Coating method

Abstract

A process for coating carrier particles with inhalable drug guest particles, the process including providing an apparatus including a processing vessel having solid walls defining a chamber for receiving the particles and adding the particles to the chamber. Next, the cylindrical processing vessel is rotated about an axis to impart a centrifugal force of between 10 and 2100 g on the particles. Further a process coats carrier particles with guest particles, wherein the carrier particles include a material or a drug and wherein the guest particles include a solubility/dissolution controlling agent.

Claims

1. A process for coating carrier particles with guest particles, the process comprising: providing an apparatus comprising a processing vessel having solid walls defining a chamber for receiving said particles, and a hollow shaft extending within said chamber at least partly along the axis of rotation of the cylindrical processing vessel, the hollow shaft defining a gas flow path connected to a gas inlet, and having one or more axially-extending slots or one or more axially-extending rows of apertures allowing fluid communication between the gas flow path and the chamber; adding the particles to the chamber; and rotating the cylindrical processing vessel about an axis to impart a centrifugal (G) force of between 10 and 2100 g on the particles whilst flowing gas from the gas inlet along the gas flow path in the hollow shaft and into the chamber, in a radially-outwards direction, through the one or more axially-extending slots or one or more axially-extending rows of apertures to reinforce the centrifugal force, wherein the guest particles comprise an inhalable drug, and the gas is flowed from the gas inlet at a flow rate of between 1 and 75 L/min to cause de-agglomeration then adherence of the guest particles on the carrier particles.

2. A process according to claim 1 comprising rotating the cylindrical processing vessel about an axis to impart a centrifugal (G) force of between 10-2000 g.

3. A process according to claim 1 comprising rotating the cylindrical processing vessel at a speed between 250-4000 rpm.

4. A process according to claim 1 comprising rotating the cylindrical processing vessel for up to 180 minutes.

5. A process according to claim 1 wherein the mean particle size of the inhalable drug guest particle is between 1-6 micrometres measured using a laser diffraction particle size analyser that measures on a by volume basis.

6. A process according to claim 5 wherein the mean particle size of the guest particles is greater than 50 nanometres measured using a laser diffraction particle size analyser that measures on a volume basis.

7. A process according to claim 1 wherein the carrier particle size is equal or greater than 5 times the mean particle size of the inhalable drug guest particles.

8. A process according to claim 7 wherein the carrier particle size is equal to or greater than 5 micrometres.

9. A process for coating carrier particles with guest particles, the process comprising: providing an apparatus comprising a processing vessel having solid walls defining a chamber for receiving said particles and a hollow shaft extending within said chamber at least partly along the axis of rotation of the cylindrical processing vessel, the hollow shaft defining a gas flow path connected to a gas inlet, and having one or more axially-extending slots or one or more axially-extending rows of apertures allowing fluid communication between the gas flow path and the chamber to reinforce the centrifugal force; adding the particles to the chamber; and rotating the cylindrical processing vessel about an axis to impart a centrifugal (G) force on the particles while flowing gas from the gas inlet along the gas flow path in the hollow shaft and into the chamber, in a radially-outwards direction, through the one or more axially-extending slots or one or more axially-extending rows of apertures, wherein one of the carrier particles and the guest particles comprises a material having a solubility/dissolution and the other comprises a solubility/dissolution controlling agent, wherein the solubility/dissolution controlling agent comprises an anionic surfactant, a cationic surfactant, a non-ionic surfactant, a zwitterionic (amphoteric) surfactant, an amino acid, a disintegrant, a water insoluble moiety, a water-soluble moiety or a combination of any of the above, and the gas is flowed from the gas inlet at a flow rate of between 1 and 75 L/min to cause de-agglomeration then adherence of the guest particles on the carrier particles.

10. A process according to claim 9 wherein the mean particle size of the guest particle is between 0.2 and 38 micrometres measured using a laser diffraction particle size analyser that measures particle volume.

11. A process according to claim 9 wherein the carrier particle size is equal or greater than 5 times the mean particle size of the guest particles.

12. A process according to claim 11 wherein the carrier particle size is equal to or greater than 5 micrometres.

13. A process according to claim 9 comprising providing an apparatus further comprising a hollow shaft extending within said chamber at least partly along the axis of rotation of the cylindrical processing vessel, the hollow shaft defining a gas flow path connected to a gas inlet, and having one or more axially-extending slots or one or more axially-extending rows of apertures allowing fluid communication between the gas flow path and the chamber, and flowing gas from the gas inlet along the gas flow path in the hollow shaft and into the chamber through the one or more axially-extending slots or one or more axially-extending rows of apertures.

14. A process for coating carrier particles with guest particles, the process comprising: providing an apparatus comprising a processing vessel having solid walls defining a chamber for receiving said particles and a hollow shaft extending within said chamber at least partly along the axis of rotation of the cylindrical processing vessel, the hollow shaft defining a gas flow path connected to a gas inlet, and having one or more axially-extending slots or one or more axially-extending rows of apertures allowing fluid communication between the gas flow path and the chamber; adding the particles to the chamber; and rotating the cylindrical processing vessel about an axis to impart a centrifugal (G) force on the particles while flowing gas from the gas inlet along the gas flow path in the hollow shaft and into the chamber, in a radially-outwards direction, through the one or more axially-extending slots or one or more axially-extending rows of apertures to reinforce the centrifugal force, wherein one of the carrier particles and the guest particles comprises a drug and the other comprises a solubility/dissolution controlling agent;agent, the solubility/dissolution controlling agent comprises an anionic surfactant, a cationic surfactant, a non-ionic surfactant, a zwitterionic (amphoteric) surfactant, an amino acid, a disintegrant, a water insoluble moiety, a water-soluble moiety or a combination of any of the above, and the gas is flowed from the gas inlet at a flow rate of between 1 and 75 L/min to cause de-agglomeration then adherence of the guest particles on the carrier particles.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) Embodiments of the invention will now be described by way of example with reference to the accompanying drawings in which:

(2) FIG. 1 shows a schematic representation of the apparatus described in WO2016/066462;

(3) FIG. 2 shows the content uniformity and RSD of fluticasone propionate/lactose formulations;

(4) FIG. 3 shows the amount of respirable fine particles collected and percentage emitted dose for the fluticasone propionate/lactose formulations;

(5) FIG. 4 shows the content uniformity and RSD of further fluticasone propionate/lactose formulations;

(6) FIG. 5 shows the amount of respirable fine particles collected and percentage emitted dose for the further fluticasone propionate/lactose formulations;

(7) FIG. 6 shows SEM images of fluticasone propionate and sample formulations;

(8) FIG. 7 shows the dissolution/time profile for dry coated carbamazepine formulations against control highlighting improved dissolution of the drug post dry coating;

(9) FIG. 8 shows the dissolution/time profile for piroxicam/PVP formulations against control highlighting improved dissolution of the drug post dry coating;

(10) FIG. 9 shows the dissolution/time profile for phenytoin/PVP formulations against control highlighting improved dissolution of the drug post dry coating;

(11) FIG. 10 shows the dissolution/time profile for carbamazepine/SLS formulations against control highlighting improved dissolution of the drug post dry coating;

(12) FIG. 11 shows the dissolution time profile for carbamazepine with different polymers used to control the rate of drug dissolution;

(13) FIG. 12 shows the dissolution time profile of Carbamazepine with varying combinations of two rate controlling polymers to tailor the rate of drug dissolution; and

(14) FIG. 13 shows the dissolution/time profile of flucloxacillin Sodium with various rate controlling polymers to control the rate of drug dissolution

DETAILED DESCRIPTION AND FURTHER OPTIONAL FEATURES OF THE INVENTION

(15) FIG. 1 the apparatus 1 for coating carrier particles with guest particles described in WO2016/066462. The apparatus comprises a cylindrical processing vessel 2 formed of acrylic or stainless steel (GMP grade) and having smooth inner walls. The vessel 2 is rotatable about its axis and has solid walls defining a chamber 3 having a volume of around 500 cm.sup.3. A hollow shaft 4 formed of stainless steel extends within the chamber 3 along the axis of the vessel 2. The hollow shaft defines a gas flow path connected to a gas inlet 5 located at one axial end 6 of the vessel 2 and connected to a gas outlet 7 at the opposing axial end 8 of the vessel 2.

(16) The hollow shaft 4 comprises four rows of axially aligned apertures 9 circumferentially-spaced around the shaft. The apertures 9 extend from the gas flow path within the hollow shaft 4 into the chamber 3.

(17) The rows of apertures are selectively blockable so that during processing, one, two or three rows may be blocked.

(18) The apertures 9 have an adjustable diameter to focus the gas flow into the chamber 3 and the apertures 9′ towards the axial ends of the hollow shaft 4 include a respective flow director (not shown) which angles the gas flow towards the axial ends of the chamber 3.

(19) The apparatus 1 further comprises a driving motor 10 for driving rotation of the vessel 2. The driving motor 10 is linked to a hub 11 affixed to axial end 6 of the vessel 2 adjacent the gas inlet 5 via a belt 12. The hollow shaft 4 passes through the axial centre of the hub 11.

(20) The driving motor 10 is adapted to rotate the vessel 2 and hub 11 via the belt 12 at a speed of up to 4000 rpm. The driving motor includes a rotation sensor (not shown) for monitoring and maintaining the speed of rotation of the hollow shaft 4.

(21) The apparatus 1 further comprises an infra-red temperature sensor 13 mounted externally of the chamber for monitoring the temperature within the chamber.

(22) The apparatus 1 further comprises a pressure regulating system 14 for regulating the pressure within the chamber to ensure that there is no build-up of pressure within the chamber 3.

(23) The rotation sensor, temperature sensor 13 and pressure regulating system 14 provide feedback to a computer system (not shown) running LabVIEW software or equivalent software.

(24) The apparatus 1 further comprises a nitrogen source 15 connected to the gas inlet 5. The gas source 15 is adapted to provide nitrogen at a pressure of up to 80 psi e.g. between 20-80 psi at the gas inlet 5.

(25) To use the apparatus 1, carrier particles and guest particles are placed within the chamber 3 of the vessel 2. These are introduced at either end of the chamber before the hollow shaft is fitted and sealed to the chamber (using stainless steel gaskets).

(26) The carrier particles have a particle size of at least 5 times that of the guest particles (when measured using a laser diffraction particle size analyser which measure particle volume).

(27) The gas inlet 5 is connected to the nitrogen gas supply 15.

(28) The vessel 2 is rotated at a speed of up to 4000 rpm by the driving motor 10 and belt 12 which rotate the hub 11 which is affixed to the axial end 6 of the vessel 2.

(29) As the vessel 2 rotates, the particles are subjected to centrifugal forces which force them towards the smooth inner surface of the walls of the vessel 2.

(30) Nitrogen from the nitrogen source 15 flows to the gas inlet 5 and through the hollow shaft 4 along the gas flow path. The remainder of the gas passes into the chamber 3 through the four rows of apertures 9.

(31) The gas passing though the apertures 9 will emanate in a radially outwards direction which will be coincident with the centrifugal force and thus will increase the collision force of the particles against the inner surface of the solid walls of the vessel. This, in turn, will increase the force with which the guest particles are adsorbed onto the carrier particles and thus will increase the adhesion between the two particles.

(32) As the apertures 9 are in a row which extend axially along the hollow shaft 4, the air exiting the hollow shaft 4 will form axially-extending “air blades” which increase the shear forces applied to the particles and thus further increase adhesion between the particles.

(33) Experimentation using fluticasone propionate and lactose monohydrate have been carried out as discussed below.

Example 1—Studies on Fluticasone Propionate/Lactose Monohydrate

(34) Fluticasone Propionate is a potent glucocorticosteroid with anti-inflammatory action. It is used in inhalable drug formulations for the treatment of asthmatic patients for the suppression of inflammation within the airways. When delivered through the respiratory system using inhalation it requires only low doses and little fluticasone is absorbed into the systemic circulation hence reducing any side effects.

(35) Lactose monohydrate is the most commonly used carrier excipient in dry powder inhaler formulations. It has the advantage of being highly investigated for its safety, stability and toxicity. It is compatible with multiple drugs and has relatively low price.

Content Uniformity for 0.5% DPI formulations

(36) Fluticasone propionate/lactose monohydrate particles were produced using the coating apparatus described in WO2016/066462. The cylindrical processing vessel had a radius of 4.125 cm.

(37) The formulations APT-1 to APT-4 were designed to deliver 50 μg of fluticasone propionate from 10 mg total dose.

(38) The lactose monohydrate carrier particles were selected from two commercial brands: Respitose SV010 with average particle size of 95-125 μm and a D90 of 160-190 μm (where D90 is the particle size of 90% of the powder); and Respitose SV003 with average particle size of 60 μm and a D90 of 90 μm.

(39) Fluticasone propionate was employed as guest particles in the form of a fine powder with average particle size of 1-6 μm.

(40) The carrier and guest particles were added to the processing vessel. The processing conditions of the three prepared batches are depicted in Table-1.

(41) TABLE-US-00001 TABLE 1 Example of DPI formulations with processing parameters Gas Process- Fluticasone Total G- pres- ing Propionate Dose Force sure Time Guest Batch (μg) (mg) (g) (bar) (min) % Carrier APT-1 50 10 190.4 0.38 30 0.5% Respitose SV010 APT-2 50 10 190.4 0.38 10 0.5% Respitose SV010 APT-3 50 10 107.1 0.38 10 0.5% Respitose SV010 APT-4 50 10 107.1 0.38 10 0.5% Respitose SV003

(42) Content uniformity of fluticasone propionate in the four batches was above 97% with low relative standard deviation (RSD) as shown in FIG. 2.

(43) Uniformity was observed across all examples but a longer processing time and/or higher G-force was found to result in a higher level of homogeneity as evident from the RSD. Respitose SV010 with larger average particle size showed higher level of homogeneity compared to Respitose SV003 owing to the higher attraction force between the guest fluticasone particles and larger carrier particles.

Aerodynamic Performance of 0.5% DPI Formulations

(44) Next, the aerodynamic performance of the four formulations using new generation impactor (NGI) apparatus form Copley Scientific was examined with the cut-off points in terms of aerodynamic particle diameter between 1-5 μm.

(45) Individual samples of 10 mg were filled into 6 gelatine capsules (size 3) and then discharged into the NGI using Aerolizer™ DPI device.

(46) The air flow rate was set at 60 L/min for 4 sec to mimic 4 L of inhaled air during human inhalation process. The emitted fraction was calculated based on the percentage of recovered and HPLC analysed fluticasone from the mouth piece, induction tube, pre-separator and stages 1-8.

(47) The amount of respirable fine particles is the sum of recovered dose within the cut-off aerodynamic diameter, whereas the fine particle fraction (FPF) is the percentage of the recovered dose within the cut-off aerodynamic diameter of 1-5 μm to the theoretical dose. Results are shown in FIG. 3.

(48) The results show the ability of the designed process parameters (G-force) and input parameters (carrier particle size) to deliver various amounts of respirable fine particles that ranges from 3-13 μg representing a tailored FPF (6-27% w/w) and emitted dose.

(49) The produced formulation showed high degree of emitted dose owing to the excellent flowability of the powder. It is noted that process optimisation can result in targeted FPF % without jeopardising content uniformity and blend homogeneity.

Example 2—Content Uniformity for 0.71% DPI Formulations

(50) Experiments were carried out using higher concentration of fluticasone propionate to deliver 100 μg from 14 mg total dose (0.71%) using the apparatus of WO2016/066462.

(51) Processing parameters are listed in Table 2 below.

(52) TABLE-US-00002 TABLE 2 Example of DPI formulations with processing parameters for batch size of 20 g Gas Process- Fluticasone Total G- pres- ing Propionate Dose Force sure Time Guest Batch (μg) (mg) (g) (bar) (min) % Carrier APT-5 100 14 107.1 0.38 10 0.71% Respetose SV010 APT-6 100 14 107.1 0.38 10 0.71% Respetose SV003 APT-7 100 14 107.1 0.38 30 0.71% Respetose SV003 APT-8 100 14 190.4 0.38 10 0.71% Respetose SV003 APT-9 100 14 190.4 0.38 10 0.71% Respetose SV003 APT-10 100 14 190.4 0.38 8.3 0.71% Respetose SV010 APT-11 100 14 84.6 0.38 5 0.71% Respetose SV010 APT-12 100 14 107.1 0.38 10 0.71% Respetose SV003

(53) As shown in FIG. 4, content uniformity was high for all formulations with low RSD for all batches APT-5-APT-12.

Aerodynamic Performance of 0.71% DPI Formulations

(54) The results for 100 μg fluticasone DPI formulations can be seen in FIG. 5 which shows the ability of the process to be engineered to deliver various percentages of FPF and emitted doses resulting from the degree of adherence/detachment whilst maintaining tight control on content uniformity.

(55) Results show that FPF as high as 40% could be achieved. The emitted dose could reach 100% as is the case with formulation APT-8.

Scanning Electron Microscopy (SEM) Images of Selected Formulations

(56) FIG. 6 shows SEM images of the surface of (A) fluticasone propionate particles with average particle size of ranging from 1-5 μm. The images at 1000× and 5000× magnification show the fine particles are agglomerated. FIGS. 6B-D show the distribution of the fluticasone propionate on the surface of the lactose monohydrate carrier after processing using the process described herein. It should be noted that the degree of distribution and deagglomeration of the fluticasone propionate increases with the reduction in FPF (B formulation has high degree of homogeneity and distribution resulting in a FPF of around 6%, C formulation had FPF of 22.6% whereas D formulation had FPF of 29.1%).

Example 3—Micronized Carbamazepine Guest Particles on Polyvinylpyrrolidone Carrier Particles

(57) Carbamazepine/polyvinylpyrrolidone dry coated functionalised particles were produced using the apparatus of WO2016/066462.

(58) Various formulations of the carbamazepine and polyvinylpyrrolidone (PVP) (Kollidon K25) were manufactured. PVP was used as the carrier particle with an average particle size of approximately 59 μm and D90 of 102 μm. Carbamazepine was employed as a model poorly soluble drug in a micronized state to act as the guest particle, with an average particle size of 5 μm and a D90 of 11.16 μm. Mixing conditions were fixed at 190.4 g, 0.38 bar of gas pressure and a mixing times varying from 30 to 60 mins.

(59) The dissolution rate was analysed using standard USP II dissolution apparatus using the basket assembly dissolution vessels. Standard 200 mg dose powders were investigated to mimic a patient dose, with dissolution conditions maintained at 37° C. and the basket apparatus rotated at 50 rpm in distilled water. Powders were placed in the basket and submerged in to the dissolution apparatus and ran over 4 h. Samples were taken at predetermined time intervals, with each sample volume replaced with the same amount of fresh dissolution media to maintain sink conditions. The samples were filtered appropriately and analysed for drug content using HPLC apparatus at each of the time points. All results were taken in triplicate, and are represented in FIG. 7.

(60) Results showed an enhanced dissolution rate, and enhanced maximum dissolution for processed powders when compared to off the shelf carbamazepine and micronized carbamazepine. All dry coated powders displayed an improved dissolution behaviour at different concentrations of solubility/dissolution controlling polymer (PVP) as well as different processing times. The 50:50 formulation mixed for 60 mins provided the most beneficial behaviour with almost 90% drug release of a poorly soluble drug over the 4 h time period, highlighting a 130% improvement in drug dissolution rate when compared to the off the shelf drug. All other formulations showed a similarly high improvement in drug dissolution highlighting the ability of the technology to control and enhance the dissolution rate of low soluble drugs.

(61) The micronized carbamazepine showed a very poor release due to agglomeration of the particles, decreasing the surface area for wettability. The inventive process allowed uniform distribution of the drug through the carrier with uniformity of content being >98%, allowing thorough wetting of the drug particles as well as an increased dissolution rate. The process does not generate any heat or use any solvents so is ideal for unstable drugs, and with 70% of new chemical entities being poorly soluble this method of processing for solubility/dissolution control/enhancement presents an ideal solution to improve drug dissolution rate.

Example 4—Micronised Piroxicam Guest Particles on Polyvinylpyrrolidone Carrier Particles

(62) Piroxicam/PVP dry coated functionalised particles were produced using the apparatus of WO2016/066462.

(63) Various formulations of the piroxicam and PVP (Kollidon K25) were manufactured. PVP was used as the carrier particle with an average particle size of approximately 59 μm and D90 of 102 μm. Piroxicam was employed as a model poorly soluble drug in a micronized state to act as the guest particle, with an average particle size of 3.36 μm and a D90 of 6.98 μm. Mixing conditions were fixed at 190.4 g, 0.38 bar of gas pressure and a mixing time of 30 mins.

(64) The dissolution rate was analysed using standard USP II dissolution apparatus using the basket assembly dissolution vessels. Standard 20 mg dose powders were investigated to mimic a patient dose, with dissolution conditions maintained at 37° C. and the basket apparatus rotated at 50 rpm in 0.1N hydrochloric acid. Powders were placed in the basket and submerged in to the dissolution apparatus and ran over 4 h. Samples were taken at predetermined time intervals, with each sample volume replaced with the same amount of fresh dissolution media to maintain sink conditions. The samples were filtered appropriately and analysed for drug content using HPLC apparatus at each of the time points. All results were taken in triplicate, and are represented in FIG. 8.

(65) Results showed an enhanced dissolution rate as well as a vastly improved maximum dissolution at the end of the 4 h interval compared to the control piroxicam alone. Both concentrations of rate controlling polymer (PVP) highlighted an improved dissolution behaviour with the 70% PVP showing the most beneficial performance. This formulation indicated 88.5% drug release compared to the control formulation showing a 29.7% release which amounted to a 197% increase in overall dissolution. A similar behaviour was observed with the 80% PVP formulation highlighting that the technology gives the ability to control and improve the dissolution behaviour through its advantageous processing conditions.

Example 5—Micronised Phenytoin Guest Particles on Polyvinylpyrrolidone Carrier Particles

(66) Phenytoin/PVP dry coated functionalised particles were produced using the apparatus of WO2016/066462.

(67) Various formulations of the phenytoin and PVP (Kollidon K25)/micronised sodium lauryl sulfate were manufactured. PVP was used as the carrier particle with an average particle size of approximately 59 μm and D90 of 102 μm. Piroxicam was employed as a model poorly soluble drug in a micronized state to act as the guest particle, with an average particle size of 11.44 μm and a D90 of 19.05 μm. Mixing conditions were fixed at 190.4 g, 0.38 bar of gas pressure and a mixing time of 30 mins.

(68) The dissolution rate was analysed using standard USP II dissolution apparatus using the basket assembly dissolution vessels. Standard 200 mg dose powders were investigated to mimic a patient dose, with dissolution conditions maintained at 37° C. and the basket apparatus rotated at 50 rpm in distilled water. Powders were placed in the basket and submerged in to the dissolution apparatus and ran over 4 h. Samples were taken at predetermined time intervals, with each sample volume replaced with the same amount of fresh dissolution media to maintain sink conditions. The samples were filtered appropriately and analysed for drug content using HPLC apparatus at each of the time points. All results were taken in triplicate, and are represented in FIG. 9.

(69) Results from the three processed formulations highlighted an improved dissolution rate alongside a higher maximum dissolution over the control phenytoin formulation. The 50:50 PVP/phenytoin formulation displayed the most improved dissolution behaviour with a 14% release, compared to the 4.7% release of the phenytoin alone. This amounted to approximately 197% increase in maximum dissolution. A similar increase was observed with the sodium lauryl sulfate/PVP combinations highlighting that the process could be tailored with excipients and processing parameters to deliver control of the drug dissolution profile to improve and tailor the release of the drug.

Example 6—Micronized Sodium Lauryl Sulphate Guest Particles on Carbamazepine Carrier Particles

(70) Carbamazepine/sodium lauryl sulphate functionalised particles were produced using the apparatus of WO2016/066462.

(71) The primary formulation comprised 25 wt % sodium lauryl sulphate with 75 wt % carbamzaepine, with a second formulation produced using 12.5 wt % sodium lauryl sulphate and 87.5% carbamazepine.

(72) Off the shelf carbamazepine was used with an average particle size of approximately 91 μm and D90 of 156 μm. Sodium lauryl sulphate was employed in a micronized state as the guest particle, with an average particle size of 8 μm and a D90 of 15.6 μm.

(73) Mixing conditions were fixed at a G force of 190.4 g, 0.38 bar of gas (nitrogen) pressure and a mixing time of 30 mins.

(74) Results indicated that dry coating carbamazepine with the micronized sodium lauryl sulphate enhanced dissolution rate, and maximum dissolution of carbamazepine when compared to the carbamazepine control.

(75) As can be seen in FIG. 10, APT formulation 2 showed around 54% drug release of the model insoluble drug carbamazepine and APT formulation 3 showed around 48% drug release compared to off the shelf carbamazepine (CBZ), which showed around 38% drug release, highlighting a 42% and 25% improvement in drug dissolution rate for APT formulation 2 and 3 respectively.

(76) The process results in dissolution rate improvement and allowed uniform distribution of the drug through the carrier with uniformity of content being >98%, allowing thorough wetting of the drug particles as well as an increased dissolution rate.

(77) The process does not require micronisation of the drug particle making it ideal for drugs which have physical instabilities. The lack of heat generation in the process, as well as absence of solvent makes this method ideal for unstable drugs.

Example 7—Micronised Dissolution Rate Controlling Guest Polymers on Carbamazepine Carrier Particles

(78) Carbamazepine/dissolution rate controlling guest polymers were processed using the apparatus of WO2016/066462.

(79) Binary mixtures of drug and dissolution rate controlling guest polymers were manufactured at various concentrations to produce a coating that would tailor/control the dissolution rate of the drug, as displayed in FIG. 11. This demonstrated the flexibility of the process to use different materials to alter the drug release to desired levels. Off the shelf carbamazepine was mixed with three different rate controlling polymers; poly(ethylene) oxide of high viscosity (excipient 1), poly(ethylene) of low viscosity (excipient 2) and ethylcellulose (excipient 3).

(80) Mixing conditions were fixed at a G force of 190.4 g, 0.38 bar of gas (nitrogen) pressure and a mixing time of 60 mins.

(81) Results indicated that the choice of rate controlling polymer could tailor the release of the drug to either match the release of the drug itself, as observed with excipient 2, or the release of the drug could be slowed/inhibited to very low levels over the 60 min time interval, with excipient 1 showing 4% release and excipient 3 displaying a 1.9% release. Low levels of drug release could be deemed useful for applications such as masking the odour/taste of the drug, as a low drug release would inhibit contact of the drug with the taste buds and therefore increase the palatability of the formulation.

(82) FIG. 12 uses combinations of two of these dissolution rate controlling polymers with carbamazepine, to tailor the release profile to achieve a desired drug release. Excipients 1 and 2 were chosen as they are different viscosity grades of poly(ethylene) oxide and they gave opposite dissolution profiles. As can be seen from FIG. 12, changing the combination of the two rate controlling polymers allowed tailoring of the release profile to achieve a different release after the 60 min time period. The 50:50 combination displayed a total release similar to the drug alone, however the release of the drug was suppressed in the first 10 mins, which would be an ideal profile for a taste masked formulation, whereby release should be minimum in the initial 5-10 mins and then should increase similar to the drug alone. When the concentration of the high viscosity poly(ethylene) oxide was increased the dissolution profile was further suppressed, suggesting the dissolution could be tailored using the technology and different combinations of polymers.

Example 8—Micronised Dissolution Rate Controlling Guest Polymers on Flucloxacillin Sodium Carrier Particles

(83) Flucloxacillin sodium/dissolution rate controlling guest polymers were processed using the apparatus of WO2016/066462.

(84) Binary mixtures of drug and dissolution rate controlling guest polymers were manufactured at various concentrations to produce a coating that would tailor/control the dissolution rate of the drug, as displayed in FIG. 13. This was to demonstrate flexibility of the process to use highly soluble drugs, such as flucloxacillin sodium alongside low soluble drugs such as carbamazepine. Off the shelf flucloxacillin sodium was mixed with three different rate controlling polymers; poly(ethylene) oxide of high viscosity (excipient 5), poly(ethylene) of low viscosity (excipient 3) and ethylcellulose (excipient 6).

(85) The dissolution rate was analysed using standard USP II dissolution apparatus using the basket assembly dissolution vessels. Standard 250 mg dose powders were investigated to mimic a patient dose, with dissolution conditions maintained at 37° C. and the basket apparatus rotated at 50 rpm in pH 6.8 phosphate buffer. Powders were placed in the basket and submerged in to the dissolution apparatus and ran over 60 mins. Samples were taken at predetermined time intervals, with each sample volume replaced with the same amount of fresh dissolution media to maintain sink conditions. The samples were filtered appropriately and analysed for drug content using HPLC apparatus at each of the time points. All results were taken in triplicate,

(86) Mixing conditions were fixed at a G force of 190.4 g, 0.38 bar of gas (nitrogen) pressure and a mixing time of 60 mins.

(87) FIG. 13 highlights results from the flucloxacillin sodium binary mixtures coated with the different dissolution rate controlling polymers. Again, it can be seen that different rate controlling polymers can alter the release profile of the drug that slows/inhibits its release. In this case, flucloxacillin sodium is very soluble, and exhibits full release within a minute when assessed alone. The data presented here shows that all dissolution rate controlling polymers slow the release of the drug at varying levels. Also, the data presented different concentrations of excipient 4, and that increasing the amount of guest excipient on to the surface of the flucloxacillin sodium slowed the release of the drug further, as a more significant coating is achieved.

(88) While the invention has been described in conjunction with the exemplary embodiments described above, many equivalent modifications and variations will be apparent to those skilled in the art when given this disclosure. Accordingly, the exemplary embodiments of the invention set forth above are considered to be illustrative and not limiting. Various changes to the described embodiments may be made without departing from the scope of the invention as defined in the claims.

(89) All references referred to above are hereby incorporated by reference.