WO1993006823A1 - Verbenone, having antielastase activity, against pulmonary emphysema - Google Patents

Verbenone, having antielastase activity, against pulmonary emphysema Download PDF

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Publication number
WO1993006823A1
WO1993006823A1 PCT/EP1992/002269 EP9202269W WO9306823A1 WO 1993006823 A1 WO1993006823 A1 WO 1993006823A1 EP 9202269 W EP9202269 W EP 9202269W WO 9306823 A1 WO9306823 A1 WO 9306823A1
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verbenone
activity
pulmonary emphysema
solutions
medicament
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PCT/EP1992/002269
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French (fr)
Inventor
Gerardo Bernasconi
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Golgi S.A.
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Priority to JP5506603A priority Critical patent/JPH06506500A/en
Publication of WO1993006823A1 publication Critical patent/WO1993006823A1/en

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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
    • 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
    • A61K31/12—Ketones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A61K47/6951—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to the use of a terpene derivative, namely (IS) (-)-4,6,6- trimethylbicyclo-(3,1,1)-hept-3-ene-2-one (hereinafter named verbenone) of formula
  • the invention also relates to a verbenone-cyclodextrin complex and the pharmaceutical compositions containing it.
  • Pulmonary emphysema is a progressive respiratory disorder characterized by an abnormal and permanent increase in the volume of the air spaces located distally to the terminal bronchiole, with destruction of the alveolar septum.
  • a number of experimental and clinical data generally ascribe the emphysema pathogenesis to an unbalance of the protease-antiprotease ratio at the alveolus level.
  • alveolar proteases exert an essential activity, which is the lysis of cell fragments, thrombi and particles. Said activity is counterbalanced be endogenous antiproteases (£ ⁇ -l antitrypsin [o lAT], ( -2 macroglobulin [ ⁇ -2M] , Bronchial Mucus Inhibitor [B.M.I.]), which protect the pulmonary tissue from the protease action.
  • the loss of the normal balance between proteases and antiproteases can be attributed to three factors: 1) congenital lack in antiproteases (particularly f ⁇ -lAT); 2) excessive protease release at the alveolus level; 3) partial inactivation of antiproteases (Ck-1AT) in the presence of a normal or enhanced protease production. Said factors are generally worsened by tobacco smoke.
  • alveolar proteases leukocytal elastase proves to have the most marked digestive activity on all the pulmonary connective components, particularly on elastin, the fibres of which constitute the alveolar septa, thus giving lung the functional elasticity.
  • verbenone exerts an unpredictable antielestase activity at the lung level, and, due to said activity, it is useful in the treatment of emphysema.
  • Verbenone is a monoterpene derivative having antiinflammatory and mucolytic activities and it is used as a mucolytic and fluidifying agent in the acute and chronic disorders of the respiratory tract.
  • verbenone showed a surprising inhibiting activity on the elastase action, particularly on the neutrophylic one. Said activity was unforeseeable from the pharmacological and clinical studies which evidenced the mucolytic and antiinflammatory activities of verbenone and the use thereof in therapy.
  • pulmonary emphysema can be favoured, or worsened, by the simultaneous presence of other pulmonary disorders, such as bronchitis and/or pneumonia, other infective forms, asthma, which involve obstructions of the respiratory tract; therefore a medicament which can at the same time have antiinflammatory and mucolytic activities and protect elastin of the alveolar septa is obviously useful.
  • Tests were carried out ⁇ n vitro to evaluate verbenone activity on the release of neutrophilic elastin from polymorphonuclear granules. Said tests evidenced the marked antielastase activity of verbenone, which activity is not dose-related nor cytotoxic.
  • Polymorphonuclear phagocytes were separate starting from heparinized peripheral blood (60 cc) fro healthy volunteers or from buffy coats (leukocytes an platelets enrichments).
  • Neutrophilic polymorphonuclears were separated b means of a 6% colloidal dextran gradient, then the erythrocytes were lysated with an ammonium chloride solution. Neutrophilic elastase release
  • the plate was centrifuged and 100 ⁇ l of supernatant were collected and incubated for 60-120' at 37 ⁇ C with a specific substrate for the neutrophilic elastase (methoxysuccinyl-ala-ala-pro-val-p-Na) to a 1 mM final concentration.
  • the reaction was stopped by adding 50 ⁇ l of 1 N acetic acid and reading was carried out by means of a multiscan photometer at a 405 nm wave length.
  • the values of the absorbance of samples challenged with fMLP were compared to those from unchallenged cells, to obtain a ⁇ value corresponding to the amount of neutrophilic elastase released following to challenge. Any interferences of verbenone on the neutrophilic elastase release were tested by addition of different concentrations of the medicament directly to the cell suspension during the test. The results are shown in Table 1.
  • verbenone is used as the active ingredient for the preparation of a medicament useful for the treatment of pulmonary emphysema.
  • verbenone has the drawbacks to be insoluble in water and to have a very unpleasant taste, therefore it cannot be used for aqueous liquid pharmaceutical forms, such as syrups, oral solutions, nasal drops, aqueous solutions for aerosol and nebulization.
  • the verbenone-cyclodextrin complex has high water solubility and, moreover, verbenone unpleasant taste is no more perceptible. Therefore, the verbenone-cyclodextrin complex is a further object of invention.
  • a further advantage of the complex of the invention is provided by its increased bioavailability.
  • the pharmaceutical forms comprising the verbenone- cyclodextrin complex can be prepared, for example, according to the methods described in "Remington's Pharmaceutical Sciences Handbook", Ralph Pub. Co., USA.
  • Examples of pharmaceutical forms are capsules, pills, tablets, sugar-coated pills, granulates, syrups, drinkable solutions, nasal drops, solutions for aerosol or inhalation, suppositories, injectable solutions or suspensions both for the intravenous and the intramuscular routes.
  • the dosages will depend on the severity of the disorder, the age, weight and sex of the patient and on the clinician's advise.
  • Examples of dosages comprise single or repeated administrations of the medicament containing verbenone or the verbenone-cyclodextrin complex so as to attain a daily dosage from 10 to 500 mg of the active ingredient.
  • the preparation of the verbenone-cyclodextrin complex is illustrated in the following examples.
  • a ⁇ -ciclodextrin amount equal to 0.1 mole is weighed and placed into a mortar of suitable size.
  • the obtained complex is in form of a flowing powder which is completely odourless.
  • the obtained product is an equimolar mixture (1:1) of verbenone and cyclodextrin (50 g theoretical, 49 g found).
  • ⁇ -Cyclodextrin ⁇ -Cyclodextrin are dispersed in 500 ml of distilled water (50 mmoles) and the solution is heated to 65 e C. under stirring, until complete dissolution. solution, with stirring. The mixture is left to cool t room temperature with stirring for 60 minutes, then i is kept at +4°C for 6 hours.
  • the solid phase is recovered by filtration and th solid is placed into a convection oven at 40°C for 18 hours, to obtain 64 g of a white powdery product, containing from 11.3 to 12.0% w/w of L-verbenone. Yield - 84.65%.

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Abstract

The use of a terpene derivative for the preparation of a medicament useful in the treatment of pulmonary emphysema.

Description

VERBENONE, HAVING ANTIELASTASE ACTIVITY.AGAINST PULMONARY EMPHYSEMA
The present invention relates to the use of a terpene derivative, namely (IS) (-)-4,6,6- trimethylbicyclo-(3,1,1)-hept-3-ene-2-one (hereinafter named verbenone) of formula
Figure imgf000003_0001
for the preparation of a medicament useful in the treatment of pulmonary emphysema. The invention also relates to a verbenone-cyclodextrin complex and the pharmaceutical compositions containing it.
Pulmonary emphysema is a progressive respiratory disorder characterized by an abnormal and permanent increase in the volume of the air spaces located distally to the terminal bronchiole, with destruction of the alveolar septum.
A number of experimental and clinical data generally ascribe the emphysema pathogenesis to an unbalance of the protease-antiprotease ratio at the alveolus level. Under normal conditions, alveolar proteases exert an essential activity, which is the lysis of cell fragments, thrombi and particles. Said activity is counterbalanced be endogenous antiproteases (£\-l antitrypsin [o lAT], ( -2 macroglobulin [<Λ-2M] , Bronchial Mucus Inhibitor [B.M.I.]), which protect the pulmonary tissue from the protease action. The loss of the normal balance between proteases and antiproteases can be attributed to three factors: 1) congenital lack in antiproteases (particularly fλ-lAT); 2) excessive protease release at the alveolus level; 3) partial inactivation of antiproteases (Ck-1AT) in the presence of a normal or enhanced protease production. Said factors are generally worsened by tobacco smoke. Among alveolar proteases, leukocytal elastase proves to have the most marked digestive activity on all the pulmonary connective components, particularly on elastin, the fibres of which constitute the alveolar septa, thus giving lung the functional elasticity. Besides the traditional treatments, which cannot remedy the elastin destruction, therapies have been studied to restore elastin synthesis and to protect elastin from elastases action. Satisfactory experimental results were obtained both administering human IX-1 T intravenously and stimulating the hepatic synthesis thereof by administration of danatrol, which is a testosterone semi-synthetic derivative. However, both methods suffers from drawbacks, the first method being particularly complex and expensive, whereas the second has antigonadotropinic effects.
Therefore there is the need for a medicament exerting an antielastase activity, directly or indi¬ rectly, and also having poor side-effects.
Now it has been found that verbenone exerts an unpredictable antielestase activity at the lung level, and, due to said activity, it is useful in the treatment of emphysema.
Verbenone is a monoterpene derivative having antiinflammatory and mucolytic activities and it is used as a mucolytic and fluidifying agent in the acute and chronic disorders of the respiratory tract.
As a consequence of further researches, verbenone showed a surprising inhibiting activity on the elastase action, particularly on the neutrophylic one. Said activity was unforeseeable from the pharmacological and clinical studies which evidenced the mucolytic and antiinflammatory activities of verbenone and the use thereof in therapy.
The use of verbenone in the treatment of pulmonary emphysema is extremely advantageous. In fact, pulmonary emphysema can be favoured, or worsened, by the simultaneous presence of other pulmonary disorders, such as bronchitis and/or pneumonia, other infective forms, asthma, which involve obstructions of the respiratory tract; therefore a medicament which can at the same time have antiinflammatory and mucolytic activities and protect elastin of the alveolar septa is obviously useful.
Tests were carried out ^n vitro to evaluate verbenone activity on the release of neutrophilic elastin from polymorphonuclear granules. Said tests evidenced the marked antielastase activity of verbenone, which activity is not dose-related nor cytotoxic.
The results from said tests are reported hereinbelow. Separation of neutrophilic polymorphonuclears
Polymorphonuclear phagocytes were separate starting from heparinized peripheral blood (60 cc) fro healthy volunteers or from buffy coats (leukocytes an platelets enrichments).
Neutrophilic polymorphonuclears were separated b means of a 6% colloidal dextran gradient, then the erythrocytes were lysated with an ammonium chloride solution. Neutrophilic elastase release
100 μl of cells at a concentration of 1x10 /ml, pretreated with cytochalasin B (5 μg/ml) for 10', were incubated for 20" at 37CC in a microtiter plate in the presence or in the absence of 50 μl of a challenge consisting of fMLP (formyl-methionyl-leucyl-peptide) at a 10 molar final concentration. After said incubation, the plate was centrifuged and 100 μl of supernatant were collected and incubated for 60-120' at 37βC with a specific substrate for the neutrophilic elastase (methoxysuccinyl-ala-ala-pro-val-p-Na) to a 1 mM final concentration. The reaction was stopped by adding 50 μl of 1 N acetic acid and reading was carried out by means of a multiscan photometer at a 405 nm wave length. The values of the absorbance of samples challenged with fMLP were compared to those from unchallenged cells, to obtain a Δ value corresponding to the amount of neutrophilic elastase released following to challenge. Any interferences of verbenone on the neutrophilic elastase release were tested by addition of different concentrations of the medicament directly to the cell suspension during the test. The results are shown in Table 1.
TABLE 1 Modulation of the elastase release from neutrophilic polymorphonuclears by addition of verbenone to the cells during the test, at different concentrations.
% inhibition compared to the control
Control Verb. 1 mM 90% Verb. 0,1 mM 86% Verb. 10 μM 94% Verb. 1 μM 94% Verb. 0,1 μM 92% Verb. 10 nM 89% Verb. 1 nM 83% Verb..0,1 nM 96% Verb. 10 pM 94%
This marked inhibiting activity is unlikely to be ascribed to a toxic action of the medicament on the cells. In fact the cell viability, as repeatedly evaluated by the tripan bleu exclusion test, turned out to be always higher than 90% after incubation of the cells with verbenone in concentrations varying from 1 mM to 10 pM.
From the industrial point of view, verbenone is used as the active ingredient for the preparation of a medicament useful for the treatment of pulmonary emphysema. For the preparation medicaments, verbenone has the drawbacks to be insoluble in water and to have a very unpleasant taste, therefore it cannot be used for aqueous liquid pharmaceutical forms, such as syrups, oral solutions, nasal drops, aqueous solutions for aerosol and nebulization.
It has been found that the verbenone-cyclodextrin complex has high water solubility and, moreover, verbenone unpleasant taste is no more perceptible. Therefore, the verbenone-cyclodextrin complex is a further object of invention. A further advantage of the complex of the invention is provided by its increased bioavailability.
The pharmaceutical forms comprising the verbenone- cyclodextrin complex can be prepared, for example, according to the methods described in "Remington's Pharmaceutical Sciences Handbook", Hack Pub. Co., USA.
Examples of pharmaceutical forms are capsules, pills, tablets, sugar-coated pills, granulates, syrups, drinkable solutions, nasal drops, solutions for aerosol or inhalation, suppositories, injectable solutions or suspensions both for the intravenous and the intramuscular routes.
The dosages will depend on the severity of the disorder, the age, weight and sex of the patient and on the clinician's advise. Examples of dosages comprise single or repeated administrations of the medicament containing verbenone or the verbenone-cyclodextrin complex so as to attain a daily dosage from 10 to 500 mg of the active ingredient. The preparation of the verbenone-cyclodextrin complex is illustrated in the following examples.
EXAMPLE 1
A β-ciclodextrin amount equal to 0.1 mole is weighed and placed into a mortar of suitable size. Verbenone (0.1 mole), previously diluted with 15 ml of
96% ethanol, is added, and the mixture is mixed with a pestle to obtain an homogeneous mass. 20 ml of distilled water are added, and a mixture is obtained which hardens upon mixing. Said mixture is worked in a mortar for about 15 minutes, then it is dried in oven thermostatized at 60°C.
The obtained complex is in form of a flowing powder which is completely odourless.
Verbenone titre .80% on theoretical. EXAMPLE 2
5.80 g of verbenone were dissolved in 100 ml of 95°C ethanol (to obtain 50 g of a mixture), then they were added to 44.3 g of β-cyclodextrin in a round bottom flask. The mixture is evaporated to dryness, keeping temperature below 35°C, then it is placed into in a thermostatized oven at about 60°C until complete dryness. After drying, the product is sieved through a 16 mesh sieve.
The obtained product is an equimolar mixture (1:1) of verbenone and cyclodextrin (50 g theoretical, 49 g found).
EXAMPLE 3
68 g of β-Cyclodextrin are dispersed in 500 ml of distilled water (50 mmoles) and the solution is heated to 65eC. under stirring, until complete dissolution. solution, with stirring. The mixture is left to cool t room temperature with stirring for 60 minutes, then i is kept at +4°C for 6 hours.
The solid phase is recovered by filtration and th solid is placed into a convection oven at 40°C for 18 hours, to obtain 64 g of a white powdery product, containing from 11.3 to 12.0% w/w of L-verbenone. Yield - 84.65%.

Claims

1. The use of [ (IS) (-)-4,6,6-trimethylbicyclo- (3,l,l)-hept-3-ene-2-one] of formula
Figure imgf000011_0001
for the preparation of a medicament having antielastase activity.
2. The use of [ (IS) (-)-4,6,6-trimethylbicyclo- (3,l,l)-hept-3-en-2-one] for the preparation of a medicament useful for the treatment of pulmonary emphysema.
3. The [ (IS) (-)-4,6,6-trimethylbicyclo-(3,l,l)-hept- 3-en-2-one]-cyclodextrin complex.
4. Pharmaceutical compositions containing the complex of claim 3.
5. Compositions according to claim 4, in form of capsules, pills, tablets, sugar-coated pills, granulates, syrups, drinkable solutions, nasal drops, solutions for aerosol or inhalation, suppositories, injectable solutions or suspensions • for both the intravenous and intramuscular routes.
PCT/EP1992/002269 1991-10-04 1992-09-30 Verbenone, having antielastase activity, against pulmonary emphysema WO1993006823A1 (en)

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ITMI912652A IT1251615B (en) 1991-10-04 1991-10-04 ANTIELASTASIC ACTIVITY MEDICATION.
ITMI91A002652 1991-10-04

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013183920A1 (en) * 2012-06-05 2013-12-12 고려대학교산학협력단 Pharmaceutical composition containing verbenone derivative for treating or preventing neurodegenerative disease
CN113603802A (en) * 2021-08-24 2021-11-05 华侨大学 Preparation method and application of verbena polysaccharide

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7157446B2 (en) * 2003-05-02 2007-01-02 Bristol Myers Squibb Company Complex of ras-farnesyltransferase inhibitor, a cyclodextrin, and ethanol

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2725247A1 (en) * 1976-06-03 1977-12-22 Corvi Mora E METHOD FOR PRODUCING VERBENONE, MYRTENAL OR PINOCARVEOL AND PHARMACEUTICAL PREPARATIONS CONTAINING THESE SUBSTANCES
WO1991004026A1 (en) * 1989-09-14 1991-04-04 Australian Commercial Research & Development Limited Drug delivery compositions

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2725247A1 (en) * 1976-06-03 1977-12-22 Corvi Mora E METHOD FOR PRODUCING VERBENONE, MYRTENAL OR PINOCARVEOL AND PHARMACEUTICAL PREPARATIONS CONTAINING THESE SUBSTANCES
WO1991004026A1 (en) * 1989-09-14 1991-04-04 Australian Commercial Research & Development Limited Drug delivery compositions

Non-Patent Citations (9)

* Cited by examiner, † Cited by third party
Title
Atemwegs- und Lungenkrankheiten, vol. 9, no. 5, May 1983, K.S. ZÄNKER: "Untersuchungen zur Wirkung von Terpenen auf den Respirationstrakt vom Kaninchen", pages 181-186, see abstract; pages 182,184-186 *
Database WPI, accession no. 80-31654C (18), Derwent Publications Ltd, London, GB, & JP,A,55038338 (KAKEN CHEM. K.K. et al.) 18 March 1980, see abstract *
Deutsche Apotheker Zeitung, vol. 127, no. 41, 8 October 1987, (Stuttgart, DE), K.-H. FRÖMMING: "Cyclodextrine. Eine neue Hilfstoffgruppe mit Zukunft?", pages 2040-2044, see pages 1040,1043-1044 *
International Journal of Clinical Pharmacology Therapy and Toxicology, vol. 23, no. 4, April 1985, J. KLEINSCHMIDT et al.: "The pharmacokinetics of the bronchosecretolytic ozothin after intravenous injection", pages 200-203, see abstract; page 202 *
La Riforma Medica, vol. 105, no. 4, 1990, G. CAMPANA et al.: "Attività del verbenone sull'infiammazione sperimentale delle vie aeree della cavia", pages 109-112, see English abstract *
La Riforma Medica, vol. 105, no. 4, 1990, P.C. CURTI: "Studio dell'effetto del verbenone per iniezione intramuscolare sul surfattante alveolare nel topo albino", pages 125-131, see English abstract *
Progress in Respiration Research, vol. 18, 1984, Karger, (Basel, DE), K.S. ZÄNKER et al.: "Theoretical and experimental evidence for the action of terpenes as modulators in lung function", pages 302-304, see the whole article *
Zeitschrift für Allgemeinmedizin, vol. 46, no. 32, 20 November 1970, Hippokrates Verlag GmbH, (Stuttgart, DE), J.F. KURZ: "Sekretolyse durch Gelomyrtol", pages 1623-1627, see page 1623 *
ZFA, vol. 52, no. 26, 1976, H. SCHEEL et al.: "Behandlungsergebnisse der Emphysembronchitis mit einer neuen Darreichungsform von Ozothin", pages 1351-1355, see abstract; page 1351 *

Cited By (9)

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Publication number Priority date Publication date Assignee Title
WO2013183920A1 (en) * 2012-06-05 2013-12-12 고려대학교산학협력단 Pharmaceutical composition containing verbenone derivative for treating or preventing neurodegenerative disease
CN104768542A (en) * 2012-06-05 2015-07-08 高丽大学校产学协力团 Pharmaceutical composition containing verbenone derivative for treating or preventing neurodegenerative disease
JP2015523982A (en) * 2012-06-05 2015-08-20 コリア ユニバーシティ リサーチ アンド ビジネス ファウンデーションＫｏｒｅａ Ｕｎｉｖｅｒｓｉｔｙ Ｒｅｓｅａｒｃｈ Ａｎｄ Ｂｕｓｉｎｅｓｓ Ｆｏｕｎｄａｔｉｏｎ PHARMACEUTICAL COMPOSITION FOR TREATMENT OR PREVENTION OF DEGRADE BRAIN DISEASE CONTAINING BERBENONE
AU2013272429B2 (en) * 2012-06-05 2016-06-23 Shin Poong Pharmaceutical Co., Ltd. Pharmaceutical composition containing verbenone derivative for treating or preventing neurodegenerative disease
US9603842B2 (en) 2012-06-05 2017-03-28 Korea University Research And Business Foundation Pharmaceutical composition containing verbenone derivative for treating or preventing neurodegenerative disease
CN106977387A (en) * 2012-06-05 2017-07-25 高丽大学校产学协力团 Nerve degenerative diseases treatment or prophylactic compositions containing verbenone derivatives
CN106977387B (en) * 2012-06-05 2020-06-09 高丽大学校产学协力团 Pharmaceutical composition for treating or preventing neurodegenerative disease containing verbenone derivative
US10710951B2 (en) 2012-06-05 2020-07-14 Shin Poong Pharmaceutical Co., Ltd. Pharmaceutical composition containing verbenone derivative for treating or preventing neurodegenerative disease
CN113603802A (en) * 2021-08-24 2021-11-05 华侨大学 Preparation method and application of verbena polysaccharide

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IT1251615B (en) 1995-05-17
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