EP4138762A1 - Particules de lactose et procédé de production associé - Google Patents

Particules de lactose et procédé de production associé

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Publication number
EP4138762A1
EP4138762A1 EP20793773.1A EP20793773A EP4138762A1 EP 4138762 A1 EP4138762 A1 EP 4138762A1 EP 20793773 A EP20793773 A EP 20793773A EP 4138762 A1 EP4138762 A1 EP 4138762A1
Authority
EP
European Patent Office
Prior art keywords
particles
lactose
spherical
adherent
solvent
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP20793773.1A
Other languages
German (de)
English (en)
Inventor
El Hassane Larhrib
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
University of Huddersfield
Original Assignee
University of Huddersfield
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by University of Huddersfield filed Critical University of Huddersfield
Publication of EP4138762A1 publication Critical patent/EP4138762A1/fr
Pending legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin

Definitions

  • 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.
  • Lactose monohydrate hereinafter referred to as lactose
  • 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.
  • 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.
  • 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.
  • a further aim of the present invention to provide a method of producing or synthesising particles of lactose that addresses the abovementioned problems.
  • a plurality of disaccharide particles wherein said disaccharide is lactose and the particles are substantially spherical in shape and/ or hollow.
  • the particles are monodisperse and/ or have a narrow size distribution.
  • the particles are highly spherical or perfectly spherical particles.
  • the particles contain at least one anti-adherent.
  • the anti adherent is a hydrophilic and/ or non-ionic compound or excipient.
  • the anti-adherent is polyvinyl pyrrolidone (PVP).
  • 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.
  • 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 lactose is oc-lactose monohydrate.
  • the lactose is anhydrous oc-lactose.
  • 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.
  • the particles are crystalline or substantially crystalline.
  • the particles are hollow.
  • the particles are substantially hollow spheres of crystalline lactose.
  • the reaction could be tuned to produce non hollow or substantially solid spherical particles.
  • the particles are porous.
  • 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.
  • 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 particles are provided as a powder.
  • volume mean diameter (VMD) of the particles is, or is substantially, 75 pm.
  • 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.
  • 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.
  • 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.
  • the first substance is lacose.
  • 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;
  • the mixing of the antisolvent mixture and the polymer solution is under controlled agitation and/ or controlled temperature;
  • the mixture is stirred for a sufficient time to allow the formation of crystalline spherical particles containing the anti- adherent;
  • the solvent and/ or anti-solvent is removed harvesting the crystalline spherical particles containing an anti-adherent.
  • the two miscible anti-solvents have substantially similar or identical densities.
  • 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.
  • 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.
  • the aqueous solution comprises from about 0.01% to about 99% weight of the anti-adherent polymer per volume of the aqueous medium.
  • the aqueous solution comprises from about 0.01% to about 2% weight of the anti-adherent polymer per volume of the aqueous medium.
  • the anti-adherent is dissolved or suspended in the anti-solvent mixture.
  • the anti-solvents have each a density of 0.79 g/ cm 3 .
  • the anti-solvents include any one or any combination of methanol, methylated spirits, ethanol, ethylated spirits, propan-l-ol, isopropyl alcohol, acetone, ethyl acetate.
  • the anti-solvent mixture includes propanediol.
  • 1,3- propanediol acts as a particle size controlling agent.
  • the anti-solvent mixture comprises ethanol and acetone.
  • At least some of the ethanol is replaced with 1,3-propanediol to control particle size.
  • volume of ethanol in the total volume of anti-solvent mixture varies from 0.1% to 99%.
  • volume of acetone in the total volume of anti-solvent mixture varies from 0.1% to 99%.
  • volume of ethanol in the volume of anti-solvent mixture varies from 0.1% to 50%.
  • volume of acetone is equal or superior to the volume of ethanol.
  • agitation can be achieved by mechanical mixing using stirrer blades, ultrasound, vortexing, masticating, centrifuging, mixing.
  • the anti-adherent polymer solution when mixed with anti solvent mixture constitutes or forms a crystallisation medium.
  • the temperature of the crystallisation medium varies between -100 °C to + 80 °C.
  • the temperature of the crystallisation medium is between -10 °C to + 30 °C.
  • the substance to be crystallised is introduced to the anti-solvent mixture in the form of a solution.
  • the substance to be crystallised is introduced to the anti-solvent mixture in the form of a suspension.
  • the suspension is a fine suspension.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the drug substance is water soluble or soluble in aqueous or polar media.
  • the excipient is selected from the group consisting of carbohydrates, amino acids, or colloidal silica. Further typically the carbohydrate is a disaccharide.
  • the disaccharide is lactose.
  • the particle formed is a composite comprising lactose and salbutamol sulphate or other such pharmaceutically acceptable salbutamol salt.
  • the crystalline spherical particles containing an anti- adherent are harvested by mean of collection by filtration.
  • 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.
  • 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.
  • 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.
  • 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.
  • PLGA polylactic co-glycolic acid
  • the crystalline spherical particles containing an anti- adherent are a carrier for use in an inhaled pharmaceutical compositions.
  • 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.
  • 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.
  • the ratio of drug to carrier ranges from 1: 67.5 w/w to 1:5 w/w.
  • 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.
  • 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.
  • 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.
  • %FPF fine particle fraction
  • 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.
  • 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.
  • 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.
  • 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).
  • solution b) is introduced to c) under controlled agitation and/ or controlled temperature.
  • 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.
  • sufficient time is allowed for the formation of crystalline spherical particles containing an anti-adherent.
  • a further final step of harvesting the crystalline spherical particles containing an anti-adherent is included.
  • a method of forming spherical lactose particles 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.
  • the stabiliser or binder is a polymer.
  • the polymer is PVP.
  • 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.
  • the formed lactose particles are porous.
  • 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.
  • the particles spherical lactose particles include a coating or layer of PVP.
  • the amount of PVP on the surface of the lactose particles and surface roughness can be adjusted.
  • this provides lactose particles with appropriate surface roughness coupled with anti-adherent properties.
  • the liquid is removed and the particles or powder dried to collect the particles on a surface.
  • a volatile liquid is used to recover the particles before drying.
  • the particles or powder are oven dried.
  • the solution is stirred at, or substantially around, 500 rpm.
  • slower stirring rates produce particles with a larger diameter.
  • a stirring rate of 300 rpm produces particles with a diameter > 150 pm.
  • the solution is stirred at, or substantially around, 1000 rpm.
  • faster stirring rates produce particles with a smaller diameter.
  • a stirring rate of 1000 rpm produces particles with a diameter ⁇ 45 pm.
  • 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.
  • 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.
  • 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, polyhydroxyalkano
  • the polymer has anti-adherent properties.
  • the selected polymer is soluble in water and ethanol.
  • the polymer is not soluble in acetone.
  • Example of such polymers is polyvinylpyrrolidone.
  • 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
  • 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.
  • 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.
  • bronchodilators such as
  • 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.
  • anticholinergics such as ipratropium, ipatropium bromide, atropine, oxitropium and oxitropium bromide, hormones such as cortisone, hydrocortisone and prednisolone
  • xanthines such as aminophyl line, choline theophyllinate, lysine theophyllinate and theophylline.
  • 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.
  • 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
  • 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
  • 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.
  • 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.
  • the agent is a therapeutic agent it will either be an anti-inflammatory drug or a bronchodilator.
  • the preferred drugs of the present invention are beclomethasone dipropionate, Salbutamol sulphate, fluticasone propionate, budesonide
  • 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.
  • 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 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);
  • AFM Atomic force microscopy
  • 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);
  • AFM Atomic force microscopy
  • 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;
  • 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.
  • 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.
  • the performance of an inhaled composition is measured by its fine particle fraction (%FPF as a percentage of fine particle dose to delivered dose).
  • %FPF fine particle fraction 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.
  • 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.
  • the drugs used here are micronized, micronized drugs are known for their highly cohesive nature.
  • 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.
  • lactose 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • BDP beclomethasone — di propionate
  • 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.
  • 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).
  • 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.
  • 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.
  • the interaction between drug and carrier is a surface phenomenon and the extent of adhesion between drug and carrier depends on the carrier surface.
  • 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.
  • 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%
  • lung deposition can be as low as —15%
  • 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.
  • 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.
  • 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.
  • Figure la shows the monodisperse perfectly spherical lactose particles obtained by crystallisation using a mixture of anti-solvents propan-l-ol/ acetone.
  • 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.
  • PVP Polyvinyl pyrrolidone
  • 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 .
  • 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.
  • BDP beclomethasone di-propionate
  • 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.
  • 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.
  • BDP Beclomethasone di-propionate
  • 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.
  • 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 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.
  • 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 %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.
  • 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).
  • SS water soluble drug Salbutamol sulphate
  • % 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.
  • FIG. 3a 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.
  • PLGA polylactic co glycolic acid
  • 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:
  • 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.
  • Figure 5b shows a close view of the PLGA coat.
  • Example 7 Composite particle: monodisperse perfectly spherical lactose-salbutamol sulphate composite.
  • FIG. 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.
  • spherical lactose 1 gram 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.
  • Figures 7c and 7d were dipped in 50 ml chloroform under stricte 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.
  • 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.
  • 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
  • lactose can be crystallised in the presence of more than one anti — adherent without affecting the shape of 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
  • FIG. 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.
  • PVP lactose/anti adherent
  • FIG 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.
  • 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.
  • 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.
  • 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 spherical particles are spherical, crystalline with very good flowability (data available) can be used for needle-less injection using supersonic drug delivery systems.
  • 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).
  • 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.
  • 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 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.
  • FIGS. 16a-16d 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.
  • DSC Differential Scanning Calorimetry
  • engineered lactose 150 pm The DSC scan of engineered lactose 150 pm is similar to Lactohale, therefore the engineered lactose 150 pm is a- lactose monohydrate
  • ⁇ 45pm is crystallised in the form of anhydrous oc-lactose.
  • FIG. 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.
  • 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.
  • 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
  • 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.
  • 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
  • Figures 24a and 24b show SEMs of the crystallised particle product.
  • Example 20 Crystallisation of lactose in the presence of PVP k90 & Polysorbate 80.
  • Figures 25a and 25b show SEMs of the crystallised spherical particle product.
  • Example 21 Crystallisation of lactose in the presence of PVP k90
  • 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.
  • 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.
  • 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.
  • 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.

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Abstract

L'invention concerne des particules sphériques et leur procédé de production, lesdites particules étant des particules de disaccharide, ledit disaccharide étant le lactose et les particules étant sensiblement sphériques en forme et/ou en creux.
EP20793773.1A 2019-10-08 2020-10-08 Particules de lactose et procédé de production associé Pending EP4138762A1 (fr)

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GB201914532A GB201914532D0 (en) 2019-10-08 2019-10-08 Lactose particles and method of production thereof
PCT/GB2020/052496 WO2021069901A1 (fr) 2019-10-08 2020-10-08 Particules de lactose et procédé de production associé

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GB0228826D0 (en) * 2002-12-11 2003-01-15 Okpala Joseph Hair technology in creating particles with improved delivery capabilities
ITMI20051999A1 (it) * 2005-10-21 2007-04-22 Eratech S R L Formulazioni inalatorie di farmaci in fora di polvere secca per somministrazione come tale o con nebulizzatore e dotate di elevata erogabilita' respirabilita' e stabilita'
EP2968163A4 (fr) * 2013-03-15 2017-01-25 Children's Medical Center Corporation Particules creuses encapsulant un gaz biologique et procédés d'utilisation

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WO2021069901A1 (fr) 2021-04-15
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GB2606306A (en) 2022-11-02

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