredient(s) empirically.

Microcrystalline cellulose excipients which have a surface area in the region of from 2 to 60 m²/g (as measured by N2 gas adsorption technique according to the Brunauer Emmett Teller (BET) method) are particularly advantageous as these substances provide a sufficiently high area of interaction with the active pharmaceutical ingredient while also providing a formulation that has good stability (i.e. in which the active pharmaceutical ingredient is maintained in an amorphous form for longer periods). Strong interactions between the active pharmaceutical ingredient and the cellulose component also help to improve the dissolution characteristics of the overall composition. The strength of the interactions is governed, at least in part, by the affinity between API and cellulose and further amplified over a large surface area. Strong interactions between cellulose and the active pharmaceutical ingredient can be observed in many ways, including FTIR spectroscopy or sometimes through colour changes associated with the active pharmaceutical ingredient itself, as well as through analysing the solid state fluorescence spectra of the mixture.

A preferred process for the formation of compositions of the invention involves the mixing together of an active pharmaceutical ingredient and a modified microcrystalline cellulose excipient having a surface area of from about 2 to about 60 m²/g. In an embodiment of such a process, the modified microcrystalline cellulose excipient is obtained by any of the methods disclosed herein. The product obtained by the above-mentioned process may further be adapted by:

heat-assisted extrusion, e.g. melt-extrusion;

static heat sealing; heat-assisted intensive mixing,

mixing under reduced pressure,

heating;

mild grinding (i.e. grinding which does not adversely affect the pore structure or the physical-chemical properties of the excipient); and/or

co-spray drying, or rotary evaporation at reduced pressure, with a solvent, preferably wherein the solvent is a mixture of water and lower alkyl alcohol;

using routine techniques in all cases. Compositions of the invention may further comprise one or more further commonly- employed pharmaceutical excipients. Suitable excipients include inactive substances that are typically used as a carrier for the active ingredients in medications. Suitable excipients also include those that are employed in the pharmaceutical arts to bulk up pharmaceutical compositions that employ very potent active ingredients, to allow for convenient and accurate dosing. Alternatively, excipients may also be employed in manufacturing processes of the compositions of the invention to aid in the handling of the active ingredient concerned. One skilled in the art will understand that in pharmaceutical formulation other additives apart from diluent may be employed such as taste masking agents, glidants, superdisintegrants, coating agents, etc.

The compositions of the invention are preferably administered orally to the gastrointestinal tract and may provide for rapid release of the active pharmaceutical ingredient in the stomach and/or, preferably, the intestinal system. In this respect, the compositions of the invention may be incorporated into various kinds of pharmaceutical preparations intended for oral administration using standard techniques (see, for example, Lachman et al, "The Theory and Practice of Industrial Pharmacy', Lea & Febiger, 3^rd edition (1986) and "Remington: The Science and Practice of Pharmacy" , Gennaro (ed.), Philadelphia College of Pharmacy & Sciences, 19^th edition (1995)), for example to form a capsule, a powder or a tablet.

The compositions of the invention may also be administered to the patient through other routes, such as via transmucosal (e.g. sublingual or buccal), rectal or vaginal administration. An appropriate route of administration is one which allows for rapid uptake of the active pharmaceutical ingredient into the bloodstream following administration. Sublingual, buccal, rectal and vaginal routes of administration are suitable in this respect as they allow the active pharmaceutical ingredient to rapidly enter into the bloodstream, thereby leading to a fast onset of action.

Pharmaceutical preparations comprising compositions of the invention contain a pharmacologically effective amount of the active ingredient. By "pharmacologically effective amount", we refer to an amount of active ingredient, which is capable of conferring a desired therapeutic effect on a treated patient, whether administered alone or in combination with another active ingredient. Such an effect may be objective (i.e. measurable by some test or marker) or subjective (i.e. the subject gives an indication of, or feels, an effect).

More preferred compositions of the invention may be adapted (for example as described herein) to provide a sufficient dose of drug over the dosing interval (irrespective of the number of doses per unit time) to produce a desired therapeutic effect.

The amounts of active ingredients that may be employed in compositions of the invention may thus be determined by the physician, or the skilled person, in relation to what will be most suitable for an individual patient. This is likely to vary with the route of administration, the type and severity of the condition that is to be treated, as well as the age, weight, sex, renal function, hepatic function and response of the particular patient to be treated.

Suitable dosages of active ingredient in one oral delivery unit (e.g. one tablet) may be below 1 g, preferably below 100 mg and above 2 mg. Similar doses may also be appropriate for delivery by other routes, particularly via sublingual, buccal, rectal and vaginal administration.

While NSAIDs are typically used as analgesics, anti-inflammatory drugs and antipyretics, they can also be useful for treatment of primary dysmenorrhea and migraine.

Dysmenorrhea is the pain associated with menstruation in women. It affects approximately 25% of women and in younger women (67-90%) it occurs without underlying problem. (Livshitz and Seidman (2010) Pharmaceuticals, 3, 2082-2089). It has been found that the over-production of uterine PGs is key factor to the painful cramps that are the major symptom of dysmenorrhea. NSAIDs decrease the menstrual pain by decreasing the intrauterine pressure and lowering PGF2a levels in menstrual fluid. (Dawood, M.Y. (1988) Am. J. Med., 20, 23-29). They relieve pain in 80-85% of patients and reduce menorrhagia (bleeding), which has also been correlated with excessive PG synthesis (Ylikorkala, O. (1994) Pharmacol. Toxicol., 75, 86-88.), in 30- 40%. Further, NSAIDs can be helpful for planning and timing in-vitro fertilization (IVF) treatments and in attenuating the progression of labour during pregnancy (Livshitz and Seidman (2010) Pharmaceuticals, 3, 2082-2089).

Enhancement of NSAIDs bioavailability may implicate important clinical effects due to two reasons: reduced side effects and rapid onset of action.

Side effects: Due to the low solubility/bioavailability NSAIDs are typically administered in high doses to achieve a therapeutic effect. The latter is partly the reason for the side effects associated with NSAIDs, such as gastric ulcers. Thus, lowering the dose when the bioavailability is enhanced may reduce toxic effects.

Onset of action: The relief in dysmenorrhea patients is associated with the rapid onset of action. It is the rapidity with which the NSAIDs are absorbed that determines how quickly the relief is obtained. Since the onset of menstrual flow is variable, it is practical to initiate the medication at the beginning of menstruation and to continue it for 3 days if necessary. With rapidly absorbed NSAIDs, pre-treatment before the onset of dysmenorrhea is unnecessary. This is of great importance since most of the women experiencing dysmenorrhea are young sexually active women. The fenamates and arylpropionic acid derivatives (profens) are the drugs of choice for treating dysmenorrhea. They act by suppression of menstrual fluid PGs and by a direct analgesic effect. Reduction of menstrual fluid is the result of direct inhibition of PG biosynthesis and release in endometrial tissue - a phenomenon that occurs during the first 48 hours of menstruation. Arylpropionic acid derivatives (such as ibuprofen, flurbiprofen, ketoprofen and naproxen) and fenamates (such as mefenamic acid and flufenamic acid) are particularly useful for treatment of dysmenorrhea. As a rule of thumb, arylpropionic acid derivatives are preferred as they give rise to fewer side-effects, while fenamates are known to have stronger action (Marjoribanks J, et ai , 2009. Nonsteroidal anti-inflammatory drugs for primary Dysmenorrhea, Cochrane report, Wiley). The stronger mechanism of fenamate action is believed to be dual, i.e. inhibition of PG synthesis and antagonism to PG in certain tissues. There is a strong correlation between the solubility, dissolution rate and bioavailability of fenamates (Shinkuma, et ai, 1984, Int. J. Pharm., 21 , 187-200). Varying bioavailability due to poor solubility was the reason why some fenamates have been removed from the market, e.g. flufenamic acid.

Another effective alternative for treatment of primary dysmenorrhea is administration of contraceptives, such as progesterone. The pain associated with dysmenorrhea is postulated to result from progesterone withdrawal before the onset of menses, which causes an increase in PGs. Therefore, administration of progesterone can alleviate the symptoms of primary dysmenorrhea. With a prevalence of 8% in males and 12-15% in females migraine is extremely common (Diener, H.C., et al. 2008, 22 (Suppl. 1), 51-58.). It is characterized by recurrent attacks of pulsatile, unilateral headache often accompanied by nausea and vomiting, photo- and phonophobia. In about 20% of patients the headache is preceded by an aura consisting of transient neurological symptoms, most frequently a scintillating scotoma. While the "triptans" -e.g., sumatriptan (Imitrex), rizatriptan (Maxalt), eletriptan (Relpax)-have been promoted over the last 2 decades, NSAIDs still remain a treatment option for acute migraine headache.

Compositions of the invention comprising NSAIDs are therefore useful in the treatment of migraine (e.g. acute migraine headache) and/or dysmenorrhea (e.g. primary dysmenorrhea). According to a further aspect of the invention there is provided a method of treatment of migraine (e.g. acute migraine headache) which method comprises administration of a composition of the invention to a person suffering from, or susceptible to, such a condition. According to a still further aspect of the invention there is provided a method of treatment of dysmenorrhea (e.g. primary dysmenorrhea) which method comprises administration of a composition of the invention to a person suffering from, or susceptible to, such a condition. Particular active pharmaceutical ingredients that are useful in such methods are non-steroidal anti-inflammatory drugs. According to a further aspect of the invention there is provided the use of an active pharmaceutical ingredient (e.g. an NSAID) in the manufacture of a composition of the invention for treating migraine (e.g. acute migraine headache). Similarly, there is provided the use of an active pharmaceutical ingredient (e.g. an NSAID or a contraceptive) in the manufacture of a composition of the invention for treating dysmenorrhea (e.g. primary dysmenorrhea). Still further, there is provided the use of a pharmaceutical composition of the invention in the manufacture of a medicament for treating dysmenorrhea or migraine, wherein the active pharmaceutical ingredient is a non-steroidal anti-inflammatory drug or a contraceptive.

For the avoidance of doubt, by "treatment" we include the therapeutic treatment, as well as the symptomatic treatment, the prophylaxis, or the diagnosis, of the condition.

When compositions of the invention comprise NSAIDs, appropriate pharmacologically effective amounts of such compounds include those that are capable of producing (e.g. immediate) relief of pain or other symptoms when administered perorally. The amount of the NSAID active ingredient may be expressed as the amount in a unit dosage form. In such a case, the amount of NSAID active ingredient that may be present may be sufficient to provide a dose per unit dosage form that is in the range of between about 2 mg and about 1000 mg (e.g. about 200mg or 400 mg). The above-mentioned dosages are exemplary of the average case; there can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.

Compositions of the invention possess the advantage of reducing the risks of producing side effects that are typically associated with high doses of drugs. By delivering the active pharmaceutical ingredient in such a way that the higher rates of dissolution than normal can be achieved, the compositions may contain a lower overall quantity of the active pharmaceutical ingredient while still providing a rapid therapeutic benefit for the patient. The use of a lower overall quantity of the active pharmaceutical ingredient helps to reduce the occurrence of unwanted side effects that may occur. NSAIDs in particular may benefit from being used in the compositions of the invention as frequent usage of these drugs is associated with a substantially increased risk of gastrointestinal problems (e.g. gastrointestinal bleeding and ulcers) and kidney problems). Compositions of the invention may also have the advantage that they may be prepared using established pharmaceutical processing methods and may employ materials that are approved for use in foods or pharmaceuticals or of like regulatory status.

Compositions of the invention may also have the advantage that they may be more efficacious than, be less toxic than, be longer acting than, be more potent than, produce fewer side effects than, be more easily absorbed than, and/or have a better pharmacokinetic profile than, and/or have other useful pharmacological, physical, or chemical properties over, pharmaceutical compositions known in the prior art, whether for use in the treatment of pain or otherwise.

Wherever the word "about" is employed herein in the context of dimensions (e.g. values, temperatures, pressures (exerted forces), relative humidities, sizes and weights, crystallinities, surface area, particle or grain sizes, etc.), amounts (e.g. relative amounts (e.g. numbers or percentages) of particles, individual constituents in a composition or a component of a composition and absolute amounts, such as doses of active ingredients, numbers of particles, etc.), deviations (from constants, degrees of degradation, etc.) it will be appreciated that such variables are approximate and as such may vary by ± 10%, for example ± 5% and preferably ± 2% (e.g. ± 1 %) from the numbers specified herein.

Preferences and options for a given aspect, feature or parameter of the invention should, unless the context indicates otherwise, be regarded as having been disclosed in combination with any and all preferences and options for all other aspects, features and parameters of the invention. For example, combinations of descriptions of the porosity of the modified microcrystalline cellulose excipient, e.g. the preferred surface area and the preferred pore volume, should be regarded as having been disclosed. The invention is best demonstrated by a comparison of a modified microcrystalline cellulose (hereinafter referred to as "P-MCC") with MCC. For each cellulose, two types of mixtures have been prepared, i.e. normal, physical mixtures and staticly heat sealed mixtures with flufenamic acid ("FFA") as a model drug substance. The invention is illustrated by the following examples in which:

Figures 1A to 1 D show SEM micrographs showing MCC (Figs 1A. and 1 B) and P-MCC (Figs 1C and 1 D) powders at high magnification (Figs. 1A and 1 C) and low magnification (Figs 1 B and 1 D). Information of specific magnification and scaling is provided in each micrograph.

Figure 2 shows an AMF height sensor image of P-MCC suspension adsorbed on gold plated surface.

Figure 3 shows a pore size distribution curve derived from N2 adsorption and desorption isotherms at 77 K of MCC and P-MCC celluloses. Figure 4 shows FTIR spectra of (i) pure FFA, (ii) a MCC-FFA mixture stored at standard conditions ("MCC-FFA-N"), and (iii) a heated MCC-FFA mixture (120 °C, 2 h) ("MCC-FFA-H"). The data is normalized with respect to the C-H stretching vibration at 2897 cm^"1. Region presented in Fig 4A: 600 - 1000 cm^"1 , and Fig 4B: 1400- 1800 cm^"1.

Figure 5 shows FTIR spectra of (i) pure FFA, (ii) a MCC-FFA mixture stored at standard conditions ("P-MCC-FFA-N"), and (iii) a heated MCC-FFA mixture (120 °C, 2 h) ("P-MCC-FFA-H"). The data is normalized with respect to the C-H stretching vibration at 2897 cm^"1. Region presented in Fig 5A: 600 - 1000 cm^"1 , and Fig 5B: 1400 - 1800 cm^"1.

Figure 6 shows a representative DSC thermogram of MCC-FFA mixtures and pure FFA. The heat flow of the mixtures is normalised with respect to the total weight of sample.

Figure 7 shows a representative DSC thermogram of P-MCC-FFA mixtures heated to 120 °C for 2 hours and pure FFA. The heat flow of the mixtures is normalised with respect to the total weight of sample.

Figure 8A shows an X-ray powder diffractogram for pure FFA and physical mixture of MCC with FFA. Figure 8B shows an X-ray powder diffractogram for pure FFA and heated mixture of MCC with FFA.

Figure 9A shows an X-ray powder diffractogram for pure FFA and physical mixture of P-MCC with FFA. Figure 9B shows an X-ray powder diffractogram for pure FFA and heated mixture of P-MCC with FFA.

Figure 10A shows dissolution profiles of FFA from MCC into SIF together with dissolution profile for pure FFA at 37.0 ± 0.5 °C. Each data point is the average of two experiments.

Figure 10B shows dissolution profiles of FFA from P-MCC into SIF together with dissolution profile for pure FFA at 37.0 ± 0.5 °C. Each data point is the average of two experiments.

Figure 11 shows X-ray powder diffractograms for (a) as-prepared normal mixture of MCC with FFA; (b) as-prepared heated mixture of MCC with FFA; and (c) heated mixture of MCC with FFA stored at RH 75% for 61 days. Figure 12 shows X-ray powder diffractograms for (a) as-prepared normal mixture of MCC with FFA; (b) as-prepared heated mixture of MCC with FFA; and (c) heated mixture of MCC with FFA stored at RH 75% for 61 days. Examples

Experimental

Flufenamic Acid ([N-(a,a,a-trifluoro-m-tolyl) anthranilic acid]), hereinafter "FFA", was used as the model drug in the following studies. FFA is a non-steroidal anti-inflammatory drug (NSAID) that was obtained from Sigma-Aldrich in the form of analytical standard for drug analysis.

Microcrystalline Cellulose ("MCC"). The specific powder for this study is provided by Sigma-Aldrich: Avicel^® PH-101 , ~50 μηι particle size.

MCC was the original cellulose used in the preparation of P-MCC (modified microcrystalline cellulose) as is detailed in Example 1.

Scanning Electron Microscopy - SEM

SEM images of cellulose powder samples were acquired with a scanning electron microscope (Merlin FEG-SEM, Zeiss, Germany). The membranes were sputtered with Au/Pd prior to analysis to minimize charging effects of the samples.

Atomic force microscopy - AFM

The AFM images were acquired using a Dimension Icon (Bruker, Germany) instrument. A gold surface was coated by submerging it in a 10 mM solution of 6-amino-1- hexanethiol hydrochloride for 2 hours and then dried by gently blowing compressed air over the surface. A drop (100 μΙ_) of highly diluted dispersion containing cellulose crystallites (0.01 % wt) was placed on the precoated gold plate surface (5 mm in diameter) and dried. The gold plate was then mounted on the AFM instrument using a double adhesive tape. The height images were acquired in the peak force tapping mode, using manufacturer's Scan Asyst cantilever and ScanAsyst optimization algorithm.

Nitrogen Gas Sorption

Nitrogen gas (N2 at 77 K) adsorption and desorption isotherms were obtained using an ASAP 2020 instrument (Micromeritics, USA). The gas absorption was conducted on pure, solid powders of P-MCC (>200 mg) and MCC (2 g). The specific surface area was calculated according to the BET method during N2 adsorption, while the pore size distribution was determined based on N2 adsorption data using DFT method. The total pore volume of the powders was obtained as the volume of adsorbed nitrogen at a relative pressure (p/pO) approximating unity. All calculations were determined using the ASAP 2020 instrument software. The samples were degassed at 100 °C under vacuum for at least 6 h prior to analysis. Filler rods were used for each sample during N2 sorption measurement.

Fourier Transform Infrared Spectroscopy - FTIR

FTIR analysis was conducted on FFA, as a pure substrate, and FFA in blend with different celluloses. Cellulose-FFA blends from both heated and normal, i.e. unheated, samples were analysed. The FTIR spectra were obtained on a Bruker Tensor 27 (Germany) with KBr pellets. A background scan on air was subtracted from all spectra using the instrument software (Opus 7.0, Bruker, Germany). The approximate sample content in 200 mg KBr pellets was 10 wt% (i.e. 1 wt% drug). The collected data was normalized with respect to C-H stretching vibration at 2897 cm^-1. The FTIR spectra were collected with the following parameters: 64 scans at a spectrum resolution of 4 cm^-1 over a range from 4000 to 400 cm^-1. Differential Scanning Calorimetry - DSC

Thermal analysis was performed with Model Q-2000 TA instrument (USA) on both cellulose-drug mixtures and pure substances. Samples were placed inside hermetically sealed aluminium crucibles with punctured lids, in order to avoid overpressure caused by water evaporation. An empty pan was used as a reference. The analysis was conducted in the temperature range from -40°C to 150°C with a heating rate of 10°C min^-1. N2 gas, at a flow of 50 ml_ min^-1 , was applied during analysis. Initially the samples were cooled from room temperature to -40°C, then heated to 150°C and finally cooled to 25°C again. All of the samples were stored at ambient conditions for 24 hours prior to DSC measurements. For the heated cellulose-FFA mixtures the heating conditions were 120 °C for 2 hours. The measurements were performed in triplicate, and the estimated amount of drug in the mixtures was 10 wt%. Enthalpies and temperatures were estimated by Universal Analysis 2000 Software (TA Instruments).

X-ray diffraction -XRD

The characteristic X-ray diffraction patterns were generated using a D8 Twin-Twin, Bruker (Germany) instrument with Bragg- Brentano geometry for both FFA, as a pure drug, and FFA in a blend with different celluloses. The samples were scanned at room temperature (25 °C), CuKa radiation was utilized (λ = 1.54 A) with 2Θ angle set between 10 and 60°. Pure FFA (5 mg) was used as the reference and 50 mg of both normal and heated samples of cellulose-FFA blends (approx. 10 wt% FFA in each sample) were scanned once during the analysis.

Example 1 - Formation of microcrystalline cellulose excipient

MCC was used to prepare P-MCC (a modified microcrystalline cellulose excipient) particles in a hydrolysis reaction with hydrochloric acid followed by high-shear homogenisation to release nanocellulose whiskers, and spray-drying.

Pure MCC powder (20 g) was soaked in water 364 mL of water for 24 h at room temperature and then stirred in a round-bottomed flask at 105°C for 60 min under reflux. Concentrated HCI (236 mL, 37%) was added to the dispersion until a final acid concentration of 4 M was obtained, and the reaction mixture was maintained in a preheated oil bath at 105 °C for an additional 60 min. Later, pH-adjustment and neutralization of the solution to pH 5.7 was made by addition of 4M sodium hydroxide solution under stirring. The prepared dispersion was washed by centrifugation at 500 rpm for 10 min 5 times until a final pH value of 6.9 was obtained. The aqueous suspension of MCC was sonicated for 20 minutes with a high intensity ultrasound processor (Sonication Pulse Rate: 30 seconds On, 30 seconds Off) at 70% amplitude to yield a thick white gel which was then homogenized using a high-pressure fluidizer. Two sets of chambers with different sizes connected in series were used with internal diameters of 400/200 μηι and 200/100 μηι, respectively. The suspension was passed once through the larger chamber and six times through the small chamber at 1600-1700 bar. The dry matter content of 1.96 wt% for the dispersion was calculated gravi metrically by drying the sample to a constant weight at 150 °C. The sample was dispersed further with additional 150 mL deionized water until a 0.96 wt% dry matter content was achieved. The sample was sonicated one more time for 20 minutes (Sonication Pulse Rate: 30 seconds On, 30 seconds Off) at 70% amplitude.

The produced dispersion was diluted with ethanol (95%) until a concentration of 50 vol% ethanol was achieved. The obtained dispersion was then spray-dried in nitrogen atmosphere at inlet temperature 195±5 °C, outlet temperature 103±3 °C, pump flow rate setting 15%, and spray flow rate 500 L/h (Buchner mini spray-dryer B-290). The collected product was stored at room temperature and 0% relative humidity in a desiccator until used. Example 2 - Characterisation of microcrystalline cellulose excipient

Scanning Electron Microscopy

At lower magnification, SEM images of the celluloses of Example 1 show roughly spherical particles of modified microcrystalline cellulose unlike rod-like particles of MCC.

Atomic force microscopy (AFM)

Figure 2 shows the cellulose crystallites, which were released upon hydrolytic cleavage in hydrochloric acid and high-shear homogenisation. The homogenization resulted in relatively well-dispersed individual or slightly aggregated cellulose fragments (whiskers). The length of the whiskers normally did not exceed 500 nm. The cellulose whiskers (in the form of a suspension) were spray-dried to produce the final P-MCC product, as shown in Figure 1. Nitrogen Gas Sorption

Nitrogen sorption isotherms were used to determine the BET specific surface areas, pore sizes and total pore volumes. The pore size characteristics and BET specific surface areas are tabulated in Table 5. Table 5: Specific surface area and pore volume

a The values are the average with standard deviation presented in parentheses (n = 2).

b Single point desorption total pore volume of pores less than 1 17 nm width at p/po = 0.9832 c Single point desorption total pore volume of pores less than 139±4 nm width at p/po = 0.9860 The obtained specific surface area and pore volume of P-MCC were about 9 m²/g and 0.022 cm³/g, respectively, which is much higher than that for ordinary MCC. Figure 3 shows a pore size distribution curve of MCC and P-MCC celluloses. It is clear that the pores having a size of from 10 to 80 nm contribute a substantially greater pore volume for P-MCC than the same sized pores do for MCC. This is consistent with the data in Table 5.

Example 3 - Formation of cellulose-API mixtures

Modified and ordinary MCC were blended with FFA in 1 :9 ratio as shown in Table 6). Table 6: Summary of cellulose-FFA blends and preparation/storage conditions

Cellulose-FFA samples for characterization and release study were prepared the day before analysis with an approximate storage time of 24 hours at ambient conditions. Typically, a 50 mg blend of cellulose and drug was prepared by mixing 5 mg FFA with 45 mg of selected cellulose powder in 1 ml_ glass vials. The vials were sealed with plastic screw caps and vortexed for 30 seconds. Each cellulose-FFA blend was analysed in both heated and unheated (normal) form. Vials containing the cellulose-FFA blends were placed in a preheated oil bath at 120 °C for 2 hours in the heat-treatment procedure.

Example 4 - Characterisation of cellulose-API mixtures

The potential interactions between the drug and cellulose in the mixtures of Example 3 were analysed and evaluated both for normal and heated samples.

Fourier Transform Infrared Spectroscopy

Figures 4 and 5 display spectra collected on FFA in formulation with different celluloses in both normal and heated mixtures together with a reference band for pure crystalline FFA. Several distinctive functional groups of FFA are detectible by FTIR spectroscopy (Jabeen S., et ai, Spectrochim. Acta. Part A Mol. Biomol. Spectrosc. vol. 96, 972-985, 2012) most of which are normally absent in the chemical structure of cellulose.

The FTIR spectra for normal blend of P-MCC-FFA (Figure 5) display an apparent difference in band characteristics for both selected regions, i.e. the characteristic bands appeared to shift to higher wavenumbers, become broader and generally decrease in intensity. This is observed particularly for bands corresponding to CF3 vibration at 659 and 652 cm^-1 , aromatic out-of-plane C-H deformations at 889 cm^-1 and in-plane aromatic C-H deformation at 1422 cm^-1. The characteristic FFA bands in normal mixture with MCC demonstrated no particular deviation from relevant band positions. The FTIR spectra for heated samples revealed substantial deviations from the characteristic band positions of FFA in reference spectra. In the selected spectral regions, a shift in band positions was observed at nearly all bands of pure FFA for each heated cellulose-FFA mixture (Figs. 4 and 5). The characteristic bands of FFA shifted in their wavenumber position and were further notable in their broader appearance and lower intensity in spectra for heated P-MCC-FFA and MCC-FFA. The shift in the band position at 1655 cm^-1 was prominent in spectra for the heated sample of P-MCC-FFA in which the band position shifted to lower wavenumber in the heated sample of P-MCC- FFA. The band associated with carbonyl stretching at 1655 cm^-1 is known to be especially sensitive to changes in the electrostatic environment of the molecule. Thus, the shift in the wavenumber position at this band is particularly indicative of interaction involving carboxylic group of FFA and cellulose. The observed shift in the band position at 1655 cm^-1 in the heated mixture of MCC-FFA was reduced when compared to FFA in formulation with P-MCC. While the positions of some peaks for heated P-MCC-FFA and MCC-FFA shifted, other peaks such as 760, 1519 and 1578 cm^-1 were diffuse and of remarkably low intensity, which could be due to interference from water in these samples. Overall, the results from FTIR analysis suggest that a potential interaction is present between FFA and the different celluloses, particularly for FFA in formulation with P-MCC in the heated samples.

Differential Scanning Calorimetry

Figures 6 and 7 display representative thermograms from differential scanning calorimetry (DSC) analysis conducted on samples of pure FFA and physical mixtures of FFA with P-MCC and MCC. The profiles for physical mixtures are normalized with respect to the total weight of the sample (i.e. 10 wt% FFA). The DSC profile for pure FFA showed a distinct endotherm at 135°C corresponding to the melting temperature of crystalline FFA. The exothermic event at about 72 °C in the back-scan DSC profile of pure FFA is representative of recrystallization of FFA from the melt upon cooling. DSC profiles for FFA in mixtures with celluloses were generally characterized by two events: evaporation of water from cellulose in the region between 40 and 110 °C and a distinct endothermic peak at temperature around 133-139 °C, which corresponds to the melting of crystalline FFA. The exothermic event on the back-scan for physical mixtures, corresponding to recrystallization of FFA, could be distinguished only in the normal samples of P-MCC mixed with FFA and. The recrystallization exotherm in the physical mixture of P-MCC-FFA is slightly shifted to higher temperatures accompanied with significant decrease in size compared with recrystallization of pure FFA. DSC profiles for heated mixtures of FFA with celluloses were characterised by the lack of endothermic peaks in the region corresponding to melting of crystalline FFA. DSC profile of MCC in mixture with FFA displayed several distinguishable peaks close to the melting region of FFA, typically below the specific melting temperature. The absence of the melting peak of FFA (at 135 °C) in the DSC profiles is indicative of an amorphous structure of FFA in the heated samples, since fully amorphous materials do not exhibit a melting endotherm. The broad halo at 40 - 110 °C, characteristic of water evaporation is present in the DSC profiles for heated samples as well. This indicates that water is resorbed in the samples during storage after heat treatment to 120 °C prior to analysis. The results from DSC analysis suggest that FFA is present predominantly in an amorphous state in the heated samples with the exception of MCC-FFA mixture. The peaks present in the region of 120 - 133 °C in the heated MCC-FFA sample suggests the presence of FFA polymorphs with different melting temperatures in the sample.

Tables 7 and 8 present enthalpies with corresponding temperatures for water evaporation, melting and recrystallization of FFA in mixtures together with values of standard deviation for each result. Table 7 - Melting enthalpies of FFA in pure form and in mixtures with different celluloses. Results are presented as averages with standard deviation in parentheses (n=3).

a Two peaks could be detected at near the melting temperature of FFA in each sample, b A peak for melting of FFA was detected only in one sample out of three. Table 8 - crystallization enthalpies of FFA in pure form and in mixtures with different celluloses. Results are presented as averages with standard deviation in parentheses (n=3).

The degree of crystallinity for FFA in each mixture is presented in Table 7 where a decreasing trend in FFA crystallinity from normal to heated samples is apparent. The highest content of crystalline FFA at 58% is observed for the mixture of FFA with MCC in normal blends. Corresponding values for crystallinity index of FFA in the normal mixture with P-MCC show that the drug is only partially crystalline.

In the heated samples, the FFA crystallinity is very low suggesting that FFA is present predominantly in the amorphous state in heated P-MCC-FFA samples. These results suggest that heated mixtures with celluloses exhibit strong tendency to stabilize the amorphous structure of FFA, while celluloses in normal mixtures have only a limited ability to conserve the amorphicity of the drug.

The recrystallization of FFA occurred explicitly in the normal sample of P-MCC-FFA and the reduced value of the enthalpy (see Table 8) is associated with the lower content of FFA in the mixture (the amount for FFA is 10 times higher in the pure sample of FFA compared to P-MCC-FFA). A repeated measurement for both pure FFA and normal mixture of P-MCC-FFA showed that the peak for recrystallization could arise at several different temperatures indicating that FFA polymorphs with different crystallization behaviour were present. X-ray diffraction

In order to further confirm the physical state of FFA in the heated and normal samples, X-ray diffraction is conducted on samples of pure FFA and FFA in physical mixtures with the different celluloses. Figures 8 and 9 displays X-ray diffraction patterns for pure FFA and physical mixtures of FFA in both heated and normal samples with celluloses. The diffractogram of FFA is displayed in each graph as a reference. Several well-defined peaks of high intensity appear in the diffraction pattern of pure FFA. The peaks at 14°, 19° and 21 ° are the most prominent. The diffraction pattern for pure MCC is expected to display a diffused peak at 13-16°, a narrow peak at 22-23° and a peak with low intensity at 35° (Mihranyan A., et al., Int. J. Pharm., vol. 269, no. 2, pp. 433-442, 2004). Consequently, the sharp diffraction peaks over-imposed in the profile for normal mixture of MCC-FFA are clearly derived from the FFA content in the mixture. Moreover, it is observed that the peaks associated with FFA in the normal mixture with MCC have shifted from their original positions when compared with the fingerprint peaks for pure FFA. This may indicate substantial molecular rearrangement and formation of FFA polymorphs upon processing. The intensity of crystalline FFA peaks in the diffractograms for heated mixtures is generally reduced compared to the normal mixture of MCC-FFA, and only residual crystalline peaks of low intensity are visible in the diffractogram, in line with the DSC analysis on the MCC-FFA mixture. In the diffractograms for mixtures of P-MCC with FFA (Figure 9) peaks with equivalent positions and appearance as the ones representative of the cellulosic content in MCC-FFA mixtures appeared and were therefore attributed to the cellulosic content of the P-MCC sample. The diffractogram for the normal mixture of P- MCC-FFA showed analogous results as the mixture of MCC with FFA, where the normal mixture displayed peaks corresponding to cellulosic content along with the characteristic peaks for crystalline FFA that continued to appear in the diffractograms. However, the peaks, corresponding to crystalline FFA, appear with a slightly different shift in the peak positions and decrease in the relative intensity. In view of the DSC results for normal mixtures of P-MCC-FFA, in which only 48 % of FFA was found to be crystalline, it is plausible that partial amorphisation is responsible for the overall decrease in relative intensity, while the shift in peak positions is likely to be related to the presence of polymorphism in FFA. The X-ray diffraction patterns for the heated sample of P-MCC-FFA revealed characteristic peaks for cellulose, identical to the peaks in normal mixture. However, the heated mixture of P-MCC-FFA showed no peaks indicating on absence of crystalline FFA. Since amorphous materials do not diffract X-rays in a coherent manner, it is regarded that FFA is present explicitly in its amorphous state in the heated mixture of P- MCC-FFA. Consequently, the results of X-ray diffraction confirmed the previous DSC results suggesting that the drug is present in its crystalline form in the normal mixtures and transformed to fully amorphous state during heat treatment. Example 5 - Dissolution studies

Dissolution measurements were made on normal and heated physical mixtures of FFA with either MCC or P-MCC to evaluate the release kinetics of FFA. A reference measurement was made using pure FFA. Dissolution kinetics of FFA in formulation with cellulose were determined by the standardized USP paddle method. Release profiles for the drug were created by spectrofluorimetric analysis on samples at various time points.

Method - Standard drug solutions and fluorimetric calibration

Stock solution containing 10 μg/mL flufenamic acid (FFA) was prepared by dissolving FFA in simulated intestinal fluid (SIF). Various amounts of stock solution between 0.1 mL and 1 mL were transferred to plastic vials and frozen at -27 °C. The vials containing stock solution were freeze-dried overnight using a Scanvac CoolSafe 55-4 (LaboGene ApS, Lynge, Denmark). Seven working standard solutions with FFA concentration range between 0.1 and 10 μg/mL were prepared by dissolving the contents of the vials containing freeze-dried stock solution with 1 mL of a polar solvent, Acetonitrile-DMSO (4: 1 , vol/vol). Fluorescence spectral measurements were performed on an Infinite M200 Tecan (Austria) microplate reader equipped with two monochromators (excitation and emission) and UV Xenon light source. Black 96-well round-bottom (Corning 96 Round Bottom, Polystyrol) microplates were used. Excitation and emission spectra were collected using the instrument software and the maximum excitation wavelengths of FFA in the solvent was estimated to A_ex = 289 with a full band scan from 200 nm to 400 nm. The maximum emission intensity of the drug in the working standards was measured spectrophotometrically at A_ex = 289 with a full band scan from 400 nm to 500 nm. A linear regression analysis was made on the collected data set.

Method - Drug Release

Dissolution measurements were performed with the rotating paddle technique at 37.0±0.5 °C and 50 rpm with SOT AX (AT7 Smart, Switzerland) dissolution apparatus. SIF was selected as the dissolution medium and prepared by diluting 20 mL of concentrated SIF with 480 mL deionized water. Normal and heated cellulose mixtures were poured into dissolution vessels with 500 mL dissolution medium and samples of 1 ml were extracted at various time points (15 min, 30 min, 1 h, 2 h, 3h, 4h and 5h). A total of seven samples with a volume of 1 mL were collected for each cellulose-FFA formulation and passed through a syringe filter into 2 ml plastic vials. The vials were frozen at -27 °C and freeze-dried further until all of the water had sublimated from the sample and the dried FFA filtrate remained. The vials containing dried FFA were filled with 1 ml_ Acetonitrile-DMSO (4: 1 , vol/vol) solvent and manually shaken until the collected FFA was dissolved. Two parallel measurements were performed for each formulation. Spectrofluorometric analysis together with previously described regression analysis was used to estimate the concentration of released FFA at different time points.

Results

The results from in vitro release experiments, conducted on heated and normal mixtures of FFA with either MCC or P-MCC are presented in Figures 10A and 10B respectively. The dissolution profiles from each physical mixture are displayed together with the profile of the drug alone in the dissolution medium (SIF).

The dissolution profile of FFA in formulation with MCC (Figure 10A) shows a pattern similar to the one of FFA alone. Generally, the release behaviour of FFA from both celluloses in normal formulations was similar to that of FFA alone. The normal FFA-cellulose mixtures and the sample with pure FFA released over 50 % of the drug after 2 hours and between 82-86 % was released after 5 hours of experiment. The dissolution profiles of FFA in the heated formulation with P-MCC (Figure 10B) displayed a considerable acceleration of the dissolution rate of the drug. An initial burst release was apparent and a rapid increase in the concentration of released drug from the heated mixture with P-MCC was observed during the first 50 minutes of the experiment. The concentration of released drug was observed to be three times as high for the heated mixture with P-MCC compared to FFA after the initial 15 minutes where the amount of FFA released from heated P-MCC-FFA mixture was 51 %, compared to 15% for pure crystalline FFA. The cumulative concentration of FFA released from P-MCC after 2 h was 95 % whereas FFA alone did not reach that value within the experimental time frame and displayed a maximum of 87 % after 5 h. It should also be noted that the heated mixture of P-MCC-FFA is the only sample that released the entire amount of preloaded FFA within 5 hours.

Example 6 - Stability studies

Glass vials containing samples were stored at constant relative humidity (75 %) over saturated NaCI solution at room temperature for 61 days inside a desiccator. X-ray diffraction was conducted on samples after 61 days according to the principle specified above. The results from the stability study showed that recrystallization and transformation of the physical state of FFA was facilitated in normal mixtures during storage where new peaks of high intensity for crystalline FFA were observed in the X-ray profiles. For the normal mixtures, MCC-FFA (Fig. 1 1a) and P-MCC-FFA (Fig. 12a), new peaks of high intensity appeared at 18° and 22° (for MCC-FFA) and 14°, 21 ° and 43° (for P-MCC-FFA). Moreover, the recurring peaks in the profiles for normal samples after storage exhibited much lower intensity than the original ones. Two of the new peaks, at 14° and 21 °, in the profile for normal mixture of P-MCC-FFA (75% RH) appeared with a high intensity at a position identical to the ones shown in the profile for pure crystalline FFA. The appearance of new peaks in the profiles for normal mixtures was accompanied by the complete disappearance of other characteristic FFA peaks present in the original X-ray profiles. This effect was most apparent in the results for the normal mixture of MCC-FFA, where the characteristic peaks at 13°, 24°, 26° and 27° had disappeared in the new profile (Fig. 1 1a). The peak positions and overall profiles differed between the two physical mixtures of selected celluloses in normal samples. The appearance of new peaks of high intensity and disappearance of some characteristic peaks of FFA in the profiles for normal samples suggest that the physical state of FFA undergoes a substantial structural transformation during storage.

X-ray profiles obtained from the stability study on heated mixtures of FFA in formulation with MCC (Figs. 11 b and 11 c) and P-MCC (Figs. 12b and 12c) showed no significant differences from the original samples. In contrast to results for normal mixtures, FFA in the heated mixtures does not undergo a phase transition and long-term exposure to moisture does not induce recrystallization of FFA when in formulation with MCC and P- MCC. The absence of new crystalline peaks in the profiles of MCC-FFA and P-MCC-FFA revealed that the physical state of FFA is preserved during storage and the drug is present in the amorphous state even when high levels of moisture were introduced in the system over time.

Claims

1. A pharmaceutical composition comprising a modified microcrystalline cellulose excipient and an active pharmaceutical ingredient, wherein the modified microcrystalline cellulose excipient has a surface area of from about 2 to about 60 m²/g.

2. The pharmaceutical composition according to Claim 1 , wherein the modified microcrystalline cellulose excipient has a surface area of from about 5 to about 50 m²/g.

3. The pharmaceutical composition according to Claim 1 or Claim 2, wherein the modified microcrystalline cellulose excipient has a total pore volume of at least about 0.005 cm³/g.

4. The pharmaceutical composition according to any one of the preceding claims, wherein the modified microcrystalline cellulose excipient has a total pore volume of from about 0.01 to about 0.1 cm³/g, preferably from about 0.01 to about 0.05 cm³/g.

5. The pharmaceutical composition according to any one of the preceding claims, wherein the active pharmaceutical ingredient is in a predominantly amorphous form.

6. The pharmaceutical composition according to Claim 5, wherein at least 80% of the active pharmaceutical ingredient in the composition is in an amorphous form.

7. The pharmaceutical composition according to any one of the preceding claims, wherein the pharmaceutical composition comprises the active pharmaceutical ingredient at an amount of between 5 and 30% by weight of the composition.

8. The pharmaceutical composition according to any one of the preceding claims, wherein the active pharmaceutical ingredient is a molecule which contains at least one aromatic ring or a polycondensed cyclic structure, optionally wherein the molecule also contains at least one hydrogen bond donor or hydrogen bond acceptor.

9. The pharmaceutical composition according to any one of the preceding claims, wherein the active pharmaceutical ingredient is a non-steroidal anti-inflammatory drug, a steroid and a cholate, optionally selected from the group consisting of ibuprofen, ketoprofen, flurbiprofen, naproxen, aspirin, ethenzamide, mefenamic acid, flufenamic acid, tolfenamic acid, indomethacin, sulindac, pyroxicam, progesterone, estradiol, progestin, estrogen, cholic acid, deoxycholic acic and ursodeoxycholic acid.

10. The pharmaceutical composition according to any one of the preceding claims, wherein the active pharmaceutical ingredient:

(a) contains at least two aromatic rings, and at least one hydrogen bond donor or hydrogen bond acceptor; and/or

(b) is an NSAID or an antineoplastic agent.

1 1. The pharmaceutical composition according to any one of the preceding claims, wherein the active pharmaceutical ingredient is selected from the group consisting of: anthranilic acid derivatives (such as azapropazone, etofenamate, flufenamic acid, flunixin, meclofenamic acid, mefenamic acid, morniflumate, niflumic acid, and tolfenamic acid); and protein-kinase inhibitor substances (such as Afatinib, Alectinib, Axitinib, Binimetinib, Bosutinib, Brigatinib, Cabozantinib, Cediranib, Ceritinib, Cobimetinib, Crizotinib, Dasatinib, Entrectinib, Erlotinib, Fostamatinib, Gefitinib, Ibrutinib, Imatinib, Lapatinib, Lenvatinib, Lestaurtinib, Masitinib, Momelotinib, Mubritinib, Neratinib, Nilotinib, Nintedanib, Olmutinib, Osimertinib, Pacritinib, Pazopanib, Ponatinib, Radotinib, Regorafenib, Rociletinib, Ruxolitinib, Selumetinib, Semaxanib, Sorafenib, Sunitinib, Tivozanib, Toceranib, Trametinib, Vandetanib and Vemurafenib).

12. A pharmaceutical composition according to any one of Claims 1 to 1 1 , wherein the composition is obtained by a process involving heating a mixture of the modified microcrystalline cellulose excipient and the active pharmaceutical ingredient to a temperature close to or above the glass transition temperature of the active pharmaceutical ingredient.

13. A process for preparing a modified microcrystalline cellulose excipient as defined in any one of Claims 1 to 4, which process comprises:

(ii) spray drying said dispersion.

14. The process according to Claim 13, wherein the microcrystalline cellulose precursor in the dispersion has a D50 value prior to the spray drying step of up to 1 μηι.

15. The process according to Claim 13, wherein the microcrystalline cellulose precursor in the dispersion is a dispersible-grade microcrystalline cellulose.

16. The process according to Claim 15, wherein the dispersible-grade microcrystalline cellulose is a mixture comprising microcrystalline cellulose and a hydrocolloid selected from the group consisting of carboxymethylcellulose, carrageenan, guar gum, sodium alginate, and mixtures thereof.

17. The process according to Claim 13 or Claim 14, further comprising acid hydrolysis of the microcrystalline cellulose precursor prior to the formation of the dispersion.

18. The process according to any one of Claims 13 to 17, wherein the one or more volatile water-miscible solvents is selected from the group consisting of methanol, ethanol, isopropanol, n-propanol, acetone, methyl ethyl ketone, tetrahydrofuran, acetonitrile, and mixtures thereof.

19. The process according to any one of Claims 13 to 18, wherein the one or more volatile water-miscible solvents are present in an amount ranging from about 10 to about 70 % by volume of the solvent system.

20. The pharmaceutical composition according to any one of Claims 1 to 12, wherein the modified microcrystalline cellulose excipient is obtainable by a process as defined in any one of Claims 13 to 19.

21. Method of treating dysmenorrhea or migraine, said method comprising administering a pharmaceutical composition as defined in any one of Claims 1 to 12 or 20 to a subject suffering from dysmenorrhea or migraine, wherein the active pharmaceutical ingredient is a non-steroidal anti-inflammatory drug.

22. A pharmaceutical composition as defined in any one of Claims 1 to 12 or 20 for use in treating dysmenorrhea or migraine, wherein the active pharmaceutical ingredient is a non-steroidal anti-inflammatory drug.

23. Use of a pharmaceutical composition as defined in any one of Claims 1 to 12 or 20 in the manufacture of a medicament for treating dysmenorrhea or migraine, wherein the active pharmaceutical ingredient is a non-steroidal anti-inflammatory drug.

24. A method of preparing a pharmaceutical composition as defined in any one of Claims 1 to 11 or 20, comprising mixing together an active pharmaceutical ingredient and a modified microcrystalline cellulose excipient having a surface area of from about 2 to about 60 m²/g, optionally wherein the modified microcrystalline cellulose excipient is obtained by a process according to any one of Claims 13 to 19.

25. The method of Claim 24, further comprising processing the mixture by:

heat-assisted-extrusion;

static heat sealing;

heat-assisted intensive mixing,

mixing under reduced pressure,

heating;

mild grinding which does not adversely affect the pore structure of excipient; and/or co-spray drying, or rotary evaporation at reduced pressure, with a solvent, preferably wherein the solvent is a mixture of water and lower alkyl alcohol.