PROCESS FOR PREPARING AN ORAL DISINTEGRATING DOSAGE FORM

Abstract

An oral disintegrating tablet (ODT) comprising an active ingredient, about 1 to about 20% w/w of at least one amphiphilic compound, about 1 to about 60% w/w of at least one disintegrant and about 0.5 to about 5% w/w of at least one binder, wherein the ODT has hardness of at least about 1 kp and wherein, when the ODT contacts a hydrophilic solvent, the amphiphilic compound self-assembles into liquid crystalline particles.

Claims

1. An oral disintegrating tablet (ODT) suitable for systemic administration of an active ingredient via the oral mucosa comprising an active ingredient, about 1 to about 20% w/w glycerol monooleate, about 1 to about 60% w/w of at least one disintegrant and about 0.5 to about 5% w/w of at least one binder, and wherein, when the ODT contacts a hydrophilic solvent, the ODT disintegrates and the amphiphilic compound self-assembles into liquid crystalline particles.

2. The ODT according to claim 1, wherein the ODT has hardness of at least about 0.5 to about 6 kp.

3. The ODT according to claim 1, wherein the hardness is about 1 to about 4 kp.

4-5. (canceled)

6. The ODT according to claim 1, wherein the liquid crystalline particles are cubosomes.

7-8. (canceled)

9. The ODT according to claim 1, wherein the ODT disintegrates within 15 minutes of contact with a hydrophilic solvent.

10. The ODT according to claim 1, wherein the ODT is formulated for sublingual or buccal administration.

11. The ODT according to claim 1, wherein the active ingredient has a log P of −0.5 to 6.4 and/or a molecular weight of 100 to 1200.

12. The ODT according to claim 1, wherein the active ingredient is 0.5 to 10% w/w of the ODT.

13. The ODT according to claim 1, wherein the amphiphilic compound has one or more of the group selected from a critical packing parameter (CPP) of >½ and a hydrophilic lipophilic balance (HLB) of 0 to <10.

14. (canceled)

15. The ODT according to claim 1, wherein when the ODT disintegrates upon contact with a hydrophilic solvent the amphiphilic compound self-assembles into liquid crystalline particles that encapsulate or entrain the active ingredient.

16. A method of preparing an ODT comprising heating an amphiphilic compound capable of self-assembly into liquid crystalline particles upon contact with a hydrophilic solvent to its melting point mixing an active ingredient with the amphiphilic compound until dispersed cooling the mixture to at least a semi-solid state combining the mix of active ingredient and amphiphilic compound with at least one pharmaceutically acceptable excipient to prepare a blend optionally adding further pharmaceutically acceptable excipients compressing the blend into an ODT wherein, when the ODT contacts a hydrophilic solvent the ODT disintegrates and the amphiphilic compound self-assembles into liquid crystalline particles.

17. The method of claim 16, wherein combining the mix of active ingredient and amphiphilic compound with at least one further excipient reduces the temperature of the amphiphilic compound to below its melting point.

18. The method of claim 16, wherein the at least one pharmaceutically acceptable excipient is added immediately following mixing of the amphiphilic compound and active ingredient.

19. The method of claim 16, wherein mixing of the amphiphilic compound and active ingredient occurs within 10 minutes.

20. The method of claim 16, wherein the amphiphilic compound is not heated more than 10° C. above its melting point.

21. A method of preparing an ODT comprising heating an amphiphilic compound capable of self-assembly into liquid crystalline particles upon contact with a hydrophilic solvent to its melting point mixing an active ingredient with the amphiphilic compound until dispersed immediately following melting of the amphiphilic compound or alternatively during melting the amphiphilic compound cooling the mixture to at least a semi-solid state immediately following dispersion of the active ingredient within the amphiphilic compound combining the mix of active ingredient and amphiphilic compound with at least one pharmaceutically acceptable excipient optionally adding further pharmaceutically acceptable excipients compressing the blend into an ODT wherein, when the ODT contacts a hydrophilic solvent the ODT disintegrates and the amphiphilic compound self-assembles into liquid crystalline particles.

22. The method of claim 16, wherein the ODT has a hardness of about 0.5 to about 6 kp.

23. The method of claim 16, wherein the ODT disintegrates within 15 minutes of contact with a hydrophilic solvent.

24. The method of claim 16, wherein the liquid crystalline particles are cubosomes.

25. The method of claim 16, wherein the ODT is formulated for sublingual or buccal administration.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0159] FIG. 1—Outline of the lyotropic liquid crystalline phases that can be formed when water is added to an anhydrous lipid. Normal (o/w) phases are designed I and inversed (w/o) phases II with decreasing packing parameter as water concentration increase. Adapted with permission from Israelachivili et al. (1994) and Nguyen (2009). Israelachvili, J., The science and applications of emulsions—an overview. Colloids Surf. Physico chem. Eng. Aspects 1994, 91, 1-8. Nguyen, T.-H. Investigation of novel liquid crystalline materials for the sustained oral delivery of poorly water soluble drugs. PhD, Monash University, Melbourne, 2009.

[0160] FIG. 2—Diagrammatic representation of the structure of the three main bicontinuous and hexagonal crystal structures where (a) Gyroid (G) Ia3d, (b) Diamond (D) Pn3m and (c) Primitive (P) Im3m. The hexagonal liquid crystals are represented by (d) inverse and (e) normal hexagonal structure. Diagram adapted from Caffrey and Cheng (1995) and Nguyen (2009).

[0161] FIG. 3—The appearance of oxycodone in the receptor chamber over time after application of SBT227 (diamond) and SBT232 (square) to porcine buccal mucosa in the donor chamber of a Ussing chamber. Data are presented as mean±SEM (n=5). Both formulations demonstrate slow release characteristics. SBT227 release the API relatively faster comparing to SBT232 due to lower quantity of GMO.

[0162] FIG. 4—The appearance of atorvastatin in the receptor chamber over time after application of SBT226 (square) and SBT233 (diamond) to porcine buccal mucosa in the donor chamber of a Ussing chamber. Data are presented as mean±SEM (n=5). Both formulations demonstrate slow release characteristics. SBT226 release the API relatively faster comparing to SBT233 due to lower quantity of GMO.

[0163] FIG. 5—The results for each individual tablet that were combined to prepare the mean results depicted in FIG. 4 are shown in FIG. 5A—SBT226 tablet testing and FIG. 5B—SBT233 testing. Release of atorvastatin into the receptor chamber at 0, 0.25, 0.5, 1, 1.5, 2, 3 and 4 hours is shown. The individual testing results demonstrate slow release continuing at 4 hours for 4 out of the 5 SBT226 tablets and 3 out of the 5 SBT233 tablets.

DETAILED DESCRIPTION OF THE EMBODIMENTS

[0164] It will be understood that the invention disclosed and defined in this specification extends to all alternative combinations of two or more of the individual features mentioned or evident from the text or drawings. All of these different combinations constitute various alternative aspects of the invention.

[0165] Reference will now be made in detail to certain embodiments of the invention. While the invention will be described in conjunction with the embodiments, it will be understood that the intention is not to limit the invention to those embodiments. On the contrary, the invention is intended to cover all alternatives, modifications, and equivalents, which may be included within the scope of the present invention as defined by the claims.

[0166] Further aspects of the present invention and further embodiments of the aspects described in the preceding paragraphs will become apparent from the following description, given by way of example.

[0167] All of the patents and publications referred to herein are incorporated by reference in their entirety.

[0168] For purposes of interpreting this specification, terms used in the singular will also include the plural and vice versa.

[0169] One skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which could be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described.

[0170] The inventors of the present invention have developed a process for preparing an ODT that prolongs release of an active ingredient. The prolonged release is achieved by including in the ODT an amphiphilic compound capable of self-assembly into liquid crystalline particles upon contact with a hydrophilic solvent.

[0171] The inventors have also developed an ODT of suitable hardness despite including significant quantities of amphiphiles normally reserved for semi-sold formulation. Not only does the ODT have suitable hardness but it also incorporate the amphiphilic compound into the ODT in a way that maintains the ability of the amphiphilic compound to self-assemble into liquid crystalline particles

[0172] The ingredient GMO has traditionally been used in the preparation of hard tablets. The inventors of the present invention have also prepared oral disintegrating tablets of pharmaceutically acceptable hardness comprising significant quantities of the ingredient GMO.

[0173] Certain ingredients at certain amounts interfere with the formation of liquid crystalline particles by the amphiphilic compound, either by preventing formation of said particles or by altering the type of particles formed. The method of the present invention allows use of ingredients that interfere with formation of the liquid crystalline particles at amounts that would otherwise be an issue. For example, the inventors of the present invention identified that mixes of the amphiphilic compound glycerol monooleate (GMO) with the active ingredient rosuvastatin were a problem at more than 15% rosuvastatin to GMO (w/w). Using the process of the invention, an ODT containing 50% rosuvastatin to GMO (w/w) was prepared and the GMO retained the ability to form liquid crystalline cubic phase.

[0174] The term ‘self-assembled particles’ as used throughout the specification is understood to mean an aggregate of amphiphiles that possess some degree of internal organisational order, for example, a colloidal particle or colloidosome or a solid lipid particle. The particles can be either nanoparticles or microparticles depending on their average size, typically less than about 1 μm, preferably in a range of about 10 nm to about 500 nm, more commonly about 200 nm. Solid lipid nanoparticles are a dispersed crystalline lamellar lipidic material. The self-assembled particles are formed by contacting the amphiphile with solvent. In some embodiments, the self-assembled particles themselves aggregate into a bulk lyotropic phase.

[0175] The term ‘bulk phase’ as used throughout the specification is understood to mean a lyotropic phase that includes but is not limited to: micellar cubic (11); normal hexagonal (H1); bicontinuous cubic (V1); lamellar (L); reversed bicontinuous cubic (V2); reversed hexagonal (H2); reversed micellar cubic (12) and sponge (L3) phases.

[0176] The term ‘cubic phase’ as used throughout the specification is understood to refer to two main classes of phases: micellar cubic and bicontinuous cubic. ‘Micellar cubic phase’ refers to a phase consisting of spherical micelles arranged in a cubic array. A ‘normal micellar cubic phase’ or ‘II phase’ consists of spherical normal micelles arranged in a cubic array, whilst an ‘inverse micellar cubic phase’ or ‘III phase’ consists of spherical inverse micelles arranged in a cubic array. ‘Bicontinuous cubic phase’ refers to a family of closely related phases that consist of a single curved lipid bilayer that forms a complex network that separates the polar solvent space into two continuous, but non-intersecting volumes. Bicontinuous cubic phases possess long range order based upon a cubic unit cell. Bicontinuous cubic phases have zero mean curvature; that is, at all points on surface of the amphiphile bilayer, the surface is as convex as it is concave. Bicontinuous cubic phases include the normal (‘vI phase’) or reverse (‘vII phase’) type. Several types of long range orientational orders have been observed for bicontinuous cubic phases; the orientational order in these phases correspond to space groups Ia3d, Pn3m, and Im3m. When a colloidosome possesses the internal structure of a bulk cubic phase the colloidosome is referred to as a ‘cubosome’.

[0177] The term ‘hexagonal phase’ as used throughout the specification is to be understood to mean an amphiphile phase consisting of long, rod-like micelles packed into a hexagonal array. A ‘normal hexagonal phase’ is a hexagonal phase consisting of long, rod-like normal micelles, whilst an ‘inverse hexagonal phase’ is a hexagonal phase consisting of long, rod-like inverse micelles. The normal hexagonal phase may be referred to as the ‘HI phase’ and the inverse hexagonal phase may be referred to as the ‘HII phase’. When a colloidosome possesses the internal structure of a bulk hexagonal phase the colloidosome may be referred to as a ‘hexosome’.

[0178] The term ‘lamellar phase’ as used throughout the specification is to be understood to mean a stacked bilayer arrangement, where opposing monolayers of the hydrophilic portion of amphiphile molecules are separated by a polar solvent domain, while the hydrophobic portion of the amphiphile molecule of the back-to-back layers are in intimate contact to form a hydrophobic layer. The planar lamellar phase is referred to as the ‘Lα phase’. There are three lamellar phases, (1) the fluid lamellar phase (Lα) where the chains are melted, (2) the gel lamellar phase (Lß) where the chains are mostly melted but some degree of short range order and (3) the lamellar crystalline phase (Lc), where the chains are crystalline with very short range order.

[0179] The term ‘sponge phase’ or ‘L3 phase’ as used throughout the specification refers to a phase that resembles a bicontinuous cubic phase, in that it possesses an amphiphile bilayer that separates the polar solvent space into two unconnected volumes, but it does not possess long range order. Accordingly, these phases are analogous to a ‘melted cubic phase’.

[0180] The term ‘prodrug’ as used throughout the specification refers to a biologically active agent including structural modifications thereto, such that in vivo the prodrug is converted, for example, by hydrolytic, oxidative, reductive or enzymatic cleavage to the biologically active agent by one or more reactions or steps. It includes an agent that requires one or more chemical conversion steps or steps of metabolism to produce the active molecule.

[0181] The term ‘pharmaceutical composition’ as used throughout the specification means a composition comprising a therapeutically effective amount of at least one active ingredient according to the current invention. The pharmaceutical composition may further include one or more of a pharmaceutically acceptable carrier, excipient, diluent, additive or vehicle selected based upon the intended form of administration, and consistent with conventional pharmaceutical practices. Suitable pharmaceutical carriers, excipients, diluents, additives and vehicles are known to those skilled in the art and are described in publications, such as, for example Remington (Remington: The Science and Practice of Pharmacy, 21st Ed, University of the Sciences in Philadelphia (eds), Lippincott Williams & Wilkins, Philadelphia, Pa., 2005.).

[0182] As used herein, ‘therapeutically effective amount’ relates to the amount or dose of a statin or other active thereof that will lead to one or more desired effects, in particular the reduction of cholesterol synthesis. A therapeutically effective amount of a statin will vary according to factors such as the disease state, age, sex, and weight of a subject, and the ability of the substance to elicit a desired response in the subject.

[0183] Liquid Crystalline Particles

[0184] There are multiple forms of liquid crystalline particles each with different structure. The self-assembled structure may be micellar (normal or reversed), lamellar, hexagonal (normal or reversed), cubic (normal discrete, reversed discrete, reversed bicontinuous—including primitive, gyroid and diamond—or reversed discontinuous), or other ‘intermediate phases’ such as the ribbon, mesh, or non-cubic ‘sponge’ bicontinuous phases. When these particles possess the internal structure of a reversed bicontinuous cubic phase, the particles are colloquially referred to as cubosomes. Similarly, when the particles possess the internal structure of a reversed hexagonal phase, they are referred to as hexosomes. When the particles possess the internal structure of a lamellar phase, they are referred to as liposomes.

[0185] The type of phase structures formed is dependent on the amphiphile structure, amphiphile concentration, temperature, pressure and solvent content (Kaasgaard, T.; Drummond, C. J., Ordered 2-D and 3-D nanostructured amphiphile self-assembly materials stable in excess solvent. Phys. Chem. Chem. Phys. 2006, 8, 4957-4975). The relationship between phase structures formation and the geometry of amphiphilic molecules can be defined by the dimensionless critical packing parameter (p)=v/al where v and I are the volume and the length of the fully extended hydrocarbon chain and a is the surface area of the hydrophilic headgroup. An increase in a may occur due to an increase in hydration and electrostatic repulsion between adjacent hydrophilic headgroups. Whilst an increase in v can be due to increases in hydrocarbon chain fluidity at elevated temperature66 or increases in the number, branching and/or size of the hydrocarbon chain. At p=1, which indicates equal hydrophilic and hydrophobic volume, lamellar (La) bilayer structure are formed. Normal (Type 1) self-assembled structure with the interface curves spontaneously towards water (positive curvature) are formed when p<1 whilst inverse structures (Type 2) with interface curves spontaneously away from water (negative curvature) are formed when p >1. In addition to micellar (p<⅓), inverse micellar (p >3) and lamellar structures, other phases such as the two dimensional normal and inverse hexagonal (H1 and H2), the three dimensional normal and inverse bicontinuous cubic (V1 and V2) and the discontinuous cubic (I1 and I2) phases are also observed (structure to be discussed in detail later). It should be noted that a range of nomenclatures are used in literature to denote the individual phase in the literature, so for this report, the abbreviations just mentioned will be utilised.

[0186] Lamellar, hexagonal and cubic phases are considered as liquid crystal phases as they exhibit both the long range order of crystalline materials and the disorder of liquid systems.

[0187] For conventional surfactants, a progressive increase in the water content induces changes in the phase structure from inverse phases to normal phases as illustrated in FIG. 1.1. Not all structures illustrated in FIG. 1.1 may be observed, but the order and progression of the general phase change is preserved.

[0188] However, some amphiphilic molecules do not follow the illustrated lyotropic phase behaviour in FIG. 1.1 all the way to micelles in addition water. These molecules only swell in contact with water to a finite degree and forms liquid crystalline phases depending on their chemical structure, and further addition of water does not induce the transition to micelles. Hence these inverse LC phases co-exist with excess water at very high dilution. The most well-known example of this behaviour is phospholipids which remain as La phase in excess water and are the critical component of cellular membranes.

[0189] Lamellar Liquid Crystals

[0190] Lamellar liquid crystal (LC) phases consist of stacked bilayers, where lipid molecules are arranged so that the hydrophobic chains meet to form a hydrophobic domain whilst the hydrophilic head groups facing opposite ends form the hydrophilic domains with other lamellae bilayers. Water occupies the hydrophilic domain and interacts with the hydrophilic head groups lining each lamellae. The lamellar liquid crystals are formed when the geometric space occupied by the hydrophilic headgroup and the hydrophobic tail are equivalent (packing parameter 1). Lamellar structures are the arguably the most ubiquitous liquid crystal structure of all lyotropic liquid crystals as they are featured in most biological membranes.

[0191] Cubic Liquid Crystals

[0192] Micellar Cubic Structures (I)

[0193] Discontinuous cubic phases (as opposed to the bicontinuous cubic phases discussed later) are micelles embedded in a three-dimensional, matrix organised in a cubic symmetry. The discontinuous cubic phases, whether normal (I1) or inverted (I2) are intermediate LC phases and reside between hexagonal LCs and micelles in the order of progression described in FIG. 1.

[0194] Bicontinuous Cubic Liquid Crystals (V)

[0195] Bicontinuous cubic LC phases, whether normal V1 or inverse V2 are viscous, optically isotropic liquid crystals located on either side of the lamellar structure and differ from the discontinuous cubic phases, as they consists of separate but continuous lipid bilayer and water regions.

[0196] The inverse bicontinuous cubic phase (V2) consists of two separate, continuous but nonintersecting hydrophilic regions divided by a single lipid bilayer in a complex 3-D cubic symmetry. It is generally believed that V2 phases have interface structures based on the infinite periodic minimal surfaces (IPMS), where the lipid surface consists of two principle curvatures which are equal but opposite in sign at every point (as convex as they are concave), resulting in zero average mean curvature (positive+negative curvature), and negative Gaussian curvature (positive×negative curvature). Using X-ray scattering measurements the existence of cubic phases in amphiphile+water systems was recognized in the 60s. Although mathematicians have found a wide variety of periodic minimal surfaces, only three types of IPMS have been observed in amphiphile-water systems: Gyriod (G), double diamond (D) and primitive (P) with corresponding space groups of Ia3d (G), Pn3m (D) and Im3m (P), respectively (see FIG. 1). The different phases can be identified by their unique X-ray scattering patterns.

[0197] Hexagonal Liquid Crystals (H)

[0198] Hexagonal LCs are designated as either H1 (normal) or inverse H2 phases. The H phases are viscous, optically birefringent liquid crystals consisting of infinitely long hexagonally close packed cylindrical micelles (see FIG. 1). The H2 phase has more negative curvature than the inverse cubic phase due to larger hydrophobic portion of the molecules.

[0199] Bulk Phase

[0200] The liquid crystalline particles of the present invention may self-assembled into bulk phase including an active ingredient. Typically, a bulk material having a certain phase will form from an amphiphile, that is, a molecule that possesses both a hydrophilic portion and a hydrophobic portion. The self-assembly behaviour of amphiphiles in solvent arises because of the preferential interaction between the solvent and either the hydrophilic or hydrophobic portion of the amphiphilic molecule. When an amphiphile is exposed to a polar solvent, the hydrophilic portion of the amphiphile tends to preferentially interact with the polar solvent, resulting in the formation of hydrophilic domains. The hydrophobic portion of the amphiphile molecules tend to be excluded from this domain, resulting in the de facto formation of a hydrophobic domain.

[0201] It is in a self-assembled form that amphiphiles are capable of acting as an inert carrier or matrix into which biologically active molecules, such as an active ingredient, may be incorporated. The nanoscale porosity of the self-assembled materials provides a high internal and external surface area. An active ingredient that is distributed within a region of this material is believed to be distributed in an ordered arrangement, and at a high loading concentration due to the large internal and external liquid crystal surface area. Self-assembled bulk phase may exhibit a variety of orientational orders. If long-range orientational order is observed within the self-assembled bulk phase at equilibrium, the self-assembled bulk phase is termed a ‘mesophase’, a ‘lyotropic liquid crystalline phase’, a ‘lyotropic phase’ or, as used herein, simply a ‘phase’.

[0202] There are 2 principal types of liquid crystalline phases: thermotropic liquid crystals and lyotropic liquid crystals. Thermotropic liquid crystals can be formed by heating a crystalline solid or by cooling an isotropic melt of an appropriate solute. Lyotropic liquid crystals can be formed by addition of a solvent to an appropriate solid or liquid amphiphile. The manipulation of parameters such as amphiphile concentration and chemical structure, solvent composition, temperature and pressure may result in the amphiphile-solvent mixture adopting lyotropic phases with distinctive characteristics.

[0203] Examples of particular phases that can be formed by self-assembled particles are set out above. It is possible to disperse the bulk phases described above to form colloidal particles (so-called ‘colloidosomes’) that retain the internal structure of the non-dispersed bulk phase. When these particles possess the internal structure of a reversed bicontinuous cubic phase, the particles are colloquially referred to as cubosomes. Similarly, when the particles possess the internal structure of a reversed hexagonal phase, they are referred to as hexosomes. When the particles possess the internal structure of a lamellar phase, they are referred to as liposomes.

[0204] Whilst the bulk materials can be of use in some circumstances, the use of bulk materials having cubic phases in drug administration is limited by their high viscosity making them difficult to administer. In these cases, colloidal dispersions of particles of these phases may be used in drug delivery. More preferred phases for use as drug delivery vehicles are bicontinuous cubic phase or reversed hexagonal phase. The inverse cubic phase affords distinct aqueous regions that form two continuous water networks (or channels) throughout the cubic phase that more readily allow diffusion of an active ingredient. The inverse cubic liquid crystal phase is thermodynamically stable and co-exists in equilibrium with excess water over a broad temperature range. Alternatively, if the bicontinuous cubic phase is viscous and difficult to administer it may be possible to administer a lamellar phase material that converts into the cubic phase upon dissolution with aqueous, water rich, body fluids (thus facilitating the conversion of one phase to another). For example, a suitable material is a phospholipid such as 1,2-dioleoyl-sn-glycero-3-phosphocholine. The cubic phase in situ provides a viscous depot from which an active ingredient can slowly be released. An inverse cubic liquid crystal phase provides an appropriate scaffold in which to distribute or load the niacin compound owing to the high surface area of the internal liquid crystal structure (up to 400 m.sup.2/g).

[0205] One of the key difficulties with using liquid crystalline particles in the formulation of dosage forms for active ingredient delivery has been the viscosity of many liquid crystalline phases, which are difficult to handle, difficult to manufacture and difficult to administer.

[0206] Suitable pharmaceutical carriers, excipients, diluents, additives and vehicles are known to those skilled in the art and are described in publications, such as, for example Remington (Remington: The Science and Practice of Pharmacy, 21st Ed, University of the Sciences in Philadelphia (eds), Lippincott Williams & Wilkins, Philadelphia, Pa., 2005.).

[0207] The formulation may include one or more binders such as hydroxypropylmethylcellulose (HPMC), ethyl cellulose, acacia, polyvinyl alcohol (PVA), and polyvinylpyrrolidone (Povidone).

[0208] The formulation may include one or more glidants such as talc, magnesium trisilicate and colloidal silicon dioxide.

[0209] The formulation may include one or more fillers such as lactose, mannitol, sorbitol, starch, maltodextrin, acacia and silicon dioxide.

[0210] The formulation may include one or more lubricants such as glyceryl behenate, stearic acid, talc, zinc stearate, calcium stearate, magnesium stearate, aluminium stearate and sodium stearyl fumarate.

[0211] The formulation may include one or more film formers such as hydroxypropylmethylcellulose (HPMC), povidone (PVP), poly ethylene glycol (PEG).

[0212] The formulation may include one or more pH modifier agents (buffering agents) such as sodium hydroxide, sodium/calcium carbonate, citric acid, tartaric acid, fumaric acid etc.

[0213] If the formulation is prepared by thermoplastic granulation the formulation may include thermoplastic granulation agents such as glycerol monostearate, and glyceryl behenate.

[0214] The presence of liquid crystalline phase can be determined using the SAX/WAX beamline of a synchrotron, cross polarised light microscopy (CPLM) or Cry-Em. In certain circumstances, such as a low proportion of amphiphilic compound in the ODT, liquid crystalline phase may not be identified using the SAX/WAX beamline of the synchrotron and an alternative, such as, CPLM may be preferred. CPLM can identify LC structures but does not provide information on the internal phase.

[0215] The CPP of an amphiphilic compound can be determined by quantum mechanics molecular simulations to determine geometrical and quantitative structure-activity relationship (QSAR) values. See, Fong 2016. The HLB of an amphiphilic compound is calculated based on the number and identity of hydrophilic/lipophilic groups.

[0216] The CPP and HLB of some amphiphilic compounds are in Table A.

TABLE-US-00001 TABLE A CPP and HLB for various amphiphilic compounds Amphiphile CPP V A.sub.0 L.sub.C HLB Phytantriol 0.650 303.5 27.9 16.8 6.36 Monolinolein 1.016 341.0 22.6 14.8 1.02 Glucose 0.456 315.3 31.2 22.2 9.28 stearate Fructose 0.421 315.3 33.8 22.2 9.28 stearate

[0217] The active ingredients melatonin and atenolol have been shown to load and release from a monoolein-water liquid crystalline system previously and are expected to be compatible with the ODT of this invention. Atropine, haloperidol, levofloxacin, indomethacin, diazepam, trans retinol, prednisolone, progesterone, hydrocortisone and dexamethasone have been shown to load an release from monoolein and/or phytantriol liquid crystals previously and are expected to be compatible with the ODT of this invention. Irinotecan and paclitaxel has also been released from inverse hexagonal phase previously and are expected to be compatible with the ODT of this invention.

[0218] The log P and molecular weight for some active ingredients are in Table B below.

TABLE-US-00002 TABLE B LogP and molecular weight for various active ingredients API MW (g/mole) logP Atorvastatin 1155.4 6.36 Oxycodone 351.9 0.3 Adrenaline 183.2 −0.5 to −1.2 Rosuvastatin 1001.1 1.80 at pH 5 0.30 at pH 7 Niacin 123.1 0.36

REFERENCES

[0219] The text of each of the following references is incorporated by reference into this specification. [0220] Caffrey, M.; Cheng, A., Kinetics of lipid phase changes. Curr. Opin. Struct. Biol. 1995, 5, 548-555. [0221] Chang, C.-M.; Bodmeier, R., Low viscosity monoglyceride-based drug delivery systems transforming into a highly viscous cubic phase. Int. J. Pharm. 1998, 173, 51-60. [0222] Clogston, J.; Rathman, J.; Tomasko, D.; Walker, H.; Caffrey, M., Phase behavior of a monoacylglycerol (Myverol 18-99K)/water system. Chem. Phys. Lipids 2000, 107, 191-220. [0223] Drummond, C. J.; Fong, C., Surfactant self-assembly objects as novel drug delivery vehicles. Current Opinion in Colloid & Interface Science 1999, 4, 449-456. [0224] Fong, W et al, Dynamic formation of nanostructured particles from vesicles via invertase hydrolysis for on-demand delivery, The Royal Society of Chemistry: Electronic Supplementary Material (ESI) for RSC Advances, 2016, S1-S22. [0225] Gu, X et al, Is epinephrine administration by sublingual tablet feasible for the first-aid treatment of anaphylaxis? A proof-of-concept study. Biopharm Drug Dispos. 2002, 23(5):213-6. [0226] Hyde, S. T., Bicontinuous structures in lyotropic liquid crystals and crystalline hyperbolic surfaces. Current Opinion in Solid State and Materials Science 1996, 1, 653-662. [0227] Israelachvili, J., The science and applications of emulsions—an overview. Colloids Surf. Physico chem. Eng. Aspects, 1994, 91, 1-8. [0228] Kaasgaard, T.; Drummond, C. J., Ordered 2-D and 3-D nanostructured amphiphile self-assembly materials stable in excess solvent. Phys. Chem. Chem. Phys. 2006, 8, 4957-4975). [0229] World Intellectual Property Office publication, WO 2014/179845.

Example 1—Testing Mixtures of GMO and Excipients/Active Ingredients for Effect on Formation of Liquid Crystal Particles

[0230] GMO and excipient or active ingredient at various weight proportions were added into small HPLC vials. To ensure adequate mixing, the samples were initially heated above the melting temperature of GMO (>40° C.) and mixed vigorously with a metal spatula. The samples were then mixed via a roller mixer at ˜10 RPM at 40° C. for at least 3 days.

[0231] One week prior to SAXS experiment, 100 mg samples were loaded into a transparent polystyrene 96 well plate (Nunc™) and immersed in 200 μL of PBS buffer (pH 6.8). The samples were stored away from light at ambient temperature, to allow the samples to reach equilibrium.

[0232] Small Angle x-Ray Scattering (SAXS) Setup

[0233] The SAXS/WAXS beamline at Australian Synchrotron, Melbourne, Australia was used to determine the liquid crystalline nanostructure in the samples.

[0234] A custom-designed plate holder was used to mount the samples plate directly onto the SAXS/WAXS beamline. Scans were automated using a pre-loaded set of position variables based on the well positions within the plate, the exposure time was 5 sec.

[0235] Data were obtained at ambient temperature (˜22° C.). The experiments used a beam of wavelength λ=1.033 Å (12.0 keV) and a typical flux of 1.2×1013 photons/s. The 2-D diffraction images were recorded on a Pilatus 1M detector and radially integrated using the in-house software “ScatterBrain”.

[0236] The liquid crystal phase structures were determined by indexing the Bragg peaks according to their corresponding reflection laws (see Hyde, S. T., Bicontinuous structures in lyotropic liquid crystals and crystalline hyperbolic surfaces. Current Opinion in Solid State and Materials Science 1996, 1, 653-662).

[0237] The results in tablet 1 to 3 below show GMO forming a bulk phase of complex crystalline particles (ie cubic or hexagonal or a mix of the two) following mixing with a number of ingredients and then emersion of the mix in a hydrophilic solvent (PBS buffer). However, when the ratio of ingredient to GMO increases, the GMO ceases to form a complex bulk phase of crystalline particles but instead forms simple lamella or reverse lamella phase. The percentage w/w of the ingredient to GMO at which complex bulk phase no longer forms is the “threshold” for the ingredient or the maximum amount of the ingredient that can be present before formation of a complex bulk phase is disrupted.

TABLE-US-00003 TABLE 1 Summary of liquid crystalline phase formation for mixes of GMO and another ingredient % w/w Liquid crystalline phase Ingredient ingredient formed Tri ethyl citrate (TEC) up to 20% cubic 35% and above reverse emulsion Sodium cyclamate up to 10% cubic 20% lamellar 50% lamellar + crystals Butylated hydroxy  1% cubic anisole (BHA)  5% cubic + hexagonal 10-20% hexagonal 30% and above reverse emulsion Sacharin sodium up to 10% cubic 20% and above mostly lamellar small amount cubic Sodium bicarbonate  1% Mostly Cubic. Hexagonal in small concentration  5-10% Hexagonal 20% Reversed micellular cubic and lamellar 35% and above Reverse emulsion Menthol  1% Cubic  5-10% Hexagonal 20% and above Lamellar Poloxamer 188 Up to 10% Cubic 20-35% Mix of cubic and Lamellar Above 35% Lamellar Poloxamer 407 Up to 10% Cubic 20-35% Mix Above 35% Lamellar Rosuvastatin up to 15% Cubic (2 types) 20% and above Lamellar

TABLE-US-00004 TABLE 2 More detail on the liquid crystalline phase formation for mixes of GMO and another ingredient Concentration Phase Phase structure Phase structure for Phase in structure for for sodium butylated hydroxy structure for GMO (%) TEC cyclamate anisole (BHA) saccharin sodium 1 V2(Pn3m) (ie V2(Pn3m) V2(Pn3m) V2(Pn3m) cubic) 5 V2(Pn3m) V2(Pn3m) V2(Pn3m) + H2 V2(Pn3m) 10 V2(Pn3m) V2(Pn3m) + other H2 V2(Pn3m) + others 15 H2 — 20 V2(Pn3m) Lα (lamella) H2 Lamellar 35 L2 (reverse Lα + other L2 Unknown lamella) 50 L2 Lα + other L2 Unknown

TABLE-US-00005 TABLE 3 More detail on the liquid crystalline phase formation for mixes of GMO and another ingredient continued Concentration Phase structure Phase structure for Phase structure for Phase structure for in GMO (%) for menthol poloxamer 188 poloxamer 407 rosuvastatin 1 V2(Pn3m) V2(Pn3m) + V2(Im3m) V2(Pn3m) + V2(Im3m) V2(Pn3m) 5 H2 V2(Im3m) V2(Im3m) V2(Pn3m) 10 H2 V2(Im3m) V2(Im3m) V2(Pn3m) 15 — — — V2(Pn3m) + V2(Im3m) 20 L2 Mixed V2(Im3m) + Lα Lα 35 L2 Lα Lα Lα + Lα 50 L2 Lα Lα Lα

Example 2—Preparing an ODT

[0238] Process for wet granulation manufacturing of ODT of Table 4: [0239] GMO was melted (about 30° C.) [0240] As soon as possible following melting of the GMO, rosuvastatin calcium was dispersed in melted GMO for the minimum time needed (about 5 minutes) [0241] Povidone and any menthol & sacharin sodium was dissolved in ethanol [0242] Any mannitol, pharmaburst, sodium chloride, sodium cyclamate and crospovidone were wet granulated with the Rosuvastatin:GMO suspension and the Povidone solution. The addition of these further ingredients lowered the temperature of the GMO so that it returned to a solid or semisolid form (for example to 25° C.) [0243] The granules were dried and milled [0244] The milled granules were blended with the remaining excipients using high shear [0245] The final blend was compressed into ODT tablets

Example 3—ODT with Increased Rosuvastatin to GMO Proportion

[0246] Example 1 shows that when GMO and rosuvastatin are directly mixed there is a 15% limit of inclusion for rosuvastatin before GMO is prevented from forming a cubic liquid crystalline structure upon contact with a hydrophilic solvent.

[0247] Using the process of Example 2 and the ingredients in Table 4 below, an ODT with 50% rosuvastatin to GMO has been developed. The GMO has retained the ability to form cubic liquid crystalline structures.

TABLE-US-00006 TABLE 4 5 mg statin formulation with 50% rosuvastatin to GMO (SBT122) Ingredient % w/w Function Mannitol 75.3 Filler/Carrier Rosuvastatin Calcium 7.3 Drug substance/API Povidone (Poly vinyl pyrrolidone) 1.7 Binder Glyceryl Monooleate (GMO) 7.3 Bioadhesive/Mucoadhesive agent, Gelling agent, nonionic surfactant, sustained release agent Sodium Starch Glycolate 5.0 Disintegration agent Colloidal Silicon Dioxide 2.0 Glidant Magnesium Stearate 1.5 Lubricant Ethanol N/A * Solvent * Evaporated during the drying process.

[0248] Disintegration testing was conducted in a basket-rack assembly and in accordance with Appendix XII A. Disintegration of the European Pharmacopoiea edition 9.0 (Ph. Eur. Method 2.9.1). The solvent was water at 37° C.

[0249] The ODT of Table 4 disintegrated within 8-10 minutes and achieved 100% dissolution in water within 15 minutes (Dissolution apparatus II, paddles, 50 rpm, 900 ml, Citrate buffer pH 6.6).

[0250] Using the process of Example 2 and the ingredients in Table 5 below, another ODT with 50% rosuvastatin to GMO has been developed. The GMO has retained the ability to form cubic liquid crystalline structures.

TABLE-US-00007 TABLE 5 5 mg statin ODT with 50% rosuvastatin to rosuvastatin/GMO total (SBT176) Ingredient % w/w Function Pharmaburst-(co-processed 68.67 Filler, Taste masking, mixture of Mannitol, Sorbitol Disintegration agent. Crospovid one & Silicon dioxide) Crospovidone XL 15.00 Disintegration agent Sodium Chloride 0.25 Osmotic agent Sodium Cyclamate 0.60 Sweetener Saccharin Sodium 0.40 Sweetener Menthol (Optional) 0.20 Flavouring agent Rosuvastatin Calcium 5.44 Drug substance/API Povidone (Poly vinyl 1.50 Binder pyrrolidone) Glyceryl Monooleate (GMO) 5.44 Bio adhesive/Mucoadhesive agent, Gelling agent, nonionic surfactant, sustained release agent Sodium Starch Glycolate 5.00 Disintegration agent Colloidal Silicon Dioxide 1.50 Glidant Magnesium Stearate 1.00 Lubricant Ethanol N/A * Solvent * Evaporated during the drying process.

[0251] ODT preparation is according to example 2 except mixing of the rosuvastatin calcium and GMO is for 0.5-1 minute.

[0252] The tablets weighed 100 mg, had a hardness of 1.3-2.1 kp, friability of 0.1%, 2.05 mm thickness and disintegrated in 30 seconds following emersion in a hydrophilic solvent.

[0253] 8 mm round tablets of this formulation were stability tested at 5° C. for 9 months. Assay of the 5 mg rosuvastatin showed 97.1% at t=0, 98.1% at t=3 months, 95.8% at t=6 months and 96% at t=9 months. The formulation was also stability tested at 25° C./60% RH for 9 months. Assay of the 5 mg rosuvastatin showed 97.1% at t=0, 94.2% at t=3 months, 96.1% at t=6 months and 94.4% at t=9 months. In addition, the assay of the tablets showed 0.03% at t=0, 0.16% at t=3 months, 0.20% at t=6 months and 0.34% at t=9 months of rosuvastatin in the lactone form and 0.15% at t=0, 0.25% at t=3 months, 0.29% at t=6 months and 0.34% at t=9 months of 5-oxo-rosuvastatin calcium (TP-13 impurity 1) at following storage at 25° C./60% RH. The assay of the tablets also showed 0.03% at t=0, 0.03% at t=3 months, 0.03% at t=6 months and 0.06% at t=9 months of rosuvastatin in the lactone form and 0.15% at t=0, 0.18% at t=3 months, 0.17% at t=6 months and 0.21% at t=9 months of the 5-oxo-rosuvastatin calcium at both 3 and 6 months at 5° C.

[0254] The structure of 5-oxo-rosuvastatin calcium is below.

##STR00001##

[0255] Using the process of Example 2 and the ingredients in Table 6 below, an ODT with 20% rosuvastatin to GMO has been developed. The GMO has retained the ability to form cubic liquid crystalline structures.

TABLE-US-00008 TABLE 6 5 mg statin ODT with 20% rosuvastatin to GMO (SBT177) Ingredient % w/w Function Pharmaburst-(co-processed 64.47 Filler, Taste masking, mixture of Mannitol, Sorbitol Disintegration agent. Crospovid one & Silicon dioxide) Crospovidone XL 15.00 Disintegration agent Sodium Chloride 0.60 Osmotic agent Sodium Cyclamate 0.25 Sweetener Saccharin Sodium 0.40 Sweetener Menthol 0.20 Flavouring agent Rosuvastatin Calcium 1.81 Drug substance/API Povidone (Poly vinyl 2.50 Binder pyrrolidone) Glyceryl Monooleate (GMO) 7.26 Bio adhesive/Mucoadhesive agent, Gelling agent, nonionic surfactant, sustained release agent Sodium Starch Glycolate 5.00 Disintegration agent Colloidal Silicon Dioxide 1.50 Glidant Magnesium Stearate 1.00 Lubricant Ethanol N/A * Solvent * Evaporated during the drying process.

[0256] ODT preparation is according to example 2 except mixing of the rosuvastatin calcium and GMO is for 1-2 minutes.

[0257] The tablets weighed 300 mg, had a hardness of 2.4-3.5 kp, friability of 0.1%, 2.65 mm thickness and disintegrated in 60-90 seconds following emersion in a hydrophilic solvent.

[0258] The ODTs of Tables 5 and 6 achieve 100% dissolution within 5 minutes (Dissolution apparatus II, paddles, 50 rpm, 900 ml, Citrate buffer pH 6.6).

[0259] The ODTs of Tables 4, 5 and 6 were each dissolved in hydrophilic solvent and analysed by the SAXS/WAXS beamline at Australian Synchrotron. The GMO of each tablet form cubic liquid crystalline phase.

[0260] The tablets were administered sublingually to three different human subjects (one Caucasian male, one Caucasian female and one Asian male) and the speed of tablet disintegration monitored. The formulation in Table 6 disintegrated within 20 to 40 seconds of administration for all three subjects. The formulation in Table 2 disintegrated within 40 to 90 seconds of administration for all three subjects.

[0261] The manufacturing of tablets involved mixing of Rosuvastatin with the GMO at its melting point for a short period, until a homogenous dispersion was obtained (approximately 5 minutes) and then mixed with other excipients using a high shear mixer. When combined with the other excipients the temperature of GMO returned to below the GMO melting point and the GMO returned to its semi-solid form.

[0262] The formulation of Table 4 disintegrated within 20-40 seconds of contact with oral mucosa (Basket-rack assembly, Ph. Eur. Method 2.9.1, water at 37° C.). The formulation of Table 4 disintegrated within 40-90 seconds of contact with oral mucosa.

[0263] 12 mm round tablets of this formulation were stability tested at 5° C. for 6 months. Assay of the 5 mg rosuvastatin showed 100.1% at t=0, 100.4% at t=3 months and 97.9% at t=6 months. The formulation was also stability tested at 25° C./60% RH for 6 months. Assay of the 5 mg rosuvastatin showed 100.1% at t=0, 98.6% at t=3 months and 97.6% at t=6 months. In addition, the assay of the tablets showed 0.05% at t=0, 0.31% at t=3 months and 0.49% at t=6 months of rosuvastatin in the lactone form and 0.3% at t=0, 0.31% at t=3 months and 0.36% at t=6 months of 5-oxo-rosuvastatin calcium (TP-13 impurity 1) at following storage at 25° C./60% RH. The assay of the tablets also showed 0.05% at t=0, 0.08% at t=3 months and 0.05% at t=6 months of rosuvastatin in the lactone form and 0.3% at t=0, 0.23% at t=3 months and 0.24% at t=6 months of the 5-oxo-rosuvastatin calcium at both 3 and 6 months at 5° C.

[0264] Using the process of Example 2 and the ingredients in Table 7 below, another ODT with 50% rosuvastatin to GMO has been developed. The GMO has retained the ability to form cubic liquid crystalline structures.

TABLE-US-00009 TABLE 7 5 mg statin ODT with 50% rosuvastatin to rosuvastatin/GMO total and 42.5% menthol to menthol/GMO total (SBT131) Ingredient % w/w Function Mannitol BP 74.9 Carrier Sodium Starch Glycolate 5.0 Disintegration agent Menthol 4.0 Flavoring/cooling agent Rosuvastatin Calcium 5.4 Drug substance/API (micronized) Povidone (Poly vinyl 1.7 Binder pyrrolidone) Glyceryl Monooleate (GMO) 5.4 Bioadhesive/Mucoadhesive agent, Gelling agent, nonionic surfactant, sustained release agent Ethanol N/A Solvent Colloidal Silicon Dioxide 2.0 Glidant Magnesium Stearate 1.5 Lubricant * Evaporated during the drying process.

[0265] Example 1 shows that when GMO and menthol are directly mixed 1% menthol results in cubic liquid crystalline structure, 5% menthol results in hexagonal liquid crystalline structure and 20 to 50% results in reverse lamella crystalline structure upon contact with a hydrophilic solvent.

[0266] Using the process of Example 2 and the ingredients in Table 8 below, another ODT with 50% rosuvastatin to GMO has been developed. The GMO has retained the ability to form cubic liquid crystalline structures.

TABLE-US-00010 TABLE 8 5 mg statin ODT with 50% rosuvastatin to rosuvastatin/GMO total and 48% sodium bicarbonate to sodium bicarbonate/GMO total (SBT127) Ingredient % w/w Function Mannitol BP 73.9 Carrier Sodium Starch Glycolate 5.0 Disintegration agent Sodium Bicarbonate 5.0 Alkalizing agent Rosuvastatin Calcium 5.4 Drug substance/API (micronized) Povidone (Poly vinyl pyrrolidone) 1.7 Binder Glyceryl Monooleate (GMO) 5.4 Bioadhesive/Mucoadhesive agent, Gelling agent, nonionic surfactant, sustained release agent Ethanol N/A Solvent Colloidal Silicon Dioxide 2.0 Glidant Magnesium Stearate 1.5 Lubricant

[0267] Example 1 shows that when GMO and menthol are directly mixed 1% sodium carbonate results in cubic and hexagonal liquid crystalline structure, 5% sodium carbonate results in hexagonal liquid crystalline structure and 35% and above results in reverse lamella crystalline structure upon contact with a hydrophilic solvent.

Example 7—Confirming Formation of Liquid Crystalline Phase

[0268] Preparation of Samples Tablets for Simulated Dissolution Study

[0269] For equilibrium samples, the tablets were loaded into a transparent polystyrene 96 well plate (Nunc™) and immersed in PBS buffer (pH 6.8). The samples were stored away from light at ambient temperature overnight prior to SAXS experiment.

[0270] For the kinetic study of SBT122 and SBT123, 2 tablets were carefully placed in a transparent polystyrene 24 well plate (2 ml per well) to ensure the X-ray beam can transmit through the tablets. The X-ray diffraction patterns were first taken without any solution added. The tablets were then immersed in 2 mL of PBS buffer or saliva donated by the author and other volunteers, the X-ray diffraction patterns were taken overtime, up to 4 hours.

[0271] For the kinetic study of SBT177, 2 tablets were disintegrated in PBS using 2 ml vials, the 0.4 ml carefully placed in a transparent polystyrene 96 well plate (0.4 ml per well). The X-ray diffraction patterns were taken overtime, up to 4 hours.

[0272] Small Angle X-Ray Scattering (SAXS) Setup

[0273] The SAXS/WAXS beamline at Australian Synchrotron, Melbourne, Australia was used to determine the liquid crystalline nanostructure in the samples.

[0274] A custom-designed plate holder was used to mount the samples plate directly onto the SAXS/WAXS beamline. Scans were automated using a pre-loaded set of position variables based on the well positions within the plate, the exposure time was 5 seconds. For the kinetic study of SBT177 a single location was tested rather than a full scan of the well.

[0275] Data were obtained at ambient temperature (˜22° C.). The experiments used a beam of wavelength λ=1.033 Å (12.0 keV) and a typical flux of 1.2×1013 photons/s. The 2-D diffraction images were recorded on a Pilatus 1M detector and radially integrated using the in-house software “ScatterBrain”.

[0276] The liquid crystal phase structures were determined by indexing the Bragg peaks according to their corresponding reflection laws (see Hyde, S. T., Bicontinuous structures in lyotropic liquid crystals and crystalline hyperbolic surfaces. Current Opinion in Solid State and Materials Science 1996, 1, 653-662).

[0277] Results

TABLE-US-00011 TABLE 9 Liquid crystalline structure results Tablet Structure obtained SBT122 (1:1) Pn3m SBT127 Pn3m SBT131 Pn3m SBT176 (1:1) Pn3m SBT177 (4:1) Pn3m

Example 8—Formulations with 1:1 w/w Ratio of Statin and Amphiphile (SBT226), Oxycodone and Amphiphile (SBT227) and Adrenaline and Amphiphile (SBT237)

[0278] A second statin containing ODT was prepared according to Table 5 above but using 5.42% w/w of atorvastatin calcium trihydrate and the same amount of GMO. The crospovidone was reduced to 10% w/w and the Pharmaburst increased to 68.21% w/w. The ODT (SBT226) had a 1:1 ratio of GMO to atorvastatin calcium trihydrate and 10 mg atorvastatin calcium trihydrate.

[0279] A third ODT (SBT227) was prepared according to Table 5 above but using 5% w/w of oxycodone hydrochloride and the same amount of GMO. The crospovidone was also reduced to 10% w/w and the Pharmaburst increased to 69.55% w/w. The ODT (SBT226) had a 1:1 ratio of GMO to oxycodone hydrochloride and 5 mg oxycodone hydrochloride.

[0280] A fourth ODT (SBT237) containing 300 μg adrenaline was prepared with a 1:1 ratio of GMO to adrenaline. The formulation is in Table 10 below.

TABLE-US-00012 TABLE 10 ODT with 1:1 GMO to adrenaline (SBT237) Material Name % w/w Notes Pharmaburst-(co-processed mixture of 77.78 Filler, Taste masking, Mannitol, Sorbitol Crospovidone & Disintegration agent. Silicon dioxide) Crospovidone XL 10.68 Disintegration agent Sodium Chloride 0.28 Osmotic agent Sodium Cyclamate 0.68 Sweetener Saccharin Sodium 0.45 Sweetener Menthol 0.23 Flavouring agent Epinephrine (Adrenaline) 0.34 Drug substance/API Povidone (Poly vinyl pyrrolidone) 1.70 Binder Glyceryl Monooleate (GMO) 0.34 Bio adhesive/Mucoadhesive agent, Gelling agent, nonionic surfactant, sustained release agent Sodium Starch Glycolate 5.00 Disintegration agent Colloidal Silicon Dioxide 1.50 Glidant Magnesium Stearate 1.00 Lubricant Ethanol N/A * Solvent

[0281] Each ODT was prepared according to the method in Example 2.

Example 9—Formulations with 1:4 w/w Ratio of Statin and Amphiphile (SBT233), a 1:4 w/w Ratio Oxycodone and Amphiphile (SBT232) and a 10:1 w/w Ratio of Adrenaline and Amphiphile (SBT238)

[0282] A second ODT (SBT233) containing 10 mg atorvastatin was prepared a 4:1 ratio of GMO to atorvastatin. The formulation is in Table 11 below.

TABLE-US-00013 TABLE 11 ODT with 4:1 GMO to atorvastatin (SBT233) Ingredient % w/w Function Pharmaburst-(co-processed mixture of 58.86 Filler, Taste masking, Disintegration agent. Mannitol, Sorbitol Crospovidone & Silicon dioxide) Crospovidone XL 13.82 Disintegration agent Sodium Chloride 0.22 Osmotic agent Sodium Cyclamate 0.53 Sweetener Saccharin Sodium 0.41 Sweetener Menthol 0.21 Flavouring agent Atorvastatin Calcium Trihydrate 3.19 Drug substance/API Povidone (Poly vinyl pyrrolidone) 2.50 Binder Glyceryl Monooleate (GMO) 12.76 Bio adhesive/Mucoadhesive agent, Gelling agent, nonionic surfactant, sustained release agent Sodium Starch Glycolate 5.00 Disintegration agent Colloidal Silicon Dioxide 1.50 Glidant Magnesium Stearate 1.00 Lubricant Ethanol N/A * Solvent

[0283] A third ODT (SBT232) was prepared according to Table 6 but using 1.67% w/w of oxycodone hydrochloride and four times as much GMO (6.67% w/w). The crospovidone was also reduced to 10% w/w and the Pharmaburst increased to 65.22% w/w, when compared to the rosuvastatin formulation in Table 6. The ODT (SBT232) had a 4:1 ratio of GMO to oxycodone hydrochloride and 5 mg oxycodone hydrochloride.

[0284] A fourth ODT (SBT238) containing 300 μg adrenaline was prepared with a 10:1 ratio of GMO to adrenaline. The formulation is in Table 12 below.

TABLE-US-00014 TABLE 12 ODT with 1:1 GMO to adrenaline (SBT238) Material Name % w/w Notes Pharmaburst-(co-processed mixture of 70.97 Filler, Taste masking, Disintegration Mannitol, Sorbitol Crospovidone & agent. Silicon dioxide) Crospovidone XL 16.00 Disintegration agent Sodium Chloride 0.28 Osmotic agent Sodium Cyclamate 0.66 Sweetener Saccharin Sodium 0.44 Sweetener Menthol 0.22 Flavouring agent Epinephrine (Adrenaline) 0.11 Drug substance/API Povidone (Poly vinyl pyrrolidone) 2.76 Binder Glyceryl Monooleate (GMO) 1.10 Bio adhesive/Mucoadhesive agent, Gelling agent, nonionic surfactant, sustained release agent Sodium Starch Glycolate 4.97 Disintegration agent Colloidal Silicon Dioxide 1.49 Glidant Magnesium Stearate 0.99 Lubricant Ethanol N/A * Solvent

[0285] Each ODT was prepared according to the method in Example 2.

[0286] Disintegration time was tested. The 1:1 oxycodone ODT disintegrated within 20-30 seconds and 4:1 oxycodone ODT disintegrated within 45-70 seconds. The 1:1 adrenaline ODT disintegrated within 15-35 seconds and the 4:1 adrenaline ODT disintegrated within 25-35 seconds.

[0287] Liquid crystalline formation was tested using the method of Example 7 but having some ODT samples hydrated for 30 min before testing and some for 18 hours before testing. Each sample was tested at 125 times/locations. The results are in table 13 below. The results were the same for the 30 min and 18 hour hydrated samples.

TABLE-US-00015 TABLE 13 Liquid crystalline structure results Structure Structure produced-Plate produced-Plate 1: Hydration 2: Hydration 30 API Batch number 18 hrs minutes Oxycodone 5 mg 1:1 SBT227 Cubic Pn3m & Cubic Pn3m & Im3m Im3m Oxycodone 5 mg 4:1 SBT232 Cubic Pn3m Cubic Pn3m Atorvastatin 10 mg 1:1 SBT226 Double Lamellar Double Lamellar Atorvastatin 10 mg 4:1 SBT233 Double Lamellar Double Lamellar Adrenaline SBT237 Hexagonal Double Lamellar (Epinephrine) 0.3 mg 1:1 Adrenaline SBT238 Hexagonal & Hexagonal (Epinephrine) 0.3 mg Cubic Pn3m 10:1 Rosuvastatin 5 mg 1:1 SBT176 Lamellar Lamellar Rosuvastatin 5 mg 1:1 SBT187 Lamellar Lamellar Rosuvastatin Placebo SBT189 Cubic Pn3m Cubic Pn3m

[0288] *SBT176 was tested when it was over 12 months old. Earlier testing of SBT122, and SBT123, which occurred only a couple months after formulation suggests that SBT176 may have formed form cubic phase if tested closer to its preparation.

[0289] A blend of the amphiphilic compound GMO and the active ingredient niacin was shown to form hexagonal phase in international patent publication no. WO 2014/179845.

Example 10—In Vitro Release Testing

[0290] Release of an active ingredient from and ODT through a mucosal membrane can be tested in vitro.

[0291] Porcine buccal mucosa was freshly isolated from pigs cheeks, mounted between modified Ussing chambers with a donor chamber, receptor chamber and the porcine buccal mucosa in between with a diffusional area of 0.64 cm.sup.2, and incubated in Krebs bicarbonate Ringer buffer (KBR, pH 7.4) for 30 min. The tablet was applied to the porcine buccal mucosa (ie in the donor chamber) and, when necessary, Parafilm was applied to cover the formulation (ie for tablets and for mixtures containing glyceryl monooleate (GMO) and rosuvastatin). The Parafilm prevented the various formulations from detaching from the buccal mucosa. KBR buffer (1.5 mL) was then added to both the donor and receptor chambers, and receptor samples (200 μL) were collected from the receptor chamber at various time points up to 4-5 hours to determine the amount of rosuvastatin that passed through the porcine buccal mucosa to the receptor chamber. 200 μL of fresh KBR was dispensed into the receptor chamber after each collection (to ensure volume balance). Receptor chamber samples were quantified by HPLC.

[0292] Positive control was tested by making solutions of 0.4 and 0.8 mg/1.5 ml active ingredient in KBR solution, equivalent to 1:1 and 7:1 ODT's.

[0293] The permeation of the active ingredient from the ODT of the invention was tested for ODTs containing oxycodone and ODTs containing atorvastatin to establish that the ODT functioned to deliver active ingredients having varied LogP values and varied dosages. This time samples were taken from the receiving chamber of the Ussing chamber repeatedly at 0.5, 1, 1.5, 2, 3 and 4 hours to establish not only that the active ingredient permeated the mucosa but that release of the active ingredient was prolonged.

[0294] The appearance of oxycodone in the receptor chamber over time is depicted in FIG. 3 after application of ODT SBT227 (diamond) and ODT SBT232 (square) to porcine buccal mucosa in the donor chamber of the Ussing chamber. Data are presented as mean±SEM (n=5). Both formulations demonstrate slow release characteristics. SBT227, with a 1:1 ratio of active ingredient to GMO, released the API relatively faster compared to SBT232, with a 1:4 ratio of active ingredient to GMO. Without being bound by theory, this is thought to be due to the lower quantity of GMO in the SBT227 formulation.

[0295] The appearance of atorvastatin in the receptor chamber over time is depicted in FIG. 4 after application of ODT SBT226 (square) and SBT233 (diamond) to porcine buccal mucosa in the donor chamber of the Ussing chamber. Data are presented as mean±SEM (n=5). Both formulations demonstrate slow release characteristics. SBT226, with a 1:1 ratio of active ingredient to GMO, released the API relatively faster comparing to SBT233, with a 1:4 ratio of active ingredient to GMO. Without being bound by theory, this is thought to be due to the lower quantity of GMO in the SBT226 formulation.

Example 11—Prolonged Release

[0296] FIG. 3 shows that in vitro release of oxycodone through a porcine mucosal membrane shows a prolonged release profile with release continuing steadily at 4 hours. Maximum blood concentration is achieved about 1 hour after administration of an OxyNorm tablet.

[0297] Similarly, FIGS. 5A and 5B shows that in vitro release of atorvastatin through a porcine mucosal membrane was slow release and continuing at 4 hours for 4 of the 5 SBT226 and 3 of the 5 SBT233 tablets tested. Without being bound by theory, Ussing chamber testing is less robust than some in vitro testing methods and it is possible that there was a technical difficulty in the testing of the tablets that did not show slow release. Lipitor oral tablets achieve maximum plasma concentration within 1-2 hours following administration.

[0298] A blend of the amphiphilic compound GMO and the active ingredient niacin was shown to exhibit prolonged release in international patent publication no. WO 2014/179845.