# US 7,744,855 B2 · Method of making particles for use in a pharmaceutical composition > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 7,744,855 B2 - Document ID: US7744855B2 - Status: Granted - Kind: B2 - Application number: 10/312,488 - Filed: 2001-06-27 - Published: 2003-08-28 - Granted: 2010-06-29 - Earliest claimed: 2000-06-27 - Assignees: Vectura Limited - Inventors: John Nicholas Staniforth; David Alexander Vodden Morton; Rosella Musa - Web page: https://patentgrep.com/patent/US7744855B2 ## CPC - A61K 9/1688: {resulting in pure drug agglomerate optionally containing up to 5% of excipient} - A61K 9/0075: {for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles} - A61K 9/145: {with organic compounds} - A61K 9/1617: {Organic compounds, e.g. phospholipids, fats} - A61K 9/1623: {Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules} - A61K 31/137: Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine {or methadone} - A61K 31/167: having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol - A61K 31/4468: having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl - A61K 31/4985: Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems - A61K 31/573: substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone - A61K 31/58: containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin (digitoxin {A61K31/7048}) - A61P 11/06: Antiasthmatics - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS ## Abstract A method for making composite excipient particles for use in a pharmaceutical composition comprises a milling step in which particles of an excipient material are milled in the presence of an additive material. The product particles are of small size and the milling requires relatively low input of time and energy. The composite particles are suitable for use in inhalable pharmaceutical compositions. ## Claims ### Claim 1 A method for making composite excipient particles for use in a pharmaceutical composition, the method comprising a milling step in which particles of an excipient material are milled in the presence of an additive material prior to adding active ingredient, wherein the milling step applies a force sufficient to break coarse excipient particles of mass median aerodynamic diameter (MMAD) greater than 100 μm down to fine particles of MMAD not more than 50 μm and involves mechanofusion, ultracentrifugal milling, jet milling, homogenisation, bead milling, media milling, hybridization, air jet milling, pin milling, hammer milling or knife milling; wherein the milling step results in the additive material being applied to the surfaces of the excipient particles; and wherein the composite particles comprise not more than 60% additive material by weight. ### Claim 2 (depends on 1) A method as claimed in claim 1, in which the mass median aerodynamic diameter of the particles of excipient material is substantially reduced during the milling step. ### Claim 3 (depends on 2) A method as claimed in claim 2, in which the mass median aerodynamic diameter (MMAD) of the particles of excipient material is reduced by at least 50% during the milling step. ### Claim 4 (depends on 1) A method as claimed in claim 1, in which the milling step is carried out in the presence of a fluid. ### Claim 5 (depends on 4) A method as claimed in claim 4, which also comprises the step of removing the fluid after the milling step. ### Claim 6 (depends on 5) A method as claimed in claim 5, in which the fluid is removed by spray drying. ### Claim 7 (depends on 1) A method according to claim 1, which comprises, after the milling step, an agglomeration step in which the composite excipient particles are agglomerated to form agglomerated particles. ### Claim 8 (depends on 7) A method as claimed in claim 7, in which the agglomeration step is a spray drying step. ### Claim 9 (depends on 1) A method as claimed in claim 1, wherein the excipient material is a crystalline sugar. ### Claim 10 (depends on 1) A method as claimed in claim 1, in which the additive material comprises an amino acid. ### Claim 11 (depends on 1) A method as claimed in claim 1, in which the additive material comprises a phospholipid. ### Claim 12 (depends on 1) A method as claimed in claim 1, in which the additive material comprises a metal stearate. ### Claim 13 (depends on 1) Composite excipient particles for use in a pharmaceutical composition as made by the method of claim 1. ### Claim 14 (depends on 13) Composite excipient particles as claimed in claim 13, the composite excipient particles having a mass median aerodynamic diameter of less than 20 μm. ### Claim 15 (depends on 1) A pharmaceutical composition comprising composite excipient particles as made by a method as claimed in claim 1 and active particles. ### Claim 16 (depends on 15) A pharmaceutical composition as claimed in claim 15, which is a dry powder and is suitable for use in a dry powder inhaler. ### Claim 17 (depends on 16) A pharmaceutical composition as claimed in claim 16, which comprises carrier particles. ### Claim 18 (depends on 17) A pharmaceutical composition as claimed in claim 17, which comprises the composite excipient particles in an amount of 1 to 40% based on the weight of the carrier particles. ### Claim 19 (depends on 17) A pharmaceutical composition as claimed in claim 17, in which the carrier particles have a fissured surface. ### Claim 20 (depends on 17) A pharmaceutical composition as claimed in claim 17, in which the carrier particles are of a crystalline sugar having a tapped density not exceeding 0.75 g/cm3. ### Claim 21 (depends on 17) A pharmaceutical composition as claimed in claim 17, in which the carrier particles have a bulk density as measured by mercury intrusion porosimetry of not exceeding 0.6 g/cm3. ### Claim 22 (depends on 17) A pharmaceutical composition as claimed in claim 17, in which the carrier particles have a mass median aerodynamic diameter of at least 175 μm. ### Claim 23 (depends on 15) A pharmaceutical composition as claimed in claim 15, which comprises a propellant and is suitable for use in a pressurised metered dose inhaler. ### Claim 24 (depends on 1) A dry powder for use in a dry powder inhaler comprising active particles, carrier particles for carrying the active particles and composite excipient particles as made by the method as claimed in claim 1, each of the composite excipient particles comprising a particle of excipient material having additive material on the surfaces of that particle of excipient material, the additive material being suitable for the promotion of the release of the active particles from the carrier particles on actuation of the inhaler. ### Claim 25 (depends on 14) A pharmaceutical composition comprising composite excipient particles as claimed in claim 14 and active particles. ### Claim 26 (depends on 14) A dry powder for use in a dry powder inhaler comprising active particles, carrier particles for carrying the active particles and composite excipient particles as claimed in claim 14, each of the composite excipient particles comprising a particle of excipient material having additive material on the surfaces of that particle of excipient material, the additive material being suitable for the promotion of the release of the active particles from the carrier particles on actuation of the inhaler. ### Claim 27 (depends on 1) The method of claim 1, wherein said particles have a fissured surface. ### Claim 28 (depends on 14) The method of claim 14, wherein said particles have a fissured surface ### Claim 29 (depends on 24) The method of claim 24, wherein said particles have a fissured surface. ### Claim 30 (depends on 29) The method of claim 29, wherein said particles have a fissured surface. ### Claim 31 (depends on 30) The method of claim 30, wherein said particles have a fissured surface.