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WO2013009271A1 - New improved dry powder formulation - Google Patents

New improved dry powder formulation Download PDF

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Publication number
WO2013009271A1
WO2013009271A1 PCT/TR2012/000096 TR2012000096W WO2013009271A1 WO 2013009271 A1 WO2013009271 A1 WO 2013009271A1 TR 2012000096 W TR2012000096 W TR 2012000096W WO 2013009271 A1 WO2013009271 A1 WO 2013009271A1
Authority
WO
WIPO (PCT)
Prior art keywords
dry powder
range
powder formulation
excipient
formulation according
Prior art date
Application number
PCT/TR2012/000096
Other languages
French (fr)
Inventor
Mahmut Bilgic
Original Assignee
Mahmut Bilgic
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
Priority claimed from TR2011/05367A external-priority patent/TR201105367A2/en
Application filed by Mahmut Bilgic filed Critical Mahmut Bilgic
Publication of WO2013009271A1 publication Critical patent/WO2013009271A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds

Definitions

  • the ratio of bulk density to tapped density can be in the range of 7.5: 10 to 9.5:10, for instance at any value in the range of 7.6:10, 7.7: 10, 7.8: 10, 7.9:10, 8: 10, 8.1 :10, 8.2: 10, 8.3: 10, 8.4: 10, 8.5: 10, 8.6:10, 8.7:10, 8.8:10, 8.9: 10, 9:10, 9.1 : 10, 9.2: 10, 9.3: 10 or 9.4: 10.
  • the ratio of fine excipient particles to coarse excipient particles comprised in said formulations is in the range of 1 : 1 to 1 :30, preferably in the range of 1 : 1 to 1 : 15, more preferably in the range of 1 : 1 to 1 :8 by weight.
  • the inventors have seen that the ratio of active agent and excipients used to each other by weight is significant for adjusting the homogeneity and flow characteristics of the formulation obtained.
  • the amount of active agent in dry powder formulation is in the range of 1 ⁇ g to 750 ⁇ g, in other words from 1 ⁇ g, 5 ⁇ g, 10 ⁇ g, 25 ⁇ g, 30 g, 40 ⁇ , 50 ⁇ g or 75 ⁇ ⁇ to 100 ⁇ ⁇ , 125 ⁇ g, 150 ⁇ ⁇ , 250 ⁇ g, 300 ⁇ g, 350 ⁇ g, 375 ⁇ ⁇ , 400 ⁇ g, 425 ⁇ ⁇ , 450 ⁇ ⁇ , 475 ⁇ g, 500 ⁇ g, 550 ⁇ g, 600 ⁇ g, 650 ⁇ g, 700 ⁇ g or 750 ⁇ g; preferably in the range of 1 ⁇ g to 500 ⁇ g, in other words froml ⁇ g, 5 ⁇ g, 15 ⁇ g, 25 ⁇ g, 50 ⁇ g or 75 ⁇ g or 100 ⁇ g to 125 ⁇ g, 150 ⁇ g, 175 ⁇ g, 250 ⁇ g,
  • the excipient in the dry powder formulation can be selected from monosaccharides (glucose, etc), disaccharides (lactose, cellobiose, saccharose, maltose, etc), oligosaccharides and polysaccharides (dextran, etc), polyalcohols (sorbitol, mannitol, xylitol, etc), salts (sodium chloride, calcium carbonate, etc), inositol and/or their isomers (myoinositol, etc) or a combination thereof, though it is preferably lactose.
  • monosaccharides glucose, etc
  • disaccharides lactose, cellobiose, saccharose, maltose, etc
  • oligosaccharides and polysaccharides oligosaccharides and polysaccharides
  • polyalcohols sorbitol, mannitol, xylitol, etc
  • salts
  • the capsule material can be selected from a group comprising hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose if the capsule is made of cellulose and its derivatives in the case that dry powder formulation within the scope of the present invention is inhaled from capsule.
  • the capsule material can be selected from a group comprising polyethylene, polyester, polyethylene terephthalate, polycarbonate or polypropylene if the capsule is made of synthetic polymer in the case that dry powder formulation within the scope of the present invention is inhaled from capsule.
  • Desiccant agents added to the layers constituting the blister strip comprising dry powder formulation of the invention are selected from silica gel, zeolite, alumina, bauxite, anhydrous calcium sulphate, activated carbon, hydrophilic clays.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Emergency Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Otolaryngology (AREA)
  • Pulmonology (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

The present invention relates to a novel dry powder formulation developed for use in respiratory tract diseases such as asthma and COPD.

Description

NEW IMPROVED DRY POWDER FORMULATION Purpose of the Invention
The present invention relates to a novel dry powder formulation developed for use in respiratory tract diseases such as asthma and COPD. Background of the Invention
Dry powder formulation transmitted to the patient's lungs via a dry powder inhaler device (DPI) is commonly used in treatment of respiratory tract diseases such as asthma and COPD. Dry powder formulation taken by the inhalation route takes effects quickly because it directly reaches the lungs and thus, the formulation provides a more effective and safer treatment even if used in low doses. However, in order for the dry powder formulation to provide a more effective treatment, first of all, the flow characteristics and therefore its potential of transmission through respiratory tract and absorption from the lungs are rather important. In order for the dry powder formulation to have good flow characteristics, parameters such as particle size and density of the active agent and excipients have to be adjusted optimally. Having good flow characteristics is a criterion that should not be ignored for dry powder formulations in order not to confront problems during the steps of preparation and transportation of the formulation and storage of this formulation in packages such as blister, capsule and/or reservoir. A dry powder formulation with good flow characteristics can be filled into packages such as blister, capsule and reservoir; therefore the precision of measurement can be obtained. Furthermore, it has been observed that during the inhalation of dry powder formulation with good flow characteristics, the dry powder formulation can easily be delivered through respiratory tract, thus the active agent is absorbed effectively when delivered to the lungs in sufficient amounts.
Inhalable dry powder formulations comprise active agent and quite a number of excipients in addition. In the case that the particle size of the active agent is very small, this causes an increase in the size of adhesion and cohesion forces between the particles, an increase in the agglomeration tendency of the particles and therefore deterioration of the formulation flow. On the other hand, in the case that the particle size of the active agent is too large, this causes the active agent to accumulate in respiratory tract and sufficient amount of active agent cannot be absorbed from the lungs. Consequently, failure to inhale sufficient active agent constitutes an obstacle for relief in patients and obtaining an effective treatment. There is need to develop dry powder formulations which have a good flow, high absorption potential and measurement precision wherein the abovementioned problems are solved, for treatment of respiratory tract diseases. According to this, the present invention relates to a dry powder formulation which is used in treatment of respiratory tract diseases such as asthma and COPD, has good flow and is effectively absorbed from lungs during inhalation.
Description of the Invention
The present invention relates to inhalable dry powder formulations comprising active agent wherein the ratio of bulk density: tapped density is in the range of 7.5: 10 to 9.5:10 and aerodynamic particle radius is in the range of 0.05-25 μπι. The inventor has surprisingly observed that formulations with good flow characteristics are obtained, the amount of active agent residue in the device is decreased and an effective inhalation treatment is performed in the case that the ratio of bulk density: tapped density is in the range of 7.5: 10 to 9.5: 10 and aerodynamic particle radius of the active agent comprised is in the range of 0.05-25 μπι, preferably in the range of 0.1-20 μηι, more preferably in the range of 0.5-10 μπι. The term bulk density refers to the ratio of the mass of an uncompressed powder sample to the total volume also comprising the clearance volume between particles. Therefore, the bulk density depends both on the density of the powder particles and the positional order of the particles.
The value of tapped density is obtained by compressing the bulk density by means of vibrational motion. The term tapped value refers to the ratio of the powder sample mass to compressed powder volume.
In dry powder formulation of the present invention; the ratio of bulk density to tapped density can be in the range of 7.5: 10 to 9.5:10, for instance at any value in the range of 7.6:10, 7.7: 10, 7.8: 10, 7.9:10, 8: 10, 8.1 :10, 8.2: 10, 8.3: 10, 8.4: 10, 8.5: 10, 8.6:10, 8.7:10, 8.8:10, 8.9: 10, 9:10, 9.1 : 10, 9.2: 10, 9.3: 10 or 9.4: 10.
In another aspect, the present invention provides a dry powder formulation comprising only coarse excipients or only fine excipients or a mixture comprising both coarse and fine excipients in a way that said excipients have two different average particle sizes. In the case that excipient particles are in two fractions, active agents and fine excipients comprised in the formulation are carried during inhalation by clinging to the active areas of coarse excipients. Coarse excipient particles, on the other hand, stick in the upper respiratory tract of the patient. During the inhalation, active agents carried by the coarse excipient particles separate from the active areas of the coarse excipient particles with the help of fine excipients clinging to the same active area and reach the lungs with the patient's breath. Therefore, the fine excipient particles prevent the active agent to stick to the upper respiratory tract and join the systemic circulation without reaching the lungs. As a result, having an excipient in two different particle sizes in the dry powder formulation of the invention provides an advantage in the treatment.
The coarse excipient mentioned in the document refers to excipient in the range of 10-90 μιη and the fine excipient refers to excipient, average particle size of which is less than 10 μιη. In another aspect the present invention relates to dry powder formulations characterized in that;
- the ratio of bulk density: tapped density is in the range of 7.5 : 10 to 9.5 : 10,
said formulation comprises an active agent, aerodynamic particle radius of which is in the range of 0.05-25 μηι, preferably in the range of 0.1-20 μπι, more preferably in the range of 0.5-10 μηι and,
said formulation comprises an excipient mixture comprising coarse excipient particles along with fine excipient particles.
As a result of the studies they conducted, the inventors have observed that the amounts of active agent and excipients used in the formulation are as effective as their particle sizes on the inhalable dry powder formulation's having a good flow characteristic. It has been observed that the formulation is mixed homogeneously and thus a formulation with good flow characteristics is obtained in the case that the ratio of the fine excipient particles to the coarse excipient particles in the mixture comprising excipients in two different particle sizes is in the range of 1 :1 to 1 :30, preferably in the range of 1 : 1 to 1 : 15, more preferably in the range of 1 :1 to 1 :8 by weight.
Another characteristic of the present invention is that the ratio of the fine excipient particles to the coarse excipient particles in the mixture comprising excipients with two different particle sizes used in dry powder formulations is in the range of 1 :1 to 1 :30, preferably in the range of 1 : 1 to 1 : 15, more preferably in the range of 1 : 1 to 1 :8 by weight. In another aspect, the dry powder formulations of the present invention are characterized in that; - the ratio of bulk density: tapped density is in the range of 7.5:10 to 9.5:10,
said formulations comprise active agent, aerodynamic particle radius of which is in the range of 0.05-25 μπι, preferably in the range of 0.1-20 μπι, more preferably in the range of 0.5-10 μπι,
- said formulations comprise an excipient mixture comprising coarse excipient particles
along with fine excipient particles,
the ratio of fine excipient particles to coarse excipient particles comprised in said formulations is in the range of 1 : 1 to 1 :30, preferably in the range of 1 : 1 to 1 : 15, more preferably in the range of 1 : 1 to 1 :8 by weight. In addition, the inventors have seen that the ratio of active agent and excipients used to each other by weight is significant for adjusting the homogeneity and flow characteristics of the formulation obtained. It has been observed that a homogeneous mixture of the active agent and excipient is provided; the formulation has a better flow and an adequate amount of active agent is conveyed to the lungs of the patient effectively when the ratio of active agent to excipient mixture comprised in the dry powder formulation is in the range of 1 :5 to 1 :90, preferably in the range of 1 :20 to 1 :80, more preferably in the range of 1 :30 to 1 :75 by weight.
Another aspect of the present invention is that the ratio of active agent to excipient mixture used in dry powder formulations is in the range of 1 :5 to 1 :90, preferably in the range of 1 :20 to 1 :80, more preferably in the range of 1 :30 to 1 : 75 by weight. According to the present invention, the active agent comprised in the dry powder formulation can be one or more agents selected from a group comprising anticholinergics such as tiotropium, ipratropium, glycopyrronium and oxitropium; p2-agonists such as carmoterol, formoterol, R- formoterol, arformoterol, bambuterol, salmaterol, carmoterol, clenbuterol, salbutamol, levosalbutamol, fenoterol, terbutaline, carbuterol and pirbuterol; corticosteroids such as beclomethasone, budesonide, ciclesonide, and mometasone; xanthines such as doxophylline, theobromine, theophylline and aminophylline; antileukotrienes such as montelukast, pranlukast, zafirlukast, ritolukast, sulukast, tomelukast, verlukast, iralukast, ablukast and cinalukast; PDEIV inhibitors such as roflumilast, piclamilast and cilomilast; and antihistamines such as levocetirizine, desloratadine, cetirizine, loratadine, fexofenadine setastine and terfenadine. Preferably, tiotropium, carmoterol, formoterol, R- formoterol, salmaterol, budesonide, ciclesonide, fluticasone, salbutamol, levosalbutamol, mometasone and combinations thereof can be used. In another aspect, according to the present invention; the active agent and/or its pharmaceutically acceptable derivatives comprises pharmaceutically acceptable solvates, hydrates, enantiomers or diastereomers, racemates, free base, organic salts, inorganic salts, esters, polymorphs, crystalline forms and amorphous forms thereof or a combination thereof. According to the present invention; the amount of active agent in dry powder formulation is in the range of 1 μg to 750 μg, in other words from 1 μg, 5 μg, 10 μg, 25 μg, 30 g, 40 μ , 50 μg or 75 μΒ to 100 μ§, 125 μg, 150 μ§, 250 μg, 300 μg, 350 μg, 375 μ§, 400 μg, 425 μ§, 450 μ§, 475 μg, 500 μg, 550 μg, 600 μg, 650 μg, 700 μg or 750 μg; preferably in the range of 1 μg to 500 μg, in other words froml μg, 5 μg, 15 μg, 25 μg, 50 μg or 75 μg or 100 μg to 125 μg, 150 μg, 175 μg, 250 μg, 300 μg, 350 μg, 400 μg, 450 μg, 475 μg or 500 μg and more preferably in the range of 1 μg to 400 g.
According to the present invention; the excipient in the dry powder formulation can be selected from monosaccharides (glucose, etc), disaccharides (lactose, cellobiose, saccharose, maltose, etc), oligosaccharides and polysaccharides (dextran, etc), polyalcohols (sorbitol, mannitol, xylitol, etc), salts (sodium chloride, calcium carbonate, etc), inositol and/or their isomers (myoinositol, etc) or a combination thereof, though it is preferably lactose.
According to the present invention; the amount of excipient in dry powder formulation comprising active agent and excipient is in the range of 0.01-30 mg and preferably in the range of 0.1 -20 mg. In another aspect, the dry powder formulations of the present invention are characterized in that; the ratio of bulk density: tapped density is in the range of 7.5: 10 to 9.5: 10,
said formulations comprise an active agent, aerodynamic particle radius of which is in the range of 0.05-25 μηι, preferably in the range of 0.1-20 μιη, more preferably in the range of 0.5-10 μηι,
said formulations comprise an excipient mixture comprising coarse excipient particles along with fine excipient particles and
the ratio of active agent to excipient mixture comprised in said formulations is in the range of 1 :5 to 1 :90, preferably in the range of 1 :20 to 1 :80, more preferably in the range of 1 :30 to 1 :75 by weight. The steps followed during the production of the dry powder formulation of the present invention are listed below:
Active agent(s), excipient with fine particles and/or excipient with coarse particles are micronized separately,
- Optionally, at least 10% of the micronized excipient by weight is subjected to spheroidization process,
Micronized active agent(s), excipient(s) and, if available, excipient particles subjected to spheroidization process are mixed,
Final dry powder formulation is obtained,
- Obtained formulation is filled into capsules, blisters or reservoirs.
During the process used in preparation of the dry powder formulation according to the present invention, excipients are preferably subjected to spheroidization process after micronized. According to this, at least 10% of the micronized excipient particles by weight, for example an amount in the range of 15%, 20%, 25%, 30%, 35%, 40% to 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, preferably an amount in the range of 30% to 90% by weight, more preferably in the range of 60% to 85% by weight is optionally subjected to spheroidization process. The excipient particles subjected to spheroidization process comprises only fine excipient particles, only coarse excipient particles or a mixture of fine and coarse excipient particles. Pharmaceutical combination of the present invention can be inhaled via single or multidose dry powder inhalation devices. According to this, pharmaceutical combination of the invention is carried and inhaled from reservoir, capsule or blister.
In the case that dry powder formulation of the invention is inhaled from capsule, which is one of the inhalation methods, the inventors have found out that inhalation is performed most effectively when the capsule volume comprising the drug in dry powder form of the invention is in the range of 0.1-0.6 ml, preferably in the range of 0.2-0.45 ml, more preferably in the range of 0.25-0.4 ml.
According to this, in the case that dry powder formulation of the invention is inhaled from capsule, the present invention is characterized in that the capsule volume used for storing and conveying the drug in dry powder form is in the range of 0.1-0.6 ml, preferably in the range of 0.2-0.45 ml, more preferably in the range of 0.25-0.4 ml. In another aspect, the inventors have seen that both the active composition in the capsule is protected from external factors and moistening possibility of the capsule resulting from its own nature is eliminated in the case that moisture content of the package in capsule form with high protection of moisture and other negative external factors is in the range of 5-15%, preferably in the range of 8-13%. Thus, the effective transmission of the formulation of the invention in dry powder form to patient's lungs is enabled by preventing the agglomeration of said formulation.
According to this, in the case that dry powder formulation according to the invention is inhaled from capsule, the present invention is characterized in that the moisture content of the package in capsule form used for storing and conveying the drug in dry powder form is in the range of 5-15%, preferably in the range of 8- 13%.
In another aspect, in the case that dry powder formulation of the invention is inhaled from capsule, the capsule preferred to be used within the scope of the present invention can be made of a material selected from a group comprising gelatine, chitosan, starch and/or starch derivatives, cellulose and/or cellulose derivatives or synthetic polymers and is comprised of interlocking upper and lower members.
According to this, the capsule material can be selected from a group comprising hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose if the capsule is made of cellulose and its derivatives in the case that dry powder formulation within the scope of the present invention is inhaled from capsule. The capsule material can be selected from a group comprising polyethylene, polyester, polyethylene terephthalate, polycarbonate or polypropylene if the capsule is made of synthetic polymer in the case that dry powder formulation within the scope of the present invention is inhaled from capsule.
Polyethylene glycol, sorbitol, glycerol, propylene glycol, polyethylene oxide - polypropylene oxide block copolymer and/or other polyalcohols and polyethers in various molecular weights can be added as supplementary material if the capsule material that will be used in the case that dry powder formulation within the scope of the present invention is inhaled from capsule is gelatine.
In another aspect, in the case that said dry powder formulation is inhaled from capsule, the inventors have found out that the drug is inhaled effectively when the fullness ratio of capsule cavity is in the range of 0.05-25%, preferably in the range of 0.1-20%, more preferably in the range of 0.5-15%.
According to this, in the case that said dry powder formulation is inhaled from the capsule, the present invention is characterized in that the fullness ratio of capsule cavity used is in the range of 0.05-25%, preferably in the range of 0.1 -20%, more preferably in the range of 0.5- 15%.
The inventors have found out that an effective inhalation is enabled in the case that cavity volume of the blister comprising the dry powder formulation of the invention is in the range of 18-30 mm , preferably in the range of 20-25 mm , more preferably in the range of 21 -24 mm in the case that the dry powder formulation of the invention is inhaled from blister which is one of the inhalation methods.
According to this, the present invention is characterized in that the cavity volume of the blister used for storage and transmission of the drug in dry powder form is in the range of 18-30 mm3, preferably in the range of 20-25 mm3, more preferably in the range of 21 -24 mm3 in the case that said dry powder formulation is inhaled from blister. The inventors have found out that the fullness ratio of cavity of the blister used for inhalation of the formulation of the invention from blister without any problem and for realizing an effective inhalation should be in the range of 15-95%, preferably in the range of 20-85% and more preferably in the range of 50-80%.
The present invention is characterized in that the fullness ratio of the blister used for storage and transmission of the drug in dry powder form is in the range of 15-95%, preferably in the range of 20-85%i and more preferably in the range of 50-80% in the case that said dry powder formulation is inhaled from blister.
In the case that dry powder formulation of the invention is inhaled from blister, the lid and the base sheets constituting the peelable blister strip where the blisters comprising the dry powder formulation of the invention are collocated are sealed by any suitable method in order to provide impermeability.
The base and lid sheets constituting the peelable blister strip comprising the dry powder formulation of the invention are comprised of a number of layers. Polymeric layers, aluminium foil and preferably Aclar® fluoropolymer film are among the layers constituting the base and the lid sheets.
Inventors have seen that adding desiccant to the polymeric layers in order to reduce moisture and gas permeability of lid and base sheets constituting the blister package is effective in protecting the stability of said dry powder formulation in the case that formulation of the invention is inhaled from blister. Desiccant agents added to the layers constituting the blister strip comprising dry powder formulation of the invention are selected from silica gel, zeolite, alumina, bauxite, anhydrous calcium sulphate, activated carbon, hydrophilic clays.
In the case that dry powder formulation of the invention is inhaled from blister, polymeric layers in the base and lid sheets of the peelable blister strip comprising said dry powder formulation are comprised of the same or different polymers. Thickness of these polymeric layers varies depending on the type and characteristics of the polymeric material used. Thus, thickness of polymeric layer varies in the range of 15-55 μπι, preferably in the range of 20-30 μπι according to the type of the polymeric material used. The layer coating the inner surface of the cavity is a polymeric layer since it results in uncontrolled dose inhalation when the layer which is in contact with dry powder formulation in the blister cavity is aluminium foil as dry powder formulation adheres to the inner surface of the blister cavity due to porous structure of the aluminium foil and electrostatic forces. Polymers constituting the polymeric layer can preferably be selected from thermoplastic polymers such as polypropylene, polystyrene, polyolefin, polyamide, polyvinylchloride, polyurethane or synthetic polymers.
Dry powder formulation of the invention can be used in treatment of several respiratory tract diseases especially asthma, allergic rhinitis and chronic obstructive pulmonary disease (COPD). According to this, said formulation is used in treatment of respiratory tract diseases comprising, but not limited to, asthma in every stage, acute lung injury (ALI), acute respiratory distress syndrome (ARDS), exacerbation of airway hyperactivity, bronchiectasis; chronic obstructive pulmonary disease, airways disease or lung disease (COPD, COAD, or COLD) including emphysema and chronic bronchitis; pneumoconiosis, aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis, tabacosis and byssinosis. This treatment can be either prophylactic or symptomatic. Nevertheless, dry powder formulation of the invention is especially used in treatment of asthma and COPD. Example 1: Dry Powder Formulation Comprising Tiotropium Suitable for Storing in Blister
Figure imgf000011_0001
For use in an inhalation device, dry powder formulation suitable for storage in blister prepared as 13 mg in total comprises 0.02 mg active agent tiotropium with an aerodynamic particle radius of 2 μιη and 12.98 mg coarse lactose anhydrous as carrier agent. 80% of micronized lactose particles are subjected to spheroidization process. Micronized tiotropium particles and micronized lactose particles and lactose particles subjected to spheroidization process are mixed. Dry powder formulations comprising tiotropium wherein the ratio of bulk density: tapped density is 8.5 are obtained. Obtained formulations are filled into blisters.
Example 2: Dry Powder Formulation Comprising Tiotropium and Carmoterol Suitable for Storing in Capsule
Figure imgf000011_0002
For use in an inhalation device, dry powder formulation suitable for storage in capsule, prepared as 13 mg in total comprises;
0.03 mg tiotropium bromide anhydrous with an aerodynamic particle radius of 2 μπι, 0.002 mg carmoterol with an aerodynamic particle radius of 2.4 μηι,
- 2.818 mg fine lactose anhydrous and 10.15 mg coarse lactose anhydrous.
Micronized fine and coarse lactose particles are mixed. Micronized tiotropium and carmoterol particles are also added to the lactose mixture obtained. Dry powder formulations wherein the ratio of bulk density: tapped density is 9.0 are obtained. Obtained formulation is filled into capsules.

Claims

Claims
I . A dry powder formulation characterized in that said formulation comprises an active agent wherein the ratio of bulk density: tapped density is in the range of 7.5:10 to 9.5: 10 and aerodynamic particle radius is in the range of 0.05-25 μιη.
2. The dry powder formulation according to claim 1 characterized in that the ratio of bulk density: tapped density is of any of the values; 7.6:10, 7.7: 10, 7.8: 10, 7.9: 10, 8: 10, 8.1 :10, 8.2: 10, 8.3: 10, 8.4: 10, 8.5: 10, 8.6: 10, 8.7:10, 8.7: 10, 8.8: 10, 8.9: 10, 9: 10, 9.1 : 10, 9.2: 10, 9.3:10 or 9.4:10.
3. The dry powder formulation according to claim 1 characterized in that aerodynamic particle radius of the active agent is in the range of 0.1 -20 μηι.
4. The dry powder formulation according to claim 4 characterized in that aerodynamic particle radius of the active agent is in the range of 0.5-10 μπι.
5. The dry powder formulation according to claims 1-4 characterized in that said formulation comprises only coarse excipients or only fine excipients or a mixture comprising both coarse and fine excipients in a way that the mixture comprises two different average particle sizes.
6. The dry powder formulation according to claim 5 characterized in that said formulation comprises a mixture comprising both coarse and fine excipients in a way that the mixture comprises two different average particle sizes.
7. The dry powder formulation according to claims 1-6 characterized in that coarse excipient has an average particle size in the range of 10-90 μπι and fine excipient has an average particle size smaller than 10 μπι.
8. The dry powder formulation according to claims 1-7 characterized in that the ratio of fine excipient particles to coarse excipient particles is in the range of 1 :1 to 1 :30 by weight.
9. The dry powder formulation according to claim 8 characterized in that the ratio of fine excipient particles to coarse excipient particles is in the range of 1 : 1 to 1 : 15 by weight.
10. The dry powder formulation according to claims 8-9 characterized in that the ratio of fine excipient particles to coarse excipient particles is in the range of 1 : 1 to 1 :8 by weight.
I I . The dry powder formulation according to claims 1-10 characterized in that the ratio of the active agent to excipient mixture is in the range of 1 :5 to 1 : 90 by weight.
12. The dry powder formulation according to claim 1 1 characterized in that the ratio of the active agent to excipient mixture is in the range of 1 :20 to 1 :80 by weight.
13. The dry powder formulation according to claims 1 1-12 characterized in that the ratio of the active agent to excipient mixture is in the range of 1 :30 to 1 :75 by weight.
14. The dry powder formulation according to claims 1 -13 characterized in that total amount of excipient comprised in said formulation is in the range of 0.1-20 mg.
15. A capsule used for storage and transmission of dry powder formulation according to claims 1-14 characterized in that volume of said capsule is in the range of 0.1-0.6 ml.
16. The capsule according to claim 15 characterized in that moisture content of said capsule is in the range of 5-15%.
17. The capsule according to claims 15-16 characterized in that the fullness ratio of cavity of said capsule is in the range of 0.05-25%.
18. A blister used for storage and transmission of dry powder formulation according to claims 1-14 characterized in that cavity volume of said blister is in the range of 18-30 mm3.
19. The blister according to claim 18 characterized in that the fullness ratio of cavity of said blister is in the range of 15-95%.
20. The dry powder formulation according to claims 1-14 characterized in that the active agent comprised in said dry powder formulation is selected from a group comprising anticholinergics such as tiotropium, ipratropium, glycopyrronium and oxitropium; p2-agonists such as carmoterol, formoterol, R-formoterol, arformoterol, bambuterol, salmaterol, carmoterol, clenbuterol, salbutamol, levosalbutamol, fenoterol, terbutaline, carbuterol and pirbuterol; corticosteroids such as beclomethasone, budesonide, ciclesonide, fluticasone and mometasone; xanthines such as doxophylline, theobromine, theophylline and aminophylline; antileukotrienes such as montelukast, pranlukast, zafirlukast, ritolukast, sulukast, tomelukast, verlukast, iralukast, ablukast and cinalukast; PDEIV inhibitors such as roflumilast, piclamilast and cilomilast; and antihistamines such as levocetirizine, desloratadine, cetirizine, loratadine, fexofenadine setastine and terfenadine.
21. The dry powder formulation according to claim 21 characterized in that the active agent comprised in said dry powder formulation is selected from tiotropium, carmoterol, formoterol,
R-formoterol, salmaterol, budesonide, ciclesonide, fluticasone, salbutamol, levosalbutamol, mometasone and combinations thereof.
22. The method for production of the dry powder formulation according to any preceding claims characterized in that said method comprises the steps of;
- micronizing active agent(s), fine excipient and/or coarse excipient separately,
optionally, spheroidizing at least 10% of the micronized excipient by weight, mixing the micronized active agent(s), excipient(s) and, if available, excipient particles subjected to spheroidization process, - obtaining final dry powder formulation and filling the obtained formulation into capsules, blisters or reservoirs.
PCT/TR2012/000096 2011-06-02 2012-05-31 New improved dry powder formulation WO2013009271A1 (en)

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TR2011/05367A TR201105367A2 (en) 2011-06-02 2011-06-02 A dry powder formulation with improved flow properties.
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WO2016071862A1 (en) * 2014-11-05 2016-05-12 Glenmark Pharmaceuticals Limited Inhalable pharmaceutical composition comprising glycopyrronium
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WO2013109219A1 (en) * 2012-01-16 2013-07-25 Mahmut Bilgic Dry powder formulations comprising tiotropium and carmoterol
CN103536582A (en) * 2013-10-12 2014-01-29 云南龙海天然植物药业有限公司 Roflumilast dry powder inhalant
WO2016071862A1 (en) * 2014-11-05 2016-05-12 Glenmark Pharmaceuticals Limited Inhalable pharmaceutical composition comprising glycopyrronium
WO2023069028A1 (en) * 2021-10-20 2023-04-27 Arven Ilac Sanayi Ve Ticaret Anonim Sirketi A process for the preparation of dry powder compositions for inhalation

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