STRAW FOR ORAL ADMINISTRATION OF PHARMACEUTICAL

FORMULATION

Field of the Invention

The present invention relates to a straw suitable for oral administration of a pharmaceutical formulation, wherein the straw contains the pharmaceutical formulation. The present invention also relates to a pharmaceutical formulation suitable for use in such a straw, and the use of said pharmaceutical formulation in the treatment of a condition in a subject in need thereof.

Background to the Invention

Pre-filled straws are described in the art. For example, in US 2003/0071136 Al a straw is described with one valve closure impressed into the body of the straw. In

CA 2230851 a drink container is described with mouthpiece with inserted valve. Valves and/or filters are added to the straw, meaning that straws and valves and optionally filters are produced separately and the straw is assembled from separate parts in later. Such straw designs use one-way valves on either inlet or outlet, and use different types of closures, i.e. caps, grids and/or filters of different mesh sizes as closures of other opening. Generally, the straw is assembled from the straw body and the closure mechanism which is inserted into the straw - either valve or filter or other form of barrier. Pre-filled straws are also described in WO 2017/111704.

The present inventors have surprisingly discovered a particularly advantageous formulation for use in such drinking straws, which has an optimum balance of desirable properties. In particular, the formulations for use in the present invention are found to (a) minimise caking when in use in the straw (which prevents flow of liquid through the straw), (b) be well-dispersed along the length of the straw when in use in the straw and (c) be flushed from the straw with an initial portion of the liquid sucked or pumped through the straw. The latter property imparts the advantage that only a small volume of liquid is required to administer the formulation to the subject in need thereof. The formulation is considered to be“in use in the straw” when a pressure gradient is applied along the length of the straw containing the formulation, e.g. by a person sucking on one end of the straw when the opposing end is inserted into a liquid. of the Invention

In one aspect, the present invention provides a straw suitable for oral administration of a pharmaceutical formulation, wherein:

(a) the straw contains the pharmaceutical formulation; and

(b) the pharmaceutical formulation comprises:

(i) an active pharmaceutical ingredient (API), food supplement or

vitamin; and

(ii) one or more pharmaceutically acceptable excipients selected from

pharmaceutically acceptable carriers, diluents, binders, glidants, release controlling agents and disintegrants;

wherein the pharmaceutical formulation is a solid in which at least 90% of the particles by number have a diameter of greater than 500 pm and in which at least 90% of the particles by number have a diameter of less than 2000 pm.

In a further aspect, the present invention provides a straw suitable for oral

administration of a pharmaceutical formulation, wherein:

(a) the straw contains the pharmaceutical formulation; and

(b) a granular pharmaceutical formulation comprising:

(i) a core phase comprising an active pharmaceutical ingredient (API), food supplement or vitamin; and

(ii) a matrix phase comprising one or more pharmaceutically acceptable fast-dissolving excipients;

wherein the core phase is dispersed within the matrix phase, and wherein the matrix phase dissolves more rapidly than the core phase in water at 25°C.

In another aspect, the present invention provides a pharmaceutical formulation suitable for use in a straw suitable for oral administration of said pharmaceutical formulation, wherein the pharmaceutical formulation comprises:

(i) an active pharmaceutical ingredient (API), food supplement or vitamin; and

(ii) one or more pharmaceutically acceptable excipients selected from

pharmaceutically acceptable carriers, diluents, binders, glidants, release controlling agents and disintegrants; wherein the pharmaceutical formulation is a solid form in which at least 90% of the particles by number have a diameter of greater than 500 pm and in which at least 90% of the particles by number have a diameter of less than 2000 pm.

In yet another aspect, the present invention provides a pharmaceutical formulation suitable for use in a straw suitable for oral administration of said pharmaceutical formulation, wherein the pharmaceutical formulation is a granular pharmaceutical formulation comprising:

(i) a core phase comprising an active pharmaceutical ingredient (API), food

supplement or vitamin; and

(ii) a matrix phase comprising one or more pharmaceutically acceptable fast

dissolving excipients;

wherein the core phase is dispersed in the matrix phase and the matrix phase dissolves more rapidly than the core phase in water at 25°C.

In a further aspect, the present invention provides a pharmaceutical formulation according to the invention for use in the treatment of a condition in a subject in need thereof, wherein said treatment comprises oral administration of the pharmaceutical formulation using a straw as defined herein, wherein the straw contains the pharmaceutical formulation.

In another aspect, the present invention provides a method of treating a condition in a subject in need thereof, said method comprising oral administration of a pharmaceutical formulation according to the invention using a straw as defined herein, wherein the straw contains the pharmaceutical formulation.

In another aspect, the present invention provides the use of a pharmaceutical formulation according to the invention for the manufacture of a medicament for the treatment of a condition in a subject in need thereof, wherein said treatment comprises oral

administration of the pharmaceutical formulation using a straw as defined herein, wherein the straw contains the pharmaceutical formulation.

In another aspect, the present invention provides a method of manufacturing a formulation according to the invention, comprising the steps of:

(a) providing particles comprising an API, food supplement or vitamin;

(b) coating said particles with a taste-masking agent and/or an enteric coating;

(c) optionally, repeating step (b) one or more times to provide particles having multiple coating layers; and (d) granulating said particles in the presence of one or more fast-dissolving excipients.

In another aspect, the present invention provides a device suitable for oral administration of a pharmaceutical formulation, wherein the device is configured to allow the pharmaceutical formulation to be flushed from the device by a volume of aqueous solvent which is 50 mL or less during oral administration and to thereby deliver the aqueous solution in which the pharmaceutical formulation is flushed into the oral cavity of a subject.

Brief Description of the Drawings

Fig· 1 shows an example of the straw body.

Fig. 2 shows examples of couplings between segments of a straw body.

Fig. 3 shows examples of cross slit valves that may be used.

Fig. 4 shows a perspective view of an example of an inlet valve.

Fig. 5 shows the inlet valve of Fig 4. in cross-section.

Fig. 6 shows an example of an outlet valve in cross-section.

Fig. 7 shows injection moulding of a straw body.

Fig. 8 shows injection moulding of a valve.

Fig. 9 shows an experimental set-up for measuring pressure in a straw.

Fig. 10 shows the general behaviour of pressure change during an experiment in which water flows through a drinking straw containing a formulation according to the invention pi = change in absolute pressure just before the top valve; p ₂ = maximum change of absolute pressure during the experiment; p ₃ = change of absolute pressure when the straw is empty; V = flush volume.

Fig. 11 shows pressure measurements pi, p ₂ and p ₃ for individual samples when water is sucked through a straw containing different example formulations. Each

formulation is tested at two different particle sizes, 250-500 pm and 1120-1400 pm.

Fig. 12 is a bar graph illustrating values of V and pi for a variety of different example formulations having a particle size of 250-500 pm.

Fig. 13 is a bar graph illustrating values of V and pi for a variety of different example formulations having a particle size of 1120-1400 pm.

Fig. 14 is a line graph showing the impact on maximal siping pressure for different particle size distributions caused by (a) volume of straw filling, (b) the addition of PVP K30 as a binder, (c) the addition of cefprozil monohydrate as API and (d) the addition of SDS as a surfactant.

Fig. 15 is a line graph showing the impact on flush volume for different particle size distributions caused by (a) volume of straw filling, (b) the addition of PVP K30 as a binder, (c) the addition of cefprozil monohydrate as API and (d) the addition of SDS as a surfactant.

Fig. 16 shows (a) a conventional granulation-coating sequence, (b) the

innovative coating-granulation process scheme using micronized API, and (c) the

innovative coating-granulation process scheme using crystals of API.

Fig. 17 shows optical microscope images of coated paracetamol crystals (left) and 20% sucrose granulates of coated paracetamol crystals (right).

Fig. 18 shows an experimental set-up for the water sorption test.

Fig. 19 shows an example of a granulate sample with ideal straw behaviour, where ki is the water absorption rate and k ₂ is the particle dissolving rate during water sorption measurement.

Fig. 20 shows water sorption curves for two types of coated particles and the corresponding sucrose granulates containing 20% of the coated particles by weight:

(a) PVA-PEG graft copolymer/PVA polymer-coated paracetamol crystals (20% by weight) in a sucrose granulate; (b) non- granulated PVA-PEG graft copolymer/PVA polymer-coated paracetamol crystals; (c) gelatin-coated paracetamol crystals (20% by weight) in a sucrose granulate; and (d) non-granulated gelatin-coated paracetamol

crystals.

Fig. 21 shows water sorption curves for Tachipirina and Aspirin Direct,

compared with a gelatin granulate (20% by weight of coated core phase) of the present invention.

Fig. 22 shows water sorption curves for three different granulate samples with differing straw behaviour: (a) sucrose granulate with 20% content of gelatin-coated particles;

(b) sucrose granulate with 40% ibuprofen content; and (c) sucrose granulate with 10% stearic acid content.

Detailed Description of the Invention

Definitions

As defined herein, the term“alkyl” refers to a linear or branched saturated

monovalent hydrocarbon radical. Typically, the term“alkyl” refers to a linear or branched saturated monovalent hydrocarbon radical having from 1 to 20 carbon atoms, unless otherwise specified. Examples of alkyl groups include, but are not limited to, methyl, ethyl, «-propyl, A - propyl, «-butyl, Ao-butyl, /e/7-butyl, and the like.

As used herein, term“active pharmaceutical ingredient” refers to any agent other than a foodstuff or vitamin which promotes a structural and/or functional change in and/or on bodies to which it has been administered.

As defined herein, the term“acyl” refers to a -COR radical, wherein R is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, or heterocyclylalkyl, each as defined herein, or poly(ethylene glycol), and wherein R is optionally further substituted with one, two, three, four or more substituents independently selected from alkyl, alkoxy, halo, haloalkoxy, -OH, -NH ₂ , alkylamino, -COOH, or alkoxycarbonyl.

As defined herein, the term“alkoxy” refers to an -OR radical where R is alkyl as defined above, e.g., methoxy, ethoxy, n-propoxy, Ao-propoxy, «-butyl, Ao-butyl, /e/7-butyl and the like.

As defined herein, the term“alkoxycarbonyl” or“ester” refers to a -C(0)OR radical where R is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl,

heteroaralkyl, heterocyclyl, or heterocyclylalkyl, each as defined herein, or poly(ethylene glycol), and wherein R is optionally further substituted with one, two, three, four or more substituents independently selected from alkyl, alkoxy, halo, haloalkoxy, -OH, -NH ₂ , alkylamino, -COOH, or alkoxycarbonyl.

As defined herein, the term“alkylamino” refers to an -NHR radical where R is alkyl as defined above, e.g. methylamino, ethylamino, «-propylamino, Ao-propylamino, and the like.

As defined herein, the term“aryl” refers to a monovalent monocyclic or bicyclic aromatic hydrocarbon radical of 6 to 10 ring atoms, e.g. phenyl or naphthyl, and the like.

As defined herein, the term“aralkyl” refers to an -(alkylene)-R radical where R is aryl as defined above.

As defined herein, the term“cycloalkyl” refers to a cyclic saturated monovalent hydrocarbon radical of three to ten carbon atoms wherein one or two carbon atoms may be replaced by an oxo group, e.g. cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, and the like.

As defined herein, the term“cycloalkylalkyl” refers to an -(alkylene)-R radical where R is cycloalkyl as defined above, e.g. cyclopropylmethyl, cyclobutylmethyl,

cyclopentylethyl, or cyclohexylmethyl, and the like.

As used herein, the term“diameter” of a particle refers to the longest linear distance from one side of the particle to the opposite side of the particle, passing through the centre point of the particle. In a method of preparing formulations of the present invention, particles are separated on the basis of their size using a sieving method: those particles with a diameter greater than or smaller than particular critical mesh sizes are excluded from the final formulation.

As defined herein, the term“halo” refers to fluoro, chloro, bromo, or iodo, preferably fluoro or chloro.

As defined herein, the term“haloalkyl” refers to an alkyl radical as defined above, which is substituted with one or more halogen atoms, preferably one to five halogen atoms, preferably fluorine or chlorine, including those substituted with different halogens, e.g. -CH2CI, -CF ₃ , -CHF ₂ , -CH2CF3, -CF2CF3, -CF(CH ₃ ) ₂ , and the like.

As defined herein, the term“haloalkoxy” refers to an -OR radical where R is haloalkyl as defined above, e.g. -OCF3, -OCHF2, and the like.

As defined herein, the term“heteroaryl” refers to a monovalent monocyclic or bicyclic aromatic radical of 5 to 10 ring atoms where one or more, preferably one, two, or three, ring atoms are heteroatom selected from N, O, or S, the remaining ring atoms being carbon. Representative examples include, but are not limited to, pyrrolyl, thienyl, thiazolyl, imidazolyl, furanyl, indolyl, isoindolyl, oxazolyl, isoxazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, and the like.

As defined herein, the term“heteroaralkyl” refers to an -(alkylene)-R radical where R is heteroaryl as defined above.

As defined herein, the term“heterocycyl” refers to a saturated or unsaturated monovalent monocyclic group of 4 to 8 ring atoms in which one or two ring atoms are heteroatoms selected from N, O, or S(0) _n , where n is an integer from 0 to 2, the remaining ring atoms being C. The heterocyclyl ring is optionally fused to a (one) aryl or heteroaryl ring as defined herein provided the aryl and heteroaryl rings are monocyclic. Additionally, one or two ring carbon atoms in the heterocyclyl ring can optionally be replaced by a -CO- group. More specifically the term heterocyclyl includes, but is not limited to, pyrrolidino, piperidino, homopiperidino, 2-oxopyrrolidinyl, 2-oxopiperidinyl, morpholino, piperazino, tetrahydropyranyl, thiomorpholino, and the like. When the heterocyclyl ring is unsaturated it can contain one or two ring double bonds, provided that the ring is not aromatic.

As defined herein, the term“heterocycloalkyl” refers to an -(alkylene)-R radical where R is heterocyclyl ring as defined above, e.g. tetraydrofuranylmethyl,

piperazinylmethyl, morpholinylethyl, and the like.

As defined herein, the term“dso” refers to the mass median diameter of a sample of particles, i.e. the diameter at which 50% of the sample mass is comprised of particles having a diameter less than this value. Typically, dso values are measured by laser diffraction.

As used herein, the term“oral cavity” refers to the cavity of the mouth, and includes the inner upper and lower lips, all parts of the inner cheek, the sublingual area under the tongue, the tongue itself, as well as the upper and lower gums and the hard and soft palate.

As used herein, the term“straw” refers to a pipe that enables a user to conveniently consume a liquid. Such straws may be used for oral administration of liquid soluble or liquid insoluble ingredients, preferably granules, which are pre-filled within the straw. To administer the ingredient which is pre-filled in the straw, one end of the pipe is positioned in the liquid and the other end of the pipe is inserted into the oral cavity of the user, and suction is applied to the pipe by the user. Sucked liquid travels through the straw towards the oral cavity of the user, flushing the ingredient through the straw and thus delivering the ingredient to the user via oral administration. Preferably, the ingredient that is pre-filled in the straw is an active pharmaceutical agent (API), food supplement or vitamin.

As used herein, the term“therapeutically effective amount” refers to an amount of the API which is sufficient to reduce or ameliorate the severity, duration, progression, or onset of a disorder being treated, prevent the advancement of a disorder being treated, cause the regression of, prevent the recurrence, development, onset or progression of a symptom associated with a disorder being treated, or enhance or improve the prophylactic or therapeutic effect(s) of another therapy. The precise amount of API administered to a patient will depend on the type and severity of the disease or condition and on the characteristics of the patient, such as general health, age, sex, body weight and tolerance to drugs. It will also depend on the degree, severity and type of the disorder being treated. The skilled artisan will be able to determine appropriate dosages depending on these and other factors.

As used herein, the terms“treat”,“treatment” and“treating” refer to the reduction or amelioration of the progression, severity and/or duration of a disorder being treated, or the amelioration of one or more symptoms (preferably, one or more discernible symptoms) of a disorder being treated resulting from the administration of a formulation according to the invention to a patient.

For the avoidance of doubt, all alternative and preferred features relating to the formulation per se apply equally to the use of said formulation in the treatment of a human patient.

Formulations of the present invention

In a first aspect, the present invention is concerned with a pharmaceutical formulation suitable for use in a straw suitable for oral administration of said pharmaceutical formulation, wherein the pharmaceutical formulation comprises (i) an active pharmaceutical ingredient (API), food supplement or vitamin, and (ii) one or more pharmaceutically acceptable excipients selected from pharmaceutically acceptable carriers, diluents, binders, glidants, release controlling agents and disintegrants, wherein the pharmaceutical formulation is a solid in which at least 90% of the particles by number have a diameter of greater than 500 pm and in which at least 90% of the particles by number have a diameter of less than 2000 pm.

The pharmaceutical formulation according to the present invention is a solid. In other words, the pharmaceutical formulation comprises solid particles. Thus, the pharmaceutical formulation is not a liquid or gaseous formulation. Typically, the pharmaceutical formulation is in any solid form that can be conveyed by a fluid passing through a straw. Thus, typically, the pharmaceutical formulation comprises powder, granules or other particulates configured to be entrained in a fluid passing through a straw. Preferably, the pharmaceutical formulation comprises granular particles which are spherical, or substantially spherical, in shape.

Alternatively, the pharmaceutical formulation consists of, or consists essentially of, granular particles which are spherical, or substantially spherical, in shape. “Granules” are therefore considered to be a sub-class of the more general term“particles”. A specific type of granule, having two distinct phases, is discussed in further detail below. These“two-phase” granules are a sub-class of the more general term“granules”, and thus also a sub-class of the more general term“particles”. The terms“granule” and“granulate” may be used interchangeably throughout this specification.

It is surprising finding of the present invention that the particle size of the solid particles within the pharmaceutical formulation is a key parameter for optimising the performance of pre-filled drinking straws which contain the formulation. Without wishing to be bound by any particular theory, it is believed that if a large number of particles in the formulation (e.g. greater than 90% of the particles in the formulation by number) have a diameter of less than 500 pm, then when the formulation is used in a drinking straw, a phenomenon referred to as“caking” may occur. This is where the particles in the

formulation clump together as liquid is drawn through the straw during use, clogging the straw and potentially resulting in an unacceptably high level of resistance to the flow of liquid through the straw. On the other hand, again without wishing to be bound by any particular theory, it is believed that if a large number of particles in the formulation (e.g. greater than 90% of the particles in the formulation by number) have a diameter of greater than 2000 pm, then when the formulation is used in a drinking straw, the particles in the formulation may sink to the bottom of the straw under gravity, rather than be effectively dispersed along the length of the straw during use, and/or the particles in the formulation may not be able to be flushed from the straw with the initial portion of the liquid sucked or pumped through the straw, which could potentially result in an undesirably large volume of liquid being required to deliver all of the formulation to the user.

Typically, the pharmaceutical formulation has a distinct particle size distribution such that at least 80% of the particles in the pharmaceutical formulation by number have a diameter of greater than 500 pm, preferably greater than 600 pm, and most preferably greater than 710 pm. Preferably, at least 90% of the particles in the pharmaceutical formulation by number have a diameter of greater than 500 pm, preferably greater than 600 pm, and most preferably greater than 710 pm. More preferably, at least 95% of the particles in the pharmaceutical formulation by number have a diameter of greater than 500 pm, preferably greater than 600 pm, and most preferably greater than 710 pm.

Further, typically, at least 80% of the particles in the pharmaceutical formulation by number have a diameter of less than 2000 pm, preferably less than 1800 pm, more preferably less than 1600 pm, and most preferably less than 1400 pm. Preferably, at least 90% of the particles in the pharmaceutical formulation by number have a diameter of less than 2000 pm, preferably less than 1800 pm, more preferably less than 1600 pm, and most preferably less than 1400 pm. More preferably, at least 95% of the particles in the pharmaceutical formulation by number have a diameter of less than 2000 pm, preferably less than 1800 pm, more preferably less than 1600 pm, and most preferably less than 1400 pm.

Typically, at least 80% of the particles in the pharmaceutical formulation by number have a diameter of from 500 pm to 2000 pm, preferably from 600 pm to 1800 pm, and most preferably from 710 pm to 1400 pm. Preferably, at least 90% of the particles in the pharmaceutical formulation by number have a diameter of from 500 pm to 2000 pm, preferably from 600 pm to 1800 pm, and most preferably from 710 pm to 1400 pm. More preferably, at least 95% of the particles in the pharmaceutical formulation by number have a diameter of from 500 pm to 2000 pm, preferably from 600 pm to 1800 pm, and most preferably from 710 pm to 1400 pm.

Alternatively, the pharmaceutical formulation may have a distinct particle size distribution such that at least 80% of the particles in the pharmaceutical formulation by volume have a diameter of greater than 500 pm, preferably greater than 600 pm, and most preferably greater than 710 pm. Preferably, at least 90% of the particles in the

pharmaceutical formulation by volume have a diameter of greater than 500 pm, preferably greater than 600 pm, and most preferably greater than 710 pm. More preferably, at least 95% of the particles in the pharmaceutical formulation by volume have a diameter of greater than 500 pm, preferably greater than 600 pm, and most preferably greater than 710 pm.

Further, at least 80% of the particles in the pharmaceutical formulation by volume may have a diameter of less than 2000 pm, preferably less than 1800 pm, more preferably less than 1600 pm, and most preferably less than 1400 pm. Preferably, at least 90% of the particles in the pharmaceutical formulation by volume have a diameter of less than 2000 pm, preferably less than 1800 pm, more preferably less than 1600 pm, and most preferably less than 1400 pm. More preferably, at least 95% of the particles in the pharmaceutical formulation by volume have a diameter of less than 2000 pm, preferably less than 1800 pm, more preferably less than 1600 pm, and most preferably less than 1400 pm.

Further, at least 80% of the particles in the pharmaceutical formulation by volume may have a diameter of from 500 pm to 2000 pm, preferably from 600 pm to 1800 pm, and most preferably from 710 pm to 1400 pm. Preferably, at least 90% of the particles in the pharmaceutical formulation by volume have a diameter of from 500 pm to 2000 pm, preferably from 600 pm to 1800 pm, and most preferably from 710 pm to 1400 pm. More preferably, at least 95% of the particles in the pharmaceutical formulation by volume have a diameter of from 500 pm to 2000 pm, preferably from 600 pm to 1800 pm, and most preferably from 710 pm to 1400 pm.

Alternatively, the pharmaceutical formulation may have a distinct particle size distribution such that at least 80% of the particles in the pharmaceutical formulation by mass have a diameter of greater than 500 pm, preferably greater than 600 pm, and most preferably greater than 710 pm. Preferably, at least 90% of the particles in the pharmaceutical formulation by mass have a diameter of greater than 500 pm, preferably greater than 600 pm, and most preferably greater than 710 pm. More preferably, at least 95% of the particles in the pharmaceutical formulation by mass have a diameter of greater than 500 pm, preferably greater than 600 pm, and most preferably greater than 710 pm.

Further, at least 80% of the particles in the pharmaceutical formulation by mass may have a diameter of less than 2000 pm, preferably less than 1800 pm, more preferably less than 1600 pm, and most preferably less than 1400 pm. Preferably, at least 90% of the particles in the pharmaceutical formulation by mass have a diameter of less than 2000 pm, preferably less than 1800 pm, more preferably less than 1600 pm, and most preferably less than 1400 pm. More preferably, at least 95% of the particles in the pharmaceutical formulation by mass have a diameter of less than 2000 pm, preferably less than 1800 pm, more preferably less than 1600 pm, and most preferably less than 1400 pm.

Further, at least 80% of the particles in the pharmaceutical formulation by mass may have a diameter of from 500 pm to 2000 pm, preferably from 600 pm to 1800 pm, and most preferably from 710 pm to 1400 pm. Preferably, at least 90% of the particles in the pharmaceutical formulation by mass have a diameter of from 500 pm to 2000 pm, preferably from 600 pm to 1800 pm, and most preferably from 710 pm to 1400 pm. More preferably, at least 95% of the particles in the pharmaceutical formulation by mass have a diameter of from 500 pm to 2000 pm, preferably from 600 pm to 1800 pm, and most preferably from 710 pm to 1400 pm.

The skilled person, having regard for the desired administration volume for a given application, will be able to select a suitable particle size distribution by simply preparing formulations having a range of different particle size distributions and testing the resultant formulations to measure the volume of liquid required to completely administer the formulation to the subject in need thereof.

In a particularly preferred embodiment, the pharmaceutical formulation is a granular formulation (i.e. consists of granular particles, or comprises at least 60%, preferably at least 70%, more preferably at least 80%, yet more preferably at least 90%, and most preferably at least 95% granular particles by weight) having two distinct phases: (i) a core phase; and (ii) a matrix phase. The core phase comprises the API, food supplement or vitamin, and is dispersed in the matrix phase. The matrix phase comprises one or more pharmaceutically acceptable fast-dissolving excipients. The function of the matrix phase is to accelerate water uptake by the granules and increase the dissolution rate of the granules in solution. Thus, typically, the matrix phase dissolves more rapidly than the core phase in water under standard conditions (e.g. at 25 °C and 1 atm pressure). Typically, the matrix phase does not comprise any API, food supplement or vitamin. Thus, typically, all of the API, food supplement or vitamin present in the pharmaceutical formulation is present in the core phase of the two- phase granulate.

It is surprising finding of the present invention that if the pharmaceutical formulation is formulated as these two-phase granules, the performance of pre-filled drinking straws which contain the formulation may be improved. Without wishing to be bound by any particular theory, it is believed that if the pharmaceutical formulation consists of such granules (or comprises a large number, e.g. at least 60%, at least 70%, at least 80%, at least 90% or at least 95%, of such granules), the pharmaceutical formulation has both a high water sorption rate and a rapid disintegration/dissolution rate in water. In particular, it has been surprisingly observed that after suspension in water for a set period of time (e.g. 1 minute), such two-phase granules may disintegrate into a particle formulation having a lower dso value (mass median diameter) than single-phase particles comprising an API, food supplement or vitamin which have not been dispersed in a matrix containing one or more fast-dissolving excipients, even when the starting size of the single-phase particles is significantly less than that of the two-phase granules.

Thus, typically a straw containing a two-phase granular formulation of this nature is configured such that when aqueous solvent is passed through the straw for 60 seconds, the dso value of the resulting formulation is typically 100 pm or more, preferably 150 pm or more, and more preferably 200 pm or more, e.g. from 200 pm to 500 pm, preferably from 200 pm to 400 mih, and more preferably from 200 to 300 pm. This feature of the formulations results from the rapid dissolution of the matrix phase of the granules but the slower dissolution of the core phase. It advantageously enables dose-uptake recognition.

The core phase of the two-phase granulate comprises the API, food supplement or vitamin. The core phase may additionally comprise one or more pharmaceutically acceptable excipients selected from carriers, diluents, binders, glidants, release controlling agents and disintegrants, such as those defined herein. In some embodiments, the core phase may comprise an outer coating layer. Typically, this coating layer comprises a taste-masking agent, a physical barrier coating and/or an enteric coating. Alternatively, this coating layer consists of a taste-masking agent, a physical barrier coating and/or an enteric coating. An “enteric coating” is a coating which is resistant to degradation in the acidic environment of the stomach after oral administration of the pharmaceutical formulation, but which dissolves in the more alkaline environment of the intestine (e.g. the small intestine). Therefore, an enteric coating ensures that the contents of the core phase are released in one or more mammalian intestinal sites chosen from the duodenum, jejunum, ileum, and colon following oral administration of the pharmaceutical formulation. Enteric coatings are discussed, for example, Loyd, V. Allen, Remington: The Science and Practice of Pharmacy, Twenty-first Ed., (Pharmaceutical Press, 2005; and P.J. Tarcha, Polymers for Controlled Drug Delivery, Chapter 3, CRC Press, 1991, all of which are incorporated herein by reference. Methods for applying enteric coatings to pharmaceutical compositions are well known in the art, and include for example, U.S. Patent Publication No. 2006/0045822, the contents of which are incorporated herein by reference. Examples of suitable enteric coatings include, but are by no means limited to, acrylic acid, methacrylic acid or ethacrylic acid polymers or copolymers, cellulose acetate (and its succinate and phthalate derivatives), hydroxypropyl methyl cellulose phthalate, polyvinyl acetate phthalate, hydroxyethyl ethyl cellulose phthalate, cellulose acetate tetrahydrophtalate, acrylic resin, shellac, cellulose acetate phthalate (CAP; dissolves above pH 6), polyvinyl acetate phthalate (PVAP, disintegrates at pH 5),

hydroxypropyl methyl cellulose phthalate (HPMCP, grade HP50 disintegrates at pH 5 and HP50 disintegrates at 5.5), and methylacrylic acid copolymers (e.g. Eudragit L 100 and L12.5 disintegrate between about 6 and about 7, Eudragit L-30 and L100-55 disintegrate at pH greater than 5.5 and Eudragit S100, S12.5 and FS 30D disintegrate at pH greater than 7).

A“physical barrier” coating is one which protects the contents of the core (i.e. the API, food supplement or vitamin) from the external environment. In particular, a“physical barrier” coating may impart moisture protection, i.e. prevents moisture from contacting the API, food supplement or vitamin during routine storage of the pharmaceutical formulation. Coating layers which have the function of a physical barrier coating and/or act as a taste- masking agent include hydroxyethylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, gelatin, poly(vinyl pyrrolidone), PVA-PEG copolymer (i.e.

poly(vinyl alcohol)-poly(ethylene glycol) copolymer), poly(vinyl alcohol), a PVA-PEG/PVA mixture, amino dimethyl methacrylate copolymer, amino diethyl-methacrylate copolymer, sodium alginate, shellac, carboxymethylcellulose, cellulose acetate phthalate, cellulose acetate butyrate, methacrylic acid copolymer, methacrylic acid copolymer (Type A), methacrylic acid copolymer (Type B), methacrylic acid copolymer (Type C), ethyl cellulose, cellulose acetate, poly(ethyl acrylate-co-methyl methacrylate) 2:1, ammonio methacrylate Type A:poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride) l:2:0.2, ammonio methacrylate Type B:poly(ethyl acrylate-co-methyl methacrylate- co-trimethylammonioethyl methacrylate chloride) 1:2:0.1, and poly(vinyl acetate). Other suitable examples of taste-masking agents are as defined elsewhere in this disclosure.

Preferred coatings include gelatin, PVA-PEG graft copolymer/PVA polymer mixture and vinylpyrrolidone-vinyl acetate copolymer.

Typically, any coating present possibly contains other coating excipients such as colorants and talc which are well known in the art. Suitable plasticizers include triethyl citrate (Citroflex 2), triacetin (glyceryl triacetate), acetyl triethyl citrate (Citroflec A2), Carbowax 400 (polyethylene glycol 400), diethyl phthalate, tributyl citrate, acetylated monoglycerides, glycerol, fatty acid esters, propylene glycol, and dibutyl phthalate. In particular, anionic carboxylic acrylic polymers will typically contain 10-25% by weight of a plasticizer, especially dibutyl phthalate, polyethylene glycol, triethyl citrate and triacetin.

The matrix phase of the two-phase granulate comprises one or more pharmaceutically acceptable fast-dissolving excipients. Preferably, said fast-dissolving excipient is a hydrophilic compound, for example a compound which has a solubility of greater than 50 g/lOO g of water at 25 °C at 1 atm pressure, preferably greater than 75 g/lOO g water, more preferably greater than 100 g/lOO g water, yet more preferably greater than 150 g/lOO g water, and most preferably greater than 200 g/lOO g water. Examples of suitable fast dissolving excipients include, but are not limited to, saccharides (such as monosaccharides, disaccharides, and polysaccharides), sugar alcohols (such as glucose, arabinose, lactose, dextrose, sucrose, fructose, maltose, trehalose, mannitol, erythritol, sorbitol, xylitol, lactitol, erythritol), poly(ethylene glycol), and mixtures thereof. Saccharides, especially sucrose, are particularly preferred fast-dissolving excipients.

Thus, the core phase may comprise an API, food supplement or vitamin, coated with a taste-masking and/or enteric coating. Alternatively, the core phase may consist of an API, food supplement or vitamin, coated with a taste-masking and/or enteric coating.

The matrix phase may additionally comprise one or more pharmaceutically acceptable excipients selected from carriers, diluents, binders, glidants, release controlling agents and disintegrants, such as those defined herein.

Typically, the two-phase granulate comprises from 0.1% to 90% by weight of the core phase, preferably from 0.5% to 80%, more preferably from 1% to 70%, yet more preferably from 2% to 60%, still more preferably from 5% to 50%, and most preferably from 10% to 40%. Typically, the two-phase granulate comprises from 10% to 99.9% by weight of the matrix phase, preferably from 20% to 99.5%, more preferably from 30% to 99%, yet more preferably from 40% to 98%, still more preferably from 50% to 95%, and most preferably from 60% to 90%. Typically, no other phases are present in the granulate other than the core phase (which is optionally coated as described above) and the matrix phase.

A formulation according to the invention comprises an API, food supplement or vitamin. Thus, typically, a formulation according to the invention comprises an API.

Alternatively, a formulation according to the invention comprises a food supplement.

Alternatively, a formulation according to the invention comprises a vitamin. Preferably, a formulation according to the invention comprises an API.

The API, food supplement or vitamin should be physiologically acceptable and compatible with the formulation. Typically, the pharmaceutical formulation comprises from 0.0001% to 99.9% by weight of the API, food supplement or vitamin, preferably from 0.001% to 95% by weight of the API, food supplement or vitamin, more preferably from 0.1% to 90% by weight of the API, food supplement or vitamin, even more preferably from 0.5% to 75% by weight of the API, food supplement or vitamin, yet more preferably from 1% to 60% by weight of the API, food supplement or vitamin, still more preferably from 2 to 50% by weight of the API, food supplement or vitamin, further preferably from 3 to 40% by weight of the API, food supplement or vitamin, still more preferably from 5 to 30% by weight of the API, food supplement or vitamin, even more preferably from 7 to 20% by weight of the API food supplement or vitamin, and most preferably from 8 to 15% by weight of the API, foor supplement or vitamin, e.g. about 10% by weight of the API, food supplement or vitamin. The API, food supplement or vitamin may be water-soluble.

Alternatively, the API, food supplement or vitamin may be poorly soluble in water.

Typically, the API is selected from the group consisting of 13 C-urea (Helicobacter test), l5-Methyl-prostaglandin F2a, la-Hydroxy vitamin D3, 2,4-dichlorbenzylalkohol, 5- aminolevulinic acid hydrochloride, 5-aminolevulinsyre (5-ALA), abacavir,

abacavir/lamivudine, abacavir/lamivudine/zidovudine, abatacept, abciximab, acamprosat, acarbose, acebutolol, acepromazin, acetaminofene, acetate, acetazolamide, acetophenazine, acetylcysteine, acetylsalicylic acid, aciclovir, acipimox, acitretin, acrivastin, acyclovir, adalimumab, adapalen, adefovir dipivoxil, adenosin, adrenalin, aesculin, agalsidase alfa, agalsidase beta, agalsidase-alfa, agalsidase-beta, agomelatin, agomelatine, alanin, albumin, humant, aldesleukin, alemtuzumab, alendronat, alendronate sodium/colecalciferol, alendronic acid/colecalciferol, alfacalcidol, alfentanil, alfuzosin, alginsyre, alglucosidase alfa, alimemazine, aliskiren, aliskiren hemifumarate/hydrochlorothiazide, alitretinoin, allopurinol, almitrin, almotriptan, alprazolam, alprenolol, alprostadil, alteplase, aluminiumaminoacetat, aluminiumhydroxid, aluminiumsaccharosesulfat, alkalic, amantadine, ambenon, ambrisentan, ambroxol, amfepramon, amidotrizoat, amiloride, aminofyllin, amino gluthe timid, aminosalyl, amiodaron, amisulprid, amitriptylin, amlodipin, amlodipine

besylate/valsartan/hydrochlorothiazide, amlodipine besylate/valsartan, amlodipine/valsartan, amorolfin, amoxicillin, amphotericin B, ampicillin, amprenavir, amsachrin, amylase, amylmetacresol, anagrelide, anakinra, anastrozol, anidulafungin, antazoline, antithrombin, antithrombin alfa, anti-thymocytglobulin, apomorphine, apraclonidin, aprepitant, aprotinin, arcitumomab, argatroban, arginin, aripiprazole, arsenic trioxide, articain, ascorbic acid, asparagin, atazanavir, atenolol, atomoxetin, atorvastatin, atosiban, atovaquon, atropine, auranofin, aurothiomalat, aviptadil, azacitidin, azacitidine, azapropazone, azathioprin, azelaic acid, azelastine, azetazolamide, azithromycin, aztreonam, aztreonam Cl -esterase-inhibitor, human, bacampicillin, bacillus Calmette Guerin (Danish strain 1331), bacillus Calmette Guerin (strain RIVM derived from strain 1173-P2), baclofen, balsalazid, bambuterol, bariumsulfat, basiliximab, bazedoxifene, becaplermin, bechlomethasone,

beclometasondipropionat, benazepril, bendroflumethiaziede, bensatropine, benserazid, bensylpenicillin, benzalkonium chloride, benzene carboxylic acid, benzenmethanol, benzocain, benzoic acid, benzoylperoxid, benzydamin, benzylpenicillin, betacarotene, betahistin, betain, betaine anhydrous, betamethason, betamethason-l7-valerat, betamethason- 2l-acetat, betamethasondipropionat, betamethasonphosphat, betanidine, betaxolol, bevacizumab, bexarotene, bicalutamid, bimatoprost, bimatoprost/timolol, biotin, biperiden, bisachodyl, bisoprololfumarat, bivalirudin, black rubber-mix (PPD-mix), bleomycin, borax, bortezomib, bosentan, botulinum toxin type a, botulinum toxin type B, brimonidin, brimonidintartrat, brinzolamide, brinzolamide/timolol, bromazepam, bromhexine, bromocriptine, brompheniramine, budesonide, bumetanide, butamirate citrate, bupivacain, buprenorphine, buprenorphine/naloxone, bupropion, buserelin, buspiron, busulfan, butylscopolamin, cabergolin, cadexomer-iodine, caffeine, cain-mix, calcipotriol, calcitirol, calcitonin, calcitonin (salmon), calcium, calciumacetate, calciumcarbonate, calciumchloride, calciumfluoride, calciumfolinate, calciumgluconate, calciumlactogluconate,

calciumpolystyrensulfonate, canakinumab, candesartancilexetil, capecitabine, capsaicin, captopril, carbamazepine, carba-mix, carbetocin, carbidopa, carbimazol, carbomer, carbocistein, arbon, active, carboplatin, carboprost, carglumic acid, carmelloseSodium, carmustin, carvedilol, caspofungin, catumaxomab, cefalexin, cefotaxim, cefoxitin, cefprozil, ceftazidim, ceftriaxon, cefuroxim, celecoxib, cephaclor, cephadroxil, cephalexin, cephalotin, cephradin, certolizumab pegol, cetirizin, cetrorelix, cetuximab, chinidine, chlofibrate, chlomethiazol, chlomipramin, chlonazepam, chloprothixene, chloralhydrat, chlorambucil, chloramphenicol, chlordiazepoxid, chlorhexidine, chloride, chloriongonadotropin, chloroquin, chlorpromazine, chlorpropamid, chlorprothixen, chlorthalidon, chlorzoxazon, chlotrimazol, cholecalciferol, vitamin D3, cholinetheophyllinate, choriogonadotropin alfa, choriongonadotropin, humant (hCG), choriongonadotropin-a (hCG), chrome, ciclopirox, ciclopiroxolamin, ciclosporin, cidofovir, cilastatin, cimetidine, cinacalcet, cinchocain, cinetazon, cinnamaldehyd, cinnamylalcohol, cinnarizine, ciprofloxacin, cis(Z)- flupenthixoldecanoat, cisatracurium, cisplatin, citalopram, Cl+Me-isothiazolinon (Kathon CG), cladribin, cladribine, clarithromycin, clavulansyre, clemastin, clemastine, clindamycin, clioquinol, clobazam, clobetasolpropionat, clobetason-l7-butyrat, clodronat, clofarabin, clomiphene, clomipramin, clonazepam, clonidine, clopamide, clopidogrel, clotrimazol, cloxacillin, clozapin, cobalt(II), cobber, cobber acetate, codeine, colesevelam, colestipol, colestyramin, colistimethatSodium, corticotropin, cortisone, cyanochobalamine,

cyanocobalamin, vitamin B12, cyclandelar, cyclizine, cyclopentolat, cyclophenile, cyclophosphamid, cyproheptadine, cyproteron, cyproteronacetat, cysteamin, cystein, cystin, cytarabin, cytarabine, dabigatran etexilate, dacarbazine, daclizumab, dalteparin, dantron, dapson, daptomycin, darbepoetin alfa, darifenacin, darifenacin, darunavir, dasatinib, daunorubicin, deferasirox, deferiprone, deferoxaminmesilat, degarelix, demeclocycline, depreotide, desfluran, desipramin, desirudin, deslanoside, desloratadine, desloratadine (as sulphate), desmopres sin, desogestrel, desoximethason, dexamethason, dexchlorpheniramine, dexibuprofen, dexketoprofen, dexpantenol, dexpanthenol, Vitamin B5, dexrazoxane, dextran 1, dextran 40, dextran 70, dextromethorphan, dextropropoxyphene, diazepam, diazoxide, dibotermin alfa, dichlophenamide, diclofenac, diclofenacSodium, dicloxacillin, diculmarole, didanosin, dienogest, digoxine, dihydralazine, dihydroergotamine, dihydrogesteron, dihydrotachysterol, dihydroxyaluminium sodiumcarbonat, dikaliumchlorazepat, diltiazem, dimeglumingadopentetat, dimenhydinate, dimethylaminodiphenylbuten, dimeticon, dimeticon, ferrofumarate, dinitrogenoxid, dinoprost, dinoproston, diosmin, diphenhydramin, diphenolxylate, dipyradamol, diSodiumclodronate, diSodiumetidronate, diSodiumphosphate, disopyramide, disulfiram, dixyrazine, dobutamine, docetaxel, docosahexaenoinsyre (DHA), docusat, dofetilide, domperidon, donepezil, dopamine, doripenem, domase alfa, dorzolamid, dosulepin, doxapram, doxazosin, doxepin, doxorubicin, doxorubicin hydrochloride, doxycyclin, doxycycline, droperidol, drospirenon, drotrecogin alfa (activated), duloxetine, dutasterid, ebastin, econazol, eculizumab, efalizumab, efavirenz,

efavirenz/emtricitabine/tenofovir disoproxil (as fumarate), eflornithine, eicosapentaenoinsyre (EPA), ekonazol, eletriptan, emedastine, emepron, emtricitabine, emtricitabine/tenofovir disoproxil, enalapril, enfuvirtide, enoxaparin, entacapone, entecavir, ephedrine, epinephrine, epirubicin, eplerenon, epoetin alfa, epoetin beta, epoetin delta, epoetin zeta, epoprostenol, epototermin alfa, epoxyresin, eprosartan, eptacog alfa (activated), eptifibatid, eptifibatide, eptotermin alfa, erdostein, ergocalciferol, vitamin D2, ergotamine, erlotinib, erlotinib, ertapenem, erythromycin, escitalopram, eslicarbazepin, eslicarbazepine acetate, esmolol, esomeprazol, estradiol, estradiolvalerat, estradiolvalerianate, estramustin,

estramustinphosphat, estriol, etambutol, etanercept, etanercept, ethacrynacide, ethambutol, ethinylestradiol, ethosuximide, ethylendiamin, ethylmorphine, etidronat, etilephrine, etodolac, etonogestrel, etoposide, etoricoxib, etravirin, etravirine, etulos, eugenol, everolimus, exemestan, exenatid, exenatide, ezetimibe, ezlocillin, factor IX, factor VIII, famciclovir, febuxostat, felodipin, felypressin, fenoterol, fentanyl, fentanyl citrate, ferri-salts, ferritetrasemisodium, ferro-salts, ferrosuccinate, ferumoxsil, fesoterodine, fexofenadin, fibrinogen, fibronektin, filgrastim, finasterid, fiskeolie, flavoxat, flecainide, flucloxacillin, fluconazol, flucytosin, fludarabinphosphat, fludrocortison, fludrocortisonacetat, flumazenil, flumedroxon, flumetasonpivalat, flunarizin, flunitrazepam, fluocinolonacetonid, fluocinonid, fluocortolon 2l-pivalat, fluorid, fluormetolon, fluoruracil, fluoxetin, fluoximesteron, flupentizol, fluphenazindecanoat, fluphenazine, flurbiprofen, flutamid, fluticasone furoate, fluticasonpropionat, fluvastatin, fluvoxamin, folic acid, folic acid heparin, follitropin alfa, follitropin beta, follitropin-a (rfSH), follitropin-b (rfSH), fomivirsen, fondaparinux, fondaparinux sodium, formaldehyde, formoterol, fosamprenavir, fosaprepitant, fosaprepitant dimeglumine, fosinoprilSodium, fosphenytoin, framycetin, frangulabark, frovatriptan, fulvestrant, furosemide, fusidic acid, gabapentin, gadobutrol, gadodiamid, gadofosveset, gadoteridol, gadoterinsyre, gadoversetamide, galantamin, galsulfase, ganciclovir, ganirelix, gefitinib, gelatine, gemcitabin, gemeprost, gemfibrozil, gentamicin, geraniol, gestoden, glatirameracetat, glibenclamid, gliclazid, glimepirid, glipizid, glucagon, glucopyrron, glucosamin, glucose, glutamin, glutathion, glycerol, glycerophosphat, glyceryl nitrate, glycerylnitrate, glyceryltrinitrate, glycin, glycopyrron, glycyl-glutamin, glycyl-tyrosin, golimumab, goserelin, gramicidin, granisetron, griseofulvin, guanetidine, guanfacine, haloperidol, hedera helix extract, heparin, heparin co-factor, heparinoid, hesperidin, hexaminolevulinat, histamine, histidine, histrelin, human coagulation factor IX, human fibrinogen/human thrombin, human normal immunoglobulin, human normal immunoglobulin (IVIg), hydralazine, hydrochloride, hydrochlorthiazide, hydrocortisonacetat, hydrocortisone, hydrocortisone- l7-butyrat, hydrocortisonsuccinat, hydro genperoxid, hydromorphon, hydroxichloroquine, hydroxiprogresterone, hydroxizine, hydroxocobalamin, vitamin B12, hydroxycarbamide, hydroxychloroquin, hydroxycitronellal, hydroxyethylrutosider, hydroxyethylstivelse starch, hydroxyurea, hyoscin, hyoscinbutylbromid, hyoscyamine, hypromellose, ibandronic acid, ibandronsyre, ibritumomab tiuxetan, ibuprofen, icatibant, ichthammol, icodextrin, idarubicin, idursulfase, ifosfamid, iloprost, imatinib, imatinib mesilate, imiglucerase, imipenem, imipramin, imiquimod, immunglobulin G, humant, immunglobulin, humant (anti-D), indapamid, indinavir, indomethacine, infliximab, inositolnico-tinate, insulin, insulin aspart, insulin aspart protamin, insulin detemir, insulin glargine, insulin glulisine, insulin human (rDNA), insulin lispro, insulin lispro protamin, insulin, humant, insulin, isophan, humant, interferon alfa-2b, interferon alfacon-l, interferon beta- la, interferon idoxuridin, interferon- alfa, interferon-alfa-2b, interferon-beta- la, interferon-beta- lb, interferon-gamma- lb, interleukin-2, iobitridol, iodidine, iodixanol, ioflupane (123 I), iohexol, iomeprol, iopromid, iotrolan, ioversol, ipratropium, irbesartan, irbesartan/hydrochlorothiazide, irinotecan, isocarboxazid, isoeugenol, isofluran, isoleucin, isoniazid, isophaninsulin, humant, isoprenaline, isosorbiddinitrate, isosorbidmononitrate, isotretinoin, isradipin, itraconazol, ivabradine, ketobemidon, ketobemidone, ketokonazol, Ketoprofen, ketorolac, ketotifen, Kolofon, kreatinin monohydrate, kreatinin monohydrate, labetalol, lacidipin, lacosamide, lactat, lactic acid, lactic acid producing bacteria, lactulose, lamivudine, lamivudine/zidovudine, lamotrigin, lanolin, lanreotid, lansoprazol, lanthanum, lapatinib, laronidase, laropiprant, lasofoxifene, latanoprost, lecithin, lefhmomide,

lenalidomide, lenograstim, lepirudin, lercanidipin, letrozol, leucin, leucovorin, leuprorelin, levetiracetam, levocabastin, levocetirizin, levodopa, levofloxacin, levofolic acid,

levomepromazine, levonorgestrel, levotyroxin, lidocain, lincomycin, linezolid, liotyronin, lipase, liraglutide, lisinopril, lithiumcarbonat, lithiumcitrat, lodoxamid, lofepramin, lomustine, loperamide, lopinavir, loratadin, lorazepam, lormetazepam, lomoxicam, losartan, lovastatin, lutropin alfa, lymecycline, lynestrenol, lypressin, lysine, macrogol 3350, magnesium, magnesium carbonate, magnesium chloride, magnesium hydroxide,

magnesiumoxide, magnesiumsulfate, malathion, mangafodipir, mangane, mannitol, maptrotilin, maraviroc, mebendazol, mebeverin, mecasermin, mecillinam, meclozine, medroxiprogresterone, medroxyprogesteronacetate, mefloquine, mefruside, megesterol, megestrolacetat, melatonin, melfalan, meloxicam, melperon, melphalan, memantine, meningokokpolysaccharid, menotropin (hmG), mepensolar, mepivacain, meprobamat, mepyramin, mercaptamine bitartrate, mercaptobenzothiazol, mercapto-mix, mercaptopurin, meropenem, mesalazin, mesna, mesterolon, mestranol, metacycline, metaoxedrin,

metenamine, metformin, meth ldopa, methadone, methenamin, methionin, metholazone, methotrexat, methoxy polyethylene glycol-epoetin beta, methylaminolevulinat, methyldopa, methylergometrin, methylergotamine, methylnaltrexon, methylnaltrexone bromide, methylperon, methylphenidat, methylprednisolon, methylprednisolonacetat,

methylprednisolonsuccinat, methylscopolamine, methyprylon, metixene, metoclopramide, metopimazin, metoprolol, metronidazole, metychlothiazide, mexiletin, mianserin,

micafungin, miconazole, midazolam, mifamurtide, miglustat, minoxidil, mirtazapin, misoprostol, mitomycin, mitotane, mitoxantron, mivacurium, moclobemid, modafinil, molybdenum, mometasonfuroat, moroctocog alfa, morphine, moxaverine, moxifloxacin, moxonidin, mupirocin, mycophenoic acid, mycophenolate mofetil, nabumeton, nadolol, nafarelin, nalbuphin, nalidixic acid, naloxone, naltrexon, nandrolon, naphazolin, naproxen, naratriptan, natalizumab, natamycine, nateglinide, nebivolol, nelarabin, nelarabine, nelfinavir, neomycin, neomycinsulfat, neostigmin, nepafenac, nevirapine, nicheritrol, nickel,

nicomorphin, nicorandil, nicotin, nicotinamid, nicotinic acid, nicotinic acid/laropiprant, nicotinyl alchol, nifedipine, nilotinib, nimodipin, niphedipin, nitisinone, nitrazepam, nitrendipin, nitric oxide, nitrofurantoin, nitrogen, nitrogen oxide, nitroprus side, nizatidin, nonacog alfa, noradrenalin, norelgestromin, norelgestromin/ethinyl estradiol, norethisteronacetat, noretisterone, norfloxacin, norgestimat, nortriptylin, noscapine, nystatin, oak moss, octocog alfa, octreotid, ofloxacin, olanzapine, olmesartanmedoxomil, olopatadine, olsalazin, omalizumab, omeprazol, ondansetron, opipramol, opium, oral Cholera vaccine, orciprenaline, orlistat, ornidazol, omithin, orphenadrine, oseltamivir, osteogent protein- 1: BMp-7, oxaliplatin, oxazepa, oxazepam, oxcarbazepin, oximetolon, oxiphencyclimine, oxitetracycline, oxprenolol, oxybutynin, oxycodon, oxygen, oxymetazolin, oxytetracyclin, oxytocin, paclitaxel, paclitaxel albumin, palifermin, palifermin, paliperidone, palivizumab, palonosetron, pamidronat, panitumumab, pantoprazole, pantotenol, vitamin B5, pantothenic acid, papaverine, paracetamol, paraffinolie, parathyroid hormone (rDNA), parecoxib, paricalcitol, paroxetin, pegaptanib, pegaptanib sodium, pegfilgrastim, peginterferon alfa-2a, peginterferon alfa- 2b, pegvisomant, pegylated interferon-alfa-2a, pegylated interferon-alfa- 2b, pemetrexed, penciclovir, penfluridol, penicillamine, pentaeritrityltetranitrate, pentazocine, pentobarbital, pentoxifyllin, pentoxiverine, perflutren, pergolid, periciazin, perindopril, permethrin, perphenazindecanoat, perphenazine, pertussistoksoid, pethidin, pethidine, phenazone, phenazonsalicylat, phenemal, phenfluramin, phenobarbital, phenoperidine, phenoxymethylpenicillin, phenprocoumon, phentanyl, phentolamin, phenylamine, phenylbutazone, phenylephrin, phenylpropanolamine, phenytoine, phosphat, phosphestrol, phytomenadion, vitamin Kl, phytominadion, pilocarpin, pimecrolimus, pimozid, pindolol, pioglitazone, pioglitazone/glimepiride, pioglitazone/metformin, pioglitazone/metformin hydrochloride, pipamperon, piperacillin, piritramide, piroxicam, pivampicillin,

pivmecillinam, pizitifen, pizotifen, plasminogen, plerixafor, podophyllotoksin, polydocanol, polyestradiolphosphat, polygelin, polymyxin B, polythiazide, posaconazole, potassium, potassium acetate, potassium chloride, potassium dihydrogen phosphate, potassium dikromat, potassium hydroxide, potassium phosphate, p-phenylendiamin, pramipexole, prasugrel, pravastatin, prazosine, prednisolon, prednisolon sodiumphosphate, prednisone, pregabalin, prenalterol, prilocain, primidone, probanteline, probenecid, procain, procainamide, procarbazine, prochlorperazine, procylidine, proetazine, progesteron, proguanil, prolin, promethazine, propafenon, propanthelinbromid, propionmazine, propofol, proproanolol, propylthiouracil, propyphenazon, proscillaridin, protamin, protein C, protein C, human, protein S, protriptylin, proxiphylline, prucalopride, pseudoephedrine (as sulphate), p-t- butylphenol-formaldehyd-resin, pyrazinamid, pyridostigmine, pyridoxin, pyridoxin, Vvtamin B6, pyrityldion, pyrvin, quetiapin, quinagolid, quinapril, quinin, quinolin-mix, rabeprazol, raffinose, raloxifene, raltegravir, ramipril, ranibizumab, ranitidine, ranolazine, rasagiline, rasburicase, reboxetin, recombinant human erythropoietin alfa, remifentanil, repaglinide, reserpine, resorcinol, retapamulin, reteplase, retinol, retinol, vitamin A, ribavirin, riboflavin, vitamin B2, rifabutin, rifampicin, riiterol, rilonacept, riluzole, rimexolon, rimonabant, risedronat, risperidon, ritonavir, rituximab, rivaroxaban, rivastigmine, rizatriptan,

rocuronium, romiplostim, ropinirol, ropivacain, rosiglitazone, rosiglitazone/glimepiride, rosiglitazone/metformin, rosuvastatin, rotavirus, rotigotine, roxithromycin, rufinamide, sagradaextract, salazosulfapyridin, salazosulfapyridine, salbutamol, salicylic acid, salicylic amide, salmeterol, samarium [l53sm] lexidronam pentas odium, sapropterin, saquinavir, saxagliptin, scopolamine, selegilin, selenium, selenium disulfid, sennaglycosides, serin, sertindol, sertralin, sevelamer, sevelamer (carbonate), sibutramin, sildenafil, simeticon (aktiveret dimeticon), simvastatin, sirolimus, sitagliptin, sitagliptin/metformin hydrochloride, sitagliptin phosphate monohydrate/metformin hydrochloride, sitaxentan, sitaxentan sodium, s-ketamin, sodium oxybate, sodium phenylbutyrate, sodium-chromoglicate,

sodiummaurothiomalate auronofin, sodiumpicosulfat, solifenacin, solvsulfadiazin, somatotropin, somatrem, somatropin, sorafenib, sorbitol, sotalol, spectinomycin, spiramycin, spironolactone, stanozolol, stavudine, stiripentol, streptokinase, strontium ranelate, sucralfat, sufentanil, sugammadex, sulbentin, sulesomab, sulfamethizol, sulfamethoxazol, sulfasalazin, sulfat, sulfisomidine, sulphur hexafluoride, sulpirid, sumatriptan, sunitinib, suxamethon, synstigmine, tacrolimus, tadalafil, tafluprost, tamoxiphene, tamsulosin, tasonermine, taurin, tazobactam, tegafur, teicoplanin, telbivudine, telithromycin, telmisartan,

telmisartan/hydrochlorothiazide, temoporfin, temozolomide, temsirolimus, tenecteplase, teniposide, tenofovir disoproxil, tenoxicam, terazosin, terbinafin, terbutalin, teriparatide, terlipres sin, terodiline, testosterone, testosteronenantat, testosteronundecanoat,

tetanustoksoid, tetrabenazin, tetracosactid, tetracycline, tetryzolin, thalidomide, theophlline, theophyllin og ethylendiamin, thiamazol, thiamin, vitamin Bl, thiethylperazine, thioguanine, thiomersal, thiopental, thioridazine, thiotepa, thithixen, threonin, thrombin, human, thyrotropin alfa, tiagabin, tiamazol, tiamin, tiaprofenic acid, tibolon, tigecyclin, tigecycline, timolol, tinidazole, tinzaparin, tiotropium, tipranavir, titandioxide, tizanidin, tobramycin, tocilizumab, tocofersolan, tocopherol, vitamin E, tokoferol, tolazamid, tolbutamid, tolcapone, tolfenamic acid, tolterodin, tolvaptan, topiramat, topotecan, toremifene, trabectedin, tramadol, trandolapril, tranexamic acid, trastuzumab, travoprost, travoprost, travoprost/timolol, treosulfan, treprostinil, triacelluvax, triamcinolonacetonid, triamcinolonhexacetonid, triazolam, trifluoperazine, triglycerid, trimetazidin, trimethaphan, trimethoprim, trimipramin, triptorelin, trombin, tropicamid, tropisetron, trospiumchlorid, tryptophan, tyrotropin, ulipristal, ulipristalacetat, urofollitropin (uFSH), urokinase, ustekinumab, valaciclovir, valdecoxib, valganciclovir, valin, valproat, valsartan, vancomycin, vardenafil, vareniclin, varenicline tartrate, vasopressin, venlafaxin, verapamil, verteporfin, vigabatrin, vildagliptin, vildagliptin/metaformin hydrochloride ldagliptin, vildagliptin/metformin hydrochloride, vinblastin, vinchristin, vindesin, vinfhmine ditartrate, vinorelbin, zonisamide, zopiclon, zuclopenthixol, zuclopenthixolacetate, zuclopenthixoldecanoat, zuclopentizol, al- proteinaseinhibitor (human), a-amylcinnamaldehyde or pharmaceutically acceptable salts thereof, and mixtures thereof.

The API may also be a prescription or non-prescription substance such as a vaccine. Non-limiting examples of vaccines include viable autologous cartilage cells expanded ex vivo expressing specific marker proteins, combined diptheria, tetanus, acellular pertussis and hepatitis B recombinant vaccine, combined hepatitis A and hepatitis B vaccine, diphtheria, tetanus, pertussis, hepatitis B, Haemophilus influenzae type b conjugate vaccine, Diphtheria, tetanus, whole cell pertussis and hepatitis B vaccine, diptheria, tetanus, acellular pertussis, hepatitis B recombinant (adsorbed), inactivated poliomyelitis and absorbed conjugate haemophilus influenzae type b vaccine, diptheria, tetanus, acellular pertussis, hepatitis B recombinant (adsorbed), inactivated poliomyelitis vaccine, haemophilus b conjugate

(Meningoccocal Protein conjugate) and hepatitis B (recombinant) vaccine, hepatitis A (inactivated), hepatitis B(rDNA)(HAB) antigen vaccine (adsorbed), hepatitis B (rDNA) vaccine (adjuvanted, adsorbed), hepatitis B (Recombinant) Vaccine, human papillomavirus vaccine, human papillomavirus vaccine [types 6, 11, 16, 18] (recombinant, adsorbed), human rotavirus, live attenuated, Inactivated Hepatitis A virus HBsAg recombinant purified, influenza vaccine (split virion, inactivated), Influenza vaccine (surface antigen, inactivated, prepared in cell culture), Japanese Encephalitis Vaccine (inactivated, adsorbed), measles, mumps and rubella vaccine (live), measles, mumps, rubella and varicella vaccine (live), Pandemic influenza vaccine, Pandemic influenza vaccine (H1N1) (split virion, inactivated, adjuvanted); A/Califomia/7/2009 (HlNl)v like strain (X-179A), Pandemic influenza vaccine (surface antigen, inactivated, adjuvanted); A/California/7/2009 (HlNl)v like strain (X- 179A), pandemic influenza vaccine (whole virion, vero cell derived, inactivated)

pneumococcal polysaccharide conjugate vaccine (adsorbed), pneumococcal saccharide conjugated vaccine, absorbed, prepandemic influenza vaccine (H5N1) (split virion, inactivated, adjuvanted) A/Vietnam/l 194/2004 NIBRG-14, rotavirus vaccine, and shingles (herpes zoster) vaccine (live). Typically, the food supplement is selected from the group consisting of retinol, retinyl acetate, retinyl palmitate, beta-carotene, cholecalciferol, ergocalciferol, D-alpha- tocopherol, DL-alpha-tocopherol, D-alpha-tocopheryl acetate, DL-alpha-tocopheryl acetate, D-alpha-tocopheryl acid succinate, phylloquinone (phytomenadione), menaquinone-7, thiamin hydrochloride, thiamin mononitrate, riboflavin, riboflavin 5'- phosphate, sodium, nicotinic acid, nicotinamide, D-pantothenate, calcium, D- pantothenate, sodium, dexpanthenol, pyridoxine hydrochloride, pyridoxine 5'- phosphate, pteroylmonoglutamic acid, calcium-L-methylfolate, (6S)-5- methyltetrahydrofolic acid, glucosamine salt, cyanocobalamin, hydroxocobalamin, D- biotin, L-ascorbic acid, sodium-L-ascorbate, calcium-L-ascorbate, potassium-L- ascorbate, L-ascorbyl 6-palmitate, calcium carbonate, calcium chloridecalcium salts of citric acid, calcium gluconate, calcium glycerophosphate, calcium lactate, calcium salts of orthophosphoric acid, calcium hydroxide, calcium oxide, magnesium acetate, magnesium carbonate, magnesium chloride, magnesium salts of citric acid, magnesium gluconate, magnesium glycerophosphate, magnesium salts of orthophosphoric acid, magnesium lactate, magnesium hydroxide, magnesium oxide, magnesium sulphate, ferrous carbonate, ferrous citrate, ferric ammonium citrate, ferrous gluconate, ferrous fumarate, ferric sodium diphosphate, ferrous lactate, ferrous sulphate, ferric diphosphate (ferric pyrophosphate), ferric saccharate, ferrous ammonium phosphate, ferric sodium EDTA, elemental iron (carbonyl+electrolytic+hydrogen reduced), ferrous bisglycinate, cupric carbonate, cupric citrate, cupric gluconate, cupric sulphate, copper lysine complex, sodium iodide, sodium iodate, potassium iodide, potassium iodate, zinc acetate, zinc chloride, zinc citrate, zinc gluconate, zinc lactate, zinc oxide, zinc carbonate, zinc sulphate, manganese carbonate, manganese chloride, manganese citrate, manganese gluconate, manganese glycerophosphate, manganese sulphate, sodium bicarbonate, sodium carbonate, sodium chloride, sodium citrate, sodium gluconate, sodium lactate, sodium hydroxide, sodium salts of orthophosphoric acic, sodium sulphate, potassium bicarbonate, potassium carbonate, potassium chloride, potassium citrate, potassium gluconate, potassium glycerophosphate, potassium lactate, potassium hydroxide, potassium salts of orthophosphoric acic, potassium sulphate, sodium selenate, sodium hydrogen selenite, sodium selenite, chromium (III) chloride, chromium (III) sulphate, chromium picolinate, chromium(III) lactate tri-hydrate, ammonium molybdate (molybdenum (VI)), sodium molybdate (molybdenum (VI)), potassium fluoride, sodium fluoride, monomethylsilanetriol (organic silicon), activated charcoal, alpha-linolenic acid (ALA), arabinoxylan produced from wheat endosperm barley grain fibre, beta-glucans, betaine, biotin, carbohydrate-electrolyte solutions, chitosan, choline, creatine, docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), glucomannan, guar gum, hydroxypropyl methylcellulose (HPMC), lactase enzyme, lactulose, linoleic acid, live yoghurt cultures, melatonin, monascus purpureus (red yeast rice),

monounsaturated and/or polyunsaturated fatty acids, oat grain fibre, oleic acid, olive oil polyphenols, pectins, plant sterols, plant stanols, resistant starch, rye fibre, xylitol, sorbitol, mannitol, maltitol, lactitol, isomalt, erythritol, sucralose and polydextrose; D- tagatose and isomaltulose, wheat bran fibre, zeaxanthin, lutein, dextrose anhydrous, dextrose monohidrate fructose, glucose, sugar, colostrum, Lactobacillus strains,

Bifidobacterium strains, Saccharomyces boulardii, Streptococcus thermophilus,

Bacillus laterosporus, Pediococcus acidilactici, Lactococcus lactis, inulin,

fructooligosaccharides, galacto-oligosaccharides, soy-oligosaccharides, xylo- oligosaccharides, isomalto-oligosaccharides, and mixtures thereof.

Typically, the vitamin is selected from the group consisting of vitamin A, vitamin Bi, vitamin B ₂ , vitamin B ₃ , vitamin Bs, vitamin B ₆ , vitamin B ₇ , vitamin B9, vitamin B12, vitamin C, vitamin D, vitamin E, vitamin K, and mixtures thereof.

A formulation according to the invention comprises one or more pharmaceutically acceptable excipients selected from carriers, diluents, binders, glidants, release control agents and disintegrants. The pharmaceutically acceptable excipients may therefore comprise a mixture of carriers, diluents, binders, glidants, release controlling agents and/or disintegrants.

Typically, the pharmaceutical formulation comprises from 0.05% to 99.9% by weight of the one or more pharmaceutically acceptable excipients selected from carriers, diluents, binders, glidants, release controlling agents and disintegrants, preferably from 1% to 99% by weight, more preferably from 5% to 95% by weight, and most preferably from 10% to 90% by weight.

Typically, when the one or more pharmaceutically acceptable excipients is a pharmaceutically acceptable carrier, the carrier is preferably a polymeric carrier. Typically, the carrier is a polymeric carrier selected from the group consisting of gelatins, ovalbumin, soybean proteins, gum arabic, non-sucrose fatty acid esters, starches, modified starches, cellulose, methylcellulose (MC), ethylcellulose (EC), hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), polycarbophil, polyethylene glycol (PEG), polyethylene oxides, polyoxyalkylene derivatives, polymethacrylates, poly(vinyl pyrrolidone) (PVP), polyvinyl acetate (PVAc), PVP- vinylacetate-copolymer (PVP-VA), a vinylpyrrolidone-vinyl acetate copolymer (such as Kollidon® VA 64), lactose, sorbitol, mannitol, maltitol, saccharose, isomalt, cyclodextrins such as a-cyclodextrins, b-cyclodextrins, g-cyclodextrins, hydroxylpropyl-cyclodextrins, hydroxypropyl- b-cyclodextrin (HR-b-CD), sodium carboxymethyl cellulose, sodium alginate, xantham gum, locust bean gum, chitosan, cross-linked high amylase starch, cross-linked polyacrylic acid (carbopol), and mixtures thereof. Preferably, the polymeric carrier is HR-b- CD.

Typically, when the one or more pharmaceutically acceptable excipients is a pharmaceutically acceptable diluent, the diluent is selected from the group consisting of saccharides (such as monosaccharides, disaccharides, and polysaccharides), sugar alcohols (such as arabinose, lactose, dextrose, sucrose, fructose, maltose, mannitol, erythritol, sorbitol, xylitol, lactitol), powdered cellulose, microcrystalline cellulose, starch, dibasic calcium phosphate, tribasic calcium phosphate, calcium carbonate, dextrose, kaolin, magnesium carbonate, magnesium oxide, purified sugar, and mixtures thereof.

Typically, when the one or more pharmaceutically acceptable excipients is a pharmaceutically acceptable binder, the binder is selected from the group consisting of methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose,

hydroxypropylmethylcellulose (HPMC), carbomers, dextrin, ethyl cellulose, methylcellulose, shellac, zein, gelatin, polymethacrylates, poly(vinyl pyrrolidone) (such as poly(vinyl pyrrolidone) K30 or poly(vinyl pyrrolidone) F90), starch, pregelatinized starch, polyvinyl alcohol, tragacanth, sodium alginate, gums, synthetic resins, silicic acid, hydrophilic polymers, and mixtures thereof. Preferably, the binder is poly(vinyl pyrrolidone), e.g. PVP K30 or PVP F90.

Typically, when the one or more pharmaceutically acceptable excipients is a pharmaceutically acceptable glidant, the glidant is selected from the group consisting of talc, metallic stearates (such as magnesium stearate, calcium stearate, and zinc stearate), colloidal silicon dioxide, finely divided silicon dioxide, stearic acid, hydrogenated vegetable oil, glyceryl palmitostearate, glyceryl monostearate, glyceryl behenate, polyethylene glycols, powdered cellulose, starch, sodium stearyl fumarate, sodium benzoate, mineral oil, magnesium trisilicate, kaolin, and mixtures thereof. It would be appreciated that a person skilled in the art is cognizant of the fact that a glidant may also be referred to as either a lubricant or an anti-tacking agent, and that these terms may be used interchangeably.

Typically, when the one or more pharmaceutically acceptable excipients is a pharmaceutically acceptable release controlling agent, the release controlling agent is present in an outer coating that covers, or substantially covers, the surface of the particles. A coating comprising a release-controlling agent is generally preferred when a slower rate of dissolution of the pharmaceutical formulation within the straw and/or the digestive tract of the subject is desired. In use, without wishing to be bound by any particular theory, a release controlling agent is swollen by, and eventually dissolves, in water. The dissolution rate of the pharmaceutical formulation (and, hence, the API, food supplement or vitamin) may therefore be controlled by the amount and molecular weight of release-controlling agent employed. In general, using a greater amount of release-controlling agent decreases the dissolution rate, as does using a release-controlling agent having a higher molecular weight. The release controlling agent may be a hydrophobic release-controlling agent or a hydrophilic release controlling agent.

An outer coating may be an enteric coating, i.e. a gastro-resistant coating which does not dissolve in aqueous solvent at low pH. An enteric coating is desirably employed when it is desirable for the solid particles in the pharmaceutical formulation to remain intact (i.e. not dissolve or dissolve at only a slow rate) in the stomach of the subject after oral

administration. Thus, the solid particles only dissolve at an appreciable rate once they have passed into the small intestine of the subject. Accordingly, the API in the pharmaceutical formulation is released predominantly in the small intestine in the subject. This may be desirable in certain cases, e.g. when the API decomposes in an acidic environment, or when the API may cause irritation to the stomach of the subject.

The release-controlling agent is typically a polymer. Typically, the release controlling agent is a hydrophobic release-controlling agent. The hydrophobic release controlling agent is typically selected from the group consisting of Ammonio methacrylate copolymers type A and B as described in the United States Pharmocopeia (USP) (also known by their respective trade names Eudragit® RL and Eudragit® RS), methacrylic acid copolymer type A, B and C as described in the USP, Polyacrylate dispersion 30% as described in the European Pharmacopoeia (Ph. Eur.) (also known by its trade name

Eudragit® NE 30D), polyvinyl acetate dispersion, ethylcellulose, cellulose acetate, cellulose propionate (lower, medium or higher molecular weight), cellulose acetate propionate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose triacetate, poly(methyl methacrylate), poly(ethyl methacrylate), poly(butyl methacrylate), poly(isobutyl

methacrylate), and poly (hexyl methacrylate). poly(isodecyl methacrylate), poly (lauryl methacrylate), poly(phenyl methacrylate), poly (methyl acrylate), poly (isopropyl acrylate), poly (isobutyl acrylate), poly (octadecyl acrylate), waxes (such as beeswax, carnauba wax, microcrystalline wax, and ozokerite), fatty alcohols (such as ceto stearyl alcohol, stearyl alcohol; cetyl alcohol and myristyl alcohol), fatty acid esters (such as glyceryl monostearate), glycerol monooleate, acetylated monoglycerides, tristearin, tripalmitin, cetyl esters wax, glyceryl palmitostearate, glyceryl behenate, hydrogenated castor oil, ethyl cellulose,

Kollicoat SR 30 D, Eudragit® S, and mixtures thereof.

Preferred examples of hydrophobic release controlling agents are ethyl cellulose, cellulose acetate, Eudragit® RS, hydrogenated castor oil, Eudragit® S, and glyceryl behenate. Other preferred hydrophobic release controlling agents comprise ammonio methacrylate co-polymers and fatty acid esters as hereinafter described. Eudragit® polymers are polymeric lacquer substances based on acrylate and/or methacrylates.

Alternatively, the release-controlling agent is a hydrophilic release-controlling agent. The hydrophilic release-controlling agent is typically selected from the group consisting of hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), poly(ethylene oxide), poly(vinyl alcohol), poly(vinyl pyrrolidone), xanthan gum, carbomer, carrageenan, carboxymethyl cellulose, sodium alginate, vinyl acetate copolymers, starch, starch-based polymers, polysaccharides, and mixtures thereof. A preferred hydrophilic release-controlling agent is HPMC. Other similar hydrophilic release-controlling agents may also be employed.

Typically, when the one or more pharmaceutically acceptable excipients is a pharmaceutically acceptable disintegrant, the disintegrant is selected from the group consisting of croscarmellose sodium, crospovidone, sodium starch glycolate, com starch, potato starch, maize starch and modified starches (such as pregelatinized starch), calcium silicates, low-substituted hydroxypropylcellulose, and mixtures thereof.

Typically, therefore, the pharmaceutical formulation according to the present invention comprises from 0.0001% to 99.9% by weight of the API and from 0.05% to 99.9% by weight of the one or more pharmaceutically acceptable excipients selected from carriers, diluents, binders, glidants, release controlling agents and disintegrants. Preferably, the pharmaceutical formulation comprises from 0.001% to 95% by weight of the API and from 1% to 99% by weight of the one or more pharmaceutically acceptable excipients selected from carriers, diluents, binders, glidants, release controlling agents and disintegrants. More preferably, the pharmaceutical formulation comprises from 0.5% to 75% by weight of the API and from 5% to 95% by weight of the one or more pharmaceutically acceptable excipients selected from carriers, diluents, binders, glidants, release controlling agents and disintegrants. Most preferably, the pharmaceutical formulation comprises from 2% to 50% by weight of the API and from 10% to 90% by weight of one or more pharmaceutically acceptable excipients selected from carriers, diluents, binders, glidants, release controlling agents and disintegrants.

In addition to the aforementioned excipients, the pharmaceutical formulations according to the invention may further comprise one or more additional excipients.

Typically, said additional excipients may be selected from the group consisting of pharmaceutically acceptable surfactants, acids, fast-dissolving small molecules, taste- masking agents, flavouring agents, sweeteners, colorants, pore-forming agents, plasticizers, preservatives, or combinations thereof.

Thus, a formulation of the present invention may optionally further comprise a surfactant. Without wishing to be bound by any particular theory, it is believed that the presence of a surfactant in the formulation may be beneficial in some circumstances, as the surfactant acts as a flocculating agent. This advantageously enables the formulation to form larger, more flocculent particles having weak links between one another, which may prevent fast sedimentation, and may also prevent caking. Thus, when the formulation is used in a drinking straw, a smaller volume of liquid needs to be drawn through the straw by the user in order to administer the entire formulation to the user. It is also believed that polymeric binding compounds, such as the“binders” referred to herein, may also act as flocculating agents.

Thus, typically, a formulation of the present invention comprises a surfactant. If a surfactant is present, the pharmaceutical formulation typically comprises from 0.05% to 75% by weight of surfactant, preferably from 0.1% to 60% by weight of surfactant, more preferably from 0.2% to 50% by weight of surfactant, yet more preferably from 0.5% to 40% by weight of surfactant, still more preferably from 0.5% to 20% by weight of surfactant, and most preferably from 0.5% to 10% by weight of surfactant. The surfactant, if present, may be dispersed uniformly, or substantially uniformly, throughout the solid particles of the formulation, i.e. the formulation comprises an intragranular surfactant. Alternatively, the surfactant, if present, may coat the surface of the solid particles of the formulation, i.e. the formulation comprises an extragranular surfactant.

Typically, the surfactant is selected from the groups consisting of a cationic surfactant, an anionic surfactant, a non-ionic surfactant, a zwitterionic surfactant, or mixtures thereof.

Suitable cationic surfactants are typically selected from the group consisting of quaternary ammonium compounds (such as benzalkonium chloride, cetyl trimethyl ammonium bromide and dodecyl dimethyl ammonium bromide), hexadecyl (cetyl) trimethylammonium bromide, dodecyl pyridinium chloride, lauryl dimethyl benzyl ammonium chloride, acyl carnitine hydrochlorides, alkyl pyridinium halides, dodecylamine hydrochloride, and mixtures thereof.

Suitable anionic surfactants are typically selected from the group consisting of salts of aliphatic monoesters of sulfuric acid and soaps (such as potassium laurate, sodium dodecyl sulfate, alkyl polyoxyethylene sulfates, sodium alginates, sodium lauryl sulfate and sodium heptadecyl sulfate), sulfonated aromatic agents (such as alkyl benzene sulfonic acids and salts thereof, such as tridecylbenzene sulfonic acid and the sodium and amino salts of

dodecylbenzene sulfonic acid), alkyl naphthalene sulfonates (such as sodium

butylnaphthalene sulfonate), sulfosuccinates (such as sodium dioctyl sulfosuccinate and N- acyl-/V-alkyl fatty acid taurates), sulfated polyoxyethylated alcohols, sulfated oils, dioctyl sodium sulfosuccinate, phosphatidyl choline, phosphatidyl glycerol, phosphatidyl inosine, phosphatidylserine, phosphatidic acid, glyceryl esters, sodium carboxymethylcellulose, cholic acid and other bile acids (such as cholic acid, deoxycholic acid, glycocholic acid, taurocholic acid, and glycodeoxycholic acid), pharmaceutically acceptable salts thereof, and mixtures thereof.

Suitable non-ionic surfactants are typically selected from the group consisting of polyoxyethylene fatty alcohol ethers (such as Macrogol and Brij), polyoxyethylene sorbitan fatty acid esters (polysorbates), polyoxyethylene fatty acid esters (such as Myrj), sorbitan esters (such as Span), glycerol monostearate, polyethylene glycols, polypropylene glycols, cetyl alcohol, cetostearyl alcohol, stearyl alcohol, aryl alkyl polyether alcohols,

polyoxyethylene-polyoxypropylene copolymers (poloxomers), polaxamines, methylcellulose, hydroxycellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, noncrystalline cellulose, poly(vinyl alcohol), poly(vinyl pyrrolidone), and mixtures thereof. Preferably, the non-ionic surfactant is a copolymer of polyoxyethylene and polyoxypropylene, more preferably a block copolymer of propylene glycol and ethylene glycol. Such polymers are sold under the tradename Poloxamer also sometimes referred to as Pluronic. Alternatively, the non-ionic surfactant is poly(vinyl pyrrolidone).

Suitable zwitterionic surfactants are typically selected from the group consisting of alkyl betaines, alkyl amidopropyl betaines, alkyl sulfobetaines, alkyl glycinates, alkyl carboxyglycinates, alkyl amphopropionates, alkyl amidopropyl hydroxysultaines, acyl taurates and acyl glutamates wherein the alkyl and acyl groups have from 8 to 18 carbon atoms such as cocamidopropyl betaine, sodium cocoamphoacetate, cocamidopropyl hydroxysultaine, sodium cocamphopropionate, and mixtures thereof.

Preferably, the surfactant is sodium dodecyl sulfate.

Typically, therefore, the pharmaceutical formulation according to the present invention comprises from 0.0001% to 99.9% by weight of the API, from 0.05% to 99.9% by weight of the one or more pharmaceutically acceptable excipients selected from carriers, diluents, binders, glidants, release controlling agents and disintegrants, and from 0.05% to 75% by weight of surfactant. Preferably, the pharmaceutical formulation comprises from 0.001% to 95% by weight of the API, from 1% to 99% by weight of the one or more pharmaceutically acceptable excipients selected from carriers, diluents, binders, glidants, release controlling agents and disintegrants, and from 0.1% to 60% by weight of surfactant. More preferably, the pharmaceutical formulation comprises from 0.5% to 75% by weight of the API, from 5% to 95% by weight of the one or more pharmaceutically acceptable excipients selected from carriers, diluents, binders, glidants, release controlling agents and disintegrants, and from 0.2% to 50% by weight of surfactant. Most preferably, the pharmaceutical formulation comprises from 2% to 50% by weight of the API, from 10% to 90% by weight the one or more pharmaceutically acceptable excipients selected from carriers, diluents, binders, glidants, release controlling agents and disintegrants, and from 0.5% to 40% by weight of surfactant.

In a particularly preferred embodiment, the pharmaceutical formulation according to the present invention comprises a binder and a surfactant. Even more preferably, the pharmaceutical formulation according to the invention comprises a binder which is poly(vinyl pyrrolidone) and a surfactant which is sodium dodecyl sulfate.

A formulation of the present invention may optionally further comprise an electrolyte. Without wishing to be bound by any particular theory, it is believed that such electrolytes may also act as flocculating agents. Examples of typical electrolytes include the sodium salts of acetates, phosphates and citrates, and mixtures thereof. Typically, the formulation may comprise from 0.05% to 75% by weight of each electrolyte, preferably from 0.1% to 60% by weight, more preferably from 0.2% to 50% by weight, and most preferably from 0.5% to 40% by weight.

A formulation of the present invention may optionally further comprise a

pharmaceutically acceptable acid. Typically, the acid is selected from the group consisting of l-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2- oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, L- ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, boric acid, (+)-camphoric acid, (+)-camphor-l0-sulfonic acid, capric acid (decanoic acid), caproic acid (hexanoic acid), caprylic acid (octanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dehydro acetic acid, dodecylsulfuric acid, edetic acid, ethane- l,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, D-glucoheptonic acid, D-gluconic acid, D-glucuronic acid, glutamic acid, glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, isobutyric acid, isostearic acid, DL-lactic acid, lactobionic acid, lauric acid, maleic acid, L-malic acid, malonic acid, DL-mandelic acid, methanesulfonic acid, naphthalene- l,5-disulfonic acid, naphthalene-2- sulfonic acid, nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, proprionic acid, (-)-L-pyroglutamic acid, salicylic acid, sebacic acid, sorbic acid, stearic acid, succinic acid, sulfuric acid, (-i-)-L-tartaric acid, thiocyanic acid, para-toluenesulfonic acid, undecylenic acid, and mixtures thereof. Preferably, the acid is citric acid. Typically, the formulation may comprise from 0.0001% to 20% by weight of each acid, preferably from 0.001% to 10% by weight, and more preferably from 0.01% to 5% by weight.

A formulation of the present invention may optionally further comprise a

pharmaceutically acceptable small molecule that is fast-dissolving in water. Typically, the small molecule is a compound wherein greater than 75% by weight of the compound, preferably greater than 85% by weight of the compound, more preferably greater than 90% by weight of the compound, even more preferably greater than 95% by weight of the compound, and most preferably greater than 98% by weight of the compound dissolves within a period of 15 minutes when 1 gram of the compound is added to 100 mL of water under stirring at 25 °C. Typically, the formulation may comprise from 0.0001% to 20% by weight of each fast-dissolving small molecule, preferably from 0.001% to 10% by weight, and more preferably from 0.01% to 5% by weight.

The formulation may additionally comprise a taste-masking agent, flavouring agent or sweetener. Examples of suitable taste-masking agents or flavouring agents comprise, e.g., cinnamon, wintergreen, eucalyptus, spearmint, peppermint, menthol, anise, fruit flavors (such as apple, pear, peach, strawberry, cherry, apricot, orange, watermelon, banana and the like), bean-derived flavors (such as coffee, cocoa and the like), or mixtures thereof. Examples of suitable sweeteners include, but are not limited to, saccharides (such as sucrose, dextrose, glucose, maltose, dextrins, D-tagatose, trehalose, dried invert sugar, fructose, levulose, galactose, corn syrup solids and the like), sodium saccharin, aspartame, sugarless sweeteners including polyhydric alcohols (such as sorbitol, mannitol, xylitol, glycerol, hydrogenated starch hydrolysates, maltitol, isomaltitol, erythritol, lactitol and the like), or mixtures thereof. Typically, the formulation may comprise from 0.0001% to 20% by weight of each taste- masking agent, flavouring agent or sweetener, preferably from 0.001% to 10% by weight, and more preferably from 0.01% to 5% by weight.

The formulation may additionally comprise a colorant. The colorants are used in amounts effective to produce a desired colour. Examples of colorants include, but are not limited to, titanium dioxide, colours of natural foods and edible dyes. Typically, the formulation may comprise from 0.0001% to 20% by weight of each colorant, flavouring agent or sweetener, preferably from 0.001% to 10% by weight, and more preferably from 0.01% to 5% by weight.

The formulation may additionally comprise a pore-forming agent. Examples of suitable pore-forming agents include, but are not limited to, water-soluble compounds and hydrophilic polymers. Typical water-soluble compounds may include alkali metal salts (such as sodium chloride, sodium bromide, and the like), alkaline earth metals (such as calcium phosphate, calcium nitrate and the like), transition metal salts (such as ferric chloride, ferrous sulfate and the like), polyglycols, ethyl vinyl alcohols, glycerin, pentaerythritol, polyvinyl alcohols, vinylpyrrolidone, /V-methyl pyrrolidone, saccharides, hydrolyzed starch, pregelatinized starch, carbohydrates (such as glyceraldehydes, erythrose, ribose, arabinose, xylose, glucose, mannose, galactose, maltose, lactose, sucrose and the like), sugar alcohols (such as mannitol and the like), and mixtures thereof. Typical hydrophilic polymers may include hydroxypropylcellulose, hydroxypropylmethylcellulose (HPMC), poly(vinyl pyrrolidone) (PVP), and mixtures thereof. Typically, the formulation may comprise from 0.001% to 20% by weight of each pore-forming agent, preferably from 0.01% to 15% by weight, and more preferably from 0.1% to 10% by weight.

The formulation may additionally comprise a plasticizer. A“plasticizer”, as defined herein, is a material that improves the processing of the release-controlling agents. Examples of suitable plasticizers include, but are not limited to, adipates, azelates, benzoates, citrates, isoebucaes, phthalates, sebacates, stearates, tartrates, polyhydric alcohols, glycols, and the like. Preferred plasticisers include acetylated monoglycerides, butyl phthalyl butyl gylcolate, dibutyl tartrate, diethyl phthalate, dimethyl phthalate, ethyl phthalyl ethyl glycolate, glycerin, ethylene glycol, propylene glycol, triethyl citrate, triacetin, acetylated triacetin, tripropinoin, diacetin, dibutyl phthalate, acetyl monoglyceride, polyethylene glycols, tributyl citrate, castor oil, polyhydric alcohols, acetate esters, glycerol triacetate, acetyl triethyl citrate, dibenzyl phthalate, dihexyl phthalate, butyl octyl phthalate, diisononyl phthalate, butyl octyl phthalate, dioctyl azelate, epoxidised tallate, triisoctyl trimellitate, diethylhexyl phthalate, di-n-octyl phthalate, di-i-octyl phthalate, di-i-decyl phthalate, di-n-undecyl phthalate, di-n-tridecyl phthalate, tri-2-ethylexyl trimellitate, di-2-ethylexyl adipate, di-2-ethylhexyl sebacate, di-2- ethylhexyl azelate, di-n-butyl sebacate, glyceryl monocaprylate, glycerol tributyrate, glycerol distearate, glyceryl monocaprate, natural, semi-synthetic and synthetic glycerides, monoglyceride, acetylated monoglycerides, fractionated coconut oil, rape oil, olive oil, sesame oil, castor oil, hydrogenated castor oil, acetyltributylcitrate, acetyltriethylcitrate, glycerin sorbitol, diethyl oxalate, diethyl malate, diethyl fumarate, dibutyl succinate, diethyl malonate, dioctyl phthalate, and mixtures thereof. Typically, the formulation may comprise from 0.01% to 60% by weight of each plasticizer, preferably from 0.1% to 55% by weight, and more preferably from 1% to 50% by weight.

The formulation may additionally comprise any suitable preservative. A

“preservative”, as defined herein, may refer to: (i) a chelating agent; (ii) an antioxidant; or (iii) an antimicrobial agent. Typically, the preservative may be any suitable chelating agent. A“chelating agent”, as defined herein, refers to a chemical compound that is a multidentate ligand that is capable of forming two or more separate bonds to a single central atom, typically a metal ion.

Examples of suitable chelating agents include, but are not limited to:

ethylenediaminetetraacetic acid (EDTA), ethylene glycol-bis(P-ami noethyl ether)-/V,/V,/V',/V'- tetraacetic acid (EGTA), 1 ,2-bis(ortho-aminophenoxy)ethane-/V,/V,/V',/V'-tetraacetic acid (BAPTA), citric acid, phosphonic acid, glutamic acid, histidine, malate, and derivatives thereof. The formulation may comprise from 0.001% to 4% by weight of each chelating agent present. Preferably, the formulation may comprise from 0.001% to 0.1% by weight of each chelating agent present.

Alternatively, the preservative may be any suitable antioxidant. An“antioxidant”, as defined herein, is any compound that inhibits the oxidation of other chemical species.

Examples of suitable antioxidants include, but are not limited to: ascorbic acid; citric acid; sodium bisulfite; sodium metabisulfite; and butyl hydroxitoluene. The formulation may comprise from 0.001% to 4% by weight of each antioxidant present. Preferably, the formulation may comprise from 0.001% to 0.1% by weight of each antioxidant present.

Alternatively, the preservative may be any suitable antimicrobial agent. An “antimicrobial agent”, as defined herein, is any compound that kills microorganisms or prevents their growth. Examples of suitable antimicrobial agents include, but are not limited to: benzyl alcohol; benzalkonium chloride; benzoic acid; methyl-, ethyl- or propyl- paraben; and quarternary ammonium compounds. The formulation may comprise from 0.001% to 4% by weight of each antimicrobial agent present. Preferably, the formulation may comprise from 0.001% to 0.1% by weight of each antimicrobial agent present.

As can be determined from the above, the skilled person will readily appreciate that a single chemical entity could be added to formulations of the present invention to achieve different technical functions. For example, poly( vinyl pyrrolidone) may be added to the formulations to act as a carrier, a binder, a release controlling agent, a surfactant, or a pore forming agent, or to act in two or more of these capacities.

In a second aspect, the present invention is concerned with a pharmaceutical formulation suitable for use in a straw suitable for oral administration of said pharmaceutical formulation, wherein the pharmaceutical formulation is a granular formulation which comprises (i) a core phase comprising an active pharmaceutical ingredient (API), food supplement or vitamin, and (ii) a matrix phase comprising one or more pharmaceutically acceptable fast-dissolving excipients, wherein the core phase is dispersed within the matrix phase, and wherein the matrix phase dissolves more rapidly than the core phase in water at 25°C.

In this aspect, typically the pharmaceutical formulation comprises one or more pharmaceutically acceptable excipients selected from pharmaceutically acceptable carriers, diluents, binders, glidants, release controlling agents and disintegrants. Preferably, the pharmaceutical formulation is a solid in which at least 90% of the particles by number have a diameter of greater than 500 pm and in which at least 90% of the particles by number have a diameter of less than 2000 pm. More preferably, the pharmaceutical formulation is a solid in which at least 90% of the particles by number have a diameter of greater than 700 pm and in which at least 90% of the particles by number have a diameter of less than 2000 pm.

Further typical and preferable features of the second aspect of the invention are as for the first aspect of the invention. For example, the disclosure from page 10, line 21 to page 32, line 4 applies equally to the second aspect of the invention as to the first aspect of the invention. In these preferred embodiments, references to“particles” (e.g. particle size distributions) can be taken as references to the specific“granules” of the second aspect.

Manufacture of the pharmaceutical formulations

Single-phase (i.e. particulate) pharmaceutical formulations according to the invention may typically be prepared using a dry sieving method. Thus, a collection of solid particles of varying sizes may be formed by any method well-known to the skilled artisan (e.g. grinding or milling), and the collection of solid particles is subsequently subjected to a dry sieving process using mechanical agitation in order to obtain the required particle size distribution. A typical dry sieving method is described in detail in the US Pharmacopeia at

htp://www.pharmacopeia.cii/v29240/usp29nf24s0 c786.html, the contents of which are herein incorporated by reference in their entirety. The ISO nominal aperture sieve sizes used for preparation of the pharmaceutical formulations of the present invention are 500 pm,

710 pm, 1.00 mm, 1.40 mm and 2.00 mm. Typically, when a sieve of a particular size is used, at least 90% of the particles by number which pass through the sieve have a diameter of less than the sieve pore size, preferably at least 95% of the particles by number, and most preferably at least 98% of the particles by number. High sieve loading can however decrease the efficiency of the sieving process. Particle size may be measured by any suitable technique known to the skilled person, such as the methods described in WO 2009/135646 or Marks and Sciarra, Journal of Pharmaceutical Sciences , 1968, 57(3), 497-504. Such techniques may include mechanical sieving methods, laser light diffraction and/or scanning electron microscopy.

The two-phase granulate formulations of the present invention are prepared via a novel granulation method which involves the following steps:

(a) providing particles comprising an API, food supplement or vitamin;

(b) coating said particles with a taste-masking agent, physical barrier coating and/or an enteric coating;

(c) optionally, repeating step (b) one or more times to provide particles having multiple coating layers; and

(d) granulating said particles in the presence of one or more fast-dissolving

excipients.

The particles comprising an API, food supplement or vitamin may be obtained via a dry sieving method as described herein. Alternatively, these particles may be crystals formed via any standard crystallization technique known to a person skilled in the art. Typically in this case, the crystals have a diameter of 200 pm or greater. Alternatively, these particles may be obtained via an agglomeration of micronized API, food supplement or vitamin using a wet or dry granulation technique (see“Handbook of Granulation Technology”, Dilip M. Parikh, 2005, for a description of granulation techniques well-known to a person of skill in the art, the contens of which are incorporated herein by reference in their entirety). Typically in this case, the agglomerate has a particle size of from 200 to 710 pm. This latter method is particularly useful when the API, food supplement or vitamin has a low water solubility.

These particles are subsequently coated. Conventional coating techniques such as fluid bed or Wurster coaters, or spray or pan coating are employed to apply coatings.

Agglomerates of larger size can more effectively be coated in a fluid bed coater machine (FBD). The coating thickness must be sufficient to ensure that the oral dosage form remains intact until the desired site of delivery in the intestinal tract is reached. Typically, the particles are coated with a single coating layer, selected from a taste-masking agent, physical barrier coating and/or an enteric coating. Alternatively, however, the coating step is repeated once, twice, three times or more, to produce particles having multiple coating layers. Each coating layer may be the same or different. Preferably, two adjacent coating layers are different to one another. Most preferably, each coating layer is different to one another.

The optionally coated particles (core phase) are then granulated in the presence of one or more fast-dissolving excipients, i.e. hydrophilic substances, to form the two-phase granules. Taste-masking agents and sweeteners may also optionally be added as excipients in the granulating step.

Unlike conventional granulation methods therefore, in the method of the present invention, the particles constituting the core phase are coated prior to the final granulation step. This reversal of method steps from the granulation methods commonly applied in the art is responsible for generating the particularly beneficial two-phase granulate structure in preferred pharmaceutical formulations of the present invention.

Uses of the pharmaceutical formulations in treatment

In general, formulations of the present invention are administered to a human patient so as to deliver to the patient a therapeutically effective amount of the active pharmaceutical ingredient (API). The formulations are administered orally.

Thus, the present invention further relates to a pharmaceutical formulation as described herein for use in the treatment of a condition in a subject in need thereof, wherein the pharmaceutical formulation comprises an API, and said treatment comprises oral administration of the pharmaceutical formulation using a straw, wherein the straw contains the pharmaceutical formulation.

In another aspect, the present invention also provides a method of treating a condition in a subject in need thereof, said method comprising oral administration of a pharmaceutical formulation as described herein using a straw, wherein the pharmaceutical formulation comprises an API, and the straw contains the pharmaceutical formulation.

In another aspect, the present invention also provides the use of a pharmaceutical formulation as described herein for the manufacture of a medicament for the treatment of a condition in a subject in need thereof, wherein the pharmaceutical formulation comprises an API, and said treatment comprises oral administration of the pharmaceutical formulation using a straw, wherein the straw contains the pharmaceutical formulation.

Typically, in the aspects described above, the oral administration is effected by the steps of: (i) insertion of one end of said straw in an aqueous solvent and insertion of the other end of said straw in the oral cavity of the subject; and (ii) the application of suction by the subject to the end of the straw situated in the oral cavity.

Typically, oral administration of at least 90% of the formulation is achieved when a volume of 100 mL or less of aqueous solvent, preferably 50 mL or less, more preferably 40 mL or less, even more preferably 30 mL or less, and most preferably 20 mL or less, is passed through the straw. Preferably, oral administration of at least 95% of the formulation is achieved when a volume of 100 mL or less of aqueous solvent, preferably 50 mL or less, more preferably 40 mL or less, even more preferably 30 mL or less, and most preferably 20 mL or less, is passed through the straw. More preferably, oral administration of at least 98% of the formulation is achieved when a volume of 100 mL or less of aqueous solvent, preferably 50 mL or less, more preferably 40 mL or less, even more preferably 30 mL or less, and most preferably 20 mL or less, is passed through the straw. Most preferably, oral administration of at least 99% of the formulation is achieved when a volume of 100 mL or less of aqueous solvent, preferably 50 mL or less, more preferably 40 mL or less, even more preferably 30 mL or less, and most preferably 20 mL or less, is passed through the straw.

Devices of the present invention comprising the formulation

The present invention further relates to a device suitable for oral administration of a pharmaceutical formulation as described above, wherein the device is configured to allow the pharmaceutical formulation to be flushed from the straw by a volume of aqueous solvent which is 30 mL or less during oral administration and to thereby deliver the aqueous solution in which the pharmaceutical formulation is flushed into the oral cavity of a subject.

Typically, the device is configured to allow suction applied by the subject to (a) bring the aqueous solvent into contact with the pharmaceutical formulation, and (b) deliver the pharmaceutical formulation into the oral cavity.

Suitable devices may include straw and lidded beakers, e.g. child drinking beakers or so-called“sippy” cups. Preferably, the device is a straw. Thus, the present invention further relates to a straw suitable for oral administration of a pharmaceutical formulation as described above, wherein the straw contains the pharmaceutical formulation as described above. Any straw suitable for this purpose falls within the scope of the present invention. Such a straw containing said pharmaceutical formulation is referred to herein as a“pre-filled” straw. A particularly preferred type of pre-filled straw suitable for oral administration of the pharmaceutical formulation is described in more detail below, with reference to Figs. 1 to 8.

The parts of a preferred pre-filled straw according to the invention are depicted in Fig. 1 and are a main straw body 1 in tubular form, which may be round or oblong shape and two cross slit valves 2, 3. The main straw body includes at least two straw segments, each having a straw body and a respective valve at one end. Valve 2 is positioned on the liquid inlet and valve 3 on the outlet of the straw. The valves 2, 3 are positioned in the way to allow only one-way flow through the body straw, as presented by arrow 4 in Fig. 1. The valves 2, 3 are initially in a closed position, but when suction in the direction of the arrow 4 is applied, both of them are opened and allow the liquid to enter the straw. When suction is stopped, both valves 2, 3 return to a closed position.

Straws consisting of two or even more than two segments are envisaged by the present invention. In the arrangement shown in Fig. 2, the straw has two straw segments, each with a respective valve 2, 3 at one end of the segment. The two straw segments are directly coupled to each other. In other arrangements, the two straw segments having a valve at one end may be coupled to each other indirectly, for example by way of one or more additional straw segments.

The segments are coupled together with a coupling 5. Such couplings may be formed from two elements formed, each formed at an end of a respective straw segment.

The elements on each segment are configured such that the element on one straw segment can engage with the element on another straw segment to couple the straw segments together. In such a way the straw segments can be coupled together after the straw segments have been formed. This is in contrast with the valves, which may be integrally formed as part of the straw segment.

Several types of coupling are depicted in Fig. 2 that may be used to couple the straw segments. Straw segments may, for example, be attached one to another by a friction fit connection, i.e. one part is slightly narrower than the other, a snap-fit connection, a press-fit connection, a weld, a section of adhesive or another suitable coupling. A snap-fit connection may be an annular snap joint, or capsule like closing system, in which one straw segment has a U-shaped annular groove around the cross-section of the straw segment that, when the straw segments are coupled, receives corresponding protrusion on the other straw segment. The thickness of the wall of the straw segment may be increased in the region of the coupling. This may increase the strength, reduce the risk of cracking and/or make it easier to mould the elements of the coupling.

Once the coupling has been completed, it may be configured to be not possible to detach the straw segments without damage. Alternatively the coupling may be configured to be detachable, permitting a user to open the straw to pour and/or wash out the contents.

In an arrangement the coupling between the straw segments may provide a gas tight, or hermetic, seal. This may ensure that, when a user sucks on one end of the straw, pressure is sufficiently reduced within the straw to draw liquid into the other end of the straw.

Depending on the coupling used, an O-ring may be provided in order to ensure a good seal between the straw segments.

As depicted in Fig. 1, first and second straw segments coupled together to form a pre-filled straw may have the same length. Alternatively, the two straw segments may have different lengths. For example, it may be desirable for one segment to be longer than the other. This may be beneficial if a pharmaceutical formulation according to the present invention as described above is to be placed in only one of the straw segments prior to coupling the two straw segments together because this may permit a greater amount of formulation to be placed within the pre-filled straw for a given total length of pre-filled straw. However, longer straw segments are more difficult to form due to cooling of the mould during straw formation. Accordingly, the length of a straw segment containing the formulation during preparation of the pre-filled straw need to be smaller than the length of the overall pre-filled straw.

In general, the choice of total length of pre-filled straw may be a compromise. It may be selected to be long enough to be convenient for a user to ensure that it reaches liquid in the bottom of a cup. However, the longer the straw, the harder the user must suck to draw up liquid into their mouth. Furthermore, longer straws cost more to manufacture and take up more space in storage and transit.

In Fig. 3 possible arrangements of slits in the cross-slit valves are presented. The slit valves per se are known. Valves are moulded and may be made of elastomer material. Slits can be cut in a shape of a cross, of a line, of a three-pointed star, of a six-pointed star or any other appropriate form. The cross-slit valves can differ in shapes, as presented in the figure with the concave round shape, duck-bill shape and similar. An inlet valve 2 according to the present disclosure is presented in Figs. 4, 5. As shown it may be integrally formed, for example connected and melded, or co-moulded, to the lower end of the straw body 1. Straw body 1 may be made of thermoplastic and the valve 2 with a membrane 7 that may be made of an elastomer, such as a thermoplastic elastomer. Other materials that can be co-moulded to the straw body. The membrane 7 of the inlet valve is bent towards the inside of the straw body 1, i.e. the membrane 7 is concave.

In an arrangement, the material used to form the straw body may be transparent or translucent. In use, this may enable the user to confirm that all of the formulation within the straw has been consumed.

In an arrangement, one or both of the inlet valve 2 and the outlet valve 3 may be formed in a distinctive colour. If both the inlet valve 2 and the outlet valve 3 are coloured they may have different distinctive colours. Arrangements with one or more valve having a distinctive colour may assist in indicating to users the correct orientation of the pre-filled straw in use. For example, user instructions may include a pictogram that uses the one or more coloured valves to clearly indicate the end to be inserted in the mouth and the end to be inserted in a liquid.

Alternatively or additionally, markings may be provided on the straw body to indicate correct orientation of the straw for use and/or the direction of liquid flow in use. Such markings may be applied to the straw body by any appropriate means, including printing on the straw body, application of stickers and the inclusion of surface patterns within the mould design.

The edge of the straw body 1 may be shaped to enable larger surface of the connection between the straw body 1 and the inlet valve 2. The said shape is preferably a recess, such as an indent or groove 8, formed inside the edge of the wall of the straw body 1. To enable the injection of the thermoplastic into the valve-shaped mould, a tongue-shaped groove 9 may be formed on the surface side on the end of the straw body 1. Said groove 9 enables that the injected thermoplastic flows from the injection unit to fill in the valve 2 mould.

An outlet valve 3 is presented in Fig. 6 and may have generally the same structure as the inlet valve 2. The outlet valve 3 is bent towards the outside of the straw body 6, i.e. the membrane 10 is convex. The inlet and outlet valves 2, 3 with the membranes 7, 10 may be injection-moulded directly onto respective straw segments of the main straw body 1. As discussed above, the straw body may have a groove 8. During the injection moulding process, when the elastomer is injected onto the straw body 1, a junction between both materials, i.e. the thermoplastic of the straw body 1 and the elastomer of valves 2, 3, is formed by the adhesive molecular forces. The provision of the groove may increase the area of this contact.

Figs. 7 and 8 depict a two component, i.e. thermoplastic and elastomer, injection moulding process. The process is performed by injecting the first component, preferably polymer, into the mould 12. In the first step the first component is injected thorough the injection nozzle 14 into the channel 15. Then the first component flows through the gate 16 to the appropriate cavity 13 in the shape of straw body segment 1. The flow enters the mould 12 through the gate 16 into the groove 9. In this cavity 13 the straw body 1 is formed. After this process is completed, the mould 12 changes the configuration in order to initiate the second step of the process.

Before the polymer is cooled-off or is hardened, the tooling configuration is changed, i.e. the mould 12 rotates and changes the configuration in order to initiate the second step of the process. Then follows the injection of the second material, preferably elastomer into the cavity and thus cross slit valve is moulded onto the straw body. In this way the valves and straw are attached by molecular adhesion. This approach allows the production cycle time to be shortened.

In the second step as presented in Fig. 8 the already formed straw body 1 comes in contact with the second cavity 20. The second cavity 20 is in the shape of the valve 2, 3.

The second component, preferably elastomer, is injected form the injection nozzle 21 through the second channel 22 and enters the cavity 20 through the gate 23. After cooling the finished piece is ejected from the mould 12.

In an arrangement, the straw bodies may be formed with a tapered shape. In particular the straw bodies may be arranged such that the cross-sectional area of the opening within the straw is smaller at the end having the cross-slit valve than its other end, namely the end that may be coupled to another straw segment. The latter end may be generally open, in contrast to the end that is closed by the cross-slit valve. Such an arrangement may facilitate the removal of the straw segment from the mould once formation of the straw segment is completed. In an arrangement one or both of the straw segments having cross- slit valves integrally formed at one end may have a frusto-conical shape.

With the said moulding process several straw sections are produced which later are to be coupled together to form a straw, as described above.

In particular, the pre-filled straw may be prepared by placing a formulation according to the present invention to be orally administered within a first straw segment that has an integrally formed cross-slit valve such as discussed above. Next, a second straw segment that has an integrally formed cross-slit valve may be coupled to the first straw segment. Such a process may be easier than previously known processes for preparing a pre-filled straw because it may preclude the need to attach a valve to a straw that contains a formulation according to the present invention to be orally administered. This may reduce spillage of the formulation during the process and/or reduce costs.

In an arrangement, when the formulation is being placed in the first straw segment, the integrally formed valve of the first segment may prevent loss of the formulation from the first straw segment. For example, during the process of placing the formulation within the first straw segment, it may be held with the integrally formed valve below the other end such that, to the extent that the formulation flows, it flows towards the integrally formed valve, which prevents the formulation leaving the straw segment. Once the second straw segment has been coupled to the first straw segment, the formulation may prevented from leaving the straw in either direction (when the straw is not in use) by the integrally formed valves at either end of the pre-filled straw.

It should be appreciated that other arrangements for filling the straw may be possible. For example, the formulation could be placed in two straw segments with integrally formed valves before the two straw segments are coupled. This may require steps to prevent the formulation falling out of one or both straw segments during coupling.

In any case, it should be appreciated that, although in preparation of the pre-filled straw the pharmaceutical formulation according to the invention and as described herein may be placed initially in one straw segment, once the pre-filled straw has been prepared, the pharmaceutical formulation may partially or completely transfer to another straw segment before use.

In an arrangement, after the formulation has been placed in the straw and the straw segments coupled together, packaging may be added. The packaging may be an enclosure that completely surrounds one or more pre-filled straws and/or may cover one or both of the integrally formed cross-slit valves. Such packaging may prevent accidental leakage of the formulation from the pre-filled straw before use. The packaging may be child-proof packaging. The packaging may also include instructions on how to use a straw according to the present invention.

According to the arrangements disclosed above in this preferred embodiment, a very good prevention against the loss of the straw content is obtained, since both of the cross-slit valves are closed in the time of non-use. The loss of the content during suction is also prevented, as the outlet valve inhibits counter pressure applied into the straw, and inlet valve prevents the loss of the liquid from the straw.

Examples

The following are Examples that illustrate the present invention. However, these Examples are in no way intended to limit the scope of the invention.

Comparative Example 1: Observations on use of a drinking straw filled with various granular formulations not comprising an API

In this Example, preferred drinking straws as shown in Fig. 1 and described in detail above, comprising a first straw segment, which contains the pharmaceutical formulation and has an integrally formed cross-slit valve at one end, and a second straw segment, which has an integrally formed cross-slit valve at one end, wherein the ends of the first and second straw segments that do not have integrally formed cross-slit valves are coupled to one another, were employed.

Each straw was pre-filled with c. 1-2 grams of one of the various formulations set out in Table 1 below. The formulations differ from one another in the nature of the excipient, carrier, diluent, binder or disintegrant used, the nature of the surfactant added, and the particle size. The formulations were prepared by a granulation method using a PROCEPT 4M8-TriX Formatrix high shear granulator, operated under the following conditions:

• High shear granulator: PROCEPT 4M8-TriX Formatrix

• Temperature: 23 °C (room temperature)

• Impeller speed: 800 rpm

• Chopper speed: 1500 rpm

• Vessel volume: 1 L

• Binding dispersion flow rate: 2.1 g/min

• Nozzle type: Two-fluid nozzle with 0.8 mm inner diameter

• Drying type: Tray dryer

• Drying duration and temperature: 1 hr 15 mins at 50.0 °C

After granulation, the formulations were subjected to a dry sieving process using mechanical agitation, which is a well-known process to a person skilled in the art (see, e.g., http://www.pharmacopeia.cii/v29240/usp29iif24s0 c786.html), in order to obtain the desired particle size groups. Each straw was then used as follows. The lower end of the straw was placed into a glass containing approximately 100 mL of water. The upper end of the straw was placed into the oral cavity of a human subject, and the subject drank water from the glass by sucking on the upper end of the straw. Drinking continued until all of the formulation in the straw had been fully consumed orally by the subject (determined by the time to complete dissolution of the formulation).

Table 1 below reports the following observations for each of the tested formulations:

1. Whether clogging of the straw (due to cake formation of the formulation) was

observed, under visual inspection.— indicates very high levels of clogging; - indicates high levels of clogging; + indicates low levels of clogging; and ++ indicates very low levels of clogging/no clogging.

2. Whether the flow of liquid through the straw was impeded due to resistance imparted by the formulation, based on how hard the subject had to suck on the upper end of the straw to drink the water. Flow was graded on a four-point scale: “excellent”; a good”;“average”;“poor” and“very poor”.

3. The emptying volume of the straw, i.e. the amount of water (in mL) that the subject had to drink in order to ingest the entire formulation initially present in the straw.

Table 1. Behaviour of different formulations when used in a drinking straw. Letters a-e for each numbered example (Ex.) denote the five different particle size distributions (a = 1400-1120; b = 1120-1000; c = 1000-710; d = 710-500; e = 500-250). The“particle size” indicates that at least 95% of the particles have a size falling within the stated range. SDS = sodium dodecyl sulfate; PVP K30 = poly(vinyl pyrrolidone) K30; cone. = concentration. * denotes that the particles attached to the walls of the straw, and that it was therefore not possible to empty the straw. ^L indicates that there was not enough of this particle fraction to obtain a meaningful test result.

In general, it can be observed that formulations having a particle size of <500 pm tend to exhibit high levels of clogging, and poor or very poor flow of liquid through the straw when in use.

Example 2: Pressure measurements of flow through a drinking straw filled with various granular formulations including an API

Preferred straws as used in Comparative Example 1 above were also used in the present working Example. Each straw was pre-filled with c. 1.5-2 grams of one of the various formulations set out in Table 2 below. The formulations differ from one another in the presence/absence, nature and amount of the API and surfactant added, and the particle size. Cefprozil monohydrate was used as an example API. The formulations were prepared via a granulation and sieving process as described in Example 1 above.

Table 2. Composition of the exemplar formulations. SDS = sodium dodecyl sulfate; PVP K30 = poly (vinyl pyrrolidone) K30; PVP F90 = poly (vinyl pyrrolidone) F90. Each of the samples was produced having two different particle size distributions, 250- 500 pm and 1120-1400 pm.

The straw was then attached to a measurement device comprising a pump, pressure sensor, valve and collection trap, as illustrated in Fig. 9. The straw was attached to the collection trap in vertical direction, so that liquid is pumped upwards. The lower end of the straw was placed into a solution containing 100 mL of water. The whole system is linked with a computer containing software to record and manipulate data. The flow was pre-set at a prescribed uniform rate (e.g. 4 mL/s) by placing a graduated pipette in place of the straw. During the experiment, the liquid (i.e. water) was pumped through the straw into the collection trap. The collection trap is graduated, so that it allows the volume pumped through the straw to be measured. The liquid is pumped upwards as the under-pressure is raised in the system by the pump. The under-pressure is continually measured by the sensor for the duration of the experiment and recorded in the software.

The following data points were measured during the course of the experiment:

• The change in absolute pressure just prior to liquid passing through the top cross- slit valve in the straw (pi);

• The maximum change of absolute pressure in the straw during the experiment (p ₂ ); • The change in absolute pressure when the straw has been entirely emptied of the formulation (p ₃ ); and

• The flush volume (V), i.e. the total volume of liquid required to fully carry the formulation out of the upper end of the straw. A graphical representation of the change in pressure during the course of the experiment is shown in Fig. 10, which also illustrates the points of the experiment at which pi, p ₂ and p ₃ were measured. At the beginning of the experiment, the pressure decreases and at the pressure value of pi, water reaches the top valve of the straw. After that, the pressure continues to fall and at p ₂ the vacuum in the straw reaches its maximum value. Subsequently, as the straw is emptied of the formulation, the vacuum rapidly decreases.

It should be noted that the most significant measured pressure point is the pressure at pl, because this reflects the pressure when the particles reach the top valve of the straw, and the probability of cake formation at this point is greatest.

Tables 3 and 4 below show the recorded values of pi, p ₂ , p ₃ and V for each of the exemplar formulations described in Table 2. The data in Table 3 is illustrated in graphical format in Fig. 11, and the data in Table 4 is illustrated in graphical format in Fig. 12 (for the formulations having a particle size of 250-500 pm) and Fig. 13 (for the formulations having a particle size of 1120-1400 pm).

Table 3. Experimental parameters for each of the tested compositions described in Table 2 above. NT = not tested.

5 Table 4. Values of V and pi for each of the different exemplar formulations described in Table 2 above.

From the above data, the following conclusions may be drawn in respect of the formulations having a smaller particle size (250-500 pm):

• The addition of API has a postive effect on the vacuum required to drink from the straw, with the pressure pi decreasing by c. 30 mbar, without an impact on flush volume (V).

• Addition of SDS (which acts as a surfactant) increases the absolute pressure pi (i.e. resistivity to drinking through the straw) but does not affect the flush volume.

• Addition of both API and SDS increases the pressure pi as for SDS alone, but the flush volume is reduced.

• Use of PVP K30 as a binder does not increase the pressure pi, but use of PVP F90 as a binder does. The pressure pi increases when either PVP K30 or PVP F90 is added in combination with SDS.

• If citric acid is added in a small amount there is little effect on pi and a small decrease in flush volume. If citric acid is added in a larger amount, it can mitigate against the increased pi caused by SDS.

• Pi does not increase when API is added in combination with PVP K30 and SDS.

As for in Comparative Example 1 above, cake formation was observed in all cases where the particle size was small (250-500 pm), but not in any case where the particle size was large (1120-1400 pm). The pressure pi is notably lower when larger particles were used as opposed to the corresponding formulations comprising smaller particles. Conversely, the flush volume increases with particle size.

The following conclusions may be drawn in respect of the formulations having a larger particle size (1120-1400 pm):

• The addition of API in general increases the pressure pi, but reduces the volume of water required to fully administer the formulation to a subject.

• The addition of SDS (which acts as a surfactant) slightly increases the required

drinking pressure but not as much as the addition of API.

• The addition of SDS results in a large reduction inbthe flush volume.

• The addition of SDS in combination with the API mitigates against the increased pi resulting from API addition, and the flush volume is further reduced. • The addition of PVP as a binder generally increases the vacuum necessary for drinking, and the addition of PVP F90 also leads to a slight increase in the flush volume.

• If citric acid is added in a large quantity, this can mitigate against the increased pi caused by SDS; however, the flush volume is increased. If citric acid is added in a smaller amount in combination with SDS and PVP, this results in an increase in the vacuum required to drink the water.

In a further experiment, an additional five granule samples were investigated in five different particle size distributions (250-500 pm, 500-710 pm, 710-1000 pm, 1000-1120 pm, and 1120-1400 pm). These samples were as follows:

(1) Placebo sucrose granulate;

(2) Placebo sucrose granulate with SDS;

(3) Sucrose granulate with cefprozil monohydrate (30 wt%);

(4) Sucrose graunlate with SDS and cefprozil monohydrate (30 wt%); and

(5) Sucrose granulate with SDS, cefprozil monohydrate (30 wt%) and PVP K30.

The effect of (a) the amount of placebo granulates filled in the straw (full or half), (b) the addition of PVP K30 (formulation (4) vs (5)), (c) the addition of cefprozil monohydrate (formulation (1) vs (3)), and (d) the addition of SDS (formulation (1) vs (2)) on the sipping pressure p ₂ and the flush volume V is shown in Figs. l4(a)-(d) and l5(a)-(d) respectively.

As can be seen from Fig. 14(a), the maximum sipping pressure correlates with the straw filling (i.e. the proportion of the straw that is filled with the particle formulation). It is observed that p ₂ is higher when a straw is half-full compared to completely full. Sipping pressures for half straw filling almost do not differ between different particle size

distributions. Smaller particle sizes in a full filled straw, on the other hand, increase the sipping pleasure greatly. For flush volume values, there were no significant differences found due to straw filling. Smaller particles may be uptaken orally using a smaller volume of fluid than the larger particle distributions. In line with the above results, it was also observed that addition of SDS as surfactant greatly reduces flush volume values but slightly increases the sipping pressure.

It was also found that cefprozil (as an example of a water-soluble API) significantly reduces flush volumes compare to placebo granulates. In the case of cefprozil addition, a lower sipping pressure was also obtained for granule particle sizes greater than 710 pm. Example 3: Effect of granulation after coating of particles

The effect of providing the pharmaceutical formulation in the straw as a two-phase granulate comprising (a) a core phase comprising the API and (b) a matrix phase comprising one or more fast-dissolving excipients was investigated.

Fig. 16 illustrates the processes by which the granulates were prepared. Unlike conventional granulation techniques (see Fig. l6a), in the granulation process according to the present invention, particles of API are coated (e.g. with an enteric coating and/or a taste- masking agent) prior to the granulation step. If the API to be used is in micronized form (e.g. the API has low water solubility), a first agglomeration step using either a dry or wet granulation technique is carried out in the presence of one or more excipients to form an API agglomerate, having a particle size of from 250 to 710 pm. These particles are subsequently coated. Agglomerates of larger size can more effectively be coated in a fluid bed coater machine (FBD). The coated particles are subsequently granulated in the presence of one or more fast-dissolving excipients, i.e. hydrophilic substances, to form the two-phase granules (see Fig. l6b). Taste-masking agents and sweeteners were also added as excipients in the granulating step.

If the API to be used is in crystalline form or amorphous form, API crystals or amorphous particles, respectively, of greater than 200 pm in size may be coated directly, and then granulation carried out in the presence of one or more fast-dissolving excipients as above to form the two-phase granules (see Fig. l6c).

Crystals of paracetamol as API were obtained and coated with one of four different coating agents: gelatin; PVA-PEG graft copolymer/PVA polymer; and vinylpyrrolidone-vinyl acetate copolymer. The coated particles are shown in Fig. 17 (left-hand panel).

Subsequently, the coated crystals were granulated in the presence of sucrose as a fast dissolving exicipient, to form two-phase granules comprising 20 wt% coated paracetamol. These granules are shown in Fig. 17 (right-hand panel).

Sipping pressures and flush volumes were measured as in Example 2 above. The particle size distribution, tested mass, pi, p ₂ and p ₃ values from the pressure experiment, and the flush volumes, are set out in Table 5 below for both granulated particles and non- granulated (control) particles. Table 5: Experimental parameters for each of the tested granulated and non- granulated compositions containing paracetamol as the API. NT = not tested. — indicates very high levels of clogging; - indicates high levels of clogging; + indicates low levels of clogging; and ++ indicates very low levels of clogging/no clogging.

It is observed from Table 5 that the larger granulates have a significantly reduced maximum sipping pressure (p ₂ ) value than the corresponding smaller non-granulated particles, require a lower flush volume, and are significantly less likely to form clogs.

Water sorption of the granulated and non-granulated particles was also tested by measurement of mass change in a particle caused by the absorption of water over time. To carry out this experiment, the test particles are placed in a glass cylinder with a water- permeable glass filter at the bottom. The cylinder is slowly lowered with controlled speed into the beaker with purified water that has been previously equilibrated to room temperature. Weight changes due to water uptake are measured when the cylinder touches the water surface. After an initial increase in particle mass, in some cases the mass then begins to decrease, which is the consequence of the particles dissolving in the water. A suitable experimental set-up is shown in Fig. 18.

The water sorption test provides two key parameters: (a) water absorption rate (an increase of weight at the beginning of the test); and (b) rate of particle dissolution after maximum weight was achieved. The water absorption rate is expressed as mass/time ratio at the beginning of the graph which is calculated from the first several measured points using a linear regression method (slope) (parameter ki illustrated on Fig. 19). The mass loss rate is expressed as the value of mass/time ratio and is determined from first several measurements after the maximum mass change is achieved using linear regression (slope) (parameter k ₂ illustrated on Fig. 19).

Water sorption experiments were carried out on each of the paracetamol-containing granulate and non-granulate formulations discussed above. The values of ki and k ₂ for each sample are shown in Table 6 below.

The particle disintegration of the paracetamol-containing formulations was also measured. In this experiment, particles were dispersed in purified water as a solvent, and particle sizes were measured by a laser diffraction technique at pre-defined time intervals using a Malvern mastersizer instrument. Measurements were taken at 30 s, 1 min and 5 min after suspension formation. The results, expressed as dso values, are also shown in Table 6. D50 is the particle diameter at which 50% of the sample mass is comprised of smaller particles.

It is apparent from these data that the granulated particles display (a) an improved water sorption (higher ki values) and (b) a more rapid dissolution/disintegration rate in water (higher k ₂ values and a faster decrease in particle size in the laser diffraction test). In most cases, the absolute mean mass particle size of the granulated particles after 60 s in suspension in water is lower than the absolute mean mass particle size of the non- granulated particles, even though the granulated particles were significantly larger on average at the beginning of the experiment. This effect is unexpected and demonstrates a clear advantage to using granulated particles over non- granulated particles in a clinical setting.

The water sorption curves for two of the granulated particle types (the“20%gelatin” and“20%PVA-PEG graft copolymer/PYA polymer” samples) and their corresponding non- granulated analogues are shown in Fig. 20. This shows clearly the improved ki and k ₂ values for the granulated particle samples.

Table 6: Results of water sorption and particle disintegration tests for each of the tested granulated and non-granulated compositions containing paracetamol as the API.

Example 4: Comparison of granulated products with products available on the market

Two commercially available products (Tachipirina 500 mg orosoluble, and Aspirin direct 500 mg) were tested for comparison with the two-phase sucrose/20% paracetamol granulates described above in Example 3. Comparative results are shown in Table 7.

Table 7: Experimental parameters for commercially available formulations tested in the sipping test, water sorption test and disintegration test. -- indicates very high levels of clogging; - indicates high levels of clogging; + indicates low levels of clogging; and ++ indicates very low levels of clogging/no clogging. * 3 value is equivalent to p2 value meaning sipping test was prematurely aborted due to high sipping pressures. Straw was not emptied at all.

Fig. 21 additionally shows water sorption curves for Tachipirina and Aspirin

Direct, compared with a gelatin granulate (20% by weight of coated core phase) of the present invention.

It is observed that the two-phase granulate formulations of the present invention provide a superior balance of properties to the commercially available formulations. In particular, the formulations of the present invention exhibit (a) a lower maximal sipping pressure, which enables the straw to be emptied in a lower flush volume, (b) significantly larger ki and k ₂ values, providing more rapid water sorption and particle dissolution, and (c) more rapid disintegration of particles as demonstrated by the laser diffraction test.

Example 5: Investigating the effect of API content on water sorption properties

An experiment was also carried out to determine the optimal amount of API by weight in the two-phase granulates. Three granulate formulations were prepared as follows: (a) two-phase sucrose granulate with 20% content of gelatin-coated paracetamol particles; (b) single-phase sucrose granulate with 40% ibuprofen content; and (c) single-phase sucrose granulate with 10% stearic acid content. Formulation (a) was prepared according to the granulation method for preparing two-phase particles as described herein. Formulations (b) and (c) were prepared using a classic granulation technique, by mixing a blend of powdered excipient/ API with milled sucrose.

The water sorption curves for each of these samples are shown in Fig. 22. It is observed that formulations (a) and (b) have more optimal water sorption properties than formulation (c), and that formulations (a) and (c) have more optimal disintegration rates than formulation (b). For a highly lipophilic excipient such as stearic acid, it is found that single phase granules have sub-optimal properties, and that two-phase granules prepared according to the present invention are more desirable.