WO2010013925A2 - Composition pharmacologique destinée à la prévention et au traitement d’une maladie respiratoire, contenant un composé de pyrazolopyrimidinone ou des sels pharmaceutiquement acceptables de celui-ci - Google Patents

Composition pharmacologique destinée à la prévention et au traitement d’une maladie respiratoire, contenant un composé de pyrazolopyrimidinone ou des sels pharmaceutiquement acceptables de celui-ci Download PDF

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Publication number
WO2010013925A2
WO2010013925A2 PCT/KR2009/004188 KR2009004188W WO2010013925A2 WO 2010013925 A2 WO2010013925 A2 WO 2010013925A2 KR 2009004188 W KR2009004188 W KR 2009004188W WO 2010013925 A2 WO2010013925 A2 WO 2010013925A2
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Prior art keywords
composition
chemical formula
compound
treatment
pyrazolopyrimidinone compound
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PCT/KR2009/004188
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English (en)
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WO2010013925A3 (fr
Inventor
Chan Ho Lee
Seul Min Choi
Dong Hwan Kim
Kyung Koo Kang
Dong Seong Kim
Byoung Ok Ahn
Moohi Yoo
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Dong-A Pharmaceutical. Co., Ltd.
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Priority claimed from KR1020090068286A external-priority patent/KR20100014133A/ko
Application filed by Dong-A Pharmaceutical. Co., Ltd. filed Critical Dong-A Pharmaceutical. Co., Ltd.
Publication of WO2010013925A2 publication Critical patent/WO2010013925A2/fr
Publication of WO2010013925A3 publication Critical patent/WO2010013925A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—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
    • A61K9/0078—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present disclosure relates to a pharmacological composition for prevention and treatment of respiratory disease.
  • Respiratory diseases affect the bronchus and lungs, and include chronic obstructive pulmonary disease, bronchiectasis, bronchial asthma, lung cancer, and bronchial adenoma.
  • COPD Chronic Obstructive Pulmonary Disease
  • the prevalence rate worldwide is estimated at about 5 to 10% in adults (Halbert RJ et al., Chest, 2003; Halbert RJ et al., Eur Respir J. 2006), and in a recent research on South and Central American regions, about 7.8 to 19.7% are reported to be patients with stage 1 of GOLD (Global Initiative for Chronic Obstructive Lung Disease) classification or higher (Menezes et al., Lancet, 2005).
  • GOLD Global Initiative for Chronic Obstructive Lung Disease
  • As for the domestic prevalence rate about 7.8% (male 10.9%, female 4.9%) from 18 years to 45 years old and about 17.2% (male 25.8%, female 9.6%) of 45 years or older are reported as GOLD stage 1 or higher. As ages increase, the prevalence rate also increases.
  • the frequency of COPD exacerbations of smokers, resulting from smoking is 3-fold higher than that of non-smokers (26.9% vs. 8.8%) and it has been revealed that as the smoking level increases, the frequency of the disease proportionally increases (the frequencies of 10 cigarettes or less, 11 to 19 cigarettes, and 20 cigarettes or more are 12.8%, 18.8%, and 35.6%, respectively) (The national COPD Survey Committee, Am J Respir Cirt Care Med, 2003). Cough, sputum, hemoptysis, and airway obstruction are representative symptoms of the disease, whose social and economical costs continuously increase.
  • Drugs currently used in chronic obstructive pulmonary disease may be largely classified into corticosteroids, bronchodilators, and combined therapy.
  • Corticosteroids are used for COPD patients with severe or recurrent symptoms, and prolonged dosage is not recommended because side effects such as muscular weakness, functional reduction, and respiratory failure are caused by the agents.
  • Bronchodilators may be sub-classified into ⁇ 2 agonists, anticholinergics, and methylxanthines.
  • ⁇ 2 agonists induce relaxation of airway smooth muscle, may be sub-classified into fast-acting and slow-acting drugs, and have side effects such as tachycardia, tremor, hypokalemia, and tachyphylaxis.
  • Xanthine derivatives non- selectively inhibit phosphodiesterase (hereinafter, it may be referred to as PDEs), thus showing bronchiectasis or anti-inflammatory activity, and it is reported that side effects such as headache, insomnia, nausea, heartburn, atrial and ventricular arrhythmia, and grand mal epilepsy may occur dosage-dependently due to the non-selective inhibition activities (Yoo Jee-Hong, Monthly Korean Pharmaceutical Industry News, 2007).
  • PDEs are a family of enzymes that hydrolyze cyclic nucleotides such as 3', 5'-cyclic adenosine monophosphate (cAMP) or 3', 5'-cyclic guanosine monophosphate (cGMP) and there are 11 families and at least 44 distinct enzymes in humans (Chung KF, Eur J Pharmacol, 2006). Among them, development of a therapeutic agent using a phosphodiesterase type 4 (PDE-4) inhibitor is most actively underway.
  • cAMP 3', 5'-cyclic adenosine monophosphate
  • cGMP 3', 5'-cyclic guanosine monophosphate
  • PDE-4 is present not only in inflammatory cells such as T cells, B cells, eosinophils, and neutrophils, but also in airway smooth muscle cells, and is an enzyme that hydrolyzes cAMP (Houslay MD and Adams DR, Biochem J, 2003). Because cAMP increased in cells inhibits the secretion of pro-inflammatory cytokine, showing anti-inflammatory activities and inducing bronchiectasis through relaxation of airway smooth muscle, PDE-4 has attracted attention as a potential therapeutic agent against diseases like COPD. However, in the case of rolipram, a representative PDE-4 inhibitor, it has side effects such as vomiting and nausea, and second generation drugs which are more selective to PDE-4 have been developed, but it is still difficult to mitigate the expression of side effects.
  • Phosphodiesterase type 5 (PDE-5) is now receiving attention as a new drug target for airway diseases including COPD.
  • PDE-5 is present not only in endothelial cells, but also in pulmonary vascular smooth muscle, bronchial blood vessel, and airway smooth muscle, and is an enzyme that hydrolyzes cGMP (Sebkhi A, Circulation, 2003; Yanaka N, Eur J Biochem, 1998).
  • sildenafil a representative PDE-5 inhibitor
  • airway hyper-responsiveness and reduction of leukocyte infiltration in bron- choalveolar fluid was induced in a pre-clinical study (Toward TJ, Am J Respir Crit Care Med, 2004), and in a brief clinical experiment on two COPD patients, whereby Forced Expiratory volume in the first second of expiration (FEVl) was increased by 24% and 12%, respectively (Charan NB, Chest, 2001).
  • the pyrazolopyrimidinone compound of the present invention remarkably enhanced the selectivity to a conventional PDE-5, thus significantly reducing the side effects, swiftly showed the efficacy of the drug with a 1 hour to peak blood concentration time, and made daily dosage possible due to sustainable duration of drug action resulting from a 12 hour elimination half-life.
  • the present inventors kept studying tissue distribution of the drug after oral administration and completed the present invention by confirming that the drug has excellent distribution in the pulmonary tissues and has effects on relaxation of airway smooth muscle, alleviation of airway hyper-responsiveness, and inhibition of alveolar damage and inflammatory cell infiltration.
  • One object of the present invention is to provide a pharmacological composition for prevention and treatment of respiratory diseases including airway diseases such as chronic obstructive pulmonary disease, chronic bronchitis, emphysema, and asthma, which has excellent distribution into the lung tissues, effectively induces bron- chodilation without any side effects through selective inhibition of the activity of PDE- 5 present in airway smooth muscle, and alleviates airway hyper-responsiveness.
  • airway diseases such as chronic obstructive pulmonary disease, chronic bronchitis, emphysema, and asthma
  • the present invention provides a pharmacological compound containing 5- [2-propyloxy-5-( 1 -methyl-2-pyrolidinylethylamidosulphonyl)phenyl] - 1 -methyl-prop yl- 1 ,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one, a pyrazolopyrimidinone compound, represented by the following Chemical Formula 1 or pharmaceutically acceptable salts thereof, as an active ingredient for prevention and treatment of respiratory diseases.
  • composition of the present invention effectively induces bronchodilation without any side effects through selective inhibition of the activity of PDE-5, alleviates airway hyper-responsiveness, and inhibits alveolar damage and inflammatory cell infiltration.
  • composition of the present invention may be used in prevention and treatment of airway diseases such as chronic obstructive pulmonary disease, chronic bronchitis, emphysema, and asthma due to rapid expression of the drug efficacy and once a day dosage resulting from more than 12 hour effective duration of the drug efficacy.
  • airway diseases such as chronic obstructive pulmonary disease, chronic bronchitis, emphysema, and asthma due to rapid expression of the drug efficacy and once a day dosage resulting from more than 12 hour effective duration of the drug efficacy.
  • FIG. 1 is a graph illustrating an inhibitory action of a histamine-induced contraction reaction after a pre-treatment of the pyrazolopyrimidinone compound of Chemical Formula 1 to an isolated guinea pig trachea.
  • FIG. 2 is a graph illustrating an evaluation of each inhibitory action of the airway hyper-responsiveness reaction after applying the pyrazolopyrimidinone compound of Chemical Formula 1 and sildenafil to a chronic obstructive pulmonary animal model.
  • FIG. 3 is a collection of representative photographs by group evaluating alveolar damage after applying the pyrazolopyrimidinone compound of Chemical Formula 1 and sildenafil to a chronic obstructive pulmonary animal model.
  • FIG. 4 is a collection of representative photographs by group evaluating inflammatory cell infiltration after applying the pyrazolopyrimidinone compound of Chemical Formula 1 and sildenafil to a chronic obstructive pulmonary animal model.
  • the pyrazolopyrimidinone compound of Chemical Formula 1 is a kind of phosphodiesterase type 5 inhibitor.
  • the compound has excellent PDE 5 inhibitory activity and selectivity. It is absorbed fast due to its improved solubility, and has high bioavailability and huge volume of distribution. It is characterized by about a 3-fold longer elimination half- life than those of sildenafil or vardenafil, drugs with the same mechanism.
  • the pyrazolopyrimidinone compound of Chemical Formula 1 is not a hydrate or solvate, but a white or light-white powder with the melting point of 158-161 0 C and the pKal and pKa2 values of about 6.5 and 12.5, respectively.
  • the compound is insoluble in water, but soluble in acetic acid, methanol, and chloroform.
  • 4-[2-propyloxy-5-(chlorosulfonyl)benzamido]-l-methyl-3-propyl-5-carbamoyl pyrazole is prepared.
  • a predetermined amount of 4-[2-propyloxy benzamido]-l-methyl-3-propyl-5-carbamoyl pyrazole is added to a predetermined amount of chlorosulfonic acid cooled at O 0 C.
  • the reaction mixture is stirred, filtered, washed and dried to obtain 4-[2-propyloxy-5-(chlorosulfonyl)benzamido]-l-methyl-3-propyl-5-carbamoyl pyrazole.
  • Step 2 4-[2-propyloxy-5-(l-methyl-2-pyrrolidinylethyl amido- sulfonyl)benzamido]-l-methyl-3-propyl-5-carbamoyl pyrazole is prepared from the pyrazole compound prepared in the above step 1.
  • a predetermined amount of 2-(2-aminoethyl)-l-methylpyrrolidine is added at O 0 C to a dichloromethane solution containing a predetermined amount of
  • step 3 5-[2-propyloxy-5-(l-methyl-2-pyrrolidinylethyl amido- sulfonyl)phenyl]-l-methyl-3-propyl-l,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one, a pyrazolopyrimidinone compound of the present invention, is prepared from the compound obtained in step 2.
  • a predetermined amount of the pyrazole compound synthesized in step 2 is dissolved in t-butanol, to which a predetermined amount of potassium t-butoxide is added, followed by stirring under reflux for a predetermined time.
  • reaction solution Upon completion of the reaction, the reaction solution is cooled down, diluted, washed and dried. Then, reduced pressure distillation, elimination of a solvent and silica gel column chromatography are performed to obtain a predetermined amount of a novel pyrazolopyrimidinone compound of the invention, represented by Chemical Formula 1.
  • the pharmaceutically acceptable salts of the present invention include pharmaceutically acceptable salts conventionally used in the pharmaceutical art, for example, sodium salts, magnesium salts, potassium salts, calcium salts, sulfates, bisulfates, hydrochlorides, besylate salts, and camsylate salts.
  • composition of the present invention may be used preferably for prevention and treatment of airway diseases among respiratory diseases and more preferably for prevention and treatment of chronic obstructive pulmonary disease, chronic bronchitis, emphysema, and asthma.
  • the present invention provides a pharmacological composition effective for prevention and treatment of airway diseases such as chronic obstructive pulmonary disease, chronic bronchitis, emphysema, and asthma, which induces effective relaxation of airway smooth muscle, alleviates airway hyper-responsiveness, and have excellent drug distribution into the lung tissue by using a pyrazolopyrimidinone compound which is excellent in selective inhibition activity to PDE-5.
  • airway diseases such as chronic obstructive pulmonary disease, chronic bronchitis, emphysema, and asthma
  • composition of the present invention prevents and treats airway diseases by bronchodilation through relaxation of smooth muscle, alleviation of airway hyper- responsiveness, and inhibition of alveolar damage and inflammatory cell infiltration, or selective inhibition of phosphodiesterase type 5 (PDE-5) enzyme.
  • PDE-5 phosphodiesterase type 5
  • the present invention also provides a method of preventing and treating respiratory diseases including chronic obstructive pulmonary disease, chronic bronchitis, emphysema, and asthma by administering a therapeutically effective amount of a pharmacological compound containing a pyrazolopyrimidinone compound of Chemical Formula 1 to a mammal including human.
  • the present invention also provides a use of a pyrazolopyrimidinone compound of
  • Chemical Formula 1 in prevention and treatment of respiratory diseases including airway diseases such as chronic obstructive pulmonary disease, chronic bronchitis, and emphysema.
  • respiratory diseases including airway diseases such as chronic obstructive pulmonary disease, chronic bronchitis, and emphysema.
  • the present invention provides a use of a pyrazolopyrimidinone compound of Chemical Formula 1 in manufacture of a drug or health food for prevention and treatment of respiratory diseases.
  • the pharmacological compound of the present invention When applied in an actual clinical setting, the pharmacological compound of the present invention may be administered in various formulations including oral administration, and inhalation, and in most preferably oral administration. In case of medical preparations, it may be also prepared using commonly used diluents or excipients such as filler, extender, binder, wetting agent, disintegrant, and surfactant.
  • the dosage of the pharmacological compound in accordance with the present invention may be varied according to weight, age, gender, health status, diet and excretion rate of patients, time and method of administration, and severity of symptoms, and the dosage of a specific constituent drug is preferably about 25 to about 200 mg once or several times a day to adults.
  • contraction reaction (%) (Shrinkage tension after compound treatment/ Shrinkage tension prior to compound treatment) x 100 [58] Table 2 [Table 2] [Table ]
  • mice Male mice (C57BL/6, body weight: 20-22 g) were exposed to cigarette smoke three times a day and 5 days a week for a total 8 week period; 1 liter of smoke was caused by 1 cigarette (tar 8.5 mg, nicotine 0.9 mg) and the mice were exposed to the smoke for 6 minutes, followed by 1 minute of ventilation. 1 liter of smoke was again caused by 1 cigarette and the mice were exposed to the smoke for 6 minutes, followed by 1 minute of ventilation. Lastly, 1 liter of smoke was caused by 1 cigarette and the mice were exposed to the smoke for 6 minutes.
  • FIG. 2 illustrates as a graph
  • the values shown in FIG. 2 are mean ⁇ standard error (SEM), and *, +, and # show statistical significances compared to a normal group (Naive), a vehicle control group (Vehicle), and a sildenafil (10 mg/kg) administered group, respectively (P ⁇ 0.05).
  • Udenafil in FIG. 2 refers to the pyrazolopyrimidinone compound of Chemical Formula 1 in the specification.
  • BALF Bron- choalveolar lavage fluid
  • ADVIA90 Bayer HealthCare
  • tissue specimen later obtained was stained with H&E staining (tissue staining), then evaluations of peribronchial and perivascular inflammation were performed (McKay A et al., J Immnunol, 2004), and the sized of the alveolar space was measured using a mean linear intercept method (Thurlbeck WM, Am Rev Respir Dis, 1967; Hautamaki RD et al., Science, 1997).
  • the alveolar wall defects were measured using a destructive index and the reference used is as follows; at least two alveolar wall defects (1), at least two intraluminal parenchymal rags in alveolar ducts (2), clearly abnormal morphology (3), classic emphysematous changes (4) (Saetta M et al., Am Rev Respir Dis, 1985; Robbesom AA et al., ModPathol, 2003).
  • Chemical Formula 1 and sidenafil (10 mg/kg) as a control drug for 8 weeks are shown in Table 6, FIG. 3, and FIG. 4 (in FIG. 3, A, no treatment group; B, vehicle control group; C, sildenafil (10 mg/kg) administered group; D, pyrazolopyrimidinone compound (10 mg/kg) of Chemical Formula 1 administered group; in FIG. 4, A, no treatment group; B, vehicle control group; C, sildenafil (10 mg/kg) administered group; D, pyrazolopyrimidinone compound (10 mg/kg) of Chemical Formula 1 administered group).
  • composition of the present invention effectively induces bronchodilation without any side effects through selective inhibition of the activity of PDE-5, alleviates airway hyper-responsiveness, and inhibits alveolar damage and inflammatory cell infiltration.
  • composition of the present invention may be used in prevention and treatment of airway diseases such as chronic obstructive pulmonary disease, chronic bronchitis, emphysema, and asthma due to rapid expression of the drug efficacy and once a day dosage resulting from more than 12 hour effective duration of the drug efficacy.

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Abstract

La présente invention concerne une composition destinée à la prévention et au traitement d’une maladie respiratoire. Ladite composition contient un composé de pyrazolopyrimidinone ou des sels pharmaceutiquement acceptables de celui-ci en tant que principe actif.
PCT/KR2009/004188 2008-07-31 2009-07-28 Composition pharmacologique destinée à la prévention et au traitement d’une maladie respiratoire, contenant un composé de pyrazolopyrimidinone ou des sels pharmaceutiquement acceptables de celui-ci WO2010013925A2 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
KR10-2008-0075219 2008-07-31
KR20080075219 2008-07-31
KR1020090068286A KR20100014133A (ko) 2008-07-31 2009-07-27 피라졸로피리미디논 화합물 또는 그의 약제학적으로 허용되는 염을 함유하는 호흡기 질환 예방 및 치료용 약제학적 조성물
KR10-2009-0068286 2009-07-27

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104208638A (zh) * 2014-09-19 2014-12-17 张萍 一种治疗肺气肿的中药制剂
CN104800495A (zh) * 2015-05-11 2015-07-29 徐东 一种治疗气胸的药物及其制备方法
CN105012644A (zh) * 2015-08-03 2015-11-04 潍坊医学院 一种治疗甲状腺腺瘤的中药制剂
CN105362958A (zh) * 2015-12-17 2016-03-02 别会荣 一种预防胎儿、新生儿abo溶血症的中药组合物

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004103407A2 (fr) * 2003-05-22 2004-12-02 Altana Pharma Ag Composition contenant un inhibiteur de pde4 et un inhibiteur de pde5
WO2004110450A1 (fr) * 2003-06-16 2004-12-23 Altana Pharma Ag Composition comprenant un surfactant pulmonaire et un inhibiteur des pde5 pour le traitement de maladies pulmonaires

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004103407A2 (fr) * 2003-05-22 2004-12-02 Altana Pharma Ag Composition contenant un inhibiteur de pde4 et un inhibiteur de pde5
WO2004110450A1 (fr) * 2003-06-16 2004-12-23 Altana Pharma Ag Composition comprenant un surfactant pulmonaire et un inhibiteur des pde5 pour le traitement de maladies pulmonaires

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104208638A (zh) * 2014-09-19 2014-12-17 张萍 一种治疗肺气肿的中药制剂
CN104800495A (zh) * 2015-05-11 2015-07-29 徐东 一种治疗气胸的药物及其制备方法
CN105012644A (zh) * 2015-08-03 2015-11-04 潍坊医学院 一种治疗甲状腺腺瘤的中药制剂
CN105362958A (zh) * 2015-12-17 2016-03-02 别会荣 一种预防胎儿、新生儿abo溶血症的中药组合物

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