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WO2000030715A1 - Composition contenant un analgesique et une xanthine ou un derive de xanthine - Google Patents

Composition contenant un analgesique et une xanthine ou un derive de xanthine Download PDF

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Publication number
WO2000030715A1
WO2000030715A1 PCT/HU1999/000079 HU9900079W WO0030715A1 WO 2000030715 A1 WO2000030715 A1 WO 2000030715A1 HU 9900079 W HU9900079 W HU 9900079W WO 0030715 A1 WO0030715 A1 WO 0030715A1
Authority
WO
WIPO (PCT)
Prior art keywords
effect
theobromine
analgin
antinociceptive
analgesic
Prior art date
Application number
PCT/HU1999/000079
Other languages
English (en)
Inventor
Péter ARÁNYI
Attila B. KOVÁCS
Zsuzsanna FÜRST
Péterné KOVÁCS
Endre Mikus
Original Assignee
Chinoin Gyógyszer És Vegyészeti
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 Chinoin Gyógyszer És Vegyészeti filed Critical Chinoin Gyógyszer És Vegyészeti
Priority to SK687-2001A priority Critical patent/SK6872001A3/sk
Priority to HU0202838A priority patent/HUP0202838A3/hu
Priority to EEP200100281A priority patent/EE200100281A/xx
Priority to PL99348631A priority patent/PL348631A1/xx
Priority to EA200100581A priority patent/EA004375B1/ru
Priority to EP99957378A priority patent/EP1131135A1/fr
Priority to AU15102/00A priority patent/AU1510200A/en
Publication of WO2000030715A1 publication Critical patent/WO2000030715A1/fr
Priority to HR20010403A priority patent/HRP20010403A2/hr
Priority to BG105616A priority patent/BG105616A/xx

Links

Classifications

    • 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
    • A61K31/52—Purines, e.g. adenine
    • 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
    • A61K31/60—Salicylic acid; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect

Definitions

  • the invention relates to pharmaceutical compositions comprising as active ingredient an analgesic compound and a compound of xanthine sturcture.
  • Analgesic compounds are divided pharmacologically into two main groups:
  • Non-steroidal antiinfiammatory drugs, (NSAID) or minor analgesics are included.
  • the minor analgesics are less potent in relieving pain than the major analgesics, but their side-effects are also considerably milder.
  • the use of major analgesics is limited by the risk of physical dependence.
  • the effect/side-effect ratio of the two pharmacological groups also sets bounds to their use.
  • Minor analgesics serve to relieve everyday pain (headache, toothache, rheumathoid pain), while major analgesics are used for the treatment of pain connected with severe trauma, malignant tumours etc.
  • Drug researchers have since long been striving to produce compounds of non-morphine structure the potency of which reaches that of major analgesics without causing physical dependence. This dream has so far not come through.
  • caffeine (1,3,7- trimethyl-lH-purine-2,6-dion).
  • the compound is found in largest quantities in the seeds of the coffee-shrub (Coffea arabica), in the leaves of the tea-shrub (Thea sinensis) and in cocoa powder prepared from the fruit of the cocoa-tree (Theobroma cacao).
  • Caffeine was isolated from the seed of coffee-shrub and its chemical structure was determined in 1875 (Prog. Drug. Res. 31:273-313,1987).
  • caffeine two other alkaloids of xanthine structure are also found in greater quantities in the above mentioned three plants.
  • One of them is theophylline (1,3-dimethyl- lH-purine-2,6-dion), the other is theobromine (3,7-dimethyl-lH-purine-2,6-dion).
  • the drawback of the use of caffeine is that its absolute contraindication is tachyarrhythmia, while its relative contraindications are ulcer, hyperthyreosis, hypertension and some neuropsychiatric diseases (Med. Monatsschr. Phar. 15,258-269.1992).
  • N3 position has great importance from the aspect of the intensity of bronchodilator effect, while H substitution in position N7 leads to the decrease of bronchodilating effect.
  • H substitution in position N9 H substitution as a rule causes general decrease of the effect, while substitution in position C8 may lead to the increase of antiallergic, adenosine antagonistic effects and the increase of toxicity (J. Allergy Clin. Immunol. 78:817-824,1986).
  • caffeine, theophylline and theobromine their intensity varies according to the type of their effect. From the aspect of smooth muscle relaxant, adenosine receptor antagonistic, diuretic, cardiac and circulatory effects, the order of sequence is theophylline > caffeine > theobromine. From the aspect of central nervous system stimulant, skeletal muscle work increasing, gastric juice secretion increasing effect the order of sequence is caffeine > theophylline > theobromine. As it can be seen, caffeine and theophylline have significant pharmacologic effects, while according to our present knowledge, theobromine is the weakest among the three xanthine derivatives.
  • the examinations were performed according to the method of D' Amour and Smith (J. Pharmacol. Exp. Ther. 72:74,1942).
  • the principle of the method is that thermal radiation is directed to the tail of the animals and the latency period until the jerk of the tail is measured.
  • the various analgesics prolong this latency period.
  • the experiments were performed in male Wistar rats of 120-140 g.
  • the animals were fixed so that thermal radiation should focus on the tip of their tail.
  • An automatic analgesia meter was used for measuring the latency period of tail flick.
  • the instrument turned out thermal radiation and stopped the digital clock measuring the latency period. In order to avoid tissue damage developing due to strong analgesic effect, thermal radiation was switched off in each case at periods twice as long as the control latency time.
  • Morphine was dissolved in physiological saline for s.c. administration. CH-13584, theophylline and 3-methylxantine were administered in 1 % methylcellulose suspension to the animals.
  • the volume injected was in each case 0,1 ml/100 g body -weight.
  • the animals were starved for 16 hours but had access to tap water ad libitum.
  • the two substances were administered simultaneously, while in case of p.o./s.c. combinations the s. c. administered substance was injected 30 minutes after p.o. treatment.
  • Mature CFLP mice of both sexes, weighing 23-27 g were used for the experiments.
  • the animals consumed a standard rodent laboratory diet (Charles River Co. Hungary) and tap water ad libitum except on the day of the experiment when they were starved for 16 hours before oral administration of the test substances and had access only to tap water.
  • the mice were kept in a room of 22 ⁇ 2°C temperature, cyclic lighting. All experiments were performed at oral administration.
  • a 1 % methylcellulose suspension was prepared from the test substances which was administered to the mice through a gastric tube in 0,1 ml/10 g body mass volume. (In case of the combinations, the powder mixture of the two components was suspended in methylcellulose).
  • Witkin et al. Witkin, L. B., Heubner, C. F., Galdi, F., 0'Keefe, E. Spitaletta, P., and Plumer A. J., Pharmacology of 2-amino-indane hydrochloride (Su-8629) a potent non-narcotic analgesic, J. Pharmacol. Exp. Ther. 133,400408,1961) was used.
  • the first measurement was performed 1 hour after the administration of the test substances.
  • acetic acid was injected 2, 3, 4 and 5 hours after their administration and the degree of antinociceptive effect was determined in the function of time. Offset of the effect was assessed by stopping measurement in the groups where the number of writhes approached the control values (20-22 writhes/mouse).
  • the time of the first of this measurement is considered as the offset of the effect.
  • the results were represented in the form of time-effect curves and the effect-half-life values (tj /2 min.) were read.
  • mice The examinations were performed in groups of 10 mice, at oral administration, after 16 hours starving.
  • the toxicity of the test substance was determined alone and in their combinations with methylxanthines. Deaths were recorded hourly, then summarized after 24 hours.
  • the degree of antinociceptive effect is expressed as the number of writhes/mouse and indicated as % of the control.
  • the mean of pain reactions (writhes/mouse), standard deviation (SD) and standard error (SE) were calculated, then significance was calculated using the paired Student's "t" test, thereafter one factor analysis of variance of the significant values was performed.
  • CH-13584 potentiated the antinociceptive effect produced by the oral ED50 (15 mg/kg) dose of morphine at several points of time and doses (Table III. 1.(2)). This potentiating effect proved significant 30, 60, 90 minutes after the combination of morphine with 100 mg/kg CH-13584 and 30, 45, 60, 90 minutes after its combination with 200 mg/kg CH-13584.
  • CH-13584 also considerably prolonged its duration (Table 111.1.(10) compared to Table III.
  • the half-life of the effect of 100 mg/kg analgin is 125 minutes.
  • the combination of 100 mg/kg analgin with 5 mg/kg 3-methylxanthine increased the half-life to 220 minutes.
  • the potentiating effect of 5 and 10 mg/kg theobromine was even more expressed when combined with 100 mg/kg analgin than found with the former ratio of combination. With its potentiation also the duration of the effect of analgin was prolonged (111.2.(9)).
  • the half-life of the effect of 100 mg/kg analgin is 125 minutes.
  • the combination of 100 mg/kg analgin with 10 mg/kg theobromine increased the half-life to 230 minutes.
  • the half-life of the effect of 200 mg/kg analgin is 230 minutes, which was increased by the combination of 10 mg/kg theobromine to 285 minutes.
  • Paracetamol in 50, 100 and 200 mg/kg doses showed short but dose-dependent antinociceptive effect.
  • the 200 mg/kg dose which had 60 % effect, is already very near to the acute toxic range (Table 111.2.(11)).
  • the half-life of the 20 mg/kg S(+)ibuprofen elicited antinociceptive effect was 105 min while in the combination with 5 mg/kg theobromine it increased to 260 min.
  • the elevation of theobromine dose did not caused further increase in the half-life of antinociceptive effect.
  • the antinociceptive effect elicited by 20 mg/kg p.o. dose of diclofenac was increased significantly by combining it with 5 mg/kg theobromine.
  • This dose of theobromine not only increased but significantly prolonged the antinociceptive effect of diclofenac.
  • Two other doses of theobromine (10 and 30 mg/kg) also prolonged the antinociceptive effect of 20 mg/kg diclofenac but less effectively than 5 mg/kg theobromine did it (Table 111.2.(20).
  • 5 mg/kg theobromine increased and prolonged both the 30 and 50 mg/kg doses of diclofenac elicited antinociceptive effect, too.
  • the antinociception potentiating effect of theobromine was weaker than in the case of 5 mg/kg theobromine (Table 111.2.(21), Table 111.2.(22).
  • theobromine significantly increased the half-life of 20 mg/kg diclofenac elicited antinociceptive effect (120 min versus 300 min).
  • the increase of theobromine dose in the combination did not produce further increase in the antinociceptive effect of S(+)ibuprofen.
  • CH-13584 definitely increased and prolonged the effect of morphine. This phenomenon unanimously indicates that the compound may be suited to reduce the morphine doses of patients needing treatment with morphine. The acute and chronic side effects of morphine could thereby be reduced.
  • the analgesia potentiating effect of theobromine becomes even more evident if the half life of the time course of the analgesic effect is compared in a group treated with 100 mg/kg analgin alone or in combination with caffeine or theobromine.
  • the half-life (t] / ) of the analgesic effect of analgin is 125 minutes.
  • the antinociceptive effect prolonging effect of theobromine is more evident in the combination with S(+)ibuprofen.
  • the half-life of 20 mg/kg p.o. S(+)ibuprofen is 105 min.
  • the half-life of the antinociceptive effect increased to 260 min.
  • Our invention is a pharmaceutical composition
  • a pharmaceutical composition comprising as active ingredient an analgesic compound and a compound of xanthine structure, where the ratio of the analgesic and the xanthine derivative is (1-20):1, advantageously 10:1.
  • the preparations according to the invention contain as analgesic compound morphine, aminophenazone, analgin, acetyl-salicylyc acid, indomethacin, ibuprofen, diclophenac, codeine, preferably analgin, ibuprofen, codeine, as xanthine derivatives 3-methylxanthine, theobromine or CH-13584 (lH-purine-2,6-dion-3,7-dihydro-3-methyl-7-(5-methyl-l,2,4- oxadiazole-3-yl)methyl), preferably theobromine.
  • the preparations of the invention may contain as further active ingredients a smooth muscle spasmolytic, preferably papaverine, drotaverine, or the theophylline-7-acetic acid salt of drotaverine.
  • a smooth muscle spasmolytic preferably papaverine, drotaverine, or the theophylline-7-acetic acid salt of drotaverine.
  • the above preparations may advantageously be used for the treatment of headache and bone pains of different origin, toothache, pain after tooth extraction, arthralgiae, ostealgiae, pains connected with surgical interventions and delivery, as well as milder pains caused by tumours.
  • the preparations of the invention can be differently formulated:
  • the three components are separately formulated, but in collective packing.
  • the drug form may be tablet, dragee, lozenge, pill, capsule, suppository, cream, solution, drop, emulsion, injection, plaster, eye-drop.
  • the preparations contain, beside the active ingredients the usual auxiliary substances.

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne une composition pharmaceutique comprenant en tant qu'ingrédient actif un composé analgésique et un composé à structure de xanthine, le rapport analgésique/dérivés de xanthine étant de (1-20):1, et de préférence de 10:1. Le composé analgésique est sélectionné dans le groupe comprenant la morphine, l'aminophénazone, l'analgine, l'acide acétylsalicylique, l'indométhacine, l'ibuprofène, le diclophénac, la codéine, les composés préférés étant l'analgine, le S(+)ibuprofène, et le diclophénac ; le composé à structure de xanthine est sélectionné dans le groupe comprenant la 3-méthylxanthine, la théobromine, ou le CH-13584((1H-purine-2,6-dione-3,7-dihydro-3-méthyl-7/5-méthyl-1,2,4-oxadiazole-2-yl/méthyle), le composé préféré étant la théobromine. Cette composition peut contenir en tant qu'ingrédient actif additionnel un spasmolytique agissant sur les muscles lisses, le composé préféré étant la drotavérine.
PCT/HU1999/000079 1998-11-25 1999-11-23 Composition contenant un analgesique et une xanthine ou un derive de xanthine WO2000030715A1 (fr)

Priority Applications (9)

Application Number Priority Date Filing Date Title
SK687-2001A SK6872001A3 (en) 1998-11-25 1999-11-23 Composition containing an analgesic and a xanthine or a xanthine derivative
HU0202838A HUP0202838A3 (en) 1998-11-25 1999-11-23 Composition containing an analgesic and a xanthine or a xanthine derivative
EEP200100281A EE200100281A (et) 1998-11-25 1999-11-23 Analgeetiline ravimkoostis
PL99348631A PL348631A1 (en) 1998-11-25 1999-11-23 Composition containing an analgesic and a xanthine or a xanthine derivative
EA200100581A EA004375B1 (ru) 1998-11-25 1999-11-23 Комбинация анальгетических лекарственных средств
EP99957378A EP1131135A1 (fr) 1998-11-25 1999-11-23 Composition contenant un analgesique et theobromine
AU15102/00A AU1510200A (en) 1998-11-25 1999-11-23 Composition containing an analgesic and a xanthine or a xanthine derivative
HR20010403A HRP20010403A2 (en) 1998-11-25 2001-05-25 Composition containing an analgesic and a xanthine or a xanthine derivative
BG105616A BG105616A (en) 1998-11-25 2001-06-18 Pharmaceutical compositions of analgesic effect

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
HU9802716A HUP9802716A3 (en) 1998-11-25 1998-11-25 Pharmaceutical composition of analgesic activity
HUP9802716 1998-11-25

Publications (1)

Publication Number Publication Date
WO2000030715A1 true WO2000030715A1 (fr) 2000-06-02

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Application Number Title Priority Date Filing Date
PCT/HU1999/000079 WO2000030715A1 (fr) 1998-11-25 1999-11-23 Composition contenant un analgesique et une xanthine ou un derive de xanthine

Country Status (12)

Country Link
EP (1) EP1131135A1 (fr)
AU (1) AU1510200A (fr)
BG (1) BG105616A (fr)
CZ (1) CZ20011847A3 (fr)
EA (1) EA004375B1 (fr)
EE (1) EE200100281A (fr)
HR (1) HRP20010403A2 (fr)
HU (1) HUP9802716A3 (fr)
PL (1) PL348631A1 (fr)
SK (1) SK6872001A3 (fr)
WO (1) WO2000030715A1 (fr)
YU (1) YU37001A (fr)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2183115C1 (ru) * 2001-06-29 2002-06-10 Государственное унитарное предприятие Межбольничная аптека Медицинского центра Управления делами Президента Российской Федерации Фармацевтическая композиция, обладающая спазмолитическим и анальгезирующим действием
BG65576B1 (bg) * 2002-04-17 2009-01-30 ПИРИМОВА Румяна Състав на болкоуспокояващо средство, по-специалнопри главоболие и мигрена
WO2011058374A1 (fr) * 2009-11-13 2011-05-19 Biocopea Limited Combinaison de médicament avec la théobromine et son utilisation en thérapie
WO2013005226A1 (fr) * 2011-07-04 2013-01-10 Zota Health Care Ltd Nouvelle composition pharmaceutique combinée contenant du diclofénac et ses procédés de fabrication et d'utilisation
US8703158B2 (en) 2009-06-16 2014-04-22 Biocopea Limited Theobromine for the treatment of cough
US8853189B2 (en) 2012-05-31 2014-10-07 Prima Innovations, Llc Antispasmodic 1,2-Diols and 1,2,3-triols
AU2015201845B2 (en) * 2009-11-13 2015-11-05 Infirst Healthcare Limited Drug combination with theobromine and its use in therapy
US9308211B2 (en) 2009-06-16 2016-04-12 Infirst Healthcare Limited Drug combinations and uses in treating a coughing condition
US9314465B2 (en) 2009-06-16 2016-04-19 Infirst Healthcare Limited Drug combinations and uses in treating a coughing condition
US10016437B2 (en) 2009-06-16 2018-07-10 Infirst Healthcare Limited Drug combinations and uses in treating a coughing condition

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1986003681A1 (fr) * 1984-12-26 1986-07-03 Abraham Sunshine Produit a base d'analgesiques, d'anti-inflammatoires et de decontractants musculaires transosseux
WO1995007103A1 (fr) * 1993-09-07 1995-03-16 The Procter & Gamble Company Compositions contenant un sel d'acide amine d'un agent anti-inflammatoire non steroidien a base d'acide propionique et au moins un decongestionnant ou un expectorant ou un antihistaminique ou un antitussif
WO1997049405A1 (fr) * 1996-06-27 1997-12-31 The Procter & Gamble Company Composition de gel topique contenant une combinaison d'un mains et d'un derive de xanthine

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1986003681A1 (fr) * 1984-12-26 1986-07-03 Abraham Sunshine Produit a base d'analgesiques, d'anti-inflammatoires et de decontractants musculaires transosseux
WO1995007103A1 (fr) * 1993-09-07 1995-03-16 The Procter & Gamble Company Compositions contenant un sel d'acide amine d'un agent anti-inflammatoire non steroidien a base d'acide propionique et au moins un decongestionnant ou un expectorant ou un antihistaminique ou un antitussif
WO1997049405A1 (fr) * 1996-06-27 1997-12-31 The Procter & Gamble Company Composition de gel topique contenant une combinaison d'un mains et d'un derive de xanthine

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2183115C1 (ru) * 2001-06-29 2002-06-10 Государственное унитарное предприятие Межбольничная аптека Медицинского центра Управления делами Президента Российской Федерации Фармацевтическая композиция, обладающая спазмолитическим и анальгезирующим действием
BG65576B1 (bg) * 2002-04-17 2009-01-30 ПИРИМОВА Румяна Състав на болкоуспокояващо средство, по-специалнопри главоболие и мигрена
US10016437B2 (en) 2009-06-16 2018-07-10 Infirst Healthcare Limited Drug combinations and uses in treating a coughing condition
US9700561B2 (en) 2009-06-16 2017-07-11 Infirst Healthcare Limited Drug combinations and uses in treating a coughing condition
US9675618B2 (en) 2009-06-16 2017-06-13 Infirst Healthcare Limited Drug combinations and uses in treating a coughing condition
US8703158B2 (en) 2009-06-16 2014-04-22 Biocopea Limited Theobromine for the treatment of cough
US9314465B2 (en) 2009-06-16 2016-04-19 Infirst Healthcare Limited Drug combinations and uses in treating a coughing condition
US9308211B2 (en) 2009-06-16 2016-04-12 Infirst Healthcare Limited Drug combinations and uses in treating a coughing condition
CN102740853B (zh) * 2009-11-13 2015-04-08 第一医疗保健有限公司 可可碱的药物组合及其在治疗中的用途
AU2015201845B2 (en) * 2009-11-13 2015-11-05 Infirst Healthcare Limited Drug combination with theobromine and its use in therapy
AU2010317668C1 (en) * 2009-11-13 2016-02-11 Infirst Healthcare Limited Drug combination with theobromine and its use in therapy
AU2010317668B2 (en) * 2009-11-13 2015-01-22 Infirst Healthcare Limited Drug combination with theobromine and its use in therapy
CN102740853A (zh) * 2009-11-13 2012-10-17 比蔻匹亚有限公司 可可碱的药物组合及其在治疗中的用途
WO2011058374A1 (fr) * 2009-11-13 2011-05-19 Biocopea Limited Combinaison de médicament avec la théobromine et son utilisation en thérapie
WO2013005226A1 (fr) * 2011-07-04 2013-01-10 Zota Health Care Ltd Nouvelle composition pharmaceutique combinée contenant du diclofénac et ses procédés de fabrication et d'utilisation
US8853189B2 (en) 2012-05-31 2014-10-07 Prima Innovations, Llc Antispasmodic 1,2-Diols and 1,2,3-triols

Also Published As

Publication number Publication date
HRP20010403A2 (en) 2002-06-30
EA200100581A1 (ru) 2001-12-24
HUP9802716A3 (en) 2000-08-28
EP1131135A1 (fr) 2001-09-12
HUP9802716A2 (hu) 2000-06-28
HU9802716D0 (en) 1999-01-28
EE200100281A (et) 2002-08-15
PL348631A1 (en) 2002-06-03
CZ20011847A3 (cs) 2002-07-17
EA004375B1 (ru) 2004-04-29
SK6872001A3 (en) 2002-05-09
YU37001A (sh) 2004-05-12
BG105616A (en) 2002-01-31
AU1510200A (en) 2000-06-13

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