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WO2001056581A1 - Preparation en poudre pour inhalation et inhalateur de poudre contenant cette preparation - Google Patents

Preparation en poudre pour inhalation et inhalateur de poudre contenant cette preparation Download PDF

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Publication number
WO2001056581A1
WO2001056581A1 PCT/JP2001/000627 JP0100627W WO0156581A1 WO 2001056581 A1 WO2001056581 A1 WO 2001056581A1 JP 0100627 W JP0100627 W JP 0100627W WO 0156581 A1 WO0156581 A1 WO 0156581A1
Authority
WO
WIPO (PCT)
Prior art keywords
inhalation
powder
oleic acid
preparation
drug
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.)
Ceased
Application number
PCT/JP2001/000627
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English (en)
Japanese (ja)
Inventor
Denichi Momose
Kazuhiko Ikegami
Yasuhiro Takeda
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Kissei Pharmaceutical Co Ltd
Original Assignee
Kissei Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Kissei Pharmaceutical Co Ltd filed Critical Kissei Pharmaceutical Co Ltd
Priority to AU2001230533A priority Critical patent/AU2001230533A1/en
Publication of WO2001056581A1 publication Critical patent/WO2001056581A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • 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
    • 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
    • A61P11/12—Mucolytics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H21/00—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
    • C07H21/02—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids with ribosyl as saccharide radical

Definitions

  • the present invention relates to a powder preparation for inhalation containing diduridine 5, tetratetraphosphate tetrasodium salt as an active ingredient, and a powder inhalant filled with the same. More particularly, the present invention comprises an oleic acid or sorbitan oleate for use as a powder inhaler, comprising:
  • the present invention relates to a powder formulation for inhalation containing a dinucleotide derivative represented by the following formula (chemical name: diperidine 5, tetrasodium tetraphosphate) as an active ingredient, and a powder inhaler filled with the same.
  • a dinucleotide derivative represented by the following formula (chemical name: diperidine 5, tetrasodium tetraphosphate) as an active ingredient, and a powder inhaler filled with the same.
  • the dinucleotide derivative represented by the above formula (I) stimulates P 2 Y 2 receptors present in the lungs and the airways, hydrates mucus secretions retained in the lungs, and promotes removal of mucus secretions It is useful for the treatment of various pulmonary diseases such as cystic fibrosis in which mucus secretions are retained in the lung, chronic bronchiolitis, asthma, bronchiectasis, postoperative aterectase, and cartagena syndrome. It is reported that there is. As a method of administering the compound, an aerosol for inhalation using an aerosol suspension has been proposed (Japanese Patent Application Laid-Open No. 11-670790).
  • Inhalants include nebulizers, aerosols and powder inhalants.
  • nebulizers are inconvenient due to lack of portability of the inhalation device, and when the amount of drug used is large, the inhalation time is long and the burden on the patient is large.
  • a sterilization step is indispensable and the production cost is high, and a special spraying device is often required.
  • a powder inhaler in which a finely divided powder is filled into a container such as a capsule and then inhaled using an inhaler.
  • powder inhalants it is desirable to use a powder with a small particle size in order to make the micronized drug reach the lungs.
  • the micronization inevitably increases the cohesiveness and adhesion of the drug, A problem arises in that the efficiency of drug delivery to the lungs decreases. Therefore, in order to solve this problem, the fine primary particles are agglomerated by an appropriate method and granulated into secondary particles having a relatively large particle size.
  • Dissociate into particles, lactose with a larger particle size than the drug used is mixed, and the finely divided drug is uniformly adsorbed on the lactose surface to separate the drug and lactose during inhalation. Improving the lung delivery rate by modifying the surface characteristics by attaching them.
  • the dinucleotide derivative represented by the formula (I) As an inhalant containing the dinucleotide derivative represented by the formula (I) as an active ingredient, only an aerosol suspending agent has been devised, and no powder inhalant has been developed up to now. . As described above, a powder inhalant is most recommended as an inhalant. However, the dinucleotide derivative represented by the formula (I) itself has a high hygroscopicity, and a simple method of pulverization causes agglomeration of powder particles. Are likely to occur, and the rate of drug delivery to the lungs is extremely poor.
  • the dinucleotide derivative cannot be expected to have a surface modified by the method of attaching ultrafine particles to the surface of drug particles, and the method of agglomeration into secondary particles has poor dissociation and improves lung reach. Can not.
  • the dose of the dinucleotide derivative is relatively larger than that of a usual inhalant, and it is expected that the method using lactose as a dispersant will increase the inhalation amount per dose and make inhalation difficult. Cannot be adopted.
  • the present inventors have made intensive studies to solve the above-mentioned problems, and as a result, by adding a certain additive to the drug powder particles as described below, significantly improved the efficiency of drug powder particles reaching the lungs, In addition, they have found that it is possible to reduce the amount of the preparation per use when using an inhalation device, and have accomplished the present invention.
  • the present invention contains oleic acid or sorbitan oleate, and contains as an active ingredient a dinucleotide derivative represented by the formula (I) (chemical name: dipyridine, tetrasodium tetraphosphate).
  • the present invention relates to a powder preparation for inhalation and a powder inhalation agent filled with the preparation.
  • the powder formulation for inhalation of the present invention comprises a fine powder having a particle size of about 0.5 to 10 / m, which is obtained by using a dinucleotide derivative represented by the formula (I), which is an active ingredient, usually using a milling machine such as a jet mill. And then mixed with oleic acid or sorbitan oleate as an additive.
  • oleic acid or sorbitan oleic acid as an additive is contained in an inert solvent such as ethanol and hexane, which is a good solvent for the additive and a poor solvent for the active ingredient.
  • a fine powder having a particle diameter of about 10 / im or less is usually used, and preferably, a particle diameter of about 0.5 to 7.0 m or an average particle diameter of 1 to 10 / im. 5 to 5.0 m.
  • the sorbitan oleate refers to various oleic esters of sorbitan such as sonorebitan monooleate and sorbitan triolate.
  • oleic acid, sorbitan monoolate or sorbitan trioleate is preferred, and oleic acid is most preferred.
  • the amount of the additive is usually about 0.5 to 5.0% by weight based on the amount of the active ingredient. And it is preferably 0.75 to 3.0%.
  • the powder inhalant of the present invention can be produced by filling the above-mentioned powder formulation for inhalation into an appropriate container such as a capsule, a blister or a reservoir.
  • the dosage of the formulation can be increased or decreased as appropriate, but is usually about 2 to 4 mg.
  • a capsule agent it is possible to use, for example, Japanese Pharmacopoeia No. 2 capsules of hydroxypropylmethylcellulose.
  • the dinucleotide derivative represented by the formula (I) used in the method for producing the powder preparation for inhalation and the powder inhalation is a known compound, and can be easily produced by a method described in a literature or a method analogous to the method. (For example, ⁇ he J ournalof Biological Chemistry,
  • the powder formulation for inhalation of the present invention has excellent inhalation characteristics as described below.
  • the lung penetration rate (the percentage reaching the lower stage than stage 2) was about 16% for the formulation without additives and about 27% for the secondary granules. %, Whereas the powder formulation for inhalation of the present invention showed an excellent reach of about 35 to 51%.
  • the powder formulation for inhalation of the present invention has a remarkably improved lung reach rate, is a formulation with good drug use efficiency, and has a small amount of drug to be filled in a container to be attached to an inhalation device. It is a preparation that can reduce
  • the powder formulation for inhalation of the present invention is improved to about 12 to 27%.
  • a preparation containing 1.0% oleic acid shows extremely excellent properties such as a drug residual ratio of about 12%.
  • the powder formulation for inhalation of the present invention is an excellent formulation that is not irritating or extremely weak, and less burdens the patient during inhalation.
  • the powder preparation for inhalation of the present invention has extremely high stability in storage of the preparation.
  • the preparation containing 1.0% oleic acid did not decrease the lung reach when left at 40 ° C and 75% relative humidity for 2 months.
  • the powder preparation for inhalation of the present invention is an extremely stable preparation that can be stored for a long time.
  • the powder formulation for inhalation of the present invention is filled into an appropriate container such as a capsule, a prister, or a reservoir, and the obtained powder formulation for inhalation of the present invention is inhaled. After attaching to the container, make a hole in the container or measure the amount and inhale.
  • the amount of drug used can be determined appropriately according to the type of disease and the condition of the patient, but it is usually possible to use it in adults at about 2 to 4 mg per day, in 1 S1 to several times. it can.
  • an inhalation device any device can be used as long as the powder formulation for inhalation of the present invention can be appropriately inhaled.
  • Jet Heller manufactured by Unicia Diex Co., Ltd.
  • the powder formulation for inhalation of the present invention and the powder inhalant filled with the same include cystic pulmonary fibrosis, chronic bronchiolitis, bronchiectasis, postoperative aterectase, Cartagener's syndrome, aspiration pneumonia, etc. It is extremely useful for the treatment of various pulmonary diseases accompanied by difficulty in excreting mucus secretions.
  • Example 1 The content of the present invention will be described in more detail in the following examples, comparative examples and test examples. The present invention is not limited to the content.
  • Example 1 The content of the present invention will be described in more detail in the following examples, comparative examples and test examples. The present invention is not limited to the content.
  • Example 1 The content of the present invention will be described in more detail in the following examples, comparative examples and test examples. The present invention is not limited to the content. Example 1
  • the average particle size is 1.5 to 3.0 ⁇ using a jet mill.
  • Approximately 20 g of diduridine 5, tetrasodium monotetraphosphate was added to the mixture and uniformly dispersed.
  • the mixture was evaporated to dryness under reduced pressure at 30-40 ° C and dried under reduced pressure at room temperature overnight.
  • the resulting dry powder is averaged with a jet mill at an average particle size of 1.
  • Example 2 0.75% oleic acid-containing preparation
  • Example 3 It was produced in the same manner as in Example 1 except that 15 Omg of oleic acid was used.
  • Example 4 The production was carried out in the same manner as in Example 1 except that 20 Omg of oleic acid was used.
  • Example 4
  • Example 5 It was produced in the same manner as in Example 1 except that 30 Omg of oleic acid was used.
  • Example 6 The production was carried out in the same manner as in Example 1 except that 40 Omg of oleic acid was used.
  • Example 6
  • Example 7 It was produced in the same manner as in Example 1 except that 60 Omg of oleic acid was used.
  • Example 10 Production was carried out in the same manner as in Example 1, except that 30 Omg of sorbitan monoolate was used instead of 10 Omg of oleic acid.
  • Example 10
  • Example 11 Production was carried out in the same manner as in Example 1, except that sorbitan monooleate 40 Omg was used instead of oleic acid 10 Omg.
  • Example 11 sorbitan monooleate 40 Omg was used instead of oleic acid 10 Omg.
  • Example 12 Production was carried out in the same manner as in Example 1 except that 10 Omg of sorbic acid was used instead of 10 Omg of oleic acid.
  • Example 12
  • Example 14 2.0% sonolevitan trioleate containing formulation
  • Example 15 Production was carried out in the same manner as in Example 1, except that 40 Omg of sorbitan triolate was used instead of 10 Omg of oleic acid.
  • Example 15
  • Example 17 20 mg of the 0.5% oleic acid-containing preparation obtained in Example 1 was prepared by filling hydroxypropylmethylcellulose into a No. 2 force capsule of Japanese Pharmacopoeia.
  • Example 17 20 mg of the 0.5% oleic acid-containing preparation obtained in Example 1 was prepared by filling hydroxypropylmethylcellulose into a No. 2 force capsule of Japanese Pharmacopoeia.
  • Example 18 20 mg of the 0.75% oleic acid-containing preparation obtained in Example 2 was This product was prepared by filling into the Japanese Pharmacopoeia No. 2 force column of pill methyl cell mouth.
  • Example 18 20 mg of the 0.75% oleic acid-containing preparation obtained in Example 2 was This product was prepared by filling into the Japanese Pharmacopoeia No. 2 force column of pill methyl cell mouth.
  • Example 19 The preparation containing 20% of the 1.0% oleic acid-containing preparation obtained in Example 3 was filled in hydroxypropylmethylcell orifice No. 2 force pharmacopoeia of Japan Pharmacopoeia.
  • Example 19 The preparation containing 20% of the 1.0% oleic acid-containing preparation obtained in Example 3 was filled in hydroxypropylmethylcell orifice No. 2 force pharmacopoeia of Japan Pharmacopoeia.
  • the preparation containing 20 mg of the 1.5% oleic acid-containing preparation obtained in Example 4 was prepared by filling hydroxypropylmethylcellulose into a Japanese Pharmacopoeia No. 2 force capsule.
  • Example 2 1 20 mg of the 2.0% oleic acid-containing preparation obtained in Example 5 was prepared by filling hydroxypropylmethylcellulose in a No. 2 force capsule of Japanese Pharmacopoeia.
  • Example 2 1 20 mg of the 2.0% oleic acid-containing preparation obtained in Example 5 was prepared by filling hydroxypropylmethylcellulose in a No. 2 force capsule of Japanese Pharmacopoeia.
  • Example 22 The preparation containing 20% of the 3.0% oleic acid-containing preparation obtained in Example 6 was filled in a hydroxypropylmethylcell orifice No. 2 force capsule of Japanese Pharmacopoeia.
  • Example 22 The preparation containing 20% of the 3.0% oleic acid-containing preparation obtained in Example 6 was filled in a hydroxypropylmethylcell orifice No. 2 force capsule of Japanese Pharmacopoeia.
  • Example 2 3 The preparation containing 20 mg of the 0.5% sorbitan monoolate-containing preparation obtained in Example 7 was filled in a hydroxypropylmethylcellulose No. 2 capsule of Japanese Pharmacopoeia.
  • Example 2 3 The preparation containing 20 mg of the 0.5% sorbitan monoolate-containing preparation obtained in Example 7 was filled in a hydroxypropylmethylcellulose No. 2 capsule of Japanese Pharmacopoeia.
  • Example 2 3 The preparation containing 20 mg of the 0.5% sorbitan monoolate-containing preparation obtained in Example 7 was filled in a hydroxypropylmethylcellulose No. 2 capsule of Japanese Pharmacopoeia.
  • Example 2 3 The preparation containing 20 mg of the 0.5% sorbitan monoolate-containing preparation obtained in Example 7 was filled in a hydroxypropylmethylcellulose No. 2 capsule of Japanese Pharmacopoeia.
  • Example 2 3 The preparation containing 20 mg of the 0.5% sorbitan monoolate-containing preparation obtained in Example 7 was filled in a hydroxypropylmethyl
  • Capsules 8 The preparation containing 20% of the 1.0% sorbitan monoolate-containing preparation obtained in Example 8 was filled in hydroxypropylmethylcellulose No. 2 capsules of Japanese Pharmacopoeia.
  • Example 2 4
  • a preparation was prepared by filling 2 O mg of the 1.5% sorbitan monoolate-containing preparation obtained in Example 9 into a Japanese Pharmacopoeia No. 2 force cell of Hydroxypropyl Methyl Cell Oral.
  • Example 2 5
  • Example 26 The preparation containing 20% of the 2.0% sorbitan monoolate-containing preparation obtained in Example 10 was filled in a hydroxypropylmethylcellulose No. 2 capsule of Japanese Pharmacopoeia.
  • Example 26 The preparation containing 20% of the 2.0% sorbitan monoolate-containing preparation obtained in Example 10 was filled in a hydroxypropylmethylcellulose No. 2 capsule of Japanese Pharmacopoeia.
  • Example 2 7 This was prepared by filling 20 mg of the 0.5% sonolevitan trioleate-containing preparation obtained in Example 11 in a Japanese Pharmacopoeia No. 2 capsule of hydroxypropyl methylcellulose.
  • Example 2 7 This was prepared by filling 20 mg of the 0.5% sonolevitan trioleate-containing preparation obtained in Example 11 in a Japanese Pharmacopoeia No. 2 capsule of hydroxypropyl methylcellulose.
  • the preparation was prepared by filling 2 mg of the 1.0% sorbitan triolate-containing preparation obtained in Example 12 into 2 capsules of Japanese Pharmacopoeia of hydroxypropylmethylcellulose.
  • Capsules 1 3 The preparation containing 20% of the 1.5% sorbitan trioleate-containing preparation obtained in Example 13 was filled in a hydroxypropylmethylcellulose Japanese Pharmacopoeia No. 2 capsule.
  • Example 2 9 The preparation containing 20% of the 1.5% sorbitan trioleate-containing preparation obtained in Example 13 was filled in a hydroxypropylmethylcellulose Japanese Pharmacopoeia No. 2 capsule.
  • Example 30 The preparation containing 20% of the 2.0% sorbitan trioleate-containing preparation obtained in Example 14 was filled in a hydroxypropylmethylcellulose No. 2 capsule of Japanese Pharmacopoeia.
  • Example 30 The preparation containing 20% of the 2.0% sorbitan trioleate-containing preparation obtained in Example 14 was filled in a hydroxypropylmethylcellulose No. 2 capsule of Japanese Pharmacopoeia.
  • Comparative Example 4 20 mg of the additive-free preparation obtained in Comparative Example 1 was prepared by filling hydroxypropylmethylcellulose in Japanese Pharmacopoeia No. 2 capsules. Comparative Example 4
  • capsules 1 to 5, 7 to 17 described in Examples 16 to 20 and 22 to 30 and Comparative Examples 3 to 4 each filled with various preparations cascade as follows: The amount of drug in each part of the impactor was measured. After fixing the above capsule on the capsule base of the inhalation device (jet heller) connected to the cascade drainer device, press the needle button to make a hole in the capsule, and with a suction flow rate of 28.3 ⁇ 0.5 LZ for 5 seconds Aspirated. After aspiration, the capsule was removed from the inhaler and placed in a triangular flask. After repeating the suction operation in the same manner as the five capsules, the inhaler and the cascade impactor were disassembled into individual parts and separately placed in polyethylene plastic bags.
  • the amount of drug in each part was measured using an ultraviolet absorption spectrophotometer based on the absorbance at 262 nm according to the absorbance measurement method (listed in the 13th revision of the Japanese Pharmacopoeia).
  • the powder formulation for inhalation of the present invention significantly improves the efficiency of drug powder particles reaching the lungs, improves the efficiency of drug use, and reduces the amount of drug used to fill a container attached to an inhalation device. Can be reduced. Furthermore, the powder formulation for inhalation of the present invention is non-irritating or extremely weak, so that the burden on the patient during inhalation is small, and the stability of the formulation is extremely high, so that long-term storage is possible. According to the present invention, it is possible to provide a powder formulation for inhalation and a powder inhaler which are suitable for treatment of various pulmonary diseases accompanied by difficulty in excreting mucus secretions.

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Abstract

La présente invention concerne une préparation en poudre à inhaler dans laquelle on a amélioré l'efficacité de distribution des particules médicamenteuses dans les poumons. La quantité de concentré médicamenteux a été réduite dans le contenant devant être fixé à un instrument d'inhalation. En outre, cette préparation contient de l'acide oléique ou un oléate de sorbitane comme adjuvant, et un dérivé dinucléotidique représenté par la formule (I) comme principe actif. Cette préparation en poudre est utilisée pour le traitement de diverses maladies pulmonaires accompagnées de difficultés à décharger les sécrétions des muqueuses. Par ailleurs, cette invention concerne un inhalateur de poudre contenant la préparation en poudre et un contenant, par exemple une capsule, placé dans l'inhalateur. On peut fabriquer la préparation en poudre à inhaler, par exemple, en dispersant d'abord uniformément de fines particules du dérivé dinucléotidique dans une solution de l'adjuvant dans un solvant, en séchant ensuite sous vide cette dispersion, en pulvérisant les agglomérats de particules fines obtenus, et enfin, en séchant sous vide la poudre obtenue.
PCT/JP2001/000627 2000-02-04 2001-01-31 Preparation en poudre pour inhalation et inhalateur de poudre contenant cette preparation Ceased WO2001056581A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2001230533A AU2001230533A1 (en) 2000-02-04 2001-01-31 Powdered preparation for inhalation and powder inhalant containing the same packed

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2000027534 2000-02-04
JP2000-27534 2000-02-04

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WO2001056581A1 true WO2001056581A1 (fr) 2001-08-09

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2007502791A (ja) * 2003-08-18 2007-02-15 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Ｃｇｒｐアンタゴニスト１−〔ｎ２−〔３，５−ジブロモ−ｎ−〔〔４−（３，４−ジヒドロ−２（１ｈ）−オキソキナゾリン−３−イル）−１−ピペリジニル〕カルボニル〕−ｄ−チロシル〕−ｌ−リシル〕−４−（４−ピリジニル）−ピペラジンを含む新規吸入粉末製剤
JP2007502789A (ja) * 2003-08-18 2007-02-15 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング 噴霧乾燥された無定形ｂｉｂｎ４０９６、その調製方法及び吸入剤としてのその使用
JP2007502790A (ja) * 2003-08-18 2007-02-15 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Ｃｇｒｐアンタゴニスト１−〔ｎ２−〔３，５−ジブロモ−ｎ−〔〔４−（３，４−ジヒドロ−２（１ｈ）−オキソキナゾリン−３−イル）−１−ピペリジニル〕カルボニル〕−ｄ−チロシル〕−ｌ−リシル〕−４−（４−ピリジニル）−ピペラジンを含む微粒子、その調製方法及び吸入粉末としてのその使用

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH08500109A (ja) * 1992-08-14 1996-01-09 ローン−プーラン・ロレ・リミテツド 新規の製剤
US5789391A (en) * 1996-07-03 1998-08-04 Inspire Pharmaceuticals, Inc. Method of treating sinusitis with uridine triphosphates and related compounds
WO1999005155A2 (fr) * 1997-07-25 1999-02-04 Inspire Pharmaceuticals, Inc. Procede de production de masse de di(uridine 5'-tetraphosphate) et de ses sels
JPH11501937A (ja) * 1995-04-07 1999-02-16 エドワード メンデル カンパニー，インコーポレーテッド 薬剤用放出制御吹入剤担体
US5935555A (en) * 1995-06-07 1999-08-10 The University Of North Carolina At Chapel Hill Dinucleotides useful for hydrating lung mucous secretions

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH08500109A (ja) * 1992-08-14 1996-01-09 ローン−プーラン・ロレ・リミテツド 新規の製剤
JPH11501937A (ja) * 1995-04-07 1999-02-16 エドワード メンデル カンパニー，インコーポレーテッド 薬剤用放出制御吹入剤担体
US5935555A (en) * 1995-06-07 1999-08-10 The University Of North Carolina At Chapel Hill Dinucleotides useful for hydrating lung mucous secretions
US5789391A (en) * 1996-07-03 1998-08-04 Inspire Pharmaceuticals, Inc. Method of treating sinusitis with uridine triphosphates and related compounds
WO1999005155A2 (fr) * 1997-07-25 1999-02-04 Inspire Pharmaceuticals, Inc. Procede de production de masse de di(uridine 5'-tetraphosphate) et de ses sels

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2007502791A (ja) * 2003-08-18 2007-02-15 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Ｃｇｒｐアンタゴニスト１−〔ｎ２−〔３，５−ジブロモ−ｎ−〔〔４−（３，４−ジヒドロ−２（１ｈ）−オキソキナゾリン−３−イル）−１−ピペリジニル〕カルボニル〕−ｄ−チロシル〕−ｌ−リシル〕−４−（４−ピリジニル）−ピペラジンを含む新規吸入粉末製剤
JP2007502789A (ja) * 2003-08-18 2007-02-15 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング 噴霧乾燥された無定形ｂｉｂｎ４０９６、その調製方法及び吸入剤としてのその使用
JP2007502790A (ja) * 2003-08-18 2007-02-15 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Ｃｇｒｐアンタゴニスト１−〔ｎ２−〔３，５−ジブロモ−ｎ−〔〔４−（３，４−ジヒドロ−２（１ｈ）−オキソキナゾリン−３−イル）−１−ピペリジニル〕カルボニル〕−ｄ−チロシル〕−ｌ−リシル〕−４−（４−ピリジニル）−ピペラジンを含む微粒子、その調製方法及び吸入粉末としてのその使用

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