WO2013109214A1 - Procédé de préparation de formulations en poudre sèche - Google Patents

Procédé de préparation de formulations en poudre sèche Download PDF

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Publication number
WO2013109214A1
WO2013109214A1 PCT/TR2013/000026 TR2013000026W WO2013109214A1 WO 2013109214 A1 WO2013109214 A1 WO 2013109214A1 TR 2013000026 W TR2013000026 W TR 2013000026W WO 2013109214 A1 WO2013109214 A1 WO 2013109214A1
Authority
WO
WIPO (PCT)
Prior art keywords
excipient
coarse grained
grained excipient
budesonide
range
Prior art date
Application number
PCT/TR2013/000026
Other languages
English (en)
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
Application filed by Mahmut Bilgic filed Critical Mahmut Bilgic
Publication of WO2013109214A1 publication Critical patent/WO2013109214A1/fr

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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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin

Definitions

  • the present invention relates to the process for the preparation of pharmaceutical formulations in dry powder form comprising budesonide or pharmaceutically acceptable derivatives thereof in order to be used in symptomatic and/or prophylactic treatment of respiratory tract diseases, particularly asthma and COPD.
  • Budesonide is used in the treatment of respiratory tract diseases such as asthma and COPD.
  • Budesonide which has the chemical name of 16,17-(butylidenebis(oxy))-l l,21-dihydroxy-, (1 l-P,16-a)-pregna-l,4-diene-3,20-dione belongs to the group of corticosteroids.
  • Budesonide was first disclosed in the patent numbered US3929768. Providing good flow characteristics of the dry powder formulations comprising budesonide is of great importance for the inhalation of said formulation effectively and thus in terms of providing an effective treatment.
  • the dry powder formulation comprising budesoniddoes not have good flow characteristics, it is observed that the formulation has low homogeneity and consequently dosing accuracy cannot be ensured during fillinginto capsules comprising one dose.Furthermore, 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.
  • the inventors have developed dry powder formulationswhich comprise budesonide and/or pharmaceutically acceptable derivatives thereof andhave good flow characteristics and high homogeneitywherein dosing accuracy is ensured and sufficient amount of active agent can be delivered to the lungs.
  • the present invention relates to the process for the preparation of pharmaceutical formulations in dry powder form comprising budesonide and/or pharmaceutically acceptable derivatives thereof.
  • the present invention relates to a process developed for production of a dry powder formulation comprising budesonide. Said process comprises the following steps:
  • Budesonid active agent is added into one of the equivalent group of the coarse grained excipient, then it is covered . by another group of coarse grained excipient and budesonide- coarse grained excipient mixture is obtained,
  • the dry powder formulations comprising budesonide prepared in accordance with the process of the present invention have good flow characteristics and have high homogeneity resulting in dosing accuracy and delivery of the sufficient amount of active agent to the lungs.
  • the excipient is divided into two fractions which are fine grained excipient and coarse grained excipient.
  • Each fraction of the excipient is micronized such that the average particle size of the fine grained excipient is in the range of ⁇ to 30 ⁇ , preferably 2- 25 ⁇ and more preferably 5-20 ⁇ .
  • Total weight of the fine grained excipient is 1-30%, preferably 2%-25%, more preferably 3%-20% of the total weight of the excipient.
  • each fraction of the excipient divided into its fractions in the process of the present invention is micronized such that the average particle size of the coarse grained excipient is in the range of 20 ⁇ to 120 ⁇ , preferably 30- 100 ⁇ and more preferably 45- 95 ⁇ .
  • Total weight of the coarse grained excipient is 60-99%, preferably 75%-98%, more preferably 80%-97% of the total weight of the excipient.
  • the present invention relates to the process for the preparation of the pharmaceutical formulation comprising budesonide in the dry powder form wherein the fine grained excipient having the average particle size in the range of 1 ⁇ to 30 ⁇ , preferably 2- 25 ⁇ and more preferably 5- 20 ⁇ is used.
  • the present invention relates to the process for the preparation of the pharmaceutical formulation comprising budesonide in the dry powder form wherein the fine grained excipient is used in an amount in the range of 1-30%, preferably 2%-25%, more preferably 3%-20% of the total weight of the excipient.
  • the present invention relates to the process for the preparation of the pharmaceutical formulation comprising budesonide in the dry powder form wherein the coarse grained excipient having the average particle size in the range of 20 ⁇ to 120 ⁇ , preferably 30- 100 ⁇ and more preferably 45-95 ⁇ is used.
  • the present invention relates to the process for the preparation of the pharmaceutical formulation comprising budesonide in the dry powder form wherein the coarse grained excipient is used in an amount in the range of 70-99%, preferably 75%-98%, more preferably 80%-97% of the total weight of the excipient.
  • Step II of the process of the present invention 55-99%, preferably 60-98%, more preferably 70-97% of total weight of the coarse grained excipient is divided into four equivalent groups. Four different groups of the coarse grained excipient having equivalent weight are obtained in Step II.
  • step III of the process of the present invention the rest of the coarse grained excipient (the portion that was not divided into four groups having equivalent weight) is mixed with the fine grained excipient. A mixture of fine grained excipient and coarse grained excipient is obtained.
  • step IV of the process of the present invention budesonid active agent is added into one of the equivalent groups of the coarse grained excipient. A mixture of budesonid and coarse grained excipient is obtained in this step.
  • Step V of the process of the present invention two equivalent groups of the coarse grained excipient, budesonide-coarse grained excipient mixture obtained in Step IV, fine grained- coarse grained excipient mixture obtained in Step III and finally the fourth equivalent group of the coarse grained excipient are added into a mixing vessel, respectively. They are mixed in 150- 500 rpm, preferably 200-450 rpm for 5-20 minutes. The final dry powder mixture is obtained.
  • the present invention relates to the process for the preparation of the pharmaceutical formulation comprising budesonide in the dry powder form wherein the final dry powder mixture is obtained by adding two equivalent groups of the coarse grained excipient, budesonide-coarse grained excipient mixture obtained in Step IV, fine grained- coarse grained excipient mixture obtained in Step III and finally the fourth equivalent group of the coarse grained excipient into a mixing vessel, respectively and then mixing them 150- 500 rpm, preferably 200-450 rpm.
  • the present invention relates to the process for the preparation of the pharmaceutical formulation comprising budesonide in the dry powder form wherein the final dry powder mixture is obtained by adding two equivalent groups of the coarse grained excipient, budesonide-coarse grained excipient mixture obtained in Step IV, fine grained- coarse grained excipient mixture obtained in Step III and finally the fourth equivalent group of the coarse grained excipient into a mixing vessel, respectively and then mixing them 150- 500 rpm, preferably 200-450 rpm for 5-20 minutes.
  • Step VI of the process of the present invention the final dry powder mixture is filled into the capsules.
  • the capsule can be made of any suitable substance though it is preferably made of a substance selected from the group comprising gelatin, chitosan, starch and/or starch derivatives, cellulose and/or cellulose derivatives or synthetic polymers and it is composed of intertwining top and bottom compartments.
  • the top and the bottom compartments of the capsule can be made of identical or different materials.
  • the capsule material can be selected from, but not limited to, a group comprising hydroxypropyl cellulose, hydroxypropylmethyl cellulose, methyl cellulose, hydroxymethyl cellulose, hydroxy ethyl cellulose.
  • the capsule material can be selected from, but not limited to, a group comprising polyethylene, polyetheleneteraphtalate, polycarbonate or polypropylene.
  • capsule material used in the process of the present invention is gelatine
  • additional agents such as polyethylene glycol, sorbitol, glycerol, propylene glycol, polyethylene oxide - polypropylene oxide block copolymers and/or other polyalcohols and polyethers at different molecular weights can be added into it.
  • 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 present invention relates to the process for the preparation of the pharmaceutical formulation comprising budesonide in dry powder form wherein budesonide having 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 ⁇ is used as active agent.
  • budesonide active agent is used in an amount in the range of 50 to 600 ⁇ g, preferably in the range of 60 to 500 ⁇ g, more preferably in the range of 75 to 450 ⁇ g.
  • the excipient is composed of finegrained excipient and coarse grained excipient.
  • excipients 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.
  • Fine grained and coarse grained excipients can be the same or different. Fine grained and coarse grained excipients are preferably lactose, more preferably lactose anhydrate.
  • the amount of the pharmaceutically acceptable excipient is in the range of 1-50 mg, preferably in the range of 2-40 mg, more preferably in the range of 5-35 mg.
  • the dry powder medicament prepared according to the process of the present invention is used in the treatment of many respiratory diseases, particularly in allergic or non-allergic asthma, allergic rhinitis and chronic obstructive pulmonary disease (COPD). Accordingly, the dry powder formulation prepared according to the process of the present invention is used in the treatment of, but not limited to, asthma at any stages, acute lung injury (ALI), acute respiratory distress syndrome (ARDS), exacerbation of airway hyperactivity, bronchiectasis, chronic obstructive pulmonary including emphysema and chronic bronchitis, respiratory diseases or lung diseases (COPD, COAD or COLD), pneumoconiosis, aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis, tabacosis, byssinosis.
  • ALI acute lung injury
  • ARDS acute respiratory distress syndrome
  • COAD chronic obstructive pulmonary including em
  • EXAMPLE 1 Inhalation of dry powder formulations comprising budesonide from capsule
  • the dry powder formulation comprising budesonide can be obtained by the process of the present invention comprising the following steps;
  • Budesonid active agent is added into one of the equivalent groups of the coarse grained excipient, then it is covered by the coarse grained excipient and budesonide-coarse grained excipient mixture is obtained,

Abstract

La présente invention concerne un procédé de préparation de formulations pharmaceutiques en poudre sèche comprenant du budésonide ou ses dérivés pharmaceutiquement acceptables. Ces formulations sont utilisables dans le traitement symptomatique et/ou prophylactique de maladies des voies respiratoires, notamment l'asthme et la broncho-pneumopathie chronique obstructive.
PCT/TR2013/000026 2012-01-16 2013-01-16 Procédé de préparation de formulations en poudre sèche WO2013109214A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
TR201200486 2012-01-16
TR2012/00486 2012-01-16

Publications (1)

Publication Number Publication Date
WO2013109214A1 true WO2013109214A1 (fr) 2013-07-25

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PCT/TR2013/000026 WO2013109214A1 (fr) 2012-01-16 2013-01-16 Procédé de préparation de formulations en poudre sèche
PCT/TR2013/000022 WO2013109210A1 (fr) 2012-01-16 2013-01-16 Formulations en poudre sèche comprenant du budésonide

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PCT/TR2013/000022 WO2013109210A1 (fr) 2012-01-16 2013-01-16 Formulations en poudre sèche comprenant du budésonide

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3175842A1 (fr) 2015-12-03 2017-06-07 Alfred E. Tiefenbacher (GmbH & Co. KG) Procédé de mélange de poudre sèche

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3826620A4 (fr) * 2018-07-12 2023-03-08 Arven Ilac Sanayi Ve Ticaret Anonim Sirketi Compositions d'inhalation comprenant des agonistes de la dopamine
EP3823602A4 (fr) * 2018-07-20 2022-04-27 Arven Ilac Sanayi Ve Ticaret Anonim Sirketi Compositions d'inhalation comprenant des agents antibactériens
WO2020055357A2 (fr) * 2018-08-10 2020-03-19 Arven Ilac Sanayi Ve Ticaret Anonim Sirketi Compositions d'inhalation comprenant un inhibiteur de phosphodiestérase -4

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3929768A (en) 1972-05-19 1975-12-30 Bofors Ab Steroids, processes for their manufacture and preparations containing same
US20030180227A1 (en) * 2000-04-17 2003-09-25 Staniforth John Nicholas Pharmaceutical formulations for dry powder inhalers in the form of hard-pellets
WO2011093812A2 (fr) * 2010-01-28 2011-08-04 Mahmut Bilgic Formulation pharmaceutique comprenant du tiotropium et du budésonide sous forme de poudre sèche
WO2011093817A1 (fr) * 2010-01-29 2011-08-04 Mahmut Bilgic Compositions pharmaceutiques comprenant du tiotropium, du formotérol et du budésonide

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3929768A (en) 1972-05-19 1975-12-30 Bofors Ab Steroids, processes for their manufacture and preparations containing same
US20030180227A1 (en) * 2000-04-17 2003-09-25 Staniforth John Nicholas Pharmaceutical formulations for dry powder inhalers in the form of hard-pellets
WO2011093812A2 (fr) * 2010-01-28 2011-08-04 Mahmut Bilgic Formulation pharmaceutique comprenant du tiotropium et du budésonide sous forme de poudre sèche
WO2011093817A1 (fr) * 2010-01-29 2011-08-04 Mahmut Bilgic Compositions pharmaceutiques comprenant du tiotropium, du formotérol et du budésonide

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3175842A1 (fr) 2015-12-03 2017-06-07 Alfred E. Tiefenbacher (GmbH & Co. KG) Procédé de mélange de poudre sèche

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