WO2021069901A1

WO2021069901A1 - Lactose particles and method of production thereof

Info

Publication number: WO2021069901A1
Application number: PCT/GB2020/052496
Authority: WO
Inventors: El Hassane Larhrib
Original assignee: University Of Huddersfield
Priority date: 2019-10-08
Filing date: 2020-10-08
Publication date: 2021-04-15
Also published as: GB201914532D0; GB2606306A; EP4138762A1; GB202210051D0

Abstract

Spherical particles and method of producing the same, said particles are disaccharide particles, wherein said disaccharide is lactose and the particles are substantially spherical in shape and/or hollow.

Description

Lactose Particles and Method of Production Thereof

The present invention relates to the formation of novel spherical, particles of lactose with a narrow size distribution and a method of synthesising the same.

Although the following description refers exclusively to particles of lactose the skilled person will appreciate that the principles of the invention could be applied to other disaccharides and sugars.

Lactose monohydrate, hereinafter referred to as lactose, is a disaccharide comprising galactose and glucose. Lactose is a powder which is widely used in the pharmaceutical industry because of its physical properties. For example lactose is used as an excipient in tablet formation because it acts as a bulking agent and has good flow properties. It is also used in dry-powder inhalation formulations as a carrier powder for drug particles.

Conventional lactose powder for such applications comprise particles of lactose which are either elongated or tomahawk shaped. These particles are non-porous with a relatively broad size distribution. These types of lactose are brittle with a low compressibility when compared to other excipients such as microcrystalline cellulose known as Avicel^® resulting in the formation of weak tablets.

It is therefore an aim of the present invention to provide a form of lactose that addresses the abovementioned problems.

It is a further aim of the present invention to provide a method of producing or synthesising particles of lactose that addresses the abovementioned problems. In a first aspect of the invention there is provided a plurality of disaccharide particles, wherein said disaccharide is lactose and the particles are substantially spherical in shape and/ or hollow. Preferably the particles are monodisperse and/ or have a narrow size distribution.

Further preferably the particles are highly spherical or perfectly spherical particles.

Typically the particles contain at least one anti-adherent. Further typically the anti adherent is a hydrophilic and/ or non-ionic compound or excipient.

In one embodiment the anti-adherent is polyvinyl pyrrolidone (PVP).

Typically, PVP is a synthetic hydrophilic non-ionic excipient. Further typically it is divided into four viscosity grades according to its prees k value (Fikentscher k value): k-15, k-30, k-60, k-90, with the average molecular weight being 10,000, 40000, 160000 and 360000, respectively. K value or molecular weight is an important factor which decides the various properties of PVP. Typically the particles have anti-adherent properties. Further typically the particles can be produced with controllable surface roughness, size, degree of crystallinity, polymorphic form and/ or particle strength.

The particles when used in the appropriate particle size and appropriate ratio as a carrier in a dry powder for inhalation they showed exceptionally high fine particle fraction of drugs (hydrophilic and hydrophobic). In addition when used in the appropriate particle size and appropriate ratio also exhibited an excellent tablet hardness when compressed into tablets. In one embodiment the lactose is oc-lactose monohydrate.

In one embodiment the lactose is anhydrous oc-lactose. Typically the particles have an elongation ratio of 0.9 — 1.1. Further typically the particles are spherical with an elongation ration of 1 or substantially 1.

Typically the particles are crystalline or substantially crystalline. Typically the particles are hollow. Further typically the particles are substantially hollow spheres of crystalline lactose. The skilled person will appreciate that although hollow particles can be produced, the reaction could be tuned to produce non hollow or substantially solid spherical particles. Typically the particles are porous.

Further typically surface roughness of the particles is adjusted in the crystallisation medium. For example when the particles are used as a carrier for an inhaled pharmaceutical, it is formulated in a dry powder formulation which would provide less contact area with the drug to facilitate its detachment during inhalation.

Preferably the size of surface roughness is designed to be smaller than the size of adhering drug particles so as the drug sit on the surface and not in the crevices of lactose.

The presence of surface roughness between carrier-carrier particles will channel the air flow through the powder bed to lift the powder more easily to increase the number of particles above the powder bed and to promote frequent collision which is necessary for drug detachment and dispersion of drug in the air stream. In one embodiment the particles are provided as a powder.

Typically the volume mean diameter (VMD) of the particles is, or is substantially, 75 pm.

Typically particle size distribution can be tuned, for tablet formulation we need large particles and for inhalation carrier particles are preferably <45 pm. Particles are spherical with narrow size distribution. They have good flow despite their small size. The frequency of collision for small spherical carrier particles is expected to be higher than irregular shapes. Furthermore, the collision between spherical particles is uniform irrespective of particle -particle orientation.

The size of carrier particles is designed so as they are small to increase the number of carrier particles to promote collision between particles but efficient drug detachment but large enough not to permeate the lungs. Desired size range is between 10-20 pm.

In a second aspect of the invention there is provided crystalline spherical particles of lactose with controlled surface roughness.

In a third aspect of the invention there is provided a crystallisation method comprising;

- dissolving at least one anti-adherent polymer in an aqueous medium to form a solution;

- dissolving a first substance to be crystallised in the anti-adherent polymer solution;

- preparing an anti-solvent mixture containing two miscible anti-solvents

- wherein the anti-adherent polymer is substantially soluble in one of the anti solvents and insoluble in the other anti-solvent; and - mixing the antisolvent mixture with the polymer solution.

In one embodiment the first substance is lacose. Preferably the volume of the anti-solvent in which the polymer is insoluble is at least equal or greater to the volume of the solvent in which the polymer is soluble. Typically this avoids removal or complete removal of the anti-adherent polymer from the surface of the particles; Typically the mixing of the antisolvent mixture and the polymer solution is under controlled agitation and/ or controlled temperature;

Typically the mixture is stirred for a sufficient time to allow the formation of crystalline spherical particles containing the anti- adherent;

Further typically the solvent and/ or anti-solvent is removed harvesting the crystalline spherical particles containing an anti-adherent.

Typically the two miscible anti-solvents have substantially similar or identical densities.

Preferably the anti-adherent is a polymer. Further preferably the anti-adherent is polyvinyl pyrrolidone. Typically the surface roughness of the spherical particles is dictated by the solubility of the anti-adherent in the solvent/ anti-solvent mixture.

In one embodiment the spherical particles have an elongation ratio from about 1 to about 1.5. In one embodiment the spherical particles have an elongation ratio of 1.

In one embodiment the aqueous solution comprises from about 0.01% to about 99% weight of the anti-adherent polymer per volume of the aqueous medium.

In one embodiment the aqueous solution comprises from about 0.01% to about 2% weight of the anti-adherent polymer per volume of the aqueous medium. Typically the anti-adherent is dissolved or suspended in the anti-solvent mixture.

In one embodiment the anti-solvents have each a density of 0.79 g/ cm³.

Typically the anti-solvents include any one or any combination of methanol, methylated spirits, ethanol, ethylated spirits, propan-l-ol, isopropyl alcohol, acetone, ethyl acetate.

In one embodiment the anti-solvent mixture includes propanediol. Typically 1,3- propanediol acts as a particle size controlling agent.

Preferably the anti-solvent mixture comprises ethanol and acetone.

In one embodiment at least some of the ethanol is replaced with 1,3-propanediol to control particle size. Typically the higher the concentration of propanol the smaller the particle size.

Typically the volume of ethanol in the total volume of anti-solvent mixture varies from 0.1% to 99%. Typically the volume of acetone in the total volume of anti-solvent mixture varies from 0.1% to 99%.

Further typically the volume of ethanol in the volume of anti-solvent mixture varies from 0.1% to 50%.

Further typically the volume of acetone is equal or superior to the volume of ethanol.

Typically the agitation can be achieved by mechanical mixing using stirrer blades, ultrasound, vortexing, masticating, centrifuging, mixing.

In one embodiment the anti-adherent polymer solution when mixed with anti solvent mixture constitutes or forms a crystallisation medium. Typically the temperature of the crystallisation medium varies between -100 °C to + 80 °C.

Further typically the temperature of the crystallisation medium is between -10 °C to + 30 °C.

Typically the substance to be crystallised is introduced to the anti-solvent mixture in the form of a solution.

In one embodiment the substance to be crystallised is introduced to the anti-solvent mixture in the form of a suspension. Typically the suspension is a fine suspension.

In one embodiment the substance to be crystallised is introduced to the anti-solvent mixture in the form of a slurry. In one embodiment the substance to be crystallised is introduced to the anti-solvent mixture in the form of a colloid.

The solvent containing the substance to be crystallised and the anti-solvent can be introduced to each other sequentially, simultaneously, gradually, intermittently or in any order.

In one embodiment the nucleus, colloid, suspension, discrete particles or any product resulting from the crystallisation of the substance whilst it still in the crystallisation medium, or after harvesting, can be further processed by treating with one or more solvents, spray drying, freeze drying or spray freeze drying and/ or the like.

In one embodiment the substance to be crystallised to produce perfectly spherical monodisperse or narrow size distribution particles with anti- adherent property is any one or any combination of; a drug, a pharmaceutical excipient, a particle composite comprising of one or more excipients and a drug.

In one embodiment one or more substances are introduced to the anti-solvent mixture to form a spherical particle composite comprising all the substances in one particle or each substance forms its own spherical particles in the same crystallisation medium.

In one embodiment said substance to be crystallised is a drug substance, an excipient or a mixture comprising one or more drugs with one or more excipients, suitable for use and/ or administration by oral route. In one embodiment said substance to be crystallised is a drug substance, an excipient or a mixture comprising one or more drugs with one or more excipients, suitable for use and/ or administered in an inhaled pharmaceutical composition. In one embodiment the drug substance is water soluble or soluble in aqueous or polar media.

Typically the excipient is selected from the group consisting of carbohydrates, amino acids, or colloidal silica. Further typically the carbohydrate is a disaccharide.

In a preferred embodiment the disaccharide is lactose.

In one embodiment the particle formed is a composite comprising lactose and salbutamol sulphate or other such pharmaceutically acceptable salbutamol salt.

In one embodiment the crystalline spherical particles containing an anti- adherent are harvested by mean of collection by filtration.

In one embodiment the crystalline spherical particles containing an anti- adherent are separated from the crystallisation medium by discarding the crystallisation medium to leave solid particles which are harvested by dipping said particles in a volatile solvent.

Typically the volatile solvent is highly volatile and selected from chlorinated or fluorinated solvents. Further typically the particles are dispersed and emptied on a glass slab or conveyer belt. This typically allows the solvent to dry leaving free flowing powder for collection. In one embodiment the spherical particles containing an anti-adherent are treated by contacting the spherical particles with a hydrophobic coating solution and/ or suspension. Typically this enhances the particles resistance to moisture. In one embodiment the crystalline spherical particles containing an anti- adherent are contacted with polylactic co-glycolic acid (PLGA) solution/ suspension and/ or colloidal silica suspension to enhance their resistance to moisture.

In a preferred embodiment the crystalline spherical particles containing an anti- adherent are a carrier for use in an inhaled pharmaceutical compositions.

Preferably said carrier has a sieve size diameter equal or smaller than 250 micrometres. Further preferably said carrier has a sieve size diameter equal or smaller than 45 micrometres.

Typically said carrier is mixed in any ratio (weight per weight) with a drug for inhalation depending on the inhaler device, the drug and the unit dose to be delivered to a patient.

Typically the ratio of drug to carrier ranges from 1: 67.5 w/w to 1:5 w/w.

Further typically the ratio of drug to carrier in a dry powder composition for inhalation is 1: 67.5 w/w, preferably 1:33 w/w, further preferably 1:20 w/w, yet further preferably 1:10 w/w, and yet further preferably 1:5 w/w.

In one embodiment the carrier is prepared by crystallisation in a crystallisation medium containing a mixture of acetone/ ethanol anti-solvents, wherein the volume of acetone is equal or greater than ethanol. Typically this minimises the loss of polyvinyl pyrrolidone anti-adherent from the surface of the carrier particles.

Typically the carrier containing the anti-adherent polyvinyl pyrrolidone enhanced drug detachment from the surface of the carrier provide high fine particle fraction (%FPF) for hydrophobic and hydrophilic drugs when delivered from a dry powder inhaler device.

In one embodiment the carrier is prepared by crystallisation in a crystallisation medium containing more acetone as anti solvent than ethanol anti solvent which enhances drug detachment from the surface of the carrier for both hydrophilic and hydrophobic drugs.

In one embodiment polyvinyl pyrrolidone is attached to the pharmaceutical substance by mixing, granulating, milling, wetting, sieving, contacting with a solvent or non solvent or by any form of treatment to promote drug detachment from the surface of the substance. Typically this is to increase the performance of an inhaled composition. In one embodiment wherein said particles are compressed into tablets, said tablets showed a tablet hardness of up to 5 times superior to tablets formed from conventional commercial lactose.

In a further aspect of the invention there is provided a crystallisation method comprising the steps of: a) dissolving the anti-adherent polymer in an aqueous medium to form a solution; b) dissolving the substance to be crystallised in the anti-adherent polymer solution; c) preparing an anti-solvent mixture containing two miscible anti-solvents, wherein the anti-adherent polymer is substantially soluble in one of the anti-solvent and insoluble in the other anti-solvent; and d) introducing the solution b) to c).

Typically solution b) is introduced to c) under controlled agitation and/ or controlled temperature.

Further typically the volume of the anti-solvent in which the polymer is insoluble must be at least equal or greater to the volume of the solvent in which the polymer is soluble so as to avoid complete removal of the anti-adherent polymer from the surface of the particles.

In one embodiment sufficient time is allowed for the formation of crystalline spherical particles containing an anti-adherent.

Typically a further final step of harvesting the crystalline spherical particles containing an anti-adherent is included. In a yet further aspect of the invention there is provided a method of forming spherical lactose particles, said method including the steps of; dissolving lactose in water, adding at least one stabiliser or binder to the lactose solution, and mixing the lactose solution with a solution of acetone and ethanol.

Preferably the stabiliser or binder is a polymer. Typically the polymer is PVP. Further typically the polymer includes polysorbate and/or polyethylene glycol (PEG) Polyvinyl pyrrolidone is freely soluble in water and ethanol but not soluble in acetone.

Lactose is soluble in water but has limited solubility in ethanol and is insoluble in acetone.

As such, it is possible to adjust the amount of PVP on the lactose particles by contacting the lactose/PVP aqueous solution in a crystallisation medium containing a mixture of anti-solvents (ethanol/acetone).

Typically at high or equal amount of ethanol, most of the polymer is washed away from the surface of lactose due to PVPs solubility in ethanol and remains in solution. Further typically the formed lactose particles are porous. In one embodiment increasing the amount of acetone compared to ethanol in the crystallisation medium will reduce the solubility of PVP in the crystallisation medium and most of the polymer lactose particles will precipitate with a coat or layer of PVP on the particles. In one embodiment the particles spherical lactose particles include a coating or layer of PVP.

Thus, by adjusting the proportion of ethanol/acetone in the crystallisation medium the amount of PVP on the surface of the lactose particles and surface roughness can be adjusted. Typically this provides lactose particles with appropriate surface roughness coupled with anti-adherent properties.

In one embodiment the liquid is removed and the particles or powder dried to collect the particles on a surface. Typically a volatile liquid is used to recover the particles before drying.

In one embodiment the particles or powder are oven dried.

Typically the solution is stirred at, or substantially around, 500 rpm. Typically slower stirring rates produce particles with a larger diameter. In one embodiment a stirring rate of 300 rpm produces particles with a diameter > 150 pm. Typically the solution is stirred at, or substantially around, 1000 rpm. Typically faster stirring rates produce particles with a smaller diameter. In one embodiment a stirring rate of 1000 rpm produces particles with a diameter < 45 pm.

In a yet further aspect of the invention there is provided a crystallisation method for making narrow size distribution or monodisperse perfectly spherical particles with anti-adherent properties, controlled surface roughness, size, polymorphic form, particle strength and providing strikingly high fine particle fraction when used in a dry powder for inhalation and exceptional crushing strength when compressed into tablet.

In one embodiment of the invention there is provided a crystallisation method comprising: a) dissolving the anti-adherent polymer in an aqueous medium to form a solution; b) dissolving the substance to be crystallised in the anti-adherent polymer solution; c) preparing an anti-solvent mixture containing two miscible anti-solvents with similar densities. The anti-adherent polymer is freely soluble in one of the anti solvent and insoluble in the other anti-solvent. The volume of the anti-solvent in which the polymer is insoluble must be at least equal or greater to the volume of the solvent in which the polymer is soluble so as to avoid complete removal of the anti adherent polymer from the surface of the particles; d) introducing the solution b) to c) under controlled agitation and controlled temperature; e) allowing the formation of crystalline spherical particles containing an anti adherent; f) harvesting the crystalline spherical particles containing an anti-adherent.

In this application polymer refers to a large molecule or macromolecule composed of many repeated subunits. A polymer may be a natural (biopolymer) e.g., proteins, carbohydrates, nucleic acids or synthetic created via polymerisation of many small molecules, known as monomers. Suitable polymers include but not limited to: cyclodextrins and derivatives thereof, Sodium caseinate, dipalmitoyl phosphatidylcholine (DPPC), human Serum albumin, phospholipids, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, ethyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, ethyl hydroxyethyl cellulose, car boxymethyl cellulose, methyl cellulose, cellulose acetate butyrate, poloxamer, poly(lactic acid), poly(lactic-co-glycolic acid), poly(lactide)S, poly(glycolide)S, poly(lactide coglycolide)S, poly(p-dioxanones), poly(caprolactone), polycarbonates, polyamides, polyanhydrides, poly(alkylene alkylate)S, polyamino acids, polyhydroxyalkanoates, polypropylenefumarates, polyorthoesters, polyacetals, poly acrylamides, polycyanoacrylates, polyalkylcyanoacrylates, polymetha polyphosphate esters, polyp ho sphaZene, polyure thanes, polyacrylates, polymethacrylate, poly(methyl meth acrylate), poly(hydroxyethyl methacrylate- co methyl meth acrylate), carbopol 934, ethylene- vinyl acetate and other acyl substituted cellulose acetates and derivatives thereof, polystyrenes, polyvinyl alcohol, polyvinyl pyrrolidone, polyvinyl chloride, polyvinyl fluoride, poly(Vinylimida Zole), chlorosulphonated polyolefins, polyethylene, polyeth ylene glycols, polypropylene, polyethylene oxide, copolymers and blends thereof.

Typically the polymer has anti-adherent properties. In another preferred aspect, the selected polymer is soluble in water and ethanol. Typically the polymer is not soluble in acetone. Example of such polymers is polyvinylpyrrolidone.

In the present application the term "anti- solvent" means a liquid having little or no solvation capacity for the substance (e.g., the substance being lactose, salbutamol sulphate, etc.). The solubility of the substance in the anti-solvent should be less than about 10 mg/ ml, determined according to known methods. Preferably, the solubility of the substance should be less than about 1 mg/ ml.

The solvents include but not limited to methanol, ethanol, n- and iso-propanol, n-, sec- and tert-butanol, pentanols, hexanols, heptanols, benzyl alcohol, THF, diethyl ether, methyl- tert-butyl ether, formamide, DMF, N,N-dimethylacetamide, acetone, methylethyl ketone, pentane, hexane, heptane, octane, cyclopentane, benzene, toluene, xylene, pyridine, methylene chloride, chloroform, carbon tetrachloride, chloromethane, ethylene dichloride, butyl chloride, trichloroethylene, 1,1,2- trichlorotrifluoroethanedioxane, chlorobenzene, ethyl acetate, butyl acetate, acetonitrile, glyme, and mixtures thereof.

The selected anti-solvent is one which is at least partially, preferably completely, miscible with the solvent over the range of pressure and temperature encountered during the operation of the process. The preferred anti-solvents are miscible with each other and with the solvent. The most preferred anti-solvents is their full miscibility with each other, similar density and miscibility with the solvent. In this application the drug is a therapeutic agents, prophylactic agents and diagnostic agents of the present invention are preferably taken from the group comprising: peptides, proteins, organic compounds, inorganic compounds, pro drugs, antigens and hormones. Corticosteroids, anti-inflammatories Such as beclomethasone, betamethasone, fluticasone, flunisolide, budesonide, dexamethasone, tipredane, triamcinolone acetonide; anti-tussives such as noscarpine; and bronchodilators such as ephedrine, adrenaline, fenoterol, formoterol, isoprenaline, metaproterenol, phenylephrine, phenyl propanolamine, pirbuterol, reprot erol, rimiterol, Salbutamol, Salmeterol, formoterol, terbutaline, isoetharine, tulobuterol, orciprenaline and (-)-4-amino 3,5-dichloro-C6-2-(2 pyridinyl) ethoxy-hexyl) amino methylbenzenemethanol.

Further examples of suitable agents include: the diuretic amiloride; anticholinergics such as ipratropium, ipatropium bromide, atropine, oxitropium and oxitropium bromide, hormones such as cortisone, hydrocortisone and prednisolone; and xanthines such as aminophyl line, choline theophyllinate, lysine theophyllinate and theophylline.

Yet further examples of suitable agents include: analgesics such as codeine, dihydromorphine, ergotamine, fentanyl and morphine, diltiazem which is an anginal preparation; antiallergics such as cromoglycate, ketotifen and nedocromyi; anti- infectives such as cephalosporin, penicillins, Streptomycin, sulphonamides, tetracyclines and pentamidines, and the anti-histamine methapy rilene. Yet further examples include: anti neoplastic agents like bleomycin, carboplatin, methotrexate and adriamycin; amphotericin B; anti-tuberculous agents such as isoniazide and ethanbutol. Therapeutic proteins and peptides (e.g. insulin and glucagon, prostaglandins and leukotrienes) and their activators and inhibitors including prostacyclin (epoprostanol), and prostaglandins E, and E2 are also considered to make suitable substances for treatment using the method of the present invention.

It will be appreciated to the person skilled in the art that, where appropriate, the above listed therapeutic agents may be used in the form of salts (e.g. as alkali metal or amine salts or as acid addition salts and other pharmaceutically acceptable salts thereof) or as esters (e.g. lower alkyl esters) or as solvates (e.g. hydrates) to optimise the activity and/ or stability of the therapeutic agent. Preferably, where the agent is a therapeutic agent it will either be an anti-inflammatory drug or a bronchodilator. More specifically the preferred drugs of the present invention are beclomethasone dipropionate, Salbutamol sulphate, fluticasone propionate, budesonide

The compositions may be formulated by dry mixing the drug and the perfectly spherical monodisperse carrier. The compositions may be formulated into capsules containing a single dose of active material which can be inserted into an appropriate inhaler. Alternatively, they may be placed in a blister or larger container and placed in an inhaler which is designed so as to meter a single dose of the composition into its air passage upon activation. The compositions may be dispensed using any of the conventional Inhalers. Their use in dry powder inhalers of all types is strongly preferred.

Specific embodiment of the invention are now described with reference to the following figures, wherein; Figures la-lc show SEMs of substantially monodisperse or narrow size distribution, near perfectly spherical lactose particles obtained by crystallisation using a mixture of anti-solvents propan-l-ol/acetone; Figures 2a and 2b show SEMs of lactose carrier particles are spherical, monodisperse, showing some surface smoothness, crystallised in the presence of 500 mL ethanol/ 600 mL acetone; Figures 3a and 3b show SEMs of spherical monodisperse lactose particles with polyvinyl pyrrolidone as anti-adherent, the anti-solvents mixture comprising 1000 mL Acetone: 500 mL ethanol;

Figure 4 is an SEM of spherical monodisperse lactose particles with polyvinyl pyrrolidone as anti-adherent where the anti-solvents mixture comprising 500 mL Acetone: 400 mL ethanol;

Figures 5 show SEMs of shell of PLGA after 4 hours immersion in water of spherical lactose of example 4;

Figures 6 show an SEM view of monodisperse spherical lactose-Salbutamol composite particles;

Figures 7a-7f show SEM view of spherical lactose particles before mixing with Aerosil 200 and coated with aerosil and treated with chloroform;

Figure 8 show monodispersed perfectly spherical lactose particles containing two anti- adherents: polyvinyl pyrrolodone and Aerosil; Figure 9 shows spherical lactose particles containing two anti-adherent polyvinyl pyrrolidone and L-leucine;

Figure 10 shows and SEM of the crystallisation of lactose suspension using 3 miscible anti-solvents: Acetone/ ethanol/ isopropyl alcohol (propan-2-ol); Figures 11a and lib show crystallisation of a fine suspension of lactose in the presence of Ant-adherent PVPk90; Figure 12 shows an SEM of a dry powder inhaler formulation comprising spherical narrow size distribution lactose carrier with adhered fluticasone propionate;

Figures 13a-13c show SEMs of engineered spherical particles before and after mixing with aerosol;

Figures 14a and 14 b show SEM views of spherical lactose-Aerosil dipped in Choloroform for 48 hours;

Figures 15a and 15b : General view of spherical lactose Lactose/L-leucine particles;

Figures 16a and 16 show DSC graphs of Lactohale ®;

Figure 16c and 16d show DSC scans of engineered lactose in accordance with the invention;

Figure 17 a shows a Scanning Electron Micrograph of tomahawk shape Lactose Lactohale® sieved size fraction 63-90pm;

Figure 17b shows lactose Lactohale® 63-90 pm;

Figure 17c shows particle size distribution of Lactose Lactohale® sieved size fraction (63-90 pm) Volume Mean Diameter (VMD) =48.72 pm; Figure 18a shows a Scanning Electron Micrograph of engineered lactose spherical particles using a combination of solvent (500 Acetone/ 500 Ethanol);

Figure 18b shows an image of Atomic force microscopy (AFM) of engineered lactose spherical particles using a combination of solvent (500 Acetone/500 Ethanol);

Figure 18c shows a particle size distribution of Engineered Lactose spherical particles using a combination of solvent (500 Acetone/ 500 Ethanol);

Figure 19a shows a Scanning Electron Micrograph of engineered lactose spherical particles (10-20 pm) using a combination of solvent (600 Acetone/500 Ethanol);

Figure 19b shows an image of Atomic force microscopy (AFM) of engineered lactose spherical particles (10-20 pm) using a combination of solvent (600 Acetone/500 Ethanol);

Figure 19c shows the particle size distribution of engineered lactose spherical particles (10-20 pm) using a combination of solvent (600 Acetone/500 Ethanol);

Figure 20 shows an SEM of engineered spherical lactose carrier-Beclomethasone propionate (20:1 ratio w/w);

Figure 21 shows an engineered spherical lactose carrier-Budesonide (20:1 ratio w/ w);

Figure 22 shows an SEM of engineered spherical lactose carrier- salbutamol sulfate (67.5:1 ratio w/w); Figures 23a-23c show SEMs views of the particles crystalised in the presence of PVP k90 + PEG400 + Polysorbate 80;

Figures 24a and 24b show SEMs of the crystallised particle product crystalised in the presence of PVP k90 & PEG400;

Figures 25a and 25b show SEMs of the crystallised particle product crystalised in the presence of PVP k90 & Polysorbate 80; Figures 26a and 26b show SEMs of the crystallised particle product crystalised in the presence of PVP k90; and

Figures 27a and 27b show plots of the differential Scanning calorimetry of Lactose oc-D-lactose monohydrate (Acros®) and Lactose oc-D-lactose monohydrate (Acros®) crystallised in the presence of PVPk90 respectively.

Engineered lactose refers to particles produced in accordance with the present invention. The present invention relates to narrow particles size distribution perfectly spherical particles with anti-adherent properties, controlled surface roughness, size, degree of crystallinity, particle strength. The particles when used in the appropriate particle size and appropriate ratio as a carrier in a dry powder for inhalation they showed exceptionally high fine particle fraction of drugs (hydrophilic and hydrophobic) and also exhibited an excellent tablet hardness when compressed into tablets. The invention also relates to the process of making the particles.

The lactose carrier particles of the invention contains a polymer with anti adherent properties. Polyvinyl pyrrolidone (PVP) is one of the most commonly used synthetic hydrophilic nonionic excipients in pharmaceutical formulations, it is divided into four viscosity grades according to its prees k value (Fikentscher k value): k-15, k-30, k-60, k-90, with the average molecular weight being 10,000, 40000, 160000 and 360000, respectively. K value or molecular weight is an important factor which decides the various properties of PVP. Its soluble in water, chlorinated solvents, alcohol, amine, nitro-paraffin and low molecular weight fatty acids, and is mutually soluble with most inorganic salts and a variety of resin, insoluble in acetone and ether (Chemicalbook of Dai Xiongfeng). PVP sprays are still widely used until now. It can form wet, transparent film on the hair which is shiny and has good lubrication effect and also used as glidant in capsule https:/ / www.chemicalbook.com/ ChemicalProductProperty_EN_cb4209342.htm)

. PVP is known in tablet formulation as a binder but not as anti-adherent.

Polyvinyl pyrrolidone is freely soluble in water and ethanol but not soluble in acetone. Lactose is soluble in water but has limited solubility in ethanol and insoluble in acetone. By contacting lactose/PVP aqueous solution in a crystallisation medium containing a mixture of anti-solvents (ethanol/ acetone) it is possible to adjust the amount of PVP on the lactose particles. At high or equal amount of ethanol, most of the polymer is washed away from the surface of lactose due to PVPs great solubility in ethanol and remains in solution and the formed lactose particles are porous, whereas increasing the amount of acetone compared to ethanol in the crystallisation medium will reduce the solubility of polyvinyl pyrrolidone in the crystallisation medium and most of the polymer will precipitate with lactose forming a coat of PVP on the particles which was obvious from scanning electron micrographs. Thus, by adjusting the proportion of ethanol/acetone in the crystallisation medium we can adjust the amount of PVP on the surface of lactose to provide lactose particles with appropriate surface roughness coupled with anti adherent properties. The performance of an inhaled composition is measured by its fine particle fraction (%FPF as a percentage of fine particle dose to delivered dose). The %FPF obtained with the lactose particles of the invention as a carrier was strikingly high exceeding 70% which was not observed with most if not all engineering and modifications brought to the carrier particles up to date. Now, the question was raised if the excellent aerosolisation was due to lactose carrying the drug down to lowest stages of the impactor or the lactose was able to ease drug detachment from the surface particles. We aerosolised lactose alone without drug particles and we found that lactose remains in the upper stages and not travelling down the impactor. The drugs used here are micronized, micronized drugs are known for their highly cohesive nature. Using lactose of the invention as a carrier was able to ease the aerosolisation and dispersion of drug particles to give a high fine particle fraction. This lactose is expected to improve drug delivery to the lungs in inhaled compositions in which it is included irrespective of the nature of drugs hydrophobic or hydrophilic as it will be shown later in the examples herein. Without changing the amount of lactose, by just changing the proportion of acetone / ethanol in the crystallisation medium we can affect the solubility of polyvinylpyrrolidone deposited on the surface of the particles to obtain the particles with appropriate roughness so as to stabilise the powder mix against segregation but weak adhesion to facilitate drug detachment from the surface of the carrier during inhalation. We showed that removal of polyvinyl pyrrolidone by using a high amount of ethanol in the crystallisation medium did not perform as well as the lactose containing polyvinyl pyrrolidone as anti-adherent. It is also important to note that lactose containing polyvinyl pyrrolidone when high amount of acetone compared to ethanol was used were smoother compared to the particles crystallised in the presence of less acetone due to washing away of PVP from the surface of lactose particles by ethanol/ water during crystallisation.

The particles of the invention are spherical to provide them with a good flow to facilitate filling the DPI, increasing dispersion of drug particles during emission and diluting the drug to improve accurate dosing during filling of capsule, blister and reservoir device. Failure to provide smooth fluidity, will affect drug content uniformity, causing a change in the drug dose in the unit dosage form that an effective treatment cannot be performed. Furthermore, the situation also poses problems at the stage of production and in quality control testing.

The narrow size distribution of carrier is important as it allows drug loading to be similar on each carrier particle. Thus, eliminating the variation in dose emission from the inhaler and drug dosing each time the patient inhales through the device.

Furthermore, the range of removal forces of drug from the carrier surface would be correspondingly narrow.

When the carrier particles all have uniform size, the degree of adhesion of drug to carrier is similar for each particles, so drug detachment from the carrier is uniform and the amount of drug reaching the lungs is consistent.

Most of micronized drugs for inhalation have nearly a flat surface. The adhesion of drug particles with a flat surface to spherical particles is less in comparison to flat- flat surface as it is the case for micronized drug with lactose carrier commonly used in dry powder inhalers (DPIs). Therefore, drug detachment from spherical carrier is easier than from inhalation lactose (tomahawk shape).

The contact between spherical-spherical carrier it resumes to one point of contact contrary to lactose-lactose particles used in the marketed products which is tomahawk shape with a flat surface. Less contact between spherical particles, means less friction between particles due to reduced points of contact between spherical particles and this is reflected in the high emitted dose from the inhaler device as it will be shown later in the examples. The contact points between spherical particles is further reduced by designing spherical particles with a mild roughness so as to provide drug particles with sufficient adhesion to form a stable mix, yet allows easy drug detachment from the surface of the carrier to enhance drug delivery to the lungs.

Although the engineering process is flexible to produce spherical particles of different sizes, we prefer using small particles £ 35 micrometer. For the same mass of lactose carrier, the number of particles is greater for small size lactose (light) particles which will result in a good response to the air flow to lift the static powder formulation and to increase the number of collision between particles themselves and between the particles and the wall of the inhaler device to deaggregate the formulation and efficiently disperse drug particles. Despite carrier particles small size (£ 35 pm), the spherical particles have a good flow contrary to current lactose for inhalation where small particles cannot be used as a main carrier because of their poor flow if the size of carrier is reduced. Furthermore, in the current practice small carrier particles are generally obtained by milling and this generate amorphous powder which is known to be unstable.

The ratio between the carrier and the drug will depend on the type of the inhaler and the drug. Flowever, the quantity of lactose used in current DPI formulations is substantial (1 portion of drug to 67.5 portions of lactose w/w is typical). We found that a small amount of carrier was efficient to disperse drug particles for enhanced drug delivery (1 portion of drug to 20 portions of spherical lactose particles). Using small amount of carrier would leave enough room for the drug making these particles suitable for delivering large dose drugs such as antibiotics and vaccines.

Furthermore, low ratio of carrier to drug in the formulation such as 20:1 w/w, will provide sufficient number of carrier particles for frequent collision between particles but also enough void space for carrier particles to move with sufficient momentum such that the energy transferred to other carrier particles and the wall of inhaler device is sufficient to overcome the adhesive forces for drug detachment.

The surface texture of the spherical particles is manipulated by playing on the solubility of the polymer in the crystallisation medium. The extent of solubility of the polymer depends on the proportion between the non-solvents used. The anti solvents used are both miscible with each other and with similar densities (0.79 g/ centimetre cube for acetone and ethanol). The polymer is freely soluble in one anti-solvent e.g. ethanol but insoluble and precipitates in the other anti-solvent e.g. acetone. Without changing the amount of the polymer in the crystallisation medium, the amount of the polymer in the carrier depends on the anti-solvent ratios. Changing the proportion between the two anti-solvents will either wash-away the polymer from the surface of the particles leaving high surface roughness on the surface of the carrier whist the particles are still in the crystallisation medium or to provide the particles with a smooth surface or mild surface roughness rough surface such as dimples, fine contiguities, hills, valley and the like but smaller than the size of the drug so as drug and carrier have less number of contact points to ease drug detachment from the surface of the carrier particles in a less than a micron size so as all drug particles remain on the surface of the carrier. Thus, the surface topography of the carrier particles can be manipulated so as to stabilise the drug particles against segregation to provide good drug content uniformity, yet lowering the adhesion between drug and carrier for optimal drug detachment from the surface of the carrier during aerosolisation to maximise drug delivery to the lungs. Polymers such as polyvinylpyrrolidone is known for its effective anti-adherent properties in preventing and reducing the adherence of oral bacteria to tooth enamel for example. Thus, polyvinylpyrrolidone is known for its anti- adherent properties but not in solid dosage forms and in particular for inhalation. This polymer was included in our dry powder formulation in this invention to lower drug adhesion to the carrier. To be effective, it is necessary not to remove all the polymer from the surface of the carrier during crystallisation or post crystallisation. The amount of anti-solvent in which the polymer is not soluble must be at least equal or higher than the solvent or anti solvent in which the polymer is soluble.

The polymer also provides strength to the particles, thus avoiding disintegration of the particles in the crystallisation medium caused by the agitation and also avoiding their disintegration post crystallisation to facilitate coating of the particles if required. The coating may be used to enhance resistance of the carrier to moisture to stabilise the dry powder formulation or to facilitate drug dispersion or both. Coating with a polymer post-crystallisation with polylactic co glycolic acid (PLGA) was found to improve the fine particle fraction of beclomethasone — di propionate (BDP) and provides resistance of particles to water ingress. The coated lactose spherical particles remained in longer in water before complete dissolution leaving the water insoluble coat and an example will be provided in the examples section. Crystallisation or precipitation of the particles in the presence of drugs and additives such as anti-adherents, lubricants was possible without deviating from the spherical shape. Crystallisation in the presence of organic substances such as salbutamol sulphate, amino acids such as L-leucine, and inorganic substances such as adsorbent and water scavenger Aerosil was possible. This shows the robustness of the crystallisation process to be able to include a composition of one or more substances in one particle. This will be interesting in many applications within inhalation and in the other fields but not limited, to pharmaceutical applications, nutrition, food industry, agriculture and the like. Composite particles comprising a drug for inhalation and carrier small enough (< 10 micrometres) to reach the lungs was also possible without deviating from spherical shape. This has the advantage of avoiding any further processing to the powder formulation, such as mixing whilst achieving 100% drug content uniformity. An example of particles composite of lactose-salbutamol sulphate is provided in the examples section.

The particles of the invention have a great crushing strength up to 6 times superior to commercial lactose when compressed into tablets. The strength of the particles is important to protect the particles against abrasion during handling, transportation, coating and packaging.

They are many fields in which the particles of the invention would be of particular advantages, for example carrier and drug particles for use in inhaled pharmaceutical formulations and tablet formulation to enhance tablet strength for poorly compressible drugs and an example for compression force- tablet hardness profile for the particles of the invention will be given in this invention.

The particles can be prepared with different degrees of crystallinity depending on the condition of crystallisation (agitation, temperature of the crystallisation medium and the proportion between the two anti-solvents).

The administration of drugs by inhalation has been recognised as a valuable technique, particularly in the treatment of diseases of the respiratory tract. The efficacy of the technique has been limited by difficulty in making appropriate dosages available to the lungs. The delivery systems currently available are nebulisers, pressurised metered dose inhalers and dry powder inhalers. Nebulisers are relatively effective but they are expensive and bulky and as a result are mainly used in hospitals. Pressurised metered dose inhalers require good co-ordination of actuation and inhalation which presents difficulties to many patients. They also require the use of propellants which may be undesirable on environmental grounds.

In order to grow uniform crystals in the presence of agitation and without the formation of any chipped crystals and aggregates, the choice of the crystallisation medium and conditions of crystallisations must be chosen judiciously. Some polymeric materials are commonly known to be used as binders in the wet granulation for tablet formulation, which provide strength to the granules not to de aggregate during handling and processing. By adding such polymeric materials in the crystallisation medium will facilitate the formation of the crystals into desired shape, provide the suspended particles with strength to resist abrasion and collusion between the agitation device-particles, particle -particle, particle-the wall of the vessel. The polymer also plays an important role as a particle surface texture modifier when it has some solubility in at least one of the anti-solvents, thus when the proportion of the anti-solvent changes, the solubility of the polymer in the anti solvent will increase or decrease to provide particles with different surface textures. In dry powder inhalers the interaction between drug and carrier is a surface phenomenon and the extent of adhesion between drug and carrier depends on the carrier surface. Thus, by choosing the right anti-solvent and the right polymer, it becomes possible to obtain the desired surface texture of the carrier that stabilises the powder mix (drug-carrier) and promotes drug detachment from the carrier surface for optimal drug delivery to the lungs.

Conventionally, despite the progress made in particle engineering drug and carrier, pulmonary drug deposition rate can be as high as 40% of the administered dose, provided patients use optimally controlled inhalation flows through the device, otherwise lung deposition can be as low as —15% [Federico Lavorini, Massimo Pistolesi and Omar S. Usmani., (2017). Recent advances in capsule-based dry powder inhaler technology. Multidisciplinary Respiratory Medicine, Vol. 12, pp. 1-11. DOI 10.1186/ s40248-017-0092-5]. An interesting review by A. H. de Boer P. Hagedoorn, M. Hoppentocht, F. Buttini, F. Grasmeijer and Ft. W. Frijlink., (2017). Dry powder inhalation: past, present and future. EXPERT OPINION ON DRUG DELIVERY, Vol.14, NO. 4, pp. 499—512] compared in vitro delivered fine particle doses as percent of label claim (FPFs < 5 pm) from various DPIs on the market. The fine particle fraction [FPF < 5 pm] measured as a percentage of label claim was as low as 10% and failed to achieve 50% for the most sophisticated inhaler devices.

In DPIs the carrier physical properties such as particle size, polydispersity, shape and surface texture play a significant role in determining DPI performance since they influence the adhesion and drug detachment from the surface of the carrier. Drug delivery to the lungs still low as more than 50% of drug is wasted. The reason for this is that most of study on carrier focused on one parameter either looking at the effect of carrier particle size ignoring surface texture, polydispersity of the carrier, drug to carrier ratio etc. or focusing on surface smoothness and ignoring other parameters. Drug delivery from DPIs is still far from ideal in terms of performance to maximise drug delivery to the lungs. The interdependence between all physicochemical properties makes it challenging to produce a desired carrier with all optimal properties for superior performance. No study so far tried to put all the teaching in one particle to produce superior carrier particles optimal for drug delivery to the lungs. Therefore, the object of this invention is to provide superior carrier particles assembling all teaching in one particle to provide a high drug dose to the lungs exceeding those reported in the literature. The Fine particles fraction achieved by engineering a novel lactose carrier exceeded 70% of the delivered dose.

The progress made in particle engineering of drugs and carrier and intensive work made in dry powder: particle size, shape, surface texture. The optimal results were not achieved in terms of drug delivery efficiency because the focus was made on one parameter such as carrier size or shape, or surface roughness and not taking into account all parameters together that is why optimal drug deposition was not fully achieved. All the teaching gained from the literature was put in to produce one single particle having all desired properties to maximise drug delivery to the lungs using hydrophilic and hydrophobic drugs.

Our Fine Particle Fraction (% FPF as a percentage of delivered dose) was exceptionally high compared to the literature using conventional anti-adherents such as silica, magnesium stearate or L-leucine. The presence of polymer polyvinyl pyrrolidone (PVP) as anti-adherent facilitates drug detachment of drug from the surface of the carrier as it will be demonstrated by examples. In this invention we used a combination of two anti-solvents namely acetone in which PVP is not soluble and ethanol in which PVP is freely soluble. When the volume of both anti-solvents is equal such as in the example 500 mL/ 500 mL the fine particle fraction (FPF) was low, this could be explained by the high solubility of PVP in this mixture and being washed away from the surface of the particles (Scanning electron micrographs showed porous structure). Where as for the experiment 1000/ 500 Acetone/ ethanol, the precipitation of the polymer with the particles was immediate, suggesting more polymer was left on the surface of the particles providing them with anti-adherent property to allow easy drug detachment.

Experimental and Examples

Example 1: Propan-l-ol and acetone as anti-solvents. It is interesting to note that the particles are perfectly spherical and all have the same size (monodiperse) as claimed in in the present invention.

Method:

1) 1 gram of polymer polyvinyl pyrrolidon (PVP k90) as anti-adherent is dissolved in 100 mL ultra purified water 2) 10 grams of lactose oc-D-lactose monohydrate, 99.5% + 2.4% beta isomer (ACROS, UK) was dissolved in the above solution at room temperature.

3) in a 5L beaker, mix the anti-solvent together: 500 mL acetone and 500 mL propan-l-ol and stir at 500 RPM using Heidolph 3 blades stirrer. 4) introduce the solution 2) to 3) to constitute a crystallisation medium under stirring for 15 minutes at room temperature.

5) allow to settle for 20 minutes.

6) discard the crystallisation medium and keep the particles settled at the bottom of the 5 Litre beaker. 7) Add about 50 mL chloroform (highly volatile solvent and does not affect the shape of the particles) to disperse the particles

8) Pour the dispersion on a glass slab, allow chloroform to evaporate leaving free flowing powder on the glass slab which was easy to remove from the glass by a mean of a razor blade and the powder is transferred to a glass petri-dish. 9) Allow the particles to dry in an oven at 50 Celcius for 48 hours before collecting the particles.

Figure la shows the monodisperse perfectly spherical lactose particles obtained by crystallisation using a mixture of anti-solvents propan-l-ol/ acetone.

The difference in the surface texture between those particles prepared using ethanol and propan-l-ol. Particles prepared using propan-l-ol are smoother than those obtained with ethanol using the same crystallisation conditions (volume, temperature, agitation).

We don’t appear to be bound by any theory: the difference between the surface texture could be due to the difference in the solubility of PVP in these two solvents. Acetone is slightly more hydrophobic compared to ethanol. Method for forming crystalline hollow porous spherical particles using ethanol:

1) In a 600 ml glass beaker, dissolve 10 grams of lactose oc-monohydrate in 100 ml of deionised water at room temperature under stirring. Add lg polyvinyl pyrrolidon k90 (PVPk90) to lactose solution and allow it to dissolve at room temperature under stirring.

2) Using a 5 Litre glass beaker, pour 500 ml acetone and 320 ml absolute ethanol and allow to stir at 500 rpm using 3 blade heidolph stirrer.

3) Add lactose/PVP K90 solution to acetone/ ethanol solution and allow it to stir at 500 rpm for 15 minutes. 4) Remove the beaker and allow the crystals to settle down until you see a clear solution on top and all particles are settled down (estimated time about 30 minutes)

5) Remove the liquid to obtain solid particles.

6) Add a highly volatile solvent to the beaker containing solid particles to obtain a suspension of solid particles in the highly volatile solvent. 7) Pour the suspension on a glass ointment slab to allow evaporation of the solvent leaving solid particles.

8) Scrape the particles by mean of a razor blade.

9) Transfer the powder into a tray and allow the particles to dry in a ventilated oven at 50°C for 48 hours. 10) Put the particles in a glass jar and store the particles at room temperature in a glass jar over silica gel in a desiccator.

Example 2: Equal volume of Ethanol and Acetone in the crystallisation medium. . Polyvinyl pyrrolidone (PVP) is freely soluble in ethanol and water. The total volume in which the PVP is soluble in this example is 600 mL (500 mL of ethanol + 100 mL of water). Therefore this volume is higher than the volume of acetone (500 mL), solvent in which PVP is not soluble. It is likely that some PVP is dissolved from the surface of lactose carrier particles resulting in less-anti-adherent on the surface of lactose particles. It is interesting to note that the particles are perfectly spherical and all have the same size (monodip erse) as claimed in claim 1.

Method: 1)1 gram of polymer polyvinyl pyrrolidon (PVP k90) as ANTI- ADHERENT is dissolved in 100 mL ultra purified water

2)10 grams of lactose lactohale® was dissolved in the above solution at room temperature.

3) in a 5L beaker, mix the anti-solvent together: 500 mL acetone and 500 mL ethanol and stir at 500 RPM using Heidolph 3 blades stirrer.

4) Introduce the solution 2) to 3) to constitute a crystallisation medium under stirring for 15 minutes at room temperature.

5) Allow to settie for 30 minutes.

6) Discard the crsytallisation medium and keep the particles settled at the bottom of the 5Litres beaker.

7) Add about 50 mL chloroform (highly volatile solvent and does not affect the shape of the particles) to disperse the particles

8) Pour the dispersion on a glass slab, allow chloroform to evaporate leaving free flowing powder on the glass slab which was easy to remove from the glass by a mean of a razor blade and the powder is transferred to a glass petri-dish.

9) Allow the particles to dry in an oven at 50 Celcius for 48 hours before collecting the particles.

Figure lb shows lactose carrier particles that are spherical, monodisperse, showing some surface roughness caused by the removal of the PVP by the water soluble solvents from the surface of lactose resulting in rough surface . Crystallised in the presence of 500 mL ethanol/ 500 mL acetone. Figure lc is a close view of lactose particles shown above. The surface texture of lactose carrier is rough with some pores on the surface.

The lactose carrier particles shown in Example 1 were formulated with beclomethasone di-propionate (BDP, volume mean diameter = 4.2 micrometers) in a ratio of l:67.5w/w. The aerosolisation was carried out using Breezhaler^® at 90 L/ min and 4 litres inhaled volume into an Andersen Cascade Impactor. Most of BDP deposited in the USP throat and preseparator. The fine particle dose was very low.

Example 3: The amount of acetone is high compared to ethanol.

To reduce the solubility of polyvinyl pyrrolidone in the crystallisation medium we have increased the volume of acetone and we reduced the temperature of the crystallisation medium to 6 degree Celcius. The particles are perfectly spherical and all have the same size (monodiperse).

Method:

1) lgram of polymer polyvinyl pyrrolidon (PVP k90) as ANTI -ADHERENT is dissolved in 100 mL ultra purified

2)10 grams of lactose lactohale () was dissolved in the above solution at room temperature.

3) in a 5L beaker, mix the cooled anti-solvent together: 600 mL acetone and 500 mL ethanol and stir at 1000 RPM using Eteidolph 3 blades stirrer. 4) Introduce the solution 2) to 3) to constitute a crystallisation medium under stirring for 15 minutes at 6degree Celcius.

5) Allow to settie for 45minutes.

6) Discard the crsytallisation medium and keep the particles settled at the bottom of the 5Litres beaker. 7) Add about 50 mL chloroform (highly volatile solvent and does not affect the shape of the particles) to disperse the particles

9) Allow the particles to dry in an oven at 50Celcius for 48 hours before collecting the particles.

Figure 2a shows the Lactose carrier particles are spherical, monodisperse, showing some surface smoothness . Crystallised in the presence of 500 mL ethanol/ 600 mL acetone.

Figure 2b shows a close view of lactose particles shown in figure 2a. The surface texture of lactose is smoother compared to the particles in example 1.

Deposition study of a water insoluble drug Beclomethasone di-propionate (BDP) from formulation containing perfectly spherical lactose with Polyviny pyrrolidon as anti-adherent (lactose of example 3). The lactose carrier of example 3 was formulated with beclomethasone di-propionate (BDP, volume mean diameter = 4.2 micrometers) using drug to carrier ratios: 1:67.5 w/w, 1:33 w/w and 1:20 w/w. The aerosolisation was carried out using Breezhaler^® at three inhalation flow rates 28.3L/ min, 60 L/ min and 90 L/ min and 4 litres inhaled volume. The BDP deposition data from an Andersen Cascade Impactor is summarised in Table 1.

Table 1: The Beclomethasone di-propionate (BDP) deposited inside the impactor and inhaler allows for the calculation of drug deposition and aerodynamic parameters. The total recovered dose (TRD) is the amount of drug quantified by HPLC and it is calculated as the sum of the amount of drug deposited in capsule, device, mouth piece, USP throat, pre-separator, stages of the Andersen cascade impactor and the filter. The Total Emitted Dose (TED) or delivered dose is the mass of drug emitted per actuation that is actually available for inhalation at the mouth. Large particle mass (LPM) is the mass of particles> 5 pm collected from the induction port and Pre- separator. Residual amount (RA) deposited in the capsule and device. The Fine Particle Dose (FPD) is the mass of drug < 5 pm calculated from log-probability plot and the Fine Particle Fraction (%FPF) is the ratio of the (FPD to the TED)*100 considered therapeutically active reaching deep lung. Extra fine Particle Dose (EFPD) <2 pm. Mass of drug associated with particles less than 2 micrometer. The mass median aerodynamic diameter (MMAD) divides the aerosol size distribution in half. It is the diameter at which 50% of the particles of an aerosol by mass are larger and 50% are smaller. The geometric Standard deviation (GSD) is the square root for the size corresponding to 84.1% less than the stated size divided by the square root of the size for 15.9% (GSD = Sq d84.1/dl5.9), where dl5.9 and d84.1 are the sizes corresponding to the mass-percentile values of 15.9% and 84.1% respectively, for the cumulative size distribution is representing the dispersion of the inhaled particles whereas Aerosols with a GSD > 1.22 are considered polydisperse and particles with GSD of £ 1.2 are monodisperse. Most therapeutic aerosols are considered polydisperse and have GSDs in the range of 2-3.

Note: The %FPF obtained in this invention equal to 70.68% is far higher when compared to the work done so far in carrier engineering including patents and publications. The high %FPF was due to drug detachment from the surface of the carrier. We aerosolised 27 mg lactose carrier of the invention into an Andersen Cascade Impactor (ACI) and we analysed the lactose using Refractive Index. No lactose was found in the lower stages of the impactor (Table 2) suggesting that the strikingly high %FPF is due to ease of drug detachment from the lactose carrier. A substantial amount of drug was released at very low inhalation flow of 28.3 L/ min suggesting the efficiency of this lactose to promote drug detachment even at very low inhalation flow.

Table 2: Results from the aerosolisation data at different flow rates for both lactose Lactohale and lactose carrier of the invention after aerosolisation of 27mg from Breezhaler into an Andersen Cascade Impactor.

Example 4: Deposition study of a water soluble drug Salbutamol sulphate (SS) from formulation containing perfectly spherical lactose with Polyviny pyrrolidon as anti adherent as carrier (Lactsoe of example 3).

Again the % FPF exceeded 50% for water soluble drugs such as Salbutamol showing good performance of the perfectiy spherical particles with anti-adherent as a carrier.

Example 5: The amount of acetone is high compared to ethanol.

To reduce even more the solubility of polyvinyl pyrrolidone in the crystallisation medium we have increased the volume of acetone and we reduced the temperature of the crystallisation medium to 5 degree Celcius. Particles are perfectly spherical and all have the same size (monodip erse).

Method:

1) lgram of polymer polyvinyl pyrrolidon (PVP k90) as ANTI-ADHERENT is dissolved in 100 mL ultra purified

2)10 grams of lactose lactohale was dissolved in the above solution at room temperature.

3) in a 5L beaker, mix the cooled anti-solvent together: 1000 mL acetone and 500 mL ethanol and stir at 1000 RPM using Heidolph 3 blades stirrer. 4) Introduce the solution 2) to 3) to constitute a crystallisation medium under stirring for 15 minutes at 5 degree Celcius.

5) Allow to settie for 2 hours. 6) Discard the crsytallisation medium and keep the particles settled at the bottom of the 5Litres beaker.

7) Add about 50 mL chloroform (highly volatile solvent and does not affect the shape of the particles) to disperse the particles 8) Pour the dispersion on a glass slab, allow chloroform to evaporate leaving free flowing powder on the glass slab which was easy to remove from the glass by a mean of a razor blade and the powder is transferred to a glass petri-dish.

Scanning electron micrographs of the [particles crystallised using 1000 mL Acetone and 500 mL ethanol are shown in figure 3a, which is a general view of perfectly spherical monodisperse lactose particles with polyvinyl pyrrolidone as anti-adherent. The anti-solvents mixture comprising 1000 mL acetone: 500 mL ethanol.

Figure 3b shows a close view of Perfectly spherical monodisperse lactose particles with polyvinyl pyrrolidone as anti-adherent. The anti-solvents mixture comprising 1000 mL Acetone: 500 mL ethanol. Example 6: Coating perfectly spherical particles with polylactic co glycolic acid (PLGA) to increase their resistance to moisture.

400 mL Ethanol and 500 mL Acetone Method: l)lgram of polymer polyvinyl pyrrolidon (PVP k90) as ANTI-ADE1ERENT is dissolved in 100 mL ultra purified

2)10 grams of lactose Lactohale oc-monohydrate was dissolved in the above solution at room temperature. 3) in a 5L beaker, mix the anti-solvent together: 500 mL acetone and 400 mL ethanol and stir at 500 RPM using Heidolph 3 blades stirrer.

4) Introduce the solution 2) to 3) to constitute a crystallisation medium under stirring for 15 minutes at room temperature. 5) Allow to settie for 30 minutes.

6) Discard the crystallisation medium and keep the particles settled at the bottom of the 5Litres beaker.

Figure 4a shows a general view of perfectly spherical monodisperse lactose particles with polyvinyl pyrrolidone as anti-adherent. The anti-solvents mixture comprising 500 mL Acetone: 400 mL ethanol. Coating the above particle using PLGA:

0.2 g PLGA was dissolved in 100 chloroform.

1 gram of the particles shown in Figure 4a was dispersed in PLGA solution to form a suspension. The suspension was stirred at room temperature for 30 minutes at room temperature under the fame hood and the suspension was poured over a glass slab. Allow the solvent to dry and recover the particles.

The particles were tested for their resistance to water. The coated particles were immersed in 50 mL ultra purified water under agitation at room temperature using a magnetic stirrer. After 4 hours the particles were collected by filtration under vacuum and taken to be viewed by scanning electron microscope.

Figure 5a shows a shell of PLGA after 4 hours immersion in water of spherical lactose of example 4. Shell shows the finger print of the surface texture of spherical lactose. Evidence that the lactose particles were coated with PLGA. Figure 5b shows a close view of the PLGA coat.

Example 7: Composite particle: monodisperse perfectly spherical lactose-salbutamol sulphate composite.

This example demonstrating that more than one substance can be crystallised to produce perfectiy monodisperse spherical particles.

Method:

1)lgram of polymer polyvinyl pyrrolidon (PVP k90) as ANTI-ADE1ERENT is dissolved in 100 mL ultra purified

2)1 gram of salbutamol sulphate and 9 gram lactose Lactohale oc-mono hydrate were dissolved in the above solution at room temperature. The ratio of drug to carrier is 1 to 9 w/w.

3) in a 5L beaker, pour the cooled anti-solvent mixture (Temperature of Anti-solvent mixture = 6 degree Celcius): 1000 mL acetone and 500 mL ethanol and stir at 1100 RPM using Eteidolph 3 blades stirrer.

4) Introduce the solution 2) to 3) to constitute a crystallisation medium under stirring for 15 minutes.

5) Allow to settie for 45minutes.

6) Discard the crsytallisation medium and keep the particles settled at the bottom of the 5 Litres beaker. 7) Add about 50 mL chloroform (highly volatile solvent and does not affect the shape of the particles) to disperse the particles

9) Allow the particles to dry in an oven at 50 Celcius for 48 hours before collecting the particles. Figure 6a shows a general view of monodisperse perfectly spherical lactose- Salbutamol composite particles and figure 6b shows a close view of monodisperse perfectly spherical lactose-Salbutamol composite particles. The particles are about 5 pm size suitable for delivery to the lungs. Example 8: Post crystallisation treatment of the perfectly monodisperse spherical particle with colloidal silica (Aerosil) as an anti-adherent.

Anti-adherent, fine sugar powder, magnesium stearate, L-leucine and the like are usually added to apowder formulation for inhalation using physical mixing. Efowever, these fine powder may reach the lungs. To avoid this we attempted to fuse the anti- adherent on the spherical lactose particles so as to smooth out lactose whilst preventing it’s detachment from lactose when used in an inhaled composition for inhalation.

The Scanning electron micrographs of figures 7a and 7b show the spherical particles before mixing with Aerosil.

Method:

1 gram of spherical lactose was mixed with 5 milligram of colloidal silica (Aerosil 200) using an order mix, followed by blending for 32 minutes in a turbula mixer at 72 min-1, followed by sieving the powder uning 250 micrometer sieve and blending in a turbula mixer again for 2 minutes. The technique of blend-sieve-blend is mandatory when using colloidal silica to achieve an excellent filling of surface crevices of lactose. A scanning electron micrograph shows the quality of the mix and full coverage of spherical lactose.

Figure 7c shows a physical mix of spherical lactose-colloidal silica and figure 7d shows a close view of physical mix of spherical lactose-collidale silica. Full coverage of lactose particles.

The particles above may release colloidal silica if inhaled in a pharmaceutical composition. To adhere the particles irreversibly on the surface of lactose we decided to treat the particles of Figure 7c and 7d with a solvent in which lactose is not soluble.

The particles of Figure 7c and 7d were dipped in 50 ml chloroform under gentile stirring using a magnetic stirrer for 10 minutes to adhere irreversibly colloidal silica on lactose as shown in the scanning electron micrographs (Figure 7e and figure 71). Figures 7e and 7f: Show views of spherical lactose particles coated with aerosil and treated with chloroform. The surface treatment of lactose has smoothed out lactose surface by attaching irreversibly colloidal silica on lactose.

Note in the previous examples we have showed that surface adjustment of lactose particles can be achieved in the crystallisation medium (Examples 1 to 3) or on the particles themselves post crystallisation as shown from Example 7 below.

Example 9: Crystallisation of lactose in the presence of Aerosil This example demonstrating that lactose can be crystallised in the presence of more than one anti-adherent without affecting its shape.

Method: l)lgram of polymer polyvinyl pyrrolidon (PVP k90) as ANTI -ADHERENT is dissolved in 100 mL ultra purified;

2)10 gram lactose Lactohale oc-mono hydrate was dissolved in the above solution at room temperature;

3) in a 5L beaker, pour a mix of 320 mL ethanol and 500 mL acetone and stir at 500 RPM using Heidolph 3 blades stirrer.

4) Add 0.5 gram colloidal silica (Aerosil 200) in the ethanol/ acetone mixture under stirring at 500 RPM to form a colloid solution;

4) Introduce the solution 2) to 4) to constitute a crystallisation medium under stirring at 500 RPM for 15 minutes. 5) Allow to settie for 30 minutes.

6) Discard the crsytallisation medium and keep the particles settled at the bottom of the 5 Litres beaker.

Ligure 8 shows a monodisperse perfectly spherical lactose particles containing two anti-adherents: polyvinyl pyrrolodone and Aerosil. The crystallisation in the presence of Aerosil did not affect the shape of the particles. The Scanning electron micrograph shows aerosil attached to the spherical particles

Example 10: Crystallisation of lactose in the presence of L-leucine

This example demonstrating that lactose can be crystallised in the presence of more than one anti — adherent without affecting the shape of the particles.

Method: l)lgram of polymer polyvinyl pyrrolidone (PVP k90) as ANTI -ADHERENT is dissolved in 100 mL ultra purified;

3) 1 gram of L-leucine was dissolved in 2) to form a solution 4) in a 5L beaker, pour a mix of 320 mL ethanol and 500 mL acetone and stir at 500

RPM using Heidolph 3 blades stirrer.

4) Introduce the solution 3) to 4) to constitute a crystallisation medium under stirring at 500 RPM for 15 minutes.

5) Allow to settie for 30 minutes. 6) Discard the crsytallisation medium and keep the particles settled at the bottom of the 5 Litres beaker.

9) Allow the particles to dry in an oven at 50 Celcius for 48 hours before collecting the particles. Figure 9 shows perfectly spherical lactose particles containing two anti-adherent polyvinyl pyrrolidone and L-leucine. The presence of L-leucine provided some surface smoothness to the lactose particle witout affecting its spherical shape.

Example 11: Crystallisation of lactose/anti adherent (PVP) using a very fine suspension of lactose in a mix of 3 miscible anti-solvents

Method:

1) lgram of polymer polyvinyl pyrrolidon (PVP k90) as ANTI-ADE1ERENT is dissolved in 100 mL ultra purified

2)10 grams of lactose lactohale was partially dissolved in the above solution at room temperature to obtain a very fine suspension. The very fine particles of lactose are observed with naked eye.

3) in a 5L beaker, mix anti-solvent together: 600 mL acetone, 500 mL ethanol and 50 mLisopropyl alcohol and stir at 500 RPM using Heidolph 3 blades stirrer.

5) Allow to settie for 30 minutes.

9) Allow the particles to dry in an oven at 50Celcius for 48 hours before collecting the particles. Figure 10 shows the crystallisation of lactose suspension using 3 miscible anti solvents: Acetone/ethanol/isopropyl alcohol (propan-2-ol). Neither the suspension nor the added anti-solvent affected the shape of the particles. Example 12: Crystallisation of lactose/anti adherent (PVP) using a very fine suspension of lactose in a mix of 3 anti-solvents: Acetone/ ethanol/Tetrahydrofuran. Aqueous phase is not miscible with tetrahydrofuran.

Method: 1) lgram of polymer polyvinyl pyrrolidon (PVP k90) as ANTI-ADE1ERENT is dissolved in 100 mL ultra purified

2)10 grams of lactose lactohale was partially dissolved in the above solution at room temperature to obtain a very fine suspension. The very fine particles of lactose are observed with the naked eye. 3) in a 5L beaker, mix anti-solvent together: 600 mL acetone, 480 mL ethanol and

20 mL tetrahydrofuran and stir at 500 RPM using Eteidolph 3 blades stirrer.

5) Allow to settie for 30 minutes. 6) Discard the crsytallisation medium and keep the particles settled at the bottom of the 5Litres beaker.

9) Allow the particles to dry in an oven at 50Celcius for 48 hours before collecting the particles. Figure 11a shows crystallisation of a fine suspension of lactose in the presence of Ant-adherent PVPk90. Some of the particles are hollow. Figure lib shows close view of a rough/hollow lactose particle containing an anti-adherent PVPk90. Crystallisation of a suspension of lactose/anti- adherent PVP in the presence of two miscible anti-solvents acetone/ ethanol and a non-miscible anti-solvent with aqueous phase tetrahydrofuran.

Example 13: Inhaled composition comprising perfectly spherical monodisperse lactose carrier with adhered fluticasone propionate in a ratio of drug to carrier 1:20 w/w.

Figure 12 shows a dry powder inhaler formulation comprising perfectly spherical monodisperse lactose carrier with adhered fluticasone propionate. Size of the carrier is smaller than 10 pm. BDP particles are adhered to the surface and available for inhalation.

Example 14: Perfectiy monodisperse spherical particles obtained by crystallising Kerry’s lactose oc-monohydrate. 400 mg Tablets were made by compressing monodisperse perfectly spherical lactose and Kerry’s lactose using a flat faced punches using a single punch press at different compression forces. Tablet hardness for monodisperse perfectly spherical lactose was up to 5 times higher to Kerry’s lactose. Results are means and standard deviation of four determinations.

Table below: Tablet hardness of tablets formed from commercial Kerry’s oc-lactose monohydrate and perfectly spherical monodiperse lacose.

Note: The spherical particles were crystallised using Kerry’s lactose as a raw ingredient.

Recovery of the crystals: Filtration can sometimes lead to the formation of a cake or paste like or slurry caused by compression of particles over each other, especially if filtration is carried out under vacuum. We developed our own method of recovering free flowing single particles as shown in the scanning electron microscopy.

The settled crystals obtained above, we discarded the solvent and we left the particles at the bottom of the beaker. We added a very small amount of a highly volatile solvent such as chloroform or FIFA or any high volatile solvent which does not dissolve the particles (Chloroform was used in our case). Working under a fume hood, the dispersed particles were emptied on a glass ointment square slab (flat glass tile). Since the solvent is highly volatile, it is dried almost immediately leaving solid particles dispersed on the glass slab. Scrapping the particles from the slab by mean of a razor blade. The particles recovered were separated from each other and free flowing immediately after recovery as shown in the scanning electron microscopy. The recovered particles were left to dry in a ventilated oven for 48hours at 50°.

We engineered lactose particles for use in different pharmaceutical applications such as tablet formulation by direct compression. Their compressibility was superior to the most compressible excipient on the market such as microcrystalline cellulose (Results are available). Therefore the engineered particles are more compressible than any other pharmaceutical excipients on the market. In inhalation these particles were found to be uniformly spherical (elongation ratio— 1), porous, hollow, a- lactose monohydrate, crystalline and stable over a range of relative humidities (RH).

Particular drawbacks associated with conventional means of producing pharmaceutical grade lactose relates to undesirable variations in particle size, size distribution and morphology. These conventional production methods are particularly problematic in that they often lead to excessive and undesirable variations in the fine particle dose of the delivered pharmaceutical active. Lactose morphology is believed to be another important parameter to control, and it is believed that the degree of surface roughness can influence the interaction between the lactose particle and excipient, and as such is now often measured as part of the lactose selection criteria.

Lactose of the present invention overcomes all above drawbacks because it is monodisperse, uniform in size, shape and surface texture as shown from the SE Micrographs.

Comparative flow properties:

Flow properties of lactose as measured by shear flow cell:

Flow function (FFC) Lactohale: 5.96 FFC Engineered lactose: 8.83.

Higher value of FFc for engineered lactose suggesting better flow.

2) Conclusion

• Tableting results showed the superiority of engineered spherical particles, therefore they can improve the tablet-ability of poorly compressible drugs using the most economical method of tableting (such as direct compression).

• Lactose is brittle and its compaction into tablet is not time dependent, therefore when tablet formulation containing the engineered particles is transferred from slow speed tableting machine such as single punch machine to fast tableting machine such as rotary machine, no or little change in the crushing strength will be observed. This is an advantage over plastically deforming material such as microcrystalline cellulose whose compressibility is time dependent and increasing the compression speed will cause a reduction in the tablet strength.

• The characterization carried out recently on the particles showed that they are hollow and porous. These particles may provide drug particles with long time of flight to promote drug detachment during inhalation by a patient to maximize drug delivery to the lungs. · Other applications: These particles have an elongation ration of 1 and they can be used as core for controlled release microparticulates.

• The spherical particles are spherical, crystalline with very good flowability (data available) can be used for needle-less injection using supersonic drug delivery systems.

Example 15 - Experiment with flow activator colloidal silica (Aerosil 200)

10 grams of engineered spherical lactose particles of the invention were mixed with 50 milligrams of Aerosil 200 using an order mix followed by blend-sieve-blend. Initial blend was carried out in a 40 mL glass vial using Turbula mixer at 45 min-1 for 2 minutes, followed by sieving using a stack of sieves comprising 500 pm, 250pm and a collecting pan. The aim of sieving was to break up aerosil agglomerates to to allow them pass through the sieves into the collecting pan. The sieved powder was further blended for 2 minutes using Turbula mixer for 2 minutes at 45 min-1. The final mix was carried out using Turbula mixer at 72 min-1 for 10 minutes.

Figure 13a shows spherical particles before mixing with aerosol and figure 13b shows the general view of the physical mix of engineered spherical lactohale-Aerosil 200. Figure 13d shows a fractured particle showing the thickness of Aerosil coating lactose particle. Example 16: Treating the engineered particles-Aerosil by dipping the particles in chloroform to enhance aerosol adhesion to lactose as shown in the scanning electron micrographs 14a and 14b (general view of spherical lactose-Aerosil dipped in Choloroform for 48 hours, and close view showing spherical lactose-Aerosil dipped in Choloroform for 48 hours respectively).

1 gram of spherical lactohale-Aerosil particles were dipped in chloroform, mixed with the mean of magnetic stirrer and stored in a cold place for 48 hours. The suspension was poured over glass slab to allow solvent evaporation and recovering the particles from the glass slab using a razor blade. The particles were left to dry in a ventilated oven at 40C for 48 hours.

The generated particles are smooth with enhanced aerosol adhesion to lactose. This is important to adhere strongly aerosol to lactose to prevent its detachment during aerosolisation from dry powder inhaler.

From this experiments, it is clear that aerosil is a lactose surface modifier. This lactose treatment with aerosil allows full coverage of lactose to fill up crevices, so when formulated into dry powder inhalers the drug will remain at the surface rather than been hidden in the crevices or cavities. The surface treatment of lactose in this way can facilitate drug detachment from the surface of the lactose carrier to enhance the amount of drug reaching the lungs.

Example 17: Crystallisation of lactose in the presence of Aerosil.

The aim of this experiment was to investigate the feasibility of crystallising more than one substance in a single particle without deviating from spherical shape. 10 grams of lactohale was dissolved in 100 mL ultra-pure water in a 1 L glass beaker. After complete dissolution of lactose we added lgram of PVP k90 and allow it to dissolve. In a 5 L glass beaker, we added 500 mL acetone and 320 mL ethanol absolute and allow it to mix for 2 minutes using 3 blades heidolph stirrer. We added 0.5 aerosil and allow it to disperse to form a colloidal solution. The above lactose solution was poured into the crystallisation medium by the mean of a 100 mL volumetric cylinder quickly and allow it to stir for 15 minutes at 500 rpm. After 15 min of stirring, the beaker was removed and allow it to stand at room temperature. The solvent was emptied into another beaker so that only solid particles are maintained. To the solid particles we added a high volatile solvent chloroform to disperse the particles. The suspension was emptied onto a glass slab to allow rapid solvent evaporation under fume hood so that only solid particles remained on the glass slab. The solid particles were recovered by scrapping them from the glass to obtain free flowing powder.

The particles were poured into a glass petri dish and left to dry at 50 C in a ventilated Memmert oven for 48 hours. Scanning electron micrographs are shown in the figures 15a and b wherein the particles look smoother than spherical particles crystallised without L-Leucine. L-Leucine can be considered a surface texture modifier.

Turning now to figures 16a-16d which are Differential Scanning Calorimetry (DSC) thermograms of Lactohale ® sieved fraction 63-90 pm (fig. 16a), Lactohale ® sieved fraction <45 pm (fig. 16b), engineered lactose according to the present invention crystallised using acetone (500 mL) /ethanol (500 mL) (fig 16c) and engineered lactose according to the present invention <45 pm. Both DSC scans (fig 16a and 16b) of Lactohale® 63-90 pm and <45pm showed that Lactohale is oc-lactose monohydrate: Endothermic transition at 147C corresponds to loose of water of dehydration and endothermic transition at 223C corresponds to melting of oc-lactose.

The DSC scan of engineered lactose 150 pm is similar to Lactohale, therefore the engineered lactose 150 pm is a- lactose monohydrate

DSC scan of engineered lactose <45 pm shows no loss of water of dehydration at 147 °C and an endothermic transition corresponding to oc-lactose: Therefore, lactose

<45pm is crystallised in the form of anhydrous oc-lactose.

The conclusion is that the polymorphic form can also be controlled during the crystallisation process

Turning now to figures 17a-17c wherein figure 17a shows a Scanning Electron Micrograph of Tomahawk shape Lactose Lactohale® sieved size fraction 63-90pm. Ligure 17b shows a Atomic Lorce Micrograph of lactose Lactohale® 63-90 pm with a smooth surface with adhered fine powder. Ligure 17c which is a graph of particle size distribution of Lactose Lactohale® sieved size fraction (63-90 pm) Volume Mean Diameter (VMD) =48.72 pm. It is clear that the Lactohale particles have a wider size distribution.

In contrast figures 18a-18c show in figure 18a a Scanning Electron Micrograph of Engineered Lactose spherical particles using a combination of solvent (500 Acetone/ 500 Ethanol) which gives a rough surface. Ligure 18b is an image of Atomic force microscopy (ALM) of Engineered Lactose spherical particles using a combination of solvent (500 Acetone/ 500 Ethanol) indicating again a rough surface. Ligure 18c shows the particle size distribution of Engineered Lactose spherical particles using a combination of solvent (500 Acetone/ 500 Ethanol): Volume Mean Diameter (VMD) =108.32 pm. Note the particles have a narrow size distribution.

As a final example of the solvent being used to tune the surface properties, figures 19a-19c show engineered lactose spherical particles (10-20 pm) using a combination of solvent (600 Acetone/500 Ethanol) to give mid- or mild surface roughness. Figure 19a is the SEM, 19b the AFM and 19c the size distribution. Note the particles have a narrow size distribution also. Figures 20, 21 and 22 show SEMs of particles constructed using formulations of the present invention wherein figure 20 is engineered spherical lactose carrier- Beclomethasone propionate (20:1 ratio w/w), figure 21 is engineered spherical lactose carrier-Budesonide (20:1 ratio w/w), and figure 22 is engineered spherical lactose carrier- salbutamol sulfate (67.5:1 ratio w/w).

Example 18: Crystallisation of lactose in the presence of PVPk90, PEG 400 and Polysorbate 80

10 grams of Lactose oc-D-lactose monohydrate (Acros®) was dissolved in 100 millilitre ultrapure water at room temperature in the presence of 1 gram polyvinyl pyrrolidone k90, 0.2 gram polyethylene glycol (PEG400) and 0.2 gram polysorbate 80.

In a 2 Litre glass beaker, Add the above solution to the cooled (temperature =-4°C) acetone (700 mL) /absolute ethanol (500 m) under stirring at 800 RPM for 20 minutes using 3 blade stirrer.

Leave to settle for 90 minutes.

Empty the clear liquid from the 2 L beaker to leave the suspended particles in a small amount of residual liquid and empty the suspended particles in a 600 mL beaker. Add a sufficient amount of molecular sieves 4A (4 to 8 mesh, Acros Organics™) to adsorb all the residual liquid.

Pour 150 mL chloroform into 600 mL beaker containing the molecular sieves and lactose particles to suspend the lactose particles. Pass the suspension through 1 mm sieve to capture molecular sieves allowing only the suspended lactose particles in chloroform to pass through the sieve into 250 mL glass beaker.

Pour a thin layer of the suspension on a glass slab

Allow chloroform to evaporate leaving dried solid particles on the glass slab. Scrap the particles from the glass slab by mean of a razor blade into a petri dish Allow the particles to dry for 48 hours at 50 °C

Store the particles in a glass vial over silica gel at room temperature until required.

Figures 23a-23c show SEM views of the particles crystalised in the presence of PVP k90 + PEG400 + Polysorbate 80. The figures show monodisperse lactose particles with smooth surface obtained by crystallisation in the presence of PVPk90, PEG400 and Polysorbate 80. The additives can bring a modification to the surface roughness, the lactose particles produced in the presence of PVP k90 + PEG400 + Polysorbate 80 are smoother compared to lactose particles produced in the presence of PVP k90 & Polysorbate 80 (Figure 26).

Example 19: Crystallisation of lactose in the presence of PVP k90 & PEG400

Similar crystallisation procedure to the example 18 above, except that crystallisation was carried out in the presence of PVPk90 and PEG400 using similar amount of lactose (10 grams) , PVPk90 (1 gram) and PEG400 (0.2 gram).

Figures 24a and 24b show SEMs of the crystallised particle product. Example 20: Crystallisation of lactose in the presence of PVP k90 & Polysorbate 80.

Similar crystallisation procedure to the example 19 above, except that crystallisation of lactose was carried out in the presence of PVPk90 and Polysorbate 80 using similar amount of lactose (lOgrams) , PVP k90 (1 gram) and Polysorbate 80 (0.2 gram).

Figures 25a and 25b show SEMs of the crystallised spherical particle product. Example 21: Crystallisation of lactose in the presence of PVP k90

20 grams of Lactose oc-D-lactose monohydrate (Acros®) was dissolved in 200 millilitre ultrapure water at room temperature in the presence of 2 gram polyvinyl pyrrolidone k90. In a 15.5 litres stainless steel pan, Add the above solution to the cooled (temperature =-3°C) acetone (1200 mL)/ absolute ethanol (1000 m) under stirring at 240 RPM for 15 minutes using 3 blade stirrer.

Empty the content of the stainless steel pan into a 5 Litre glass beaker and allow to settle for 54 minutes. Empty the clear liquid from the 5 L beaker to leave the suspended particles in a small amount of residual liquid and empty the suspended particles in a 2 Litres glass beaker. introducing sufficient amount of de-dusted molecular sieves 4A (4 to 8 mesh, Acros Organics™)into 2 Litres beaker to adsorb any residual solvent. Add sufficient chloroform into 2 L beaker to suspend the lactose particles.

Pass the suspension with molecular sieves through 250 pm sieve to retain the molecular sieves and allowing the suspension to empty into a 5 Litre beaker.

Allow the suspension to stir at room temperature using a magnetic stirrer. Pass the suspension through 38pm sieve onto the glass slab to ensure removal of any agglomerate formed on the glass slab.

Allow evaporation of the chloroform and scrap the particles by mean of a razor blade into a petri dish.

Allow the particles to dry for 16 hours at 50 °C,

Store the particles in a glass jar over silica gel until required.

Figures 26a and 26b show SEMs of the crystallised spherical particle product.

Figure 27a shows a plot of the differential Scanning calorimetry of Lactose oc-D- lactose monohydrate (Acros®) and Figure 27b shows a plot of the differential scanning calorimetry of Lactose oc-D-lactose monohydrate (Acros®) crystallised in the presence of PVPk90. The Lactose oc-D-lactose monohydrate (Acros®) shows two endothermic transitions at 147° C and 224 °C corresponding to the loss of water of crystallisation and melting of oc-lactose monohydrate respectively. Whereas, crystallised lactose showed one endothermic transition corresponding to anhydrous oc-lactose.

Dry powder inhaler formulation

Beclomethasone dipropionate (400 pg per dose) was formulated with crystallised lactose of example 4 in a ratio of 1 to 20 w/ w. The formulation showed a good drug content uniformity of 98%. The aersolisation at 60 L/min and 4 Litre inhaled volume from an Ambreez Breezhaler device showed a fine particle fraction (%FPF) of 65% Fine particle fraction as a percentage of the recovered dose.

Conclusion: PVP k90 as a spherical former. Irrespective of the additive the particles showed aspherical shape and monodisperse (all having approximately the same size). The additive influences surface texture but not the shape of particles. Crystalliosed lactose can be in the form of monohydrate as shown in our previous examples or in anhydrous form as shown in example 4.

Lactose provided excellent drug content uniformity about 98% of the nominal dose and excellent aerosolization with a %FPF of 65% in example 4 and 74% in our previous examples crystallising small batch of lactose 10 grams, 20 grams or 100 grams.

Claims

1. A plurality of disaccharide particles, wherein said disaccharide is lactose and the particles are substantially spherical in shape and/ or hollow.

2. Particles according to claim 1 wherein the particles are monodisperse and/ or have a narrow size distribution.

3. Particles according to claims 1 or 2 wherein the particles are highly spherical or perfectly spherical particles.

4. Particles according to claims 1-3 wherein the particles contain at least one anti adherent.

5. Particles according to claim 4 wherein the anti adherent is a hydrophilic and/ or non-ionic compound or excipient.

6. Particles according to claim 5 wherein the anti-adherent is polyvinyl pyrrolidone (PVP).

7. Particles according to claim 6 wherein PVP is a synthetic hydrophilic non-ionic excipient divided into viscosity grades k-15, k-30, k-60, or k-90 with the average molecular weight being 10,000, 40000, 160000 and 360000, respectively.

8. Particles according to claim 1 wherein the lactose is oc-lactose monohydrate.

9. Particles according to claim 1 wherein the lactose is anhydrous oc-lactose.

10. Particles according to claim 3 wherein the particles have an elongation ratio of 0.9 - 1.1.

11. Particles according to claim 10 wherein the particles are spherical with an elongation ration of 1.

12. Particles according to any preceding claim wherein the particles are provided as a powder.

13. Particles according to claim 1 wherein the volume mean diameter (VMD) of the particles is, or is substantially, 75 pm.

14. Particles according to any preceding claim for use as a carrier in a dry powder for inhalation

15. Particles according to any preceding claim compressed into tablet form.

16. Particles according to claim 14 wherein are a carrier for use in an inhaled pharmaceutical compositions.

17. Particles according to claim 16 wherein said carrier has a sieve size diameter equal or smaller than 250 micrometres.

18. Particles according to claim 17 wherein the carrier has a sieve size diameter equal or smaller than 45 micrometres.

19. Particles according to claim 15 wherein the ratio of drug to carrier ranges from 1: 67.5 w/w to 1:5 w/w.

20. A crystallisation method to produce substantially spherical lactose particles comprising;

- dissolving lactose in the anti- adherent polymer solution;

- preparing an anti-solvent mixture containing two miscible anti-solvents

21. A method according to claim 20 wherein the volume of the anti-solvent in which the polymer is insoluble is at least equal or greater to the volume of the solvent in which the polymer is soluble.

22. A method according to claim 20 wherein the mixing of the antisolvent mixture and the polymer solution is under controlled agitation and/ or controlled temperature;

23. A method according to claim 20 wherein the solvent and/or anti-solvent is removed thereby harvesting the crystalline spherical particles containing an anti adherent.

24. A method according to claim 20 wherein the two miscible anti-solvents have substantially similar or identical densities.

25. A method according to claim 20 wherein the anti-adherent is a polymer.

26. A method according to claim 25 wherein the anti-adherent is polyvinyl pyrrolidone.

27. A method according to claim 20 wherein the surface roughness of the spherical particles is dictated by the solubility of the anti-adherent in the solvent/ anti-solvent mixture.

28. A method according to claim 20 wherein the aqueous solution comprises from about 0.01% to about 2% weight of the anti-adherent polymer per volume of the aqueous medium.

29. A method according to claim 20 wherein the anti-solvents have each a density of 0.79 g/ cm3.

30. A method according to claim 20 wherein the anti-solvents include any one or any combination of methanol, methylated spirits, ethanol, ethylated spirits, propan- l-ol, isopropyl alcohol, 1,3-propanediol, acetone, ethyl acetate.

31. A method according to claim 20 wherein the anti-solvent mixture comprises ethanol and acetone.

32. A method according to claim 31 wherein at least some of the ethanol is replaced with 1,3-propanediol to control particle size.

33. A method according to claim 21 wherein the volume of ethanol in the volume of anti-solvent mixture varies from 0.1% to 50%.

34. A method according to claim 20 wherein the anti-adherent polymer solution when mixed with anti-solvent mixture constitutes or forms a crystallisation medium.

35. A method according to claim 34 wherein the temperature of the crystallisation medium is between -10 °C to + 30 °C.

36. A method according to claim 20 wherein the method includes adding any one or any combination of; a drug, a pharmaceutical excipient, a particle composite comprising of one or more excipients and a drug.

37. A method according to claim 36 wherein one or more substances are introduced to the anti-solvent mixture to form a spherical particle composite comprising all the substances in one particle or each substance forms its own spherical particles in the same crystallisation medium, or said one or more substances are introduced to the anti- adherent polymer solution.

38. A method according to claim 37 wherein said substances include a drug substance, an excipient or a mixture comprising one or more drugs with one or more excipients, suitable for use and/ or administration by oral route or in an inhaled pharmaceutical composition.

39. A method according to claim 34 wherein the particles are separated from the crystallisation medium by discarding the crystallisation medium to leave solid particles which are harvested by exposing said particles to a volatile solvent.

40. A method according to claim 39 wherein the particles are dispersed in a volatile solvent before being emptied on a glass slab or conveyer belt.

41. A method according to claim 20 wherein particles are treated by contacting the spherical particles with a hydrophobic coating solution and/ or suspension.

42. A method according to claim 41 wherein the crystalline spherical particles containing an anti-adherent are contacted with polylactic co-glycolic acid (PLGA) solution/ suspension and/ or colloidal silica suspension to enhance their resistance to moisture.

43. A method according to claim 20 or 26 wherein polyvinyl pyrrolidone is a spherical particle former.

44. A method according to any of claims 20-43 wherein the particles of the invention are used as they are produced or further processed via coating in a formulation in which are included.

45. A method according to claim 44 wherein the particles are milled.