EP2804589A1 - Formulations pharmaceutiques comprenant de l'aztréonam - Google Patents

Formulations pharmaceutiques comprenant de l'aztréonam

Info

Publication number
EP2804589A1
EP2804589A1 EP13720139.8A EP13720139A EP2804589A1 EP 2804589 A1 EP2804589 A1 EP 2804589A1 EP 13720139 A EP13720139 A EP 13720139A EP 2804589 A1 EP2804589 A1 EP 2804589A1
Authority
EP
European Patent Office
Prior art keywords
range
excipient
pharmaceutical formulation
formulation according
particle size
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.)
Withdrawn
Application number
EP13720139.8A
Other languages
German (de)
English (en)
Inventor
Mahmut Bilgic
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.)
Individual
Original Assignee
Individual
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 Individual filed Critical Individual
Publication of EP2804589A1 publication Critical patent/EP2804589A1/fr
Withdrawn legal-status Critical Current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
    • 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
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings

Definitions

  • the present invention relates to pharmaceutical formulations in dry powder form comprising aztreonam or pharmaceutically acceptable derivatives thereof in order to be used in symptomatic and/or prophylactic treatment of respiratory tract diseases, particularly asthma and COPD.
  • Aztreonam is used in the treatment of respiratory tract diseases such as asthma and COPD.
  • Aztreonam which has the chemical name of 2-( ⁇ [(lZ)-l-(2-amino-l,3-thiazol-4-yl) -2- ⁇ [(2S,3S)-2-methyl-4-oxo-l-sulfoazetidin-3-yl]amino ⁇ -2- oxoethylidene]amino ⁇ oxy)-2- methylpropanoic acid belongs to the group of beta-lactam antibiotics. Aztreonam was first disclosed in the patent numbered NL8100571.
  • the dry powder formulation comprising aztreonam has good flow characteristics is an important criterion in terms of inhalation of said formulation effectively and therefore in terms of providing an effective treatment.
  • a dry powder formulation which does not have good flow characteristics is obtained, it is seen that the formulation has low homogeneity and consequently dosing accuracy cannot be ensured during filling the dry powder formulation prepared into reservoirs of multi dose inhalators comprising more than one dose or into blister cavities of a blister package, each of them comprising one dose, or into capsules comprising one dose.
  • the fact that the dry powder formulation does not have good flow characteristics affects emptying capacity and emptying attribute negatively during inhalation of the formulation from capsule, blister or reservoir. As a result, due to the reasons listed above, the active agent cannot reach to the lungs in sufficient amounts.
  • the active agent is diluted by various non-functional excipients.
  • the physical characteristics of these excipients, used in quite high amounts as compared to the active agent amount in the formulations, such as average particle size have an important role in providing good flow in the dry powder formulation. Since the active agent used is delivered to the lungs in a sufficient amount and in a controlled manner in the dry powder formulation having good flow characteristics, desired therapeutic effect is obtained.
  • the inventors have developed dry powder formulations which comprise aztreonam and/or pharmaceutically acceptable derivatives thereof and have high homogeneity and good flow characteristics wherein dosing accuracy is ensured and sufficient amount of active agent can be delivered to the lungs.
  • the present invention relates to pharmaceutical formulations in dry powder form comprising aztreonam and/or pharmaceutically acceptable derivatives thereof.
  • dry powder formulations comprising aztreonam in the range of 5 to 70 ⁇ g, preferably in the range of 10 to 50 ⁇ g and also at least one pharmaceutically acceptable fine grained and coarse grained excipient having an average particle size ratio to each other in the range of 1 :30 to 1 :2, preferably in the range of 1 :20 to 1 :5, more preferably in the range of 1 : 15 to 1 : 10 have good flow characteristics and high homogeneous dispersion, therefore dose accuracy is obtained in the formulations and sufficient amount of active agent can be delivered to the lungs.
  • the fine grained excipient used in the text refers to an excipient having an average particle size less than 10 ⁇ , preferably in the range of 0.1 to 9.9 ⁇ , more preferably in the range of 2 to 8 ⁇ , for instance in the range of 0.3, 0.5, 0.7, 0.9, 1.1, 1.3, 1.5, 1.7, 1.9, 2.3, 2.5, 3.0, 3.5, 4.0, 4.5 to 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5 ⁇ ;
  • the coarse grained excipient used in the text refers to an excipient having an average particle size in the range of 10 to 90 ⁇ , preferably in the range of 12 to 85 ⁇ , more preferably in the range of 15 to 80 ⁇ , for instance in the range of 15, 20, 25, 30, 35, 40, 45 to 50, 55, 60, 65, 70, 75, 80, 85 ⁇ .
  • the subject of the present invention is the pharmaceutical formulation in dry powder form comprising aztreonam and/or pharmaceutically acceptable derivatives thereof, characterized in that the amount of aztreonam in said formulation is in the range of 5 to 70 ⁇ g, preferably in the range of 10 to 50 ⁇ g, - the excipient comprised in said formulation is composed of at least one pharmaceutically acceptable excipient mixture comprising fine grained excipient and coarse grained excipient and
  • the average particle size ratio of the fine grained excipient to the coarse grained excipient is in the range of 1 :30 to 1 :2, preferably in the range of 1 :20 to 1 :5, more preferably in the range of 1 : 15 to 1 : 10.
  • aztreonam and/or pharmaceutically acceptable derivatives thereof which is the active agent comprised in the dry powder formulation of the invention comprise its free base, pharmaceutically acceptable solvates, hydrates, enantiomers or diastereomers, racemates, organic salts, inorganic salts, esters, polymorphs, crystalline forms and amorphous forms and/or a combination thereof, though it is preferably used in aztreonam lysine form.
  • the inhalation formulation comprising aztreonam and/or pharmaceutically acceptable derivatives thereof can be delivered to the patient in dry powder form.
  • Said dry powder formulations further comprise at least one physiologically and pharmaceutically acceptable excipient along with the active agent.
  • This excipient is composed of fine grained excipient, coarse grained excipient or a combination thereof, preferably a combination of fine grained excipient and coarse grained excipient.
  • This excipient can be selected from monosaccharides (glucose etc.), disaccharides (lactose, saccharose, maltose or pharmaceutically acceptable hydrates, anhydrates or a combination thereof etc.), oligosaccharides and polysaccharides (dextrant etc.), polyalcohols (sorbitol, mannitol, xylitol etc.), salts (sodium chloride, calcium carbonate etc.) or a combination thereof. Same or different substances are used as fine grained excipient and coarse grained excipient, though preferably the same substance is used. Fine grained and coarse grained excipients are preferably lactose, more preferably lactose anhydrate. According to the present invention, the amount of the pharmaceutically acceptable excipient is preferably in the range of 1 -50 mg, preferably in the range of 2-40 mg, more preferably in the range of 3-30 mg.
  • the average particle size of the active agent used is quite important in order that the formulation to be obtained has good flow characteristics and therefore an effective inhalation is performed.
  • the inventors have seen that use of an active agent having an average particle size in the range of 1 ⁇ to 10 ⁇ , preferably in the range of 1.5 ⁇ to 7.5 ⁇ , more preferably in the range of 1.5 ⁇ to 5 ⁇ has a significant contribution to the formulation obtained for having proper flow characteristics and for having dose uniformity and to delivery of the active agent to the lungs in sufficient amount.
  • the subject of the present invention is pharmaceutical formulations in dry powder form comprising aztreonam and/or pharmaceutically acceptable derivatives thereof, characterized in that the amount of aztreonam in said formulation is in the range of 5 to 70 ⁇ g, preferably in the range of 10 to 50 ⁇ g,
  • the average particle size ratio of fine grained excipient: coarse grained excipient is in the range of 1 :30 to 1 :2, preferably in the range of 1 :20 to 1 :5, more preferably in the range of 1 : 15 to 1 : 10 and
  • the average particle size of the active agent used is in the range of 1 ⁇ to 10 ⁇ , preferably in the range of 1.5 ⁇ to 7.5 ⁇ , more preferably in the range of 1.5 ⁇ to 5 ⁇ .
  • the amounts of said fine grained and coarse grained excipients constituting the excipient combination having two different average particle sizes as fine grained and coarse grained comprised in the dry powder formulation of the present invention is an important criterion in obtaining the characteristics that can provide an effective treatment.
  • the inventors have seen that characteristics such as proper flow, particularly homogenous particle dispersion and dose uniformity of the formulation are ensured and therefore the sufficient amount of the active agent reaches to the lungs more easily in the case that the ratio of fine grained excipient to coarse grained excipient constituting the excipient combination is in the range of 1 : 1 to 1 :25 by weight, preferably in the range of 1 :1 to 1 :10 by weight, more preferably in the range of 1:1.5 to 1 :5 by weight.
  • the subject of the present invention is the pharmaceutical formulations in dry powder form comprising aztreonam and/or pharmaceutically acceptable derivatives thereof, characterized in that - the amount of aztreonam in said formulation is in the range of 5 to 70 ⁇ g, preferably in the range of 10 to 50 ⁇ g, - the average particle size ratio of fine grained excipient: coarse grained excipient is in the range of 1 :30 to 1 :2, preferably in the range of 1 :20 to 1 :5, more preferably in the range of 1 : 15 to 1 :10 and
  • the ratio of fine grained excipient to coarse grained excipient is in the range of 1 : 1 to 1 :25 by weight, preferably in the range of 1 : 1 to 1 : 10 by weight, more preferably in the range of 1 : 1.5 to 1 :5 by weight.
  • the process for preparation of the pharmaceutical formulations of the present invention in dry powder form comprising aztreonam and/or pharmaceutically acceptable derivatives thereof is composed of the following steps: I. micronizing aztreonam so as to bring it to the desired particle size,
  • the present invention relates to inhalation of the dry powder formulations comprising aztreonam and/or pharmaceutically acceptable derivatives thereof by using inhalation devices comprising capsule, blister or reservoir.
  • inhalation devices comprising capsule, blister or reservoir.
  • the inhalation is performed most productively when capsule volume comprising the drug in dry powder form of the present invention comprising aztreonam and/or pharmaceutically acceptable derivatives thereof is in the range of 0.1 to 0.5 ml, preferably in the range of 0.15-0.45 ml, more preferably in the range of 0.2-0.4 ml.
  • the present invention is characterized in that volume of the capsule used for storage and delivery of the drug in dry powder form comprising aztreonam and/or pharmaceutically acceptable derivatives thereof is in the range of 0.1 to 0.5 ml, preferably in the range of 0.15-0.45 ml, more preferably in the range of 0.2-0.4 ml.
  • the inventors have seen that the active agent comprised in the capsule is protected from external factors as well as the possibility of moistening that can arise from the nature of the capsule itself is removed in the case that moisture ratio of the package in capsule form having high protection property against moisture and other negative external factors is in the range of 5-20%, preferably in the range of 7-15%.
  • moisture ratio of the package in capsule form having high protection property against moisture and other negative external factors is in the range of 5-20%, preferably in the range of 7-15%.
  • the present invention is characterized in that moisture ratio of the package in capsule form used for storage and delivery of the drug in dry powder form comprising aztreonam and/or pharmaceutically acceptable derivatives thereof is in the range of 5-20%, preferably in the range of 7-15%.
  • the capsule preferred to be used in the scope of the present invention can be made of a substance selected from a group comprising gelatine, chitosan, starch and/or starch derivatives, cellulose and/or cellulose derivatives or synthetic polymers, and it is composed of telescoping body and cap parts.
  • capsule material in the case that the dry powder formulation of the present invention is inhaled from capsule, capsule material can be selected from a group comprising hydroxypropyl cellulose, hydroxypropylmethyl cellulose, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose if the capsule to be used is made of cellulose and its derivatives.
  • capsule material can be selected from a group comprising polyethylene, polyester, polyethyleneterephthalate, polycarbonate or polypropylene if the capsule to be used is made of synthetic polymer.
  • various molecular weighted polyethylene glycol, sorbitol, glycerol, propylene glycol, polyethylene oxide-propylene oxide block copolymers and/or other polyalcohols and polyethers can be added as adjuvant if the capsule material to be used is made of gelatine.
  • the inventors have found that in the case that fullness ratio of the capsule cavity used is in the range of 0.05 to 25 %, preferably in the range of 0.1 to 20%, more preferably in the range of 0.5-15%, an effective inhalation of the drug is ensured in the case that said dry powder formulation is inhaled from capsule.
  • the present invention is characterized in that fullness ratio of capsule cavity is in the range of 0.05 to 25%, preferably in the range of 0.1 to 20%, more preferably in the range of 0.5 to 15%.
  • the dry powder formulation of the present invention is inhaled from blister, which is one of the inhalation methods
  • the inventors have found that an effective inhalation is performed in the case that cavity volume of the blister comprising the drug in dry powder form comprising aztreonam and/or pharmaceutically acceptable derivatives thereof 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 .
  • the present invention is characterized in that cavity volume of the blister used for storage and delivery of the drug in dry powder form comprising aztreonam and/or pharmaceutically acceptable derivatives thereof is 18-30 mm 3 , preferably in the range of 20 to 25 mm , more preferably in the range of 21-24 mm in the case that said dry powder formulation is inhaled from blister.
  • fullness ratio of the blister cavity used should be in the range of 15-95%, preferably in the range of 20-85% and more preferably in the range of 50-80% in order to inhale the formulation of the present invention from blister without any problem and in order to perform an effective inhalation.
  • the present invention is characterized in that fullness ratio of the blister used for storage and delivery of the drug in dry powder form comprising aztreonam and/or pharmaceutically acceptable derivatives thereof is in the range of 15-95%, preferably in the range of 20-85% and more preferably in the range of 50- 80%.
  • the base and the lid sheets constituting the peelable blister strip pack wherein the blisters comprising the dry powder formulation of the present invention are collocated, are sealed tightly by any suitable method in order to provide impermeability.
  • the base and lid sheets constituting the peelable blister strip package comprising the dry powder formulation of the present invention are composed of many layers. Polymeric layers, aluminium foil and preferably Aclar® fluoropolymer film are among the layers constituting the base and the lid sheets.
  • Desiccant agents added to the layers constituting blister strip package comprising dry powder formulation of the present invention are selected from silica gel, zeolite, alumina, bauxite, anhydrous calcium sulphate, activated carbon, hydrophilic chyles.
  • polymeric layers in the base and lid sheets of peelable blister strip package comprising said dry powder formulation are made of the same or different polymers. Thickness of these polymeric layers varies depending on the type and characteristics of the polymeric material used. Therefore, thickness of the polymeric layer varies in the range of 15-55 ⁇ , preferably in the range of 20-30 ⁇ according to the type of the polymeric material used.
  • the layer covering the inner surface of the cavity is a polymeric layer because of the fact that when the layer in contact with the dry powder formulation in the blister cavity is aluminium foil, some part of dry powder formulation adheres to the inner surface of the blister cavity due to porous structure of the aluminium foil and electrostatic forces and this causes uncontrolled dose inhalation.
  • Polymers constituting the polymeric layer can preferably be selected from thermoplastic polymers such as polyethylene, polypropylene, polystyrene, polyolefin, polyamide, polyvinyl chloride, polyurethane or synthetic polymers.
  • the drug composition in dry powder form described in the present invention comprising aztreonam and/or pharmaceutically acceptable derivatives thereof can be used in the treatment of many respiratory diseases particularly asthma, Chronic Obstructive Pulmonary Disease (COPD) and allergic rhinitis.
  • the drug composition of the present invention is used in the treatment of respiratory tract diseases comprising, but not limited to, allergic or non allergic asthma in every stage, acute lung injury (ALI), acute respiratory distress syndrome (ARDS), exacerbation of airways hyperactivity, chronic obstructive pulmonary disease including bronchiectasis, emphysema and chronic bronchitis; airways or lung diseases (COPD, COAD or COLD) pneumoconiosis, aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis, tabacosis and byssinosis.
  • This treatment may be prophylactic or symptomatic.
  • EXAMPLE 1 Inhalation of dry powder formulations comprising aztreonam from capsule
  • fine grained lactose and coarse grained lactose are stirred in a mixer after sieved separately.
  • Aztreonam is added into this mixture, sieved again and stirred.
  • the powder mixture obtained at the end of the process is filled into capsules.
  • EXAMPLE 2 Inhalation of dry powder formulations comprising aztreonam from capsule
  • fine grained lactose and coarse grained lactose are stirred in a mixer after sieved separately.
  • Aztreonam is added into this mixture, sieved again and stirred.
  • the powder mixture obtained at the end of the process is filled into capsules.

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

Abstract

La présente invention concerne des formulations pharmaceutiques en poudre sèche comprenant de l'aztréonam, utilisables dans des maladies des voies respiratoires.
EP13720139.8A 2012-01-16 2013-01-16 Formulations pharmaceutiques comprenant de l'aztréonam Withdrawn EP2804589A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
TR201200485 2012-01-16
PCT/TR2013/000029 WO2013109217A1 (fr) 2012-01-16 2013-01-16 Formulations pharmaceutiques comprenant de l'aztréonam

Publications (1)

Publication Number Publication Date
EP2804589A1 true EP2804589A1 (fr) 2014-11-26

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
EP13720139.8A Withdrawn EP2804589A1 (fr) 2012-01-16 2013-01-16 Formulations pharmaceutiques comprenant de l'aztréonam

Country Status (2)

Country Link
EP (1) EP2804589A1 (fr)
WO (1) WO2013109217A1 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104784159A (zh) * 2015-04-15 2015-07-22 苏州惠仁生物科技有限公司 氨曲南粉雾剂的制备方法

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NZ196202A (en) 1980-02-07 1984-07-31 Squibb & Sons Inc Beta-lactam antibiotics (of azetidine-sulphonic acid type)
US7214364B2 (en) * 2000-12-27 2007-05-08 Corus Pharma, Inc. Inhalable aztreonam lysinate formulation for treatment and prevention of pulmonary bacterial infections
DK1353647T3 (da) * 2000-12-27 2011-06-14 Gilead Sciences Inc Inhalerbar aztreonam til behandling og forebyggelse af bakterielle lungeinfektioner
US9259376B2 (en) * 2010-06-03 2016-02-16 Sima Patent Ve Lisanslama Hizmetleri Ltd. Sti. Process for dry powder formulations

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2013109217A1 *

Also Published As

Publication number Publication date
WO2013109217A1 (fr) 2013-07-25

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