US20060257330A1 - Powdery pharmaceutical compositions for inhalation - Google Patents
Powdery pharmaceutical compositions for inhalation Download PDFInfo
- Publication number
- US20060257330A1 US20060257330A1 US11/492,105 US49210506A US2006257330A1 US 20060257330 A1 US20060257330 A1 US 20060257330A1 US 49210506 A US49210506 A US 49210506A US 2006257330 A1 US2006257330 A1 US 2006257330A1
- Authority
- US
- United States
- Prior art keywords
- carrier
- composition according
- powder composition
- magnesium stearate
- dose
- 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.)
- Abandoned
Links
- 239000008194 pharmaceutical composition Substances 0.000 title abstract description 6
- 239000002245 particle Substances 0.000 claims abstract description 65
- 239000000843 powder Substances 0.000 claims abstract description 47
- 239000000203 mixture Substances 0.000 claims abstract description 43
- 239000000314 lubricant Substances 0.000 claims abstract description 23
- 239000004480 active ingredient Substances 0.000 claims abstract description 10
- 238000000034 method Methods 0.000 claims abstract description 7
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 90
- 235000019359 magnesium stearate Nutrition 0.000 claims description 45
- KUVIULQEHSCUHY-XYWKZLDCSA-N Beclometasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(Cl)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)COC(=O)CC)(OC(=O)CC)[C@@]1(C)C[C@@H]2O KUVIULQEHSCUHY-XYWKZLDCSA-N 0.000 claims description 44
- NDAUXUAQIAJITI-UHFFFAOYSA-N albuterol Chemical compound CC(C)(C)NCC(O)C1=CC=C(O)C(CO)=C1 NDAUXUAQIAJITI-UHFFFAOYSA-N 0.000 claims description 9
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 claims description 8
- 229960002052 salbutamol Drugs 0.000 claims description 8
- VOVIALXJUBGFJZ-KWVAZRHASA-N Budesonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C[C@H]3OC(CCC)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O VOVIALXJUBGFJZ-KWVAZRHASA-N 0.000 claims description 6
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- 150000003431 steroids Chemical class 0.000 claims description 4
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- XWTYSIMOBUGWOL-UHFFFAOYSA-N (+-)-Terbutaline Chemical compound CC(C)(C)NCC(O)C1=CC(O)=CC(O)=C1 XWTYSIMOBUGWOL-UHFFFAOYSA-N 0.000 claims description 2
- GIIZNNXWQWCKIB-UHFFFAOYSA-N Serevent Chemical compound C1=C(O)C(CO)=CC(C(O)CNCCCCCCOCCCCC=2C=CC=CC=2)=C1 GIIZNNXWQWCKIB-UHFFFAOYSA-N 0.000 claims description 2
- 208000006673 asthma Diseases 0.000 claims description 2
- 229950000210 beclometasone dipropionate Drugs 0.000 claims description 2
- 229940112141 dry powder inhaler Drugs 0.000 claims description 2
- 229960000676 flunisolide Drugs 0.000 claims description 2
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- BPZSYCZIITTYBL-UHFFFAOYSA-N formoterol Chemical compound C1=CC(OC)=CC=C1CC(C)NCC(O)C1=CC=C(O)C(NC=O)=C1 BPZSYCZIITTYBL-UHFFFAOYSA-N 0.000 claims description 2
- MIXMJCQRHVAJIO-TZHJZOAOSA-N qk4dys664x Chemical compound O.C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]2(C)C[C@@H]1O.C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]2(C)C[C@@H]1O MIXMJCQRHVAJIO-TZHJZOAOSA-N 0.000 claims description 2
- 229960004017 salmeterol Drugs 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
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- 239000000556 agonist Substances 0.000 claims 2
- 239000010419 fine particle Substances 0.000 abstract description 17
- 239000011248 coating agent Substances 0.000 abstract description 11
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- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 12
- 239000011777 magnesium Substances 0.000 description 10
- 238000009472 formulation Methods 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 7
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 6
- 229960001375 lactose Drugs 0.000 description 6
- 239000008101 lactose Substances 0.000 description 6
- NBMKJKDGKREAPL-DVTGEIKXSA-N beclomethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(Cl)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O NBMKJKDGKREAPL-DVTGEIKXSA-N 0.000 description 5
- 238000009826 distribution Methods 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 3
- 230000000181 anti-adherent effect Effects 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 229910052749 magnesium Inorganic materials 0.000 description 3
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- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 239000003380 propellant Substances 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 235000021355 Stearic acid Nutrition 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 2
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- 230000000694 effects Effects 0.000 description 2
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- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 2
- 210000003300 oropharynx Anatomy 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 239000008117 stearic acid Substances 0.000 description 2
- 229910021653 sulphate ion Inorganic materials 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 229910002016 Aerosil® 200 Inorganic materials 0.000 description 1
- 208000000884 Airway Obstruction Diseases 0.000 description 1
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 1
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 1
- CBENFWSGALASAD-UHFFFAOYSA-N Ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 description 1
- 208000002200 Respiratory Hypersensitivity Diseases 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 239000004141 Sodium laurylsulphate Substances 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- XZAGBDSOKNXTDT-UHFFFAOYSA-N Sucrose monopalmitate Chemical compound CCCCCCCCCCCCCCCC(O)=O.OC1C(O)C(CO)OC1(CO)OC1C(O)C(O)C(O)C(CO)O1 XZAGBDSOKNXTDT-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
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- 230000001154 acute effect Effects 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
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- 208000037883 airway inflammation Diseases 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000001088 anti-asthma Effects 0.000 description 1
- 239000003911 antiadherent Substances 0.000 description 1
- 239000000924 antiasthmatic agent Substances 0.000 description 1
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- 229940125388 beta agonist Drugs 0.000 description 1
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- 239000012876 carrier material Substances 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 229940075614 colloidal silicon dioxide Drugs 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000000254 damaging effect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
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- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
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- 230000004047 hyperresponsiveness Effects 0.000 description 1
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- 239000004615 ingredient Substances 0.000 description 1
- 238000002664 inhalation therapy Methods 0.000 description 1
- 229960001361 ipratropium bromide Drugs 0.000 description 1
- KEWHKYJURDBRMN-ZEODDXGYSA-M ipratropium bromide hydrate Chemical compound O.[Br-].O([C@H]1C[C@H]2CC[C@@H](C1)[N@@+]2(C)C(C)C)C(=O)C(CO)C1=CC=CC=C1 KEWHKYJURDBRMN-ZEODDXGYSA-M 0.000 description 1
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- GOQYKNQRPGWPLP-UHFFFAOYSA-N n-heptadecyl alcohol Natural products CCCCCCCCCCCCCCCCCO GOQYKNQRPGWPLP-UHFFFAOYSA-N 0.000 description 1
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- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
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- 238000009738 saturating Methods 0.000 description 1
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- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
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Classifications
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/27—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation
- C07C45/29—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation of hydroxy groups
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- C07C45/27—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation
- C07C45/29—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation of hydroxy groups
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- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
- C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
- C07C45/70—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form
- C07C45/71—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form being hydroxy groups
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- C07C47/47—Unsaturated compounds having —CHO groups bound to carbon atoms of rings other than six—membered aromatic rings containing ether groups, groups, groups, or groups
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- C07C59/40—Unsaturated compounds
- C07C59/58—Unsaturated compounds containing ether groups, groups, groups, or groups
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- C07C59/40—Unsaturated compounds
- C07C59/58—Unsaturated compounds containing ether groups, groups, groups, or groups
- C07C59/72—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings and other rings
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- C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
- C07C69/734—Ethers
Definitions
- This invention relates to improved powdery pharmaceutical compositions for use in dry powder inhalers.
- the improvement is concerned with mechanical stability, performances and safety.
- Inhalation anti-asthmatics are widely used in the treatment of reversible airway obstruction, inflammation and hyperresponsiveness.
- MDIs pressurised metered dose inhalers
- DPIs Dry powder inhalers
- DPIs can be divided into two basic types:
- MDPIs are considered more convenient to the patient than single dose DPIs, not only because they provide a number of doses sufficient for. longer treatment cycles but also because of their ease of use and unobtrusiveness.
- Dry powder dosage forms are generally formulated by mixing the cohesive micronised drug with coarse carrier particles, giving rise to ordered mixture where the micronised active particles adhere to the surface of the carrier particles whilst in the inhaler device.
- the carrier material most commonly lactose, makes the micronised powder less cohesive and improves its flowability, making easier handling the powder during the manufacturing process (pouring, filling etc.).
- the small drug particles separate from the surface of carrier particles and penetrates into the lower lungs, while the larger carrier particles are mostly deposited in the oropharyngeal cavity.
- the redispersion of drug particles from the carrier surface is regarded as the most critical factor which governs the availability of the medicament to the lungs. This will depend on the mechanical stability of the powder mix and the way this is influenced by the adhesion characteristics between the drug and the carrier and the external forces required to break up the non covalent bonds formed between adhering particles. Too strong bonds between adhering particles may prevent indeed the separation of the micronised drug particles from the surface of carrier particles. ID particular, the efficiency of the redispersion process is strictly dependent on the carrier surface properties, the actual particle size of both the drug and the carrier and the drug to carrier ratio.
- Fisons patents GB 1242211 and GB 1381872 described powders for inhalation obtained by simple mixing of a medicament with a particle size of less than 10 microns and a coarse carrier whose particle size falls in a well defined range. They also disclosed that it may be useful to coat the surfaces of the particles and/or carrier with pharmaceutically acceptable material, such as stearic acid or polymers for giving a sustained release action to the medicament.
- Chiesi WO A 87 05213 described a carrier, comprising a conglomerate of a solid water-soluble carrier and a lubricant, preferably 1% magnesium stearate, for improving the technological properties of the powder in such a way as to remedy to the reproducibility problems encountered after the repeated use of the inhaler device.
- the reported drawbacks can be solved by adding physiologically acceptable/water-soluble additives with anti-adherent properties which do not make segregation of the active particles from the surfaces of the carrier particles during manufacturing of the dry powder and in the delivery device before use.
- the anti-adherent material preferably 1-2% leucine in particulate form, promote the release of the active particles by saturating the high energy sites of the carrier particles.
- magnesium stearate being highly surface active, should be added in particularly small amounts', the use of such excipient is considered not advisable.
- lubricants like magnesium stearate can be advantageously and safely used as excipient for powdery pharmaceutical composition in such amount by weight based on the total weight of the powder of less than 0.5%; for steroids, the optimum amount of additive turned out to be 0.25%, whereas, for salbutamol base, it turned out to be 0.10%. Contrary to the teaching of the prior art (Peart et al. Pharm. Res. 14, S 142, 1997), 0.1% of magnesium stearate is sufficient for increasing in a significant way the fine particle dose, when salbutamol base instead of sulphate is used.
- the invention also provides a method for producing a homogeneous carrier for powders for inhalation independently on the scale of mixing, the method including a step for coating the most as possible surface of the carrier particles with a little amount of lubricant.
- a step for coating the most as possible surface of the carrier particles with a little amount of lubricant we have indeed found that it is advantageous to attain the highest as possible degree of coating of the carrier particles surface with the lubricant to increase the release of the active particles and, hence, the ‘respirable’ fraction.
- the film forming properties of lubricants depend on the mixing time and significantly affect the compressibility characteristics of powders for tablets, but an advantageous relationship between the degree of coating and the ‘respirable’ fraction has never been reported before.
- this is another aspect of the invention that use of lubricants in such little amount for coating the carrier, is sufficient for improving the flowability of the powder without causing mechanical stability problems of the mixture before use.
- magnesium stearate in such a small amount is safe and does not produce any toxicologically relevant effect after repeated administration.
- the carrier of the invention is prepared by mixing the carrier particles and the lubricant particles for at least 2 min in a mixer in such a way as that no significant change in the particle size of the carrier particle occurs.
- the carrier is mixed for at least 30 min using a rotating body mixer with a rotating speed between 5-100 r.p.m. or a stationary body mixer with a rotating mixing blade or a high-speed mixer. More preferably, the carrier is mixed for al least two hours in a Turbula mixer at 16 r.p.m.
- the carrier particles and the lubricant particles are mixed until the degree of molecular surface coating is more than 10% as determined by water contact angle measurement.
- carrier particles and lubricant particles made of magnesium stearate are mixed until the water contact angle of the ‘coated’ carrier particles is more than 36° corresponding to more than 10% degree of molecular surface coating; more preferably, the water contact angle should be more than 50° corresponding to more than 23% degree of molecular surface coating.
- the carrier particles may be composed of any pharmacologically inert material or combinations of material acceptable for inhalation.
- the carrier particles are composed on one or more crystalline sugars.
- the carrier particles are particles of ⁇ -lactose monaohydrate.
- all the carrier particles have a particle size in the range 20-1000 ⁇ m, more preferably in the range 90-150 ⁇ m.
- the preferred lubricant is any type of magnesium stearate which may be crystalline or amorphous; its use is described in the embodiments of the invention by way of examples which do not limit it in any way.
- lubricants such as stearic acid, sodium lauryl sulphate, sodium stearyl fumarate, stearyl alcohol, sucrose monopalmitate and sodium benzoate, could turn out to be suitable depending on the type of carrier and drug used.
- At least 50% by weight of the lubricant particles have a particle size more than 4 ⁇ m.
- at least 60% of the lubricant particles made of magnesium stearate have a particle size more than 5 ⁇ m, with a specific surface area in the range 0.5-2.5 m 2 /g measured by Malvern.
- the ratio between the carrier and the drug are mixed will depend on the type of inhaler device used and the required dose.
- the at least 90% of the particles of the drug have a particle size less than 10 ⁇ m, preferably less than 6 ⁇ m.
- Drugs include those products which are usually administered by inhalation for the treatment of respiratory diseases, i.e. ⁇ -agonists, like salbutamol, formoterol, salmeterol, terbutaline and their salts, steroids like beclometasone dipropionate, flunisolide, budesonide, others like ipratropium bromide.
- ⁇ -agonists like salbutamol, formoterol, salmeterol, terbutaline and their salts
- steroids like beclometasone dipropionate
- flunisolide flunisolide
- budesonide others like ipratropium bromide.
- the invention also provides a powdery pharmaceutical composition for use in a dry powder inhaler, the powder including active particles and a carrier where the surface of the carrier particles carrying the active particles is partially coated with a film of lubricant.
- Samples of the carrier were prepared by mixing of ⁇ -lactose monohydrate (Meggle D 30) fraction 90-150 ⁇ m with 0.1%, 0.25% or 0.5% magnesium stearate for several hours in a Turbula mixer. Powders mixtures with different BDP concentrations (100, 200 and 400 ⁇ g/dose) were prepared by mixing of the carrier and the active ingredient for 30 min in a Turbula mixer at 32 r.p.m.
- Multidose devices (Pulvinal®) filled with the mixtures were then tested by using a twin-stage impinger (TSI), Apparatus A (BP 93, Appendix XVII C, A194).
- the fine particle dose is calculated as a percentage of the total amount of drug delivered from the device (stage 1+stage 2), that reaches stage 2 of TSI.
- the results are summarised in Tables 1, 2 and 3 (standard deviations S.D., given in parentheses).
- Powder mixtures containing 200 ⁇ g/dose of micronised salbutamol base were prepared by mixing of the carrier and the active ingredient for 30 min in a Turbula mixer at 32 r.p.m.
- a sample of the carrier was prepared by mixing of ⁇ -lactose monohydrate (Meggle D 30) fraction 90-150 ⁇ m with 0.25% magnesium stearate for two hours in Turbula-T100 mixer at 16 r.p.m.
- Powder mixtures containing 100 ⁇ g/dose of micronised budesonide were prepared by mixing of the carrier and the active ingredient for 30 min in a Turbula mixer at 32 r.p.m.
- Magnesium stearate significantly increases the fine particle dose of budesonide (t 8.8, p ⁇ 0.001); TABLE 5 Formulation Mg Shot Fine particle (100 stearate weight Stage 2 Delivered dose* ⁇ g/dose) (%) (mg) ( ⁇ g) dose ( ⁇ g) (Budesonide %) BUD 1 0 22.0 — 80.0 21.4 (4.7) BUD 2 0.25 21.5 — 79.3 33.6 (2.6) *Average values obtained from three inhalers by actuating 5 shots from each inhaler.
- Powder mixtures containing 200 ⁇ g/dose of micronised BDP were prepared by mixing of the carrier and the active ingredient for 30 min in a Turbula mixer at 32 r.p.m.
- Composition of BDP Pulvinal® (100, 200 and 400 ⁇ g/dose): Strength ( ⁇ g/dose) Ingredient (mg) 100 200 400 BDP 0.100 0.200 0.400 ⁇ -Lactose monohydrate 25.832 25.735 25.536 Magnesium stearate 0.067 0.064 0.064
- Typical values in coefficient of variation (CV) of BDP samples drawn from, a mix judged to be satisfactory are ⁇ 5.0%. After the imposition of an enhanced gravitational stress, BDP samples show a CV which varies from 2.7% and 7.8%. Despite the intense vibration, these variations have not increased significantly and are consistent with good inhaler performance when judged in terms of dose uniformity. Samples taken from the top of the bed are very similar to the bottom samples.
- a batch of BDP 400 ⁇ g/shot powder was prepared by mixing of the drug and the carrier (lactose/magnesium stearate 99.75/0.25% w/w) under the conditions reported in Example 1. Devices were filled with the mixture and the fine particle delivery of magnesium stearate was determined using a TSI apparatus. The results are reported in Table 12. TABLE 12 Total Mg Total Shot weight stearate Mg stearate Mg stearate stage 2 (mg) (%) ( ⁇ g) ( ⁇ g) Mean 26.4 0.259 68 19 S.D. 0.31 0.017 4.18 2.39 CV % 1.18 6.52 6.13 12.5
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Abstract
Powdery pharmaceutical compositions including an active ingredient and carrier particles containing only a small amount of lubricant, 0.05-0.5% by weight, are used to prepare dry powder inhalers in order to increase the fine particle dose. A process for coating the surface of the carrier particles with such little amount of lubricant is also provided. Use of limited amount of lubricant is safe and provides ordered stable mixtures without segregation of the active particles during handling and before use.
Description
- This invention relates to improved powdery pharmaceutical compositions for use in dry powder inhalers. The improvement is concerned with mechanical stability, performances and safety.
- Inhalation anti-asthmatics are widely used in the treatment of reversible airway obstruction, inflammation and hyperresponsiveness.
- Presently, the most widely used systems for inhalation therapy are the pressurised metered dose inhalers (MDIs). which use a propellant to expel droplets containing the pharmaceutical product to the respiratory. tract.
- However, despite their practicality and popularity, MDIs have some disadvantages:
- i) the majority of the dose released deposits in the oropharynx by impaction and only a small percentage penetrates directly into the lower lungs;
- ii) the already small proportion of drug which penetrates the bronchial tree may be further reduced by poor inhalation technique;
- iii) last but not least, chlorofluorocarbons (CFCs), such as freons contained as propellants in MDIs, are disadvantageous on environmental grounds as they have a proven damaging effect on the atmosphenic ozone layer.
- Dry powder inhalers (DPIs) constitute a valid alternative to MDIs for the administration of drugs to airways. The main advantages of DPIs are:
- i) being breath-actuated delivery systems, they do not require co-ordination of actuation since release of the drug is dependent on the patient own inhalation;
- ii) they do not contain propellants acting as environmental hazards;
- iii) the quantity deposited by impaction in the oropharynx is lower.
- DPIs can be divided into two basic types:
- i) single dose inhalers, for the administration of single subdivided doses of the active compound;
- ii) multidose dry powder inhalers (MDPIs), pre-loaded with quantities of active principles sufficient for longer treatment cycles.
- MDPIs are considered more convenient to the patient than single dose DPIs, not only because they provide a number of doses sufficient for. longer treatment cycles but also because of their ease of use and unobtrusiveness.
- Dry powder dosage forms are generally formulated by mixing the cohesive micronised drug with coarse carrier particles, giving rise to ordered mixture where the micronised active particles adhere to the surface of the carrier particles whilst in the inhaler device.
- The carrier material, most commonly lactose, makes the micronised powder less cohesive and improves its flowability, making easier handling the powder during the manufacturing process (pouring, filling etc.). During inhalation, the small drug particles separate from the surface of carrier particles and penetrates into the lower lungs, while the larger carrier particles are mostly deposited in the oropharyngeal cavity.
- The redispersion of drug particles from the carrier surface is regarded as the most critical factor which governs the availability of the medicament to the lungs. This will depend on the mechanical stability of the powder mix and the way this is influenced by the adhesion characteristics between the drug and the carrier and the external forces required to break up the non covalent bonds formed between adhering particles. Too strong bonds between adhering particles may prevent indeed the separation of the micronised drug particles from the surface of carrier particles. ID particular, the efficiency of the redispersion process is strictly dependent on the carrier surface properties, the actual particle size of both the drug and the carrier and the drug to carrier ratio. Consequently, different approaches aimed at modulating one or more of these parameters have been proposed to promote the release of the drug particles from the carrier particles and, hence, to increase the percentage of the respirable fraction. In the prior art, the use of a ternary component, with lubricant or anti-adherent properties, has been also suggested as a solution of the technical problem.
- Fisons patents GB 1242211 and GB 1381872 described powders for inhalation obtained by simple mixing of a medicament with a particle size of less than 10 microns and a coarse carrier whose particle size falls in a well defined range. They also disclosed that it may be useful to coat the surfaces of the particles and/or carrier with pharmaceutically acceptable material, such as stearic acid or polymers for giving a sustained release action to the medicament.
- Chiesi WO A 87 05213 described a carrier, comprising a conglomerate of a solid water-soluble carrier and a lubricant, preferably 1% magnesium stearate, for improving the technological properties of the powder in such a way as to remedy to the reproducibility problems encountered after the repeated use of the inhaler device.
- Staniforth et al. (J. Pharm. Pharmacol. 34, 141-145, 1982) observed that magnesium stearate is able to modify the adhesion of salicylic acid to sucrose but, the amount used (0.5-4.0%) destabilises the mixture to the extent that significant segregation occurs.
- Kassem (London University Thesis, 1990) studied the effect of 1.5% w/w magnesium stearate or Aerosil 200 (trade name for colloidal silicon dioxide) on the de-aggregation of powders made of salbutamol sulphate and lactose. Although the ‘respirable’ fraction increased when magnesium stearate was added, the reported amount is too great and reduces the mechanical stability of the mixture before use. Furthermore, being magnesium stearate poorly water-soluble, its presence in such amount may rise some concerns as to a potential irritation or toxicity of this excipient, part of which can be inhaled by the patient together with the active ingredient. According to Staniforth (WO 96/23485), the reported drawbacks can be solved by adding physiologically acceptable/water-soluble additives with anti-adherent properties which do not make segregation of the active particles from the surfaces of the carrier particles during manufacturing of the dry powder and in the delivery device before use. In the said document, the anti-adherent material, preferably 1-2% leucine in particulate form, promote the release of the active particles by saturating the high energy sites of the carrier particles. Although it is generically disclosed that magnesium stearate, being highly surface active, should be added in particularly small amounts', the use of such excipient is considered not advisable.
- It has now been discovered, and this is an object of the present invention, that lubricants like magnesium stearate can be advantageously and safely used as excipient for powdery pharmaceutical composition in such amount by weight based on the total weight of the powder of less than 0.5%; for steroids, the optimum amount of additive turned out to be 0.25%, whereas, for salbutamol base, it turned out to be 0.10%. Contrary to the teaching of the prior art (Peart et al. Pharm. Res. 14, S 142, 1997), 0.1% of magnesium stearate is sufficient for increasing in a significant way the fine particle dose, when salbutamol base instead of sulphate is used.
- The invention also provides a method for producing a homogeneous carrier for powders for inhalation independently on the scale of mixing, the method including a step for coating the most as possible surface of the carrier particles with a little amount of lubricant. We have indeed found that it is advantageous to attain the highest as possible degree of coating of the carrier particles surface with the lubricant to increase the release of the active particles and, hence, the ‘respirable’ fraction. In the prior art, it was already known that the film forming properties of lubricants depend on the mixing time and significantly affect the compressibility characteristics of powders for tablets, but an advantageous relationship between the degree of coating and the ‘respirable’ fraction has never been reported before. We have also found, and this is another aspect of the invention, that use of lubricants in such little amount for coating the carrier, is sufficient for improving the flowability of the powder without causing mechanical stability problems of the mixture before use.
- Finally we have found that the introduction of magnesium stearate in such a small amount is safe and does not produce any toxicologically relevant effect after repeated administration.
- Advantageously the carrier of the invention is prepared by mixing the carrier particles and the lubricant particles for at least 2 min in a mixer in such a way as that no significant change in the particle size of the carrier particle occurs. Preferably, the carrier is mixed for at least 30 min using a rotating body mixer with a rotating speed between 5-100 r.p.m. or a stationary body mixer with a rotating mixing blade or a high-speed mixer. More preferably, the carrier is mixed for al least two hours in a Turbula mixer at 16 r.p.m.
- Advantageously, the carrier particles and the lubricant particles are mixed until the degree of molecular surface coating is more than 10% as determined by water contact angle measurement. Preferably, carrier particles and lubricant particles made of magnesium stearate are mixed until the water contact angle of the ‘coated’ carrier particles is more than 36° corresponding to more than 10% degree of molecular surface coating; more preferably, the water contact angle should be more than 50° corresponding to more than 23% degree of molecular surface coating.
- The carrier particles may be composed of any pharmacologically inert material or combinations of material acceptable for inhalation. Advantageously, the carrier particles are composed on one or more crystalline sugars. Preferably, the carrier particles are particles of α-lactose monaohydrate.
- Advantageously, all the carrier particles have a particle size in the range 20-1000 μm, more preferably in the range 90-150 μm.
- The preferred lubricant is any type of magnesium stearate which may be crystalline or amorphous; its use is described in the embodiments of the invention by way of examples which do not limit it in any way.
- Other lubricants, such as stearic acid, sodium lauryl sulphate, sodium stearyl fumarate, stearyl alcohol, sucrose monopalmitate and sodium benzoate, could turn out to be suitable depending on the type of carrier and drug used.
- Advantageously, at least 50% by weight of the lubricant particles have a particle size more than 4 μm. Preferably, at least 60% of the lubricant particles made of magnesium stearate have a particle size more than 5 μm, with a specific surface area in the range 0.5-2.5 m2/g measured by Malvern.
- The ratio between the carrier and the drug are mixed will depend on the type of inhaler device used and the required dose.
- Advantageously, the at least 90% of the particles of the drug have a particle size less than 10 μm, preferably less than 6 μm.
- Drugs include those products which are usually administered by inhalation for the treatment of respiratory diseases, i.e. β-agonists, like salbutamol, formoterol, salmeterol, terbutaline and their salts, steroids like beclometasone dipropionate, flunisolide, budesonide, others like ipratropium bromide.
- In a general aspect, the invention also provides a powdery pharmaceutical composition for use in a dry powder inhaler, the powder including active particles and a carrier where the surface of the carrier particles carrying the active particles is partially coated with a film of lubricant.
- Determination of the Suitable Amount of Magnesium Stearate to be Added in beclomethasone-17,21-dipropionate (BDP) Powders for Inhalation
- Samples of the carrier were prepared by mixing of α-lactose monohydrate (Meggle D 30) fraction 90-150 μm with 0.1%, 0.25% or 0.5% magnesium stearate for several hours in a Turbula mixer. Powders mixtures with different BDP concentrations (100, 200 and 400 μg/dose) were prepared by mixing of the carrier and the active ingredient for 30 min in a Turbula mixer at 32 r.p.m.
- Multidose devices (Pulvinal®) filled with the mixtures were then tested by using a twin-stage impinger (TSI), Apparatus A (BP 93, Appendix XVII C, A194). The fine particle dose is calculated as a percentage of the total amount of drug delivered from the device (stage 1+stage 2), that reaches stage 2 of TSI. The results are summarised in Tables 1, 2 and 3 (standard deviations S.D., given in parentheses).
- No significant increase in fine particle dose is obtained from increasing the concentration of magnesium stearate above 0.25%.
TABLE 1 Formulation Mg Shot Fine particle (100 stearate weight Stage 2 Delivered dose* μg/dose) (%) (mg) (μg) dose (μg) (BDP %) BDP 1 0.10 26.7 (0.3) 22.5 (3.5) 99.7 (0.6) 21.9 (2.8) BDP 2 0.25 26.8 (0.1) 33.0 (5.6) 95.3 (0.6) 34.5 (6.2) -
TABLE 2 Fine Formulation Mg Shot particle (200 stearate weight Stage 2 Delivered dose* μg/dose) (%) (mg) (μg) dose (μg) (BDP %) BDP 1 0 24.8 (0.4) 14.2 (5.7) 192 (14.0) 7.3 (2.6) BDP 2 0.10 26.6 (0.4) 20.3 (4.6) 215 (2.3) 9.5 (2.2) BDP 3 0.25 26.8 (0.6) 48.0 (8.5) 192 (7.8) 25.0 (3.7) BDP 4 0.50 26.7 (0.2) 32.3 (2.3) 193 (4.6) 16.7 (1.0) -
TABLE 3 Formulation Mg Shot Fine particle (400 stearate weight Stage 2 Delivered dose* μg/dose) (%) (mg) (μg) dose (μg) (BDP %) BDP 1 0 — — 355 (22.8) 7.3 (0.4) BDP 2 0.10 25.4 (0.3) 100 (11.0) 351 (4.5) 28.7 (3.4) BDP 3 0.25 25.1 (0.4) 142 (22.1) 375 (9.3) 37.9 (5.7) BDP 4 0.50 25.5 (0.3) 98 (44.7) 421 (18.4) 23.2 (10.3) - Determination of the Suitable Amount of Magnesium Stearate to be Added in Salbutamol Base Powders for Inhalation
- Samples of the carrier were prepared as reported in Example 1.
- Powder mixtures containing 200 μg/dose of micronised salbutamol base were prepared by mixing of the carrier and the active ingredient for 30 min in a Turbula mixer at 32 r.p.m.
- The powder mixtures were filled into inhalers and tested as reported in Example 1.
- The results are summarised in Table 4.
- 0.1% Magnesium stearate is sufficient for increasing in a significant way (t=10.47, p<0.001) the fine particle dose, when salbutamol base instead of sulphate is used; no increase is obtained from increasing the concentration of magnesium stearate above this percentage.
TABLE 4 Fine particle Formulation Mg Shot dose* (200 stearate weight Stage 2 Delivered (Salbutamol μg/dose) (%) (mg) (μg) dose (μg) %) SALB 1 0 22.4 (0.4) 62.7 (5.3) 185 (5.1) 33.6 (2.9) SALB 2 0.1 26.8 (0.5) 71.3 (3.1) 171 (5.0) 41.8 (0.9) SALB 3 0.25 26.9 (0.2) 71.7 (6.1) 171 (1.7) 41.6.(3.2) SALB 4 0.5 26.5 (0.5) 68.7 (6.4) 172 (6.0) 39.9 (3.5) - Determination of the Suitable Amount of Magnesium Stearate to be Added in Budesonide Powders for Inhalation
- A sample of the carrier was prepared by mixing of α-lactose monohydrate (Meggle D 30) fraction 90-150 μm with 0.25% magnesium stearate for two hours in Turbula-T100 mixer at 16 r.p.m.
- Powder mixtures containing 100 μg/dose of micronised budesonide were prepared by mixing of the carrier and the active ingredient for 30 min in a Turbula mixer at 32 r.p.m.
- The powder mixtures were filled into inhalers and tested as reported in Example 1.
- The results are summarised in Table 5.
- 0.25% Magnesium stearate significantly increases the fine particle dose of budesonide (t=8.8, p<0.001);
TABLE 5 Formulation Mg Shot Fine particle (100 stearate weight Stage 2 Delivered dose* μg/dose) (%) (mg) (μg) dose (μg) (Budesonide %) BUD 1 0 22.0 — 80.0 21.4 (4.7) BUD 2 0.25 21.5 — 79.3 33.6 (2.6)
*Average values obtained from three inhalers by actuating 5 shots from each inhaler.
- Preparation of the Carrier—Study of the Mixing Conditions
- 40.528 kg (99.75% w/w) of α-Lactose monohydrate fraction 90-150 μm and 0.102 kg (0.25% w/w) of magnesium stearate were mixed in a Turbula mixer T 100 at 16 r.p.m. for several hours. At different mixing times samples were withdrawn and tested for uniformity of distribution of magnesium stearate, particle size, water contact angle and degree of molecular surface coating calculated according to Cassie et al. (Transactions of the Faraday Society 40; 546, 1944). To validate the process, three batches (40 kg) of the carrier were prepared.
- The results are reported in Tables 6 and 7, respectively.
- A uniform distribution of magnesium stearate was already achieved at 60 minutes blending time (mean value, {overscore (x)}, and coefficient of variation, CV %, are given); no significant change in the particle size was observed after both Malvern light-scattering and Alpine sieving analyses. By increasing the mixing time, an increase of the degree of coating occurs.
- The three different batches give comparable results.
TABLE 6 Particle size Particle size Mg stearate Water contact Degree of Time Alpine Malvern uniformity angle coating min % <80μ % <90μ % <80μ % 90μ x % CV % degree % 10′ — — — — — — 34 15 20′ — — — — — — 36 17 30′ 1.5 4.8 0.9 2.7 0.228 6.8 36 17 60′ 0.3 2.8 0.9 2.6 0.235 6.1 36 17 90′ 0.6 3.8 1.0 2.9 0.244 3.7 37 18 120′ 0.7 3.4 0.9 2.7 0.239 7.2 39 20 180′ 0.8 4.2 0.8 2.6 0.246 2.9 46 29 240′ 1.4 6.3 0.8 2.6 — — 48 32 300′ 0.7 6.6 0.9 2.6 — — 50 34 360′ 0.7 7.0 1.0 2.8 — — 51 36 420′ 0.9 7.0 0.9 2.8 — — 51 36 480′ 0.8 7.5 0.8 2.6 — — 51 36
α-Lactose monohydrate water contact angle 12°
Magnesium stearate water contact angle 118°
-
TABLE 7 Magnesium Particle size Particle size stearate Water Distribution distribution content contact Mixing (Alpine) (Malvern) uniformity angle Time % <80 μm % <90 μm % <80 μm % <90 μm x (%) CV (%) (degree) CARRIER 1 10 min 34 20 min 37 30 min 1.5 4.8 0.9 2.7 0.228 6.8 36 60 min 0.3 2.8 0.9 2.6 0.235 6.1 36 90 min 0.6 3.8 1.0 2.9 0.244 3.7 37 120 min 0.7 3.4 0.9 2.7 0.239 7.2 39 CARRIER 2 10 min 32 20 min 36 30 min 38 60 min 0.9 7.2 1.0 3.1 0.196 9.6 38 90 min 40 120 min 1.5 8.1 1.1 3.3 0.231 10.4 42 CARRIER 3 10 min 32 20 min 31 30 min 33 60 min 0.8 6.9 2.0 4.5 0.237 7.3 38 90 min 42 120 min 0.8 7.3 1.8 4.2 0.229 3.8 42 - Relationship Between Different Mixing Time of the Carrier and Delivered Fine Particle Dose
- 40.528 kg (99.75% w/w) of a-Lactose monohydrate fraction 90-150. μm and 0.102 kg (0.25% w/w) of magnesium stearate were mixed for several hours in Turbula T100 mixer at 16 r.p.m. At different mixing times, 2 kg samples were withdrawn and micronised BDP was added to each sample so that the nominal weight delivered by Pulvinale inhaler contained 200 μg BDP. The powder mixtures were filled into inhalers and tested as reported in Example 1.
- The results are reported in Table 8.
- By increasing the mixing time, a significant increase at 420 min of the fine particle dose occurs (t=5.2, p<0.001).
TABLE 8 Formulation (BDP 200 μg/dose) BDP 1 BDP 2 BDP 3 Mixing time (min) 60 120 420 Shot weight (mg) 27.8 (0.6) 28.1 (0.7) 28.2 (0.5) Fine particle dose* (%) 34.1 (8.1) 37.4 (4.7) 49.5 (7.8) Stage 2 (μg) 63.1 (12.0) 63.5 (8.1) 102.6 (17.1) Delivered dose (μg) 188.4 (21.1) 169.7 (7.1) 207.2 (9.0)
*Average values obtained from three inhalers by actuating 5 shots from each inhaler
- Preparation of the Carrier—Comoarison Between Different Mixers
- 40.528 kg (99.75% w/w) of α-Lactose monohydrate fraction 90-150 μm and 0.102 kg (0.25 % w/w) of magnesium stearate were mixed in a sigma-blade mixer for 30 min (water contact angle of 53° corresponding to 26% of molecularcoating)
- Powder mixtures containing 200 μg/dose of micronised BDP were prepared by mixing of the carrier and the active ingredient for 30 min in a Turbula mixer at 32 r.p.m.
- The powder mixtures were filled into inhalers and tested as reported in Example 1.
- The results are surniarised in Table 9.
- No significant difference was observed in the fine particle dose with respect to the powder obtained with the carrier prepared by using a Turbula mixer at 16 r.p.m. for 2 hours.
TABLE 9 Fine particle Formulation Shot Stage 2 Delivered dose (200 μg/dose) weight (mg) (μg) dose (μg) (BDP %) Turbula mixer 25.7 (2.8) 96.2 (7.6) 167.5 (5.7) 57.4 (4.3) Sigma-blade 26.6 (2.3) 106.2 (11.2) 192.1 (7.0) 55.2 (6.0) mixer - Segregation Tendency of BDP Bulk Powder Formulation Containing 0.25% Magnesium Stearate
- Composition of BDP Pulvinal® (100, 200 and 400 μg/dose):
Strength (μg/dose) Ingredient (mg) 100 200 400 BDP 0.100 0.200 0.400 α-Lactose monohydrate 25.832 25.735 25.536 Magnesium stearate 0.067 0.064 0.064 - The tendency of the powder to segregate was assessed according to Staniforth et al. J. (Pharm. Pharmacol. 34, 700-706, 1982).
- Approximately 15 g of powder was filled into a small plastic cylinder, 80 mm long and 12 mm in diameter, closed at one end and which could be split along its axis. This allowed the characterisation of both BDP and magnesium stearate on the same level in the same bulk mixture. The tube was mounted in a vibrator (Derrinton VP4) and vibrated at 50 Hz at a force of 2 g for ten minutes. The tube was then placed in a horizontal position, divided and 15 samples, each of about 50 mg accurately weighed, taken from along its length. The samples were analysed for BDP by HPLC and for magnesium stearate by atomic absorption. The experiments were carried out in duplicate. The results are reported in Tables 10 and 11.
- Typical values in coefficient of variation (CV) of BDP samples drawn from, a mix judged to be satisfactory are ≦5.0%. After the imposition of an enhanced gravitational stress, BDP samples show a CV which varies from 2.7% and 7.8%. Despite the intense vibration, these variations have not increased significantly and are consistent with good inhaler performance when judged in terms of dose uniformity. Samples taken from the top of the bed are very similar to the bottom samples.
- In the case of magnesium stearate, variability between samples was somewhat greater than for BDP due to its lower concentration. However, no consistent change in the uniformity of distribution occurred after vibration and, as with BDP, the content of samples drawn from the top of the bed were not different to those drawn from the bottom. It can be concluded that the ordered mix is very stable and no segregation of BDP and magnesium stearate occurs.
TABLE 10 DRUG ASSAY (μg/mg) BDP BDP BDP 400 μg/dose 200 μg/dose 100 μg/dose SAMPLE 1 2 1 2 1 2 Top of Cylinder 1 17.9 17.3 8.6 8.5 4.4 4.4 2 20.5 17.1 7.5 7.6 3.5 3.5 3 16.9 17.6 7.7 7.7 3.7 3.9 4 18.0 16.9 7.7 7.8 3.8 3.9 5 17.0 17.0 7.5 9.0 4.1 4.2 6 17.2 17.1 7.6 7.8 3.9 3.8 7 17.4 17.6 7.4 8.1 3.7 3.8 8 17.2 17.1 7.6 7.7 4.2 3.8 9 16.8 17.3 7.7 7.6 4.5 3.9 10 16.9 16.5 8.3 8.0 3.6 3.8 11 16.9 18.9 7.8 8.0 4.4 4.0 12 21.1 18.1 7.9 7.9 3.9 3.9 13 17.3 17.5 7.8 7.3 3.9 4.2 14 19.4 17.1 7.7 7.7 4.2 4.1 15 18.0 19.1 7.8 8.0 4.4 3.9 Bottom of Cylinder Mean 17.9 17.5 7.8 7.9 4.0 3.9 SD 1.4 0.8 0.2 0.4 0.3 0.2 CV(%) 7.6 4.3 2.7 5.0 7.8 4.7 -
TABLE 11 MAGNESIUM ASSAY (μg/mg) BDP 400 μg/dose BDP 200 μg/dose BDP 100 μg/dose SAMPLE 1 2 UN-VIBRATED 1 2 UN-VIBRATED 1 2 UN-VIBRATED Top of cylinder 1 0.115 0.124 0.101 0.101 0.092 0.125 0.082 0.076 0.103 2 0.116 0.122 0.103 0.105 0.091 0.121 0.105 0.073 0.150 3 0.114 0.123 0.107 0.108 0.093 0.125 0.096 0.091 0.104 4 0.113 0.119 0.109 0.100 0.093 0.118 0.107 0.085 0.101 5 0.114 0.126 0.110 0.115 0.089 0.135 0.094 0.083 0.110 6 0.108 0.108 0.107 0.103 0.100 0.208 0.098 0.080 0.109 7 0.111 0.113 0.110 0.111 0.096 0.107 0.104 0.114 0.109 8 0.118 0.108 0.108 0.107 0.096 0.101 0.102 0.076 0.102 9 0.107 0.104 0.106 0.106 0.094 0.102 0.099 0.082 0.103 10 0.113 0.119 0.107 0.094 0.097 0.101 0.104 0.081 0.109 11 0.114 0.120 0.109 0.091 0.094 0.096 0.090 0.086 0.105 12 0.116 0.117 0.105 0.083 0.093 0.098 0.100 0.084 0.107 13 0.112 0.101 0.103 0.114 0.077 0.100 0.092 0.079 0.104 14 0.115 0.104 0.107 0.081 0.095 0.097 0.091 0.072 0.107 15 0.106 0.097 0.102 0.080 0.076 0.100 0.086 0.085 0.105 Bottom of Cylinder Mean 0.113 0.114 0.106 0.100 0.092 0.116 0.097 0.083 0.109 SD 0.003 0.009 0.003 0.012 0.007 0.028 0.007 0.010 0.012 (CV %) 3.1 8.2 2.7 11.6 7.3 24.6 7.6 12.0 10.9 - Fine Particle Delivery of Magnesium Stearate
- A batch of BDP 400 μg/shot powder was prepared by mixing of the drug and the carrier (lactose/magnesium stearate 99.75/0.25% w/w) under the conditions reported in Example 1. Devices were filled with the mixture and the fine particle delivery of magnesium stearate was determined using a TSI apparatus. The results are reported in Table 12.
TABLE 12 Total Mg Total Shot weight stearate Mg stearate Mg stearate stage 2 (mg) (%) (μg) (μg) Mean 26.4 0.259 68 19 S.D. 0.31 0.017 4.18 2.39 CV % 1.18 6.52 6.13 12.5 - Considering the low concentration of magnesium stearate in the formulation and the quantity found in stage 2 of TSI, the amount to be respirable will be very low.
- This amount has been demonstrated to be safe after toxicity studies in dog.
- Furthermore, acute and long term tolerance trials were carried out to evaluate toxicity of magnesium stearate in humans.
- In the former, 18 healthy volunteers, included in a double blind randomised controlled cross-over design study, received a single dose containing 25.72 mg of lactose and 0.065 mg of magnesium stearate via Pulvinal® inhaler. The introduction of 0.25% magnesium stearate in powdery pharmaceutical formulation resulted to be safe.
- In the long term randomised, controlled, parallel group study, the safety of magnesium stearate as a carrier was compared to that of lactose. 28 Mild asthmatic patients were treated for 3 months with 400 μg BDP b.i.d. delivered either with Pulvinal®, containing 0.065 mg of magnesium stearate per dose, or another commercially available DPI, containing 25.536 mg of lactose per dose. Bronchial biopsies and broncho-alveolar lavages performed at the beginning and at the end of trial did not evidence accumulation of magnesium in bronchi or in alveolar cells either in Pulvinal® or control group.
Claims (16)
1-26. (canceled)
27. A powder composition comprising active ingredient particles and carrier particles, the carrier comprising one or more crystalline sugars coated with a lubricant wherein said lubricant comprises magnesium stearate in an amount between 0.1 and 0.5 percent by weight of the composition.
28. A powder according to claim 27 wherein the crystalline sugar is made of α-lactose monohydrate.
29. A powder composition according to claim 27 wherein the carrier particles have a size within the range 90 and 150 μm.
30. A powder composition according to claim 27 wherein the active ingredient particles have a particle size less than 6 μm.
31. A powder composition according to claim 27 wherein the active ingredient particles include a steroid.
32. A powder composition according to claim 31 wherein the steroid is selected from the group consisting of beclometasone dipropionate, budesonide and its epimers and flunisolide.
33. A powder composition according to claim 27 wherein the active ingredient includes a β2-agonist.
34. A powder composition according to claim 33 , wherein the β2-agonist is selected from the group consisting of salbutamol base, formoterol, salmeterol, terbutaline and the salts thereof.
35. A powder composition according to claim 27 wherein the carrier particles have a size within the range 20 and 1000 μm.
36. A powder composition according to claim 27 wherein the carrier consists of said one or more crystalline sugars coated with said lubricant.
37. A powder composition according to claim 27 wherein said lubricant consists of said magnesium stearate.
38. A powder composition according to claim 36 wherein said lubricant consists of said magnesium stearate.
39. A dry powder inhaler containing the powder composition according to claim 27 therein.
40. A method of treating the lungs in a patient in need thereof comprising administering an effective amount of the powder composition according to claim 27 to said patient.
41. The method according to claim 40 , wherein the patient is treated for asthma.
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US10/358,174 US20030133880A1 (en) | 1999-03-05 | 2003-02-05 | Powdery pharmaceutical compositions for inhalation |
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Families Citing this family (81)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB9501841D0 (en) | 1995-01-31 | 1995-03-22 | Co Ordinated Drug Dev | Improvements in and relating to carrier particles for use in dry powder inhalers |
SK284889B6 (en) | 1998-11-13 | 2006-02-02 | Jago Research Ag | Use of magnesium stearate in dry powder formulations for inhalation |
US20070212422A1 (en) * | 1999-11-10 | 2007-09-13 | Manfred Keller | Dry powder for inhalation |
DZ2947A1 (en) | 1998-11-25 | 2004-03-15 | Chiesi Farma Spa | Pressure metered dose inhaler. |
IT1309592B1 (en) * | 1999-03-05 | 2002-01-24 | Chiesi Farma Spa | VEHICLE PARTICLES MODIFIED FOR USE IN THE PREPARATION OF PHARMACEUTICAL FORMULATIONS IN THE FORM OF POLYMERS FOR INHALATION AND |
US9006175B2 (en) | 1999-06-29 | 2015-04-14 | Mannkind Corporation | Potentiation of glucose elimination |
ITMI991582A1 (en) | 1999-07-16 | 2001-01-16 | Chiesi Farma Spa | DUST CONSTITUTED FROM PARTICLES HAVING THE PERFECTLY SMOOTH SURFACE FOR USE AS VEHICLES FOR THE PREPARATION OF INALA MIXTURES |
IT1313553B1 (en) | 1999-07-23 | 2002-09-09 | Chiesi Farma Spa | OPTIMIZED FORMULATIONS CONSTITUTED BY SOLUTIONS OF STEROIDS GIVEN BY INHALATION. |
IT1317846B1 (en) | 2000-02-22 | 2003-07-15 | Chiesi Farma Spa | FORMULATIONS CONTAINING AN ANTICOLINERGIC DRUG FOR THE TREATMENT OF CHRONIC OBSTRUCTIVE BRONCOPNEUMOPATHY. |
GB0009468D0 (en) * | 2000-04-17 | 2000-06-07 | Vectura Ltd | Improvements in or relating to formulations for use in inhaler devices |
GB0009469D0 (en) | 2000-04-17 | 2000-06-07 | Vectura Ltd | Improvements in or relating to formalities for use in inhaler devices |
PE20011227A1 (en) * | 2000-04-17 | 2002-01-07 | Chiesi Farma Spa | PHARMACEUTICAL FORMULATIONS FOR DRY POWDER INHALERS IN THE FORM OF HARD AGGLOMERATES |
IT1318514B1 (en) * | 2000-05-12 | 2003-08-27 | Chiesi Farma Spa | FORMULATIONS CONTAINING A GLUCOCORTICOSTEROID DRUG FOR THE TREATMENT OF BRONCOPOLMONARY DISEASES. |
AU2000250701B2 (en) | 2000-05-22 | 2004-07-01 | Chiesi Farmaceutici S.P.A. | Stable pharmaceutical solution formulations for pressurised metered dose inhalers |
AU2002222118A1 (en) † | 2000-11-30 | 2002-06-11 | Vectura Limited | Pharmaceutical compositions for inhalation |
DK1337240T4 (en) | 2000-11-30 | 2015-01-05 | Vectura Ltd | A process for the preparation of particles for use in a pharmaceutical composition |
AU2002220857A1 (en) | 2000-11-30 | 2002-06-11 | Vectura Limited | Particles for use in a pharmaceutical composition |
WO2003024396A2 (en) | 2001-09-17 | 2003-03-27 | Glaxo Group Limited | Dry powder medicament formulations |
DE60318938T2 (en) | 2002-03-20 | 2009-01-22 | Mannkind Corp., Valencia | INHALER |
JP2005530725A (en) * | 2002-04-12 | 2005-10-13 | カンピナ・ネーデルラント・ホールディング・ベスローテン・フェンノートシャップ | Excipients used in dry powder inhalation formulations |
GB0219511D0 (en) * | 2002-08-21 | 2002-10-02 | Norton Healthcare Ltd | Method of preparing dry powder inhalation compositions |
US20050158248A1 (en) * | 2002-08-21 | 2005-07-21 | Xian-Ming Zeng | Method of preparing dry powder inhalation compositions |
EA007377B1 (en) | 2002-08-21 | 2006-10-27 | Нортон Хелткэа Лтд. | Inhalation composition |
JP2006516531A (en) * | 2002-08-21 | 2006-07-06 | ノートン ヘルスケアー リミテッド | Inhalation composition |
CN102688224A (en) * | 2003-04-14 | 2012-09-26 | 维克特拉有限公司 | Device and pharmaceutical composition enhancing administration efficiency |
US20050042179A1 (en) * | 2003-08-18 | 2005-02-24 | Boehringer Ingelheim International Gmbh | Inhalative powder formulations containing the CGRP-antagonist 1-[N2-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine |
GB0326632D0 (en) | 2003-11-14 | 2003-12-17 | Jagotec Ag | Dry powder formulations |
ES2385934T3 (en) | 2004-08-20 | 2012-08-03 | Mannkind Corporation | CATALYSIS OF THE SYNTHESIS OF DICETOPIPERAZINA. |
EP2314298B1 (en) | 2004-08-23 | 2015-05-27 | MannKind Corporation | Microparticles comprising diketopiperazine salts for drug delivery |
GB0425758D0 (en) | 2004-11-23 | 2004-12-22 | Vectura Ltd | Preparation of pharmaceutical compositions |
JPWO2007001094A1 (en) * | 2005-06-29 | 2009-01-22 | 相男 李 | Artificial lung surfactant composition |
EP1910394A4 (en) * | 2005-07-29 | 2010-10-27 | Rhode Island Education | Modified oligonucleotides containing diphosphodiester internucleotide linkages |
KR20160022404A (en) | 2005-09-14 | 2016-02-29 | 맨카인드 코포레이션 | Method of drug formulation based on increasing the affinity of crystalline microparticle surfaces for active agents |
GB0525254D0 (en) | 2005-12-12 | 2006-01-18 | Jagotec Ag | Powder compositions for inhalation |
MX2008010721A (en) | 2006-02-22 | 2008-09-01 | Mannkind Corp | A method for improving the pharmaceutic properties of microparticles comprising diketopiperazine and an active agent. |
US8003663B2 (en) | 2006-08-01 | 2011-08-23 | Glaxo Group Limited | Pyrazolo[3,4-b]pyridine compounds, and their use as PDE4 inhibitors |
GB0712316D0 (en) * | 2007-06-26 | 2007-08-01 | Entripneur Ltd | A novel powder and its method of manufacture |
EP2080508A1 (en) | 2008-01-15 | 2009-07-22 | CHIESI FARMACEUTICI S.p.A. | Dry powder formulation comprising an anticholinergic drug |
DE102008014237A1 (en) * | 2008-03-14 | 2009-09-17 | J. Rettenmaier & Söhne Gmbh + Co. Kg | Directly compressible tableting aid |
EP3281663B8 (en) | 2008-06-13 | 2022-09-21 | MannKind Corporation | Breath powered dry powder inhaler for drug delivery |
US8485180B2 (en) | 2008-06-13 | 2013-07-16 | Mannkind Corporation | Dry powder drug delivery system |
MX2010014240A (en) | 2008-06-20 | 2011-03-25 | Mankind Corp | An interactive apparatus and method for real-time profiling of inhalation efforts. |
TWI614024B (en) | 2008-08-11 | 2018-02-11 | 曼凱公司 | Use of ultrarapid acting insulin |
US8314106B2 (en) | 2008-12-29 | 2012-11-20 | Mannkind Corporation | Substituted diketopiperazine analogs for use as drug delivery agents |
PL2400950T3 (en) | 2009-02-26 | 2019-12-31 | Glaxo Group Limited | Pharmaceutical formulations comprising 4-{(1 r)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)phenol |
CA2754595C (en) | 2009-03-11 | 2017-06-27 | Mannkind Corporation | Apparatus, system and method for measuring resistance of an inhaler |
PL3106149T3 (en) | 2009-05-29 | 2020-06-01 | Pearl Therapeutics, Inc. | Compositions for pulmonary delivery of long-acting muscarinic antagonists and long-acting beta-2 adrenergic receptor agonists and associated methods and systems |
US8815258B2 (en) | 2009-05-29 | 2014-08-26 | Pearl Therapeutics, Inc. | Compositions, methods and systems for respiratory delivery of two or more active agents |
US8551528B2 (en) | 2009-06-12 | 2013-10-08 | Mannkind Corporation | Diketopiperazine microparticles with defined specific surface areas |
GB0918249D0 (en) | 2009-10-19 | 2009-12-02 | Respivert Ltd | Compounds |
GB0918450D0 (en) | 2009-10-21 | 2009-12-09 | Innovata Ltd | Composition |
EP2496295A1 (en) | 2009-11-03 | 2012-09-12 | MannKind Corporation | An apparatus and method for simulating inhalation efforts |
GB0921075D0 (en) | 2009-12-01 | 2010-01-13 | Glaxo Group Ltd | Novel combination of the therapeutic agents |
EP2552424B1 (en) * | 2010-04-01 | 2018-05-09 | Chiesi Farmaceutici S.p.A. | Process for preparing carrier particles for dry powders for inhalation |
BR112012033060A2 (en) | 2010-06-21 | 2018-02-27 | Mannkind Corp | Dry powder drug release system methods |
JP2013529606A (en) | 2010-06-22 | 2013-07-22 | シエシー ファルマセウティチィ ソシエタ ペル アチオニ | Dry powder formulation containing antimuscarinic drugs |
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Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6045828A (en) * | 1994-12-22 | 2000-04-04 | Astra Aktiebolag | Powders for inhalation |
Family Cites Families (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3145146A (en) * | 1961-10-31 | 1964-08-18 | Warner Lambert Pharmaceutical | Modified mannitol for pharmaceutical tablets |
US5260306A (en) * | 1981-07-24 | 1993-11-09 | Fisons Plc | Inhalation pharmaceuticals |
IT1204826B (en) * | 1986-03-04 | 1989-03-10 | Chiesi Farma Spa | INHALATION PHARMACEUTICAL COMPOSITIONS |
US5376386A (en) * | 1990-01-24 | 1994-12-27 | British Technology Group Limited | Aerosol carriers |
GB9501841D0 (en) * | 1995-01-31 | 1995-03-22 | Co Ordinated Drug Dev | Improvements in and relating to carrier particles for use in dry powder inhalers |
GB9606188D0 (en) * | 1996-03-23 | 1996-05-29 | Danbiosyst Uk | Pollysaccharide microspheres for the pulmonary delivery of drugs |
US5874064A (en) * | 1996-05-24 | 1999-02-23 | Massachusetts Institute Of Technology | Aerodynamically light particles for pulmonary drug delivery |
SK284889B6 (en) * | 1998-11-13 | 2006-02-02 | Jago Research Ag | Use of magnesium stearate in dry powder formulations for inhalation |
IT1309592B1 (en) * | 1999-03-05 | 2002-01-24 | Chiesi Farma Spa | VEHICLE PARTICLES MODIFIED FOR USE IN THE PREPARATION OF PHARMACEUTICAL FORMULATIONS IN THE FORM OF POLYMERS FOR INHALATION AND |
PE20011227A1 (en) * | 2000-04-17 | 2002-01-07 | Chiesi Farma Spa | PHARMACEUTICAL FORMULATIONS FOR DRY POWDER INHALERS IN THE FORM OF HARD AGGLOMERATES |
GB0009469D0 (en) * | 2000-04-17 | 2000-06-07 | Vectura Ltd | Improvements in or relating to formalities for use in inhaler devices |
US20040202516A1 (en) * | 2003-04-11 | 2004-10-14 | Lanser Jerry L. | Attitude independent portable press for hand held tool and method |
-
1999
- 1999-03-05 PT PT99915547T patent/PT1158958E/en unknown
- 1999-03-05 WO PCT/EP1999/001449 patent/WO2000053157A1/en active IP Right Grant
- 1999-03-05 DE DE69936268T patent/DE69936268T2/en not_active Expired - Lifetime
- 1999-03-05 EP EP99915547A patent/EP1158958B1/en not_active Revoked
- 1999-03-05 BR BR9917246-1A patent/BR9917246A/en active Search and Examination
- 1999-03-05 AT AT99915547T patent/ATE363892T1/en active
- 1999-03-05 CZ CZ20013185A patent/CZ298489B6/en not_active IP Right Cessation
- 1999-03-05 TR TR2001/02567T patent/TR200102567T2/en unknown
- 1999-03-05 AU AU34093/99A patent/AU3409399A/en not_active Abandoned
- 1999-03-05 SK SK1248-2001A patent/SK286981B6/en not_active IP Right Cessation
- 1999-03-05 DK DK99915547T patent/DK1158958T3/en active
- 1999-03-05 ES ES99915547T patent/ES2286881T3/en not_active Expired - Lifetime
- 1999-03-05 HU HU0200185A patent/HUP0200185A3/en unknown
- 1999-03-05 PL PL354841A patent/PL196951B1/en unknown
- 1999-03-05 SI SI9930970T patent/SI1158958T1/en unknown
-
2000
- 2000-06-26 US US09/603,620 patent/US6528096B1/en not_active Expired - Lifetime
-
2003
- 2003-02-05 US US10/358,174 patent/US20030133880A1/en not_active Abandoned
-
2006
- 2006-07-25 US US11/492,105 patent/US20060257330A1/en not_active Abandoned
-
2007
- 2007-08-13 CY CY20071101082T patent/CY1106817T1/en unknown
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6045828A (en) * | 1994-12-22 | 2000-04-04 | Astra Aktiebolag | Powders for inhalation |
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PL354841A1 (en) | 2004-02-23 |
DE69936268D1 (en) | 2007-07-19 |
SK12482001A3 (en) | 2002-01-07 |
SI1158958T1 (en) | 2007-10-31 |
WO2000053157A1 (en) | 2000-09-14 |
TR200102567T2 (en) | 2002-01-21 |
DE69936268T2 (en) | 2008-02-14 |
CY1106817T1 (en) | 2012-05-23 |
CZ20013185A3 (en) | 2002-01-16 |
ES2286881T3 (en) | 2007-12-01 |
ATE363892T1 (en) | 2007-06-15 |
BR9917246A (en) | 2002-03-26 |
CZ298489B6 (en) | 2007-10-17 |
HUP0200185A2 (en) | 2002-06-29 |
PT1158958E (en) | 2007-08-13 |
EP1158958B1 (en) | 2007-06-06 |
PL196951B1 (en) | 2008-02-29 |
US20030133880A1 (en) | 2003-07-17 |
HUP0200185A3 (en) | 2006-07-28 |
DK1158958T3 (en) | 2007-10-08 |
EP1158958A1 (en) | 2001-12-05 |
SK286981B6 (en) | 2009-08-06 |
US6528096B1 (en) | 2003-03-04 |
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