WO2016159542A1 - Capsule for inhalation with improved stability of combined active ingredients - Google Patents

Capsule for inhalation with improved stability of combined active ingredients Download PDF

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Publication number
WO2016159542A1
WO2016159542A1 PCT/KR2016/002623 KR2016002623W WO2016159542A1 WO 2016159542 A1 WO2016159542 A1 WO 2016159542A1 KR 2016002623 W KR2016002623 W KR 2016002623W WO 2016159542 A1 WO2016159542 A1 WO 2016159542A1
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Prior art keywords
capsule
inhalation
active ingredients
hpmc
pharmaceutically acceptable
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PCT/KR2016/002623
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French (fr)
Inventor
Young Min Yoon
Hyuk Jun Cho
Ho Taek IM
Yong Il Kim
Jae Hyun Park
Jong Soo Woo
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Hanmi Pharm. Co., Ltd.
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Publication of WO2016159542A1 publication Critical patent/WO2016159542A1/en

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    • 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
    • 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
    • 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
    • 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
    • A61K31/46—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
    • 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
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K9/007—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
    • A61K9/4816—Wall or shell material
    • 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
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics

Definitions

  • Various medicaments in the form of an inhalation formulation for the treatment of respiratory diseases for example, asthma and chronic obstructive pulmonary disease (COPD) are available in the market.
  • drugs such as short acting beta agonists (SABAs), long acting beta agonists (LABAs), inhaled corticosteroid (ICS), or long acting muscarinic antagonists (LAMAs) are in wide use for the prevention and treatment of respiratory diseases such as asthma or COPD.
  • SABAs, LABAs, and LAMAs may have a bronchial dilatation effect based on their pharmacological mechanism, and ICS may alleviate inflammation known as a cause of asthma.
  • the treatment guideline for COPD by Global Initiative for Chronic Obstructive Lung Disease suggests using a combination formulation for simultaneously inhalating drugs having different or complementary action mechanisms.
  • a LABA is mostly prescribed to COPD patients with a FEV1 level of less than 80%
  • ICS is further prescribed to COPD patients with a FEV1 level of less than 50% or who experience frequent acute exacerbations, in addition to a LABA.
  • Expected improved therapeutic effects from such simultaneous inhalation of drugs having complementary action mechanisms are already proved based on various research results (Non-patent documents 1 and 2).
  • Patent document 1 discloses an inhalation formulation for the treatment of respiratory disease comprising salmeterol xinafoate (LABA), fluticasone propionate (ICS), and tiotropium bromide (LAMA).
  • LABA salmeterol xinafoate
  • ICS fluticasone propionate
  • LAMA tiotropium bromide
  • a capsule for inhalation comprising dry powder for inhalation including: at least two combined active ingredients selected from the group consisting of salmeterol or a pharmaceutically acceptable salt thereof, tiotropium or a pharmaceutically acceptable salt thereof, and fluticasone or a pharmaceutically acceptable salt thereof; and a diluent, wherein the dry powder is filled in a hydroxypropyl methylcellulose (HPMC) hard capsule not containing a gelation agent or in a HPMC hard capsule containing gellan gum as a gelation agent.
  • HPMC hydroxypropyl methylcellulose
  • a method of using a HPMC hard capsule containing no gelation agent or a HPMC hard capsule containing gellan gum as a gelation agent to prepare a capsule for inhalation, the capsule being filled with dry powder for inhalation including: at least two combined active ingredients selected from the group consisting of salmeterol or a pharmaceutically acceptable salt thereof, tiotropium or a pharmaceutically acceptable salt thereof, and fluticasone or a pharmaceutically acceptable salt thereof; and a diluent.
  • FIGS. 2 to 4 are graphs illustrating the amount of GR97980X as a related compound of salmeterol in each of the inhalation formulations of Examples 1 to 6, Comparative Examples 1 to 4, and Comparative Example 6, as a result of the accelerated test with respect to time.
  • gelatin hard capsule refers to a hard capsule prepared using gelatin as a main capsule material.
  • delayed dose refer to the amount of active ingredient that is practically delivered to a target subject by inhalation after an inhalation formulation in dry powder is administered by being ejected to the target subject via an inhaler.
  • target-delivered dose refers to a target amount of active ingredient that is expected to be delivered to a target subject by inhalation after an inhalation formulation is administered by being ejected to the target subject via an inhaler.
  • a gelation agent may be used as an additive to prepare a HPMC hard capsule with increased mechanical film intensity as strong as a gelatin hard capsule.
  • the additive are carrageenan, which is the most frequently used one, gellan gum, pectin, glycerin, sorbitol, and the like.
  • HPMC hard capsules and in particular, HPMC hard capsules including no gelation agent or including gellan gum as a gelation agent, instead of conventional aluminum blisters or gelatin capsules, to encapsulate mixed dry powder for inhalation was found to remarkably lower the generation of various related compounds with time and ensure high delivered dose.
  • inhalation formulations using gelatin capsules such as Spiriva ® and Fluterol ® had a significantly increase in the amount of related compounds of the active ingredients with time
  • inhalation formulations according to embodiments, including HPMC capsules had a remarkably small increase in the amount of related compounds of the active ingredients with time, and thus significantly improved stability of the active ingredients, compared to the commercially available inhalation formulations using gelatin capsules.
  • inhalation formulations using HPMC capsules including other gelation agents, not gellan gum (Comparative Examples 1 to 3) were found to have a remarkable increase in the amount of related compounds of the active ingredients with time. Therefore, it was found that inhalation formulations using HPMC capsules including no gelation agent or HPMC capsules including gellan gum as a gelation agent may have high stability of active ingredients.
  • HPMC capsules including no gelation agent or HPMC capsules including gellan gum as a gelation agent may ensure remarkably improved stability of active ingredients and a similar ratio of achievement to target-delivered dose of active ingredients, compared to conventional commercially available inhalation formulations.
  • the diluent may be any known diluent available in the art to prepare dry powder for an inhalation formulation for the treatment of respiratory disease.
  • the diluent may be selected from the group consisting of monosaccharides such as glucose or arabinose; disaccharides such as lactose, maltose, or sucrose; polysaccharides such as starch, dextrin, or dextran; polyalcohols such as sorbitol, mannitol, or xylitol; and hydrates thereof, but are not limited thereto.
  • the diluent may be a monosaccharide or a disaccharide.
  • the diluent may be lactose.
  • the diluent may have an average particle diameter (X 50 ) of about 30 ⁇ m to about 120 ⁇ m to effectively deliver the active ingredients in the inhalation formulation.
  • the active ingredients may be at least two selected from the group consisting of salmeterol xinafoate, tiotropium bromide, and fluticasone propionate. In some other embodiments, the active ingredients may include all three of salmeterol xinafoate, tiotropium bromide, and fluticasone propionate.
  • the capsule for inhalation may include about 5 mg to about 25 mg of the diluent per unit dosage form, and in some other embodiments, about 15 mg to about 25 mg of the diluent per unit dosage form.
  • the amount of the diluent exceeds the upper limit, a patient may be reluctant to take the inhalation formulation due to an unpleasant feeling during inhalation, and also the diluent as an external material may cause asthma.
  • the amount of the diluent is less than the lower limit, uniformity between the diluent and the active ingredients may not be ensured, and it may be hard to weigh and fill a unit dose of the dry powder into a capsule.
  • the diluent may be filled into a capsule by a general production method, and the capsule for inhalation may be prepared using general pharmaceutical production facilities for producing capsules without need for specific equipment for producing the capsule for inhalation.
  • a capsule for inhalation may use a capsule having a capsule size, for example, No. 1 to No. 4.
  • the capsule size may be No. 3.
  • a capsule to be filled with the dry powder may be transparent. Using a transparent capsule allows patients to see immediately after inhalation whether the mixed dry powder in the capsule was inhaled and to visually inspect stability deterioration or product defects, such as agglomeration or discoloration, of the mixed dry powder before inhalation.
  • a capsule for inhalation according to any of the above-described embodiments may be administered to a patient using any conventional known dry powder inhaler (DPI).
  • a DPI may include a device which breaks or punches the capsule, or a device to open the capsule in any other ways to allow delivery of weighed dry powder in the capsule to the lungs of the patient.
  • the DPI may further include an air inlet which creates an air flow to supply air into the device, an air outlet via which the active ingredients are discharged upon patient's inhalation through the mouth put thereto, and a filter for filtering out any impurities.
  • DPIs currently available in the market are ROTAHALER ® (available from GSK), HANDIHALER ® (available from Boehringer Ingelheim), and AEROLIZER ® (available from PLASTIAPE).
  • the DPI may be AEROLIZER ® .
  • the AEROLIZER ® includes a hole in a cap thereof to receive a capsule, wherein pins come out from opposite sides of the hole when a button is pressed, to punch the capsule, and is a small and portable device.
  • the amounts of the active ingredients may vary depending on the race, gender, age, weight, and respiratory disease condition of a patient.
  • the capsule for inhalation may include about 25 ⁇ g to about 100 ⁇ g of salmeterol or a pharmaceutically acceptable salt thereof, about 5 ⁇ g to about 50 ⁇ g of tiotropium or a pharmaceutically acceptable salt thereof, and about 25 ⁇ g to about 500 ⁇ g of fluticasone or a pharmaceutically acceptable salt thereof, each as a free base per unit dosage form.
  • the capsule for inhalation may include about 25 ⁇ g to about 100 ⁇ g of salmeterol xinafoate, about 5 ⁇ g to about 50 ⁇ g of tiotropium bromide, and about 25 ⁇ g to about 500 ⁇ g of fluticasone propionate, each as a free base per unit dosage form.
  • a capsule for inhalation according to any of the above-described embodiments may be used to treat or relieve any respiratory diseases in which the combined active ingredients are known to be effective.
  • the capsule for inhalation may effectively suppress bronchoconstriction, inflammation, and airway mucus secretions, and thus may be widely used for the treatment of a wider range of respiratory diseases.
  • the capsule for inhalation may be used for the treatment of, for example, asthma or chronic obstructive pulmonary disease (COPD).
  • COPD chronic obstructive pulmonary disease
  • the respiratory diseases are not limited thereto.
  • Another aspect of the present disclosure provides a method of using a hydroxypropyl methylcellulose (HPMC) hard capsule containing no gelation agent or a HPMC hard capsule containing gellan gum as a gelation agent to prepare a capsule for inhalation, the capsule being filled with dry powder for inhalation including:
  • At least two combined active ingredients selected from the group consisting of salmeterol or a pharmaceutically acceptable salt thereof, tiotropium or a pharmaceutically acceptable salt thereof, and fluticasone or a pharmaceutically acceptable salt thereof;
  • the method of using such a HPMC hard capsule to prepare the capsule for inhalation including the dry powder for inhalation may be conducted according to a method of preparing a conventional capsule for inhalation known in the art.
  • a method of preparing a capsule for inhalation according to any of the above-described embodiments by using an HPMC hard capsule may include: weighing and sieving appropriate amounts of the active ingredients and a diluent, and mixing the sieved active ingredients and diluent to obtain a mixture; stabilizing the mixture; and filling the HPMC capsule with the stabilized mixture.
  • the stabilizing of the mixture may include leaving the mixture at room temperature for about 10 hours to about 20 hours.
  • Salmeterol xinafoate, fluticasone propionate, tiotropium bromide, lactose, and micronized lactose (about 20% of a total lactose) (Respitose ® ML006, available from DMV) having an average particle diameter (X 50 ) of about 17 ⁇ m were weighed according to the compositions of Table 1, sieved, and then mixed in a mixer for about 30 minutes. The resulting mixtures were each stabilized for about 12 hours or longer, and filled into a transparent, gellan gum-including hydroxypropyl methylcellulose (HPMC) capsule of No. 3 by using a capsule filling device.
  • HPMC hydroxypropyl methylcellulose
  • Dry powder inhalation formulations were prepared in the same manner as in Examples 1 to 3, respectively, but according to the compositions of Table 2, not Table 1, using HPMC capsules including no gelation agent, instead of gellan gum-including HPMC capsules.
  • Dry powder inhalation formulations were prepared in the same manner as in Examples 1 to 3, respectively, but according to the compositions of Table 3, not Table 1, using carrageenan-including HPMC capsules, instead of gellan gum-including HPMC capsules.
  • a stability test was performed using the inhalation capsules of Examples 1 to 6 and Comparative Examples 1 to 6 by measuring the amounts of related compounds of the active ingredients under the following conditions.
  • the number of inhalation formulations used in this stability test was 20 for the inhalation formulations of each of Examples 1 to 6, Comparative Examples 1 to 3, and Comparative Example 4 (as Seretide ® Diskus ® ), and Comparative Example 6 (as Fluterol ® ), and 10 for Spiriva HandiHaler ® of Comparative Example 5.
  • the stability test on each inhalation formulation was repeated three times to obtain an average therefrom.
  • UV-absorption detector (absorbance at 228 nm for the unknown related compounds, and 240 nm for GR97980X)
  • ⁇ Mobile phase A 0.05M aqueous ammonium dihydrogen phosphate solution adjusted to pH 2.9 with 10% (v/v) phosphoric acid
  • UV-absorption detector (absorbance at 240 nm)
  • ⁇ Mobile phase A Solution obtained by dissolving 1.0 g of sodium methanesulfonate and 5.0 g of potassium dihydrogen phosphate in 980 mL of deionized water, adjusting pH to 3.0 with dilute phosphoric acid, and adding water to a volume of 1000 mL.
  • FIG. 1 is a graph illustrating a total amount of unknown related compounds of fluticasone propionate in each of the inhalation capsules of Examples 1 to 6, Comparative Examples 1 to 4, and Comparative Example 6, as a result of the accelerated test with respect to time.
  • FIGS. 2 to 4 are graphs illustrating the amount of GR97980X as a related compound of salmeterol in each of the inhalation formulations of Examples 1 to 6, Comparative Examples 1 to 4, and Comparative Example 6, as a result of the accelerated test with respect to time.
  • the inhalation formulations of Comparative Examples 1 to 3 using HPMC capsules including carragenan as a gelation agent, and the commercially available inhalation formulations of Comparative Examples 4 and 6 were found to have a remarkable increase in the amount of the related compound with time, while the inhalation formulations of Examples 1 to 6 had a very gentle increase in the amount of the related compounds with time, which was significantly low, compared to the increased amounts of the related compound in the inhalation formulations of the comparative examples. Therefore, it is found that capsules for inhalation according to embodiments may have remarkably higher stability of salmeterol compared to the commercially available inhalation formulations.
  • FIGS. 5 to 7 are graphs illustrating the amount of BIIH27SE as a related compound of tiotropium in each of the inhalation formulations of Examples 1 to 6, Comparative Examples 1 to 3, and Comparative Example 5, as a result of the accelerated with respect to time.
  • Test Example 2 Dosage unit sampling apparatus ( DUSA ) test
  • UV-absorption detector (absorbance at 228 nm)
  • Mobile phase A solution obtained by dissolving 0.6% (w/v) of ammonium in a mixed solution of methanol, acetonitrile, and water in a ratio of 50:16:34 (v/v)
  • capsules for inhalation may have a similar ratio of achievement to target-delivered dose to that of the commercially available inhalation formulations with improved stability of the active ingredients.
  • a brittleness test was performed using 20 inhalation capsules of each of Examples 3 and 6 and Comparative Examples 3 and 5 in the following manner. The number of fragments generated in the brittleness test was counted as a measure of brittleness. The results are shown in Table 6.
  • the brittleness test was performed using a device appropriate for the inhalation capsules. Each inhalation formulation was punched three times with a constant force under the constant humidity conditions of about 40% to about 60%.
  • capsules for inhalation according to embodiments were found to have a smaller number of fragments per capsule, compared to the commercially available inhalation formulation of Comparative Example 5, and thus pharmaceutically desirable.

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Abstract

A capsule for inhalation is provided. The capsule includes dry powder for inhalation, the dry powder including: at least two combined active ingredients selected from the group consisting of salmeterol or a pharmaceutically acceptable salt thereof, tiotropium or a pharmaceutically acceptable salt thereof, and fluticasone or a pharmaceutically acceptable salt thereof; and a diluent, wherein the dry powder is filled in a hydroxypropyl methylcellulose (HPMC) hard capsule not containing a gelation agent or in a HPMC hard capsule containing gellan gum as a gelation agent.

Description

CAPSULE FOR INHALATION WITH IMPROVED STABILITY OF COMBINED ACTIVE INGREDIENTS
The present disclosure relates to capsules for inhalation including at least two combined active ingredients selected from salmeterol, tiotropium, fluticasone, and a pharmaceutically acceptable salt thereof, and more particularly, to capsules for inhalation with improved stability and high delivered doses of combined active ingredients.
Various medicaments in the form of an inhalation formulation for the treatment of respiratory diseases, for example, asthma and chronic obstructive pulmonary disease (COPD), are available in the market. In particular, drugs such as short acting beta agonists (SABAs), long acting beta agonists (LABAs), inhaled corticosteroid (ICS), or long acting muscarinic antagonists (LAMAs) are in wide use for the prevention and treatment of respiratory diseases such as asthma or COPD. SABAs, LABAs, and LAMAs may have a bronchial dilatation effect based on their pharmacological mechanism, and ICS may alleviate inflammation known as a cause of asthma. Due to these effects, SABAs, LABAs, LAMAs, and ICS may improve the level of forced expiratory volume in 1 second (FEV1), respiratory distress, and exacerbation of COPD. Frequently used examples of SABAs are salbutamol and terbutaline. Examples of LABAs are salmeterol, formoterol, and indacaterol. Examples of ICS are fluticasone and budesonide. Examples of LAMA are tiotropium and glycopyrronium.
The treatment guideline for COPD by Global Initiative for Chronic Obstructive Lung Disease (GOLD) suggests using a combination formulation for simultaneously inhalating drugs having different or complementary action mechanisms. For example, a LABA is mostly prescribed to COPD patients with a FEV1 level of less than 80%, and ICS is further prescribed to COPD patients with a FEV1 level of less than 50% or who experience frequent acute exacerbations, in addition to a LABA. Expected improved therapeutic effects from such simultaneous inhalation of drugs having complementary action mechanisms are already proved based on various research results (Non-patent documents 1 and 2).
Combined formulations of two drugs as mentioned above are already in wide clinical use. A typical example of such combinations is Seretide® Diskus® including salmeterol and fluticasone. Seretide® Diskus® provides an effective therapeutic effect in airway dilatation and inflammation treatment due to the simultaneous inhalation of LABA and ICS.
Based on the reported research results that simultaneous administration of LABA, ICS, and LAMA may provide a further improved therapeutic effect, research into such triple composite formulations has been conducted (Non-patent document 3). For example, Patent document 1 discloses an inhalation formulation for the treatment of respiratory disease comprising salmeterol xinafoate (LABA), fluticasone propionate (ICS), and tiotropium bromide (LAMA).
Such inhalation formulations for respiratory diseases may be prepared by filling aluminum blisters or gelatin hard capsules with mixed dry powder of active ingredients. Currently commercially available Seretide® Diskus® (GlaxoSmithkline) is an inhalation formulation of mixed dry powder of salmeterol xinafoate and fluticasone propionate filled in aluminum blister, and Spiriva® inhalation capsule which is used for Spiriva® HandiHaler® (Boehringer Ingelheim), is an inhalation capsule of dry powder including tiotropium bromide filled in gelatin hard capsules. Fluterol® (Hanmi Pharmaceutical Co., Ltd.) is an inhalation capsule of mixed dry powder of salmeterol xinafoate and fluticasone propionate filled in gelatin hard capsule.
A typical feature of inhalation formulations is that their active ingredient is micronized to a particle size of about 5 ㎛ or less. Accordingly, the active ingredient particles of an inhalation formulation may have a large surface area due to the micronization. Consequently, the active ingredient may not have ensured stability against external environments. The stability of the active ingredient in an inhalation formulation is very crucial in medicinal quality control because the unit dose of the active ingredient is small. The stability issue of the active ingredient is particularly important in an inhalation formulation containing a combination of at least two active ingredients as described above, since interaction of the active ingredients having a large surface area may accelerate generation of related compounds (i.e., impurities). Therefore, there is a need for pharmaceutical research to ensure the improved stability and high delivered doses of individual active ingredients in an inhalation formulation for respiratory disease treatment including a combination of at least two active ingredients.
[Prior art document]
[Patent document]
1. WO2013-187626
[Non-patent document]
1. Aaron, Shawn D. et al., Annals of internal medicine 146.8 (2007): 545-555.
2. J.Y. Sohn et al., Tuberculosis and Respiratory Diseases 67.6 (2009): 536-544; Hanania, Nicola A. et al., CHEST Journal 124.3 (2003): 834-843].
3. Singh, Dave et al., Thorax 63.7 (2008): 592-598.
The present disclosure provides an inhalation formulation including at least two active ingredients for the treatment of respiratory diseases with improved stability and high delivered doses of the at least two active ingredients.
According to an aspect of the present disclosure, there is provided a capsule for inhalation comprising dry powder for inhalation including: at least two combined active ingredients selected from the group consisting of salmeterol or a pharmaceutically acceptable salt thereof, tiotropium or a pharmaceutically acceptable salt thereof, and fluticasone or a pharmaceutically acceptable salt thereof; and a diluent, wherein the dry powder is filled in a hydroxypropyl methylcellulose (HPMC) hard capsule not containing a gelation agent or in a HPMC hard capsule containing gellan gum as a gelation agent.
According to another aspect of the present disclosure, there is provided a method of using a HPMC hard capsule containing no gelation agent or a HPMC hard capsule containing gellan gum as a gelation agent to prepare a capsule for inhalation, the capsule being filled with dry powder for inhalation including: at least two combined active ingredients selected from the group consisting of salmeterol or a pharmaceutically acceptable salt thereof, tiotropium or a pharmaceutically acceptable salt thereof, and fluticasone or a pharmaceutically acceptable salt thereof; and a diluent.
According to the one or more embodiments of the present disclosure, a capsule for inhalation using a HPMC hard capsule including no gelation agent or a HPMC hard capsule including gellan gum as a gelation agent may ensure remarkably improved stability of combined active ingredients for the treatment of respiratory diseases, compared to currently commercially available inhalation formulations using gelatin hard capsules or HPMC hard capsules including other gelation agents, not gellan gum, and may ensure a high ratio of achievement to target-delivered dose of about 90% or more. Therefore, a capsule for inhalation including at least two combined active ingredients, according to any embodiments may ensure a stable effect of the combined active ingredients for the treatment of respiratory diseases, leading to improving patient's medication compliance.
FIG. 1 is a graph illustrating a total amount of unknown related compounds of fluticasone propionate in each of the inhalation compounds of Examples 1 to 6, Comparative Examples 1 to 4, and Comparative Example 6, as a result of an accelerated test with respect to time.
FIGS. 2 to 4 are graphs illustrating the amount of GR97980X as a related compound of salmeterol in each of the inhalation formulations of Examples 1 to 6, Comparative Examples 1 to 4, and Comparative Example 6, as a result of the accelerated test with respect to time.
FIGS. 5 to 7 are graphs illustrating the amount of BⅡH27SE as a related compound of tiotropium in each of the inhalation formulations of Examples 1 to 6, Comparative Examples 1 to 3, and Comparative Example 5, as a result of the accelerated test with respect to time.
Unless otherwise defined, all terms (including technical and scientific terms) used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although exemplary methods or materials are listed herein, other similar or equivalent ones are also within the scope of the present invention. All publications disclosed as references herein are incorporated in their entirety by reference.
The terminology used herein is defined as follows.
As used herein, the terms "HPMC hard capsule" refer to a hard capsule prepared using hydroxypropyl methylcellulose (HPMC) as a main capsule material.
The terms "gelatin hard capsule" refers to a hard capsule prepared using gelatin as a main capsule material. The terms "delivered dose" refer to the amount of active ingredient that is practically delivered to a target subject by inhalation after an inhalation formulation in dry powder is administered by being ejected to the target subject via an inhaler.
The terms "target-delivered dose" refers to a target amount of active ingredient that is expected to be delivered to a target subject by inhalation after an inhalation formulation is administered by being ejected to the target subject via an inhaler.
The terms "ratio of achievement to target-delivered dose" refers to a ratio of delivered dose to target-delivered dose that is reached after administration of the inhalation formulation.
An aspect of the present disclosure provides a capsule for inhalation, including a dry powder for inhalation including: at least two combined active ingredients selected from the group consisting of salmeterol or a pharmaceutically acceptable salt thereof, tiotropium or a pharmaceutically acceptable salt thereof, and fluticasone or a pharmaceutically acceptable salt thereof; and a diluent, wherein the dry powder is filled in a hydroxypropyl methylcellulose (HPMC) hard capsule not containing a gelation agent or in a HPMC hard capsule containing gellan gum as a gelation agent.
The HPMC hard capsules may be prepared using a widely known method in the art, or may be commercially purchased. For example, the HPMC capsule not containing a gelation agent may be VcapPlusTM (Capsugel), and the HPMC hard capsule containing gellan gum as a gelation agent may be VcapTM (Capsugel). However, examples of these HPMC hard capsules are not limited thereto.
It is known that a gelation agent may be used as an additive to prepare a HPMC hard capsule with increased mechanical film intensity as strong as a gelatin hard capsule. Examples of the additive are carrageenan, which is the most frequently used one, gellan gum, pectin, glycerin, sorbitol, and the like. As a result of research into development of an inhalation formulation according to the present disclosure with paying attention to capsules for filling dry powder for inhalation, the inventors of the present disclosure found that using HPMC hard capsules including no gelation agent or HPMC hard capsules including gellan gum as a gelation agent may ensure improved stability and high delivered dose of the active ingredients in dry powder for inhalation.
Currently commercially available inhalation formulations including combined active ingredients for the treatment of respiratory diseases are filled in aluminum blisters or gelatin hard capsules. However, as an experimental result, such inhalation formulations were found to have reduced stability of the active ingredients due to generation of related compounds with time. For this reason, research was conducted for the development of an inhalation formulation with improved stability of the active ingredients and ensured target-delivered dose, which is regarded as a crucial factor in inhalation formulations. As a result, using HPMC hard capsules, and in particular, HPMC hard capsules including no gelation agent or including gellan gum as a gelation agent, instead of conventional aluminum blisters or gelatin capsules, to encapsulate mixed dry powder for inhalation was found to remarkably lower the generation of various related compounds with time and ensure high delivered dose.
In particular, according to Test Example 1, commercially available inhalation formulations using gelatin capsules, such as Spiriva® and Fluterol® had a significantly increase in the amount of related compounds of the active ingredients with time, while inhalation formulations according to embodiments, including HPMC capsules, had a remarkably small increase in the amount of related compounds of the active ingredients with time, and thus significantly improved stability of the active ingredients, compared to the commercially available inhalation formulations using gelatin capsules. Furthermore, inhalation formulations using HPMC capsules including other gelation agents, not gellan gum (Comparative Examples 1 to 3) were found to have a remarkable increase in the amount of related compounds of the active ingredients with time. Therefore, it was found that inhalation formulations using HPMC capsules including no gelation agent or HPMC capsules including gellan gum as a gelation agent may have high stability of active ingredients.
According to Test Example 2, as a result of a dosage unit sampling apparatus (DUSA) test, inhalation formulations according to embodiments, using HPMC capsules, mostly had a ratio of achievement to target-delivered dose of about 90wt% or more. A ratio of achievement to the target-delivered dose of tiotropium was high in all of the tested inhalation formulations (Examples and Comparative Examples). However, the ratios of achievement to the target-delivery doses of fluticasone and salmeterol were significantly higher in the inhalation formulations of Examples 4 to 6 using HPMC capsules including no gelation agent, and the inhalation formulations of Examples 1 to 3 using HPMC capsules including gellan gum as a gelation agent, than in the inhalation formulations of Comparative Examples 1 to 3 using HPMC capsules including carrageenan as a gelation agent. The inhalation formulations of Examples 1 to 6 were also found to have a similar ratio of achievement to target-delivery dose to that of the commercially available inhalation formulations of Comparative Examples 4 and 5. Therefore, it was found that using HPMC capsules including no gelation agent or HPMC capsules including gellan gum as a gelation agent may ensure remarkably improved stability of active ingredients and a similar ratio of achievement to target-delivered dose of active ingredients, compared to conventional commercially available inhalation formulations.
The diluent may be any known diluent available in the art to prepare dry powder for an inhalation formulation for the treatment of respiratory disease. For example, the diluent may be selected from the group consisting of monosaccharides such as glucose or arabinose; disaccharides such as lactose, maltose, or sucrose; polysaccharides such as starch, dextrin, or dextran; polyalcohols such as sorbitol, mannitol, or xylitol; and hydrates thereof, but are not limited thereto. In some embodiments, the diluent may be a monosaccharide or a disaccharide. For example, the diluent may be lactose. The diluent may have an average particle diameter (X50) of about 30 μm to about 120 μm to effectively deliver the active ingredients in the inhalation formulation.
As used herein, the term "average particle diameter (X50)" refers to a particle size corresponding to 50% in a cumulative particle size distribution graph, which means that 50% of a total number of particles is smaller than X50 and the remaining 50% is larger than X50.
In some embodiments, the active ingredients may be at least two selected from the group consisting of salmeterol xinafoate, tiotropium bromide, and fluticasone propionate. In some other embodiments, the active ingredients may include all three of salmeterol xinafoate, tiotropium bromide, and fluticasone propionate.
In some embodiments, the capsule for inhalation may include about 5 mg to about 25 mg of the diluent per unit dosage form, and in some other embodiments, about 15 mg to about 25 mg of the diluent per unit dosage form. When the amount of the diluent exceeds the upper limit, a patient may be reluctant to take the inhalation formulation due to an unpleasant feeling during inhalation, and also the diluent as an external material may cause asthma. On the other hand, when the amount of the diluent is less than the lower limit, uniformity between the diluent and the active ingredients may not be ensured, and it may be hard to weigh and fill a unit dose of the dry powder into a capsule. When the amount of the diluent is within any of the above ranges, the diluent may be filled into a capsule by a general production method, and the capsule for inhalation may be prepared using general pharmaceutical production facilities for producing capsules without need for specific equipment for producing the capsule for inhalation.
A capsule for inhalation according to any of the above-described embodiments may be prepared using a conventional known method of preparing a capsule for inhalation. For example, a method of preparing a capsule for inhalation according to any of the above-described embodiments may include: weighing and sieving appropriate amounts of the active ingredients and a diluent, and mixing the sieved active ingredients and diluents to obtain a mixture within a mixer; stabilizing the mixture; filling a capsule with the stabilized mixture. For example, the stabilizing of the mixture may include leaving the mixture at room temperature for about 10 hours to about 20 hours.
A capsule for inhalation according to any of the above-described embodiments may use a capsule having a capsule size, for example, No. 1 to No. 4. For example, the capsule size may be No. 3. For example, a capsule to be filled with the dry powder may be transparent. Using a transparent capsule allows patients to see immediately after inhalation whether the mixed dry powder in the capsule was inhaled and to visually inspect stability deterioration or product defects, such as agglomeration or discoloration, of the mixed dry powder before inhalation.
A capsule for inhalation according to any of the above-described embodiments may be administered to a patient using any conventional known dry powder inhaler (DPI). For example, a DPI may include a device which breaks or punches the capsule, or a device to open the capsule in any other ways to allow delivery of weighed dry powder in the capsule to the lungs of the patient. The DPI may further include an air inlet which creates an air flow to supply air into the device, an air outlet via which the active ingredients are discharged upon patient's inhalation through the mouth put thereto, and a filter for filtering out any impurities. Examples of such DPIs currently available in the market are ROTAHALER® (available from GSK), HANDIHALER® (available from Boehringer Ingelheim), and AEROLIZER® (available from PLASTIAPE). For example, the DPI may be AEROLIZER®. The AEROLIZER® includes a hole in a cap thereof to receive a capsule, wherein pins come out from opposite sides of the hole when a button is pressed, to punch the capsule, and is a small and portable device.
In a capsule for inhalation according to any of the above-described embodiments, the amounts of the active ingredients may vary depending on the race, gender, age, weight, and respiratory disease condition of a patient. In some embodiments, the capsule for inhalation may include about 25 μg to about 100 μg of salmeterol or a pharmaceutically acceptable salt thereof, about 5 μg to about 50 μg of tiotropium or a pharmaceutically acceptable salt thereof, and about 25 μg to about 500 μg of fluticasone or a pharmaceutically acceptable salt thereof, each as a free base per unit dosage form. In some other embodiments, the capsule for inhalation may include about 25 μg to about 100 μg of salmeterol xinafoate, about 5 μg to about 50 μg of tiotropium bromide, and about 25 μg to about 500 μg of fluticasone propionate, each as a free base per unit dosage form.
A capsule for inhalation according to any of the above-described embodiments may be used to treat or relieve any respiratory diseases in which the combined active ingredients are known to be effective. For example, the capsule for inhalation may effectively suppress bronchoconstriction, inflammation, and airway mucus secretions, and thus may be widely used for the treatment of a wider range of respiratory diseases. For example, the capsule for inhalation may be used for the treatment of, for example, asthma or chronic obstructive pulmonary disease (COPD). However, the respiratory diseases are not limited thereto.
Another aspect of the present disclosure provides a method of using a hydroxypropyl methylcellulose (HPMC) hard capsule containing no gelation agent or a HPMC hard capsule containing gellan gum as a gelation agent to prepare a capsule for inhalation, the capsule being filled with dry powder for inhalation including:
at least two combined active ingredients selected from the group consisting of salmeterol or a pharmaceutically acceptable salt thereof, tiotropium or a pharmaceutically acceptable salt thereof, and fluticasone or a pharmaceutically acceptable salt thereof; and
a diluent.
The above-detailed description of embodiments of the capsule for inhalation may apply to embodiments of the method of using a HPMC hard capsule containing no gelation agent or a HPMC hard capsule containing gellan gum as a gelation agent.
The method of using such a HPMC hard capsule to prepare the capsule for inhalation including the dry powder for inhalation may be conducted according to a method of preparing a conventional capsule for inhalation known in the art. For example, a method of preparing a capsule for inhalation according to any of the above-described embodiments by using an HPMC hard capsule may include: weighing and sieving appropriate amounts of the active ingredients and a diluent, and mixing the sieved active ingredients and diluent to obtain a mixture; stabilizing the mixture; and filling the HPMC capsule with the stabilized mixture. For example, the stabilizing of the mixture may include leaving the mixture at room temperature for about 10 hours to about 20 hours.
One or more embodiments of the present disclosure will now be described in detail with reference to the following examples. However, these examples are only for illustrative purposes and are not intended to limit the scope of the one or more embodiments of the present disclosure.
Examples 1 to 3: Preparation of dry powder inhalation formulations using HPMC capsules including gellan gum
Salmeterol xinafoate, fluticasone propionate, tiotropium bromide, lactose, and micronized lactose (about 20% of a total lactose) (Respitose® ML006, available from DMV) having an average particle diameter (X50) of about 17 μm were weighed according to the compositions of Table 1, sieved, and then mixed in a mixer for about 30 minutes. The resulting mixtures were each stabilized for about 12 hours or longer, and filled into a transparent, gellan gum-including hydroxypropyl methylcellulose (HPMC) capsule of No. 3 by using a capsule filling device.
[Table 1]
Figure PCTKR2016002623-appb-I000001
Examples 4 to 6: Preparation of dry powder inhalation formulations using HPMC capsules including no gelation agent
Dry powder inhalation formulations were prepared in the same manner as in Examples 1 to 3, respectively, but according to the compositions of Table 2, not Table 1, using HPMC capsules including no gelation agent, instead of gellan gum-including HPMC capsules.
[Table 2]
Figure PCTKR2016002623-appb-I000002
Comparative Examples 1 to 3: Preparation of dry powder inhalation formulations using carrageenan -including HPMC capsules
Dry powder inhalation formulations were prepared in the same manner as in Examples 1 to 3, respectively, but according to the compositions of Table 3, not Table 1, using carrageenan-including HPMC capsules, instead of gellan gum-including HPMC capsules.
[Table 3]
Figure PCTKR2016002623-appb-I000003
Comparative Example 4
A currently commercially available product Seretide® Diskus® (using aluminum blister) including salmeterol xinafoate and fluticasone propionate as active ingredients was used.
Comparative Example 5
A currently commercially available product Spiriva® HandiHaler® (using gelatin capsule) including tiotropium bromide as an active ingredient was used.
Comparative Example 6
A currently commercially available product Fluterol® (using gelatin capsule) including salmeterol xinafoate and fluticasone propionate as active ingredients was used.
Test Example 1: Stability test
A stability test was performed using the inhalation capsules of Examples 1 to 6 and Comparative Examples 1 to 6 by measuring the amounts of related compounds of the active ingredients under the following conditions. The number of inhalation formulations used in this stability test was 20 for the inhalation formulations of each of Examples 1 to 6, Comparative Examples 1 to 3, and Comparative Example 4 (as Seretide® Diskus®), and Comparative Example 6 (as Fluterol®), and 10 for Spiriva HandiHaler® of Comparative Example 5. The stability test on each inhalation formulation was repeated three times to obtain an average therefrom.
- Storage conditions: in Al-Al blister pack at about 75℃
- Testing time: Initial, after 5 days, after 10 days, and after 30 days
- Target analyte: unknown related compounds from fluticasone propionate
GR97980X from salmeterol
BⅡH27SE from tiotropium
- Analysis method of the unknown related compounds and GR97980X
·Detector: UV-absorption detector (absorbance at 228 nm for the unknown related compounds, and 240 nm for GR97980X)
·Column: Inertsil ODS-2 (250 mm μ x 4.6 mm, 3.5 μm)
·Mobile phase A: 0.05M aqueous ammonium dihydrogen phosphate solution adjusted to pH 2.9 with 10% (v/v) phosphoric acid
·Mobile phase B: Acetonitrile
·Flow rate: about 1.0 mL/min
·Injection volume: 50 μL
·Column temperature: 35℃
Figure PCTKR2016002623-appb-I000004
- Analysis method of BⅡH27SE
·Detector: UV-absorption detector (absorbance at 240 nm)
·Column: Propylsiyl silica gel for chromatography R (150 mm x 3.0 mm, 3.5 μm)
·Mobile phase A: Solution obtained by dissolving 1.0 g of sodium methanesulfonate and 5.0 g of potassium dihydrogen phosphate in 980 mL of deionized water, adjusting pH to 3.0 with dilute phosphoric acid, and adding water to a volume of 1000 mL.
·Mobile phase B: Methanol, acetonitrile, and Mobile phase A in a ratio of 10:40:50 (v/v/v)
·Flow rate: 1.2 mL/min
·Injection volume: 15 μL
·Column temperature: 50 ℃
Figure PCTKR2016002623-appb-I000005
The test results are shown in FIGS. 1 to 9.
FIG. 1 is a graph illustrating a total amount of unknown related compounds of fluticasone propionate in each of the inhalation capsules of Examples 1 to 6, Comparative Examples 1 to 4, and Comparative Example 6, as a result of the accelerated test with respect to time.
Referring to FIG. 1, Comparative Examples 1 and 2 which are HPMC capsules including carragenan as a gelation agent, and the commercially available inhalation capsules of Comparative Examples 4 and 6 were found to have a remarkable increase in the amount of the related compounds with time, while the inhalation formulations of Examples 1 to 6 had nearly no significant increase in the amount of the related compound with time. Therefore, it is found that capsules for inhalation according to embodiments may have remarkably higher stability of fluticasone propionate compared to the commercially available inhalation formulations.
FIGS. 2 to 4 are graphs illustrating the amount of GR97980X as a related compound of salmeterol in each of the inhalation formulations of Examples 1 to 6, Comparative Examples 1 to 4, and Comparative Example 6, as a result of the accelerated test with respect to time.
Referring to FIGS. 2 to 4, the inhalation formulations of Comparative Examples 1 to 3 using HPMC capsules including carragenan as a gelation agent, and the commercially available inhalation formulations of Comparative Examples 4 and 6 were found to have a remarkable increase in the amount of the related compound with time, while the inhalation formulations of Examples 1 to 6 had a very gentle increase in the amount of the related compounds with time, which was significantly low, compared to the increased amounts of the related compound in the inhalation formulations of the comparative examples. Therefore, it is found that capsules for inhalation according to embodiments may have remarkably higher stability of salmeterol compared to the commercially available inhalation formulations.
FIGS. 5 to 7 are graphs illustrating the amount of BⅡH27SE as a related compound of tiotropium in each of the inhalation formulations of Examples 1 to 6, Comparative Examples 1 to 3, and Comparative Example 5, as a result of the accelerated with respect to time.
Referring to FIGS. 5 to 7, the inhalation formulations of Comparative Examples 1 to 3 using HPMC capsules including carragenan as a gelation agent, and the commercially available inhalation formulation of Comparative Example 5 were found to have a remarkable increase in the amount of the related compound with time, while the inhalation formulations of Examples 1 to 6 had a very gentle increase in the amount of the related compound with time, which was significantly low, compared to the increased amounts of the related compound in the inhalation formulations of the comparative examples. Therefore, it is found that capsules for inhalation according to embodiments may have remarkably higher stability of tiotropium compared to the commercially available inhalation formulation.
Test Example 2 : Dosage unit sampling apparatus ( DUSA ) test
A dosage unit sampling apparatus (DUSA) test was performed using 10 inhalation capsules of each of Examples 1 to 6 and Comparative Examples 1 to 6 in the following manners to measure a delivered dose of each of the ingredients. The results are shown in Tables 4 and 5.
< Test method >
The DUSA test was performed using Apparatus B, according to the DUSA test method for dry powder inhalers among the general test items in the U.S. Pharmacopoeia (USP).
After Apparatus B is connected, adjustment is performed to have a pressure tap value (P1) of 4.0 kPa displayed on a flow rate controller. When the pressure tap value (P1) value reaches 4.0 kPa, a mouthpiece adapter is removed, a flow rate meter is connected according to Assembly method 2, and then a flow rate (Q) displayed on the flow rate meter is recorded. The inhalation time (T) is calculated using the following equation.
Figure PCTKR2016002623-appb-I000006
T: Inhalation time (sec)
Q: Flow rate at which a pressure drop is 4.0 kPa
After turning on a vacuum pump to adjust the air flow rate to Q, a mouthpiece adapter that may fit to an inhaler device is connected to Apparatus B. The inhaler device with a capsule therein is fit to the mouthpiece adapter, and the capsule is broken by pressing a button on the inhaler device, followed by inhalation for a duration (T) that is set using a switch on the flow rate controller.
< Analysis method >
Detector: UV-absorption detector (absorbance at 228 nm)
Column: Inertsil ODS-3, 5 ㎛, 4.6x150 mm (GL Science)
Column temperature: a constant temperature around 40℃
Mobile phase: A solution obtained by dissolving 0.6% (w/v) of ammonium in a mixed solution of methanol, acetonitrile, and water in a ratio of 50:16:34 (v/v)
Flow rate: 1.7 mL/min
Injection volume: 100 ㎕
[Table 4]
Figure PCTKR2016002623-appb-I000007
[Table 5]
Figure PCTKR2016002623-appb-I000008
According to the test results, in the combined dry powder inhalation formulations including fluticasone, salmeterol, and tiotropium, a ratio of achievement to the target-delivered dose of tiotropium was high in all of the tested inhalation formulations of Examples and Comparative Examples. However, the ratios of achievement to the target-delivery doses of fluticasone and salmeterol were significantly higher in the inhalation formulations of Examples 4 to 6 using HPMC capsules including no gelation agent, and the inhalation formulations of Examples 1 to 3 using HPMC capsules including gellan gum as a gelation agent, than in the inhalation formulations of Comparative Examples 1 to 3 using HPMC capsules including carrageenan as a gelation agent. The inhalation formulations of Examples 1 to 6 were also found to have a similar ratio of achievement to target-delivery dose to that of the commercially available inhalation formulations of Comparative Examples 4 and 5.
Therefore, by using HPMC capsules including no gelation agent or HPMC capsules including gellan gum as a gelation agent, capsules for inhalation according to embodiments may have a similar ratio of achievement to target-delivered dose to that of the commercially available inhalation formulations with improved stability of the active ingredients.
Test Example 3 : Brittleness Test
A brittleness test was performed using 20 inhalation capsules of each of Examples 3 and 6 and Comparative Examples 3 and 5 in the following manner. The number of fragments generated in the brittleness test was counted as a measure of brittleness. The results are shown in Table 6.
< Test method >
The brittleness test was performed using a device appropriate for the inhalation capsules. Each inhalation formulation was punched three times with a constant force under the constant humidity conditions of about 40% to about 60%.
[Table 6]
Figure PCTKR2016002623-appb-I000009
According to the results of Table 6, capsules for inhalation according to embodiments were found to have a smaller number of fragments per capsule, compared to the commercially available inhalation formulation of Comparative Example 5, and thus pharmaceutically desirable.
While this invention has been particularly shown and described with reference to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims. The disclosed embodiments should be considered in descriptive sense only and not for purposes of limitation. Therefore, the scope of the invention is defined not by the detailed description of the invention but by the appended claims, and all differences within the scope will be construed as being included in the present invention.

Claims (12)

  1. A capsule for inhalation comprising dry powder for inhalation comprising:
    at least two combined active ingredients selected from the group consisting of salmeterol or a pharmaceutically acceptable salt thereof, tiotropium or a pharmaceutically acceptable salt thereof, and fluticasone or a pharmaceutically acceptable salt thereof; and
    a diluent,
    wherein the dry powder is filled in a hydroxypropyl methylcellulose (HPMC) hard capsule not containing a gelation agent or in a HPMC hard capsule containing gellan gum as a gelation agent.
  2. The capsule of claim 2, wherein the diluent is selected from the group consisting of monosaccharides, disaccharides, polysaccharides, polyalcohols, and hydrates thereof.
  3. The capsule of claim 3, wherein the diluent is lactose.
  4. The capsule of claim 1, wherein the at least two combined active ingredients are selected from the group consisting of salmeterol xinafoate, tiotropium bromide, and fluticasone propionate.
  5. The capsule of claim 1, wherein about 25 μg to about 100 μg of salmeterol, about 5 μg to about 50 μg of tiotropium, and about 25 μg to about 500 μg of fluticasone, each as a free base, are filled in a capsule.
  6. The capsule of claim 1, wherein the capsule is used for the suppression of bronchoconstriction, inflammation, or airway mucus secretions.
  7. The capsule of claim 1, wherein the capsule is used for the treatment of asthma or chronic obstructive pulmonary disease (COPD).
  8. A method of using a hydroxypropyl methylcellulose (HPMC) hard capsule containing no gelation agent or a HPMC hard capsule containing gellan gum as a gelation agent to prepare a capsule for inhalation, the capsule being filled with dry powder for inhalation comprising:
    at least two combined active ingredients selected from the group consisting of salmeterol or a pharmaceutically acceptable salt thereof, tiotropium or a pharmaceutically acceptable salt thereof, and fluticasone or a pharmaceutically acceptable salt thereof; and
    a diluent.
  9. The method of claim 8, wherein the diluent is selected from the group consisting of monosaccharides, disaccharides, polysaccharides, polyalcohols, and hydrates thereof.
  10. The method of claim 8, wherein the diluent is lactose.
  11. The method of claim 8, wherein the at least two combined active ingredients are selected from the group consisting of salmeterol xinafoate, tiotropium bromide, and fluticasone propionate.
  12. The method of claim 8, wherein about 25 μg to about 100 μg of salmeterol, about 5 μg to about 50 μg of tiotropium, and about 25 μg to about 500 μg of fluticasone, each as a free base are filled in a capsule.
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KR20050003416A (en) * 2002-05-07 2005-01-10 넥타르 테라퓨틱스 Capsules for dry powder inhalers and methods of making and using same
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