WO1986001108A1 - Composition pharmaceutique - Google Patents

Composition pharmaceutique Download PDF

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Publication number
WO1986001108A1
WO1986001108A1 PCT/CH1985/000120 CH8500120W WO8601108A1 WO 1986001108 A1 WO1986001108 A1 WO 1986001108A1 CH 8500120 W CH8500120 W CH 8500120W WO 8601108 A1 WO8601108 A1 WO 8601108A1
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WO
WIPO (PCT)
Prior art keywords
theophylline
ketotifen
asthma
pharmaceutical composition
preventive
Prior art date
Application number
PCT/CH1985/000120
Other languages
German (de)
English (en)
French (fr)
Inventor
Joseph Agius
John Morley
Wolf-Dieter Roth
Karl-Heinz Hahn
Original Assignee
Sandoz Ag
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 Sandoz Ag filed Critical Sandoz Ag
Publication of WO1986001108A1 publication Critical patent/WO1986001108A1/de

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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

Definitions

  • the present invention relates to a new pharmaceutical preparation, in particular a new pharmaceutical preparation in the form of a fixed combination, containing a) ketotifen and b) an anti-asthmatic xanthine.
  • the compound is a known therapeutically active compound that has valuable anti-anaphylactic properties.
  • it has a strong inhibitory effect on the transmission systems responsible for the anaphylactic reaction and has been widely used in the long-term prevention or prophylaxis of all forms of bronchial asthma, allergic bronchitis and asthmatic symptoms associated with hay fever.
  • the compound is also used in the prevention and treatment of multi-system allergy, allergic rhinitis and allergic skin reactions. As already mentioned, it mainly affects the transmission systems. It is essentially free of any noticeable direct bronchodilator effect when used, for example, to treat asthma and in practical use, it is essentially preventive or prophylactic.
  • anti-asthmatic xanthines comprise a wide and recognized class of compounds, of which the most widely used representative is the anti-asthmatic compound theophylline, which has the formula II a
  • the xanthines are pharmacologically characterized by a relaxing effect on smooth muscles, which, in contrast to ketotifen, on their bronchodilator effect, i.e. is based on their ability to prevent or prevent bronchoconstriction during an asthma attack.
  • ketotifen and theophylline co-therapy In view of the complex aetiology of asthma, its treatment is generally carried out using mixed therapy, and reports of co-therapy using ketotifen and theophylline are abundant in the prior art.
  • the first incentive for ketotifen / theophylline co-therapy was, of course, the complementary benefit that could be drawn from the preventive (prophylactic) effectiveness of ketotifen in bronchial asthma and the direct bronchodilator effect of theophylline.
  • numerous reports have drawn attention to the advantageous compensatory effect resulting from the interaction of the ketotifen inherent CNS depressive and the theophylline inherent CNS stimulating effect.
  • the therapeutic efficacy in patients with sub-bronchodilator blood levels can be observed, for example, in the case of theophylline of less than 10 ⁇ ggml and it is common practice in theophylline use that these are less than the bronchodilatatori see plasma levels [Woodcock et al., Lancet ii, 610-613 (1983)].
  • PAF platelet activating factor
  • ketotifen and, for example, theophylline inhibit bronchospasm caused by PAF [Saunders et al., Thrombos.Haemastas. 50, 1493 (1983) and Medieras et al., J. Pharmacology 14, 98 (1983)].
  • a combination of ketotifen and the anti-asthmatic xanthines for example theophylline
  • theophylline as a characteristic representative of the anti-asthmatic xanthine, it was found that the combination of the effect of ketotifen and theophylline on the transmitter level, i.e. in terms of their preventive or prophylactic effects, is mutual and synergistically enhanced.
  • ketotifen has the preventive or prophylactic anti-asthmatic activity of, for example, theophylline at theophylline doses which are classically below the therapeutically effective, i.e. in doses insufficient to effect bronchodilation, synergistically enhanced.
  • An equivalent synergistic interaction at the transmitter level can also be demonstrated if ketotifen and another anti-asthmatic xanthine are used, as described below, for example.
  • a pharmaceutical composition which comprises a) ketotifen and b) an anti-asthmatic xanthine in a fixed combination .
  • the present invention allows a full and practical, ie clinical realization of the therapeutic advantage of a synergistic interaction at the transmitter level of the components a) and b) defined above, as discussed above.
  • the synergistic interaction at the transmitter level can bring advantages to the treated patient not only with regard to the preventive or prophylactic effect, but also in related transmitter level systems, for example a synergistic reduction in airway overreaction and development of mucus secretion and inflammation, etc., as evidence of an improved patient response, for example according to the degree of airway obstruction, particularly during an asthma attack.
  • this airway obstruction which can be determined according to the usual clinical standard, for example as described below, can be reduced synergistically by administration of compositions according to the invention which contain both component a) and component b), as compared to results obtained in patients who have only received component a) or component b).
  • This interaction obtained when using the compositions according to the invention is particularly evident during the initial phase of the asthma treatment, for example during the first 4 to 6 weeks after the start of the therapy.
  • ketotifen can be present in the preparation according to the invention in free form or in the form of a pharmaceutically acceptable acid addition salt, for example in the form of its hydrogen fumarate. Such salt forms are well tolerated and have a potency that corresponds to that of the free form.
  • ketotifen in the present context means both the free form and the pharmaceutically acceptable acid addition salt form, unless stated otherwise.
  • Component a) is preferably present in the compositions in the form of its hydrogen fumarate.
  • Suitable anti-asthmatic xanthines for use as component b) in the compositions of the present invention include those of Formula II
  • R 1 , R 3 and R 4 are each hydrogen and R 2 is n-propyl, or ii) R 1 and R 2 are each methyl, R 3 is - (CH 2 ) 2 N (C 2 H 5 ) CH 2 CH 2 OH and R 4 are benzyl, iii) R 1 and R 2 are each methyl, R 4 is hydrogen and R 3 is
  • the compounds i) to iii) are known and described together with the process for their preparation, for example i) in Europ. Patent No. 0011 609, ii) in Belgian Patent No. 602888 and iii) in European Patent No. 0089028.
  • the preferred compound for use in the compositions according to the invention is also known compound i) and hereinafter referred to as enprophylline .
  • the most preferred anti-asthmatic xanthine for use in the composition of the present invention is the compound theophylline of Formula IIa, which was previously indicated.
  • Component b) can be used in the preparation according to the invention as such or in the form of one of the various known mixtures with pharmaceutically acceptable additives, in particular pharmaceutically acceptable amines, in particular choline, diethanolamine, ethanolamine etc. or in the form of pharmaceutically acceptable acid addition salts including the pharmaceutically acceptable acid addition salts thereof Mixture can be used.
  • pharmaceutically acceptable additives in particular pharmaceutically acceptable amines, in particular choline, diethanolamine, ethanolamine etc.
  • pharmaceutically acceptable acid addition salts including the pharmaceutically acceptable acid addition salts thereof Mixture can be used.
  • Such forms are known in the art and generally have the advantage of improved solubility compared to the free compound or its salts.
  • anti-asthmatic xanthine theophylline include the compounds theophylline calcium salicylate, theophylline diethanolamine, theophylline isopropanolamine and especially aminophylline, a 2: 1 (weight ratio) mixture of theophylline and ethylenediamine.
  • Such mixtures and salts are also well tolerated and references to antistatic xanthines and specific xanthines of this class, such as theophylline, include both the free forms and the mixed forms and their salts, unless stated otherwise.
  • Preferred anti-asthmatic xanthines, including the preferred xanthine theophylline, which are present as component b) in the composition according to the invention are contained therein as free compounds, for example as free theophylline.
  • compositions according to the invention comprise any form which is suitable for administration either enterally or parenterally and comprise components a) and b) in the form of a fixed combination, which together and each in a predetermined amount, for example in predetermined relative ratios.
  • Preferred compositions according to the invention are forms suitable for oral administration, including capsules, tablets, syrups or the like.
  • the compositions according to the invention preferably form a unit dose form, for example for oral administration, each unit dose containing a predetermined amount of each of components a) and b).
  • Compositions according to the invention include systems in which components a) and b) are obviously separate, for example present or kept separate within the composition, and systems in which the specified components are intimately mixed or both are uniformly dispersed within a common matrix .
  • compositions of the former type include capsules, for example for oral administration, containing a) and b) each in independent granulated, powdered, tableted or similar form (whether mixed or not) or separately, for example in individual independent compartments of a two-part capsule or in separate layers a coat tablet.
  • Compositions of the latter type include, for example, tablets or the like, in which a) and b) are each substantially uniformly distributed within the tablet mass or matrix. In such cases, the tablet mass or matrix becomes an essentially uniform matrix, for example containing a carrier, solid diluent! and / or binders, etc., as commonly used in the art.
  • Such compositions can be prepared according to methods known in the art, for example as described below in the accompanying examples.
  • component b) in the composition according to the invention is in a form with a delayed onset of action, i.e. in a form which enables component b) to be released continuously within the body or the body tissues over a longer period of time or which allows a relatively constant component b) to be present in the blood serum level for a longer period of time following the administration,
  • Suitable forms with delayed onset of action of component b) are known in the prior art and can be made using any known technique which is usually used in galenics, are obtained, in particular based on formulations with delayed release of xanthines, see. for example Europ. Patent Publication No. 0 122077, US Pat. Nos. 4415 547 and 3400 185 and PCT Application No. WO 83 00 284. They include sustained release pellet forms, for example in which individual particles of granules, powder or the like. containing b) are provided with a suitable coating for delayed release.
  • component b) obtained in this way can be changed as desired, for example by selecting the coating material, by changing the applied coating and / or by changing the particle size of the coated material. Since the release rate of the anti-asthmatic xanthine derivatives, for example theophylline, is strongly subject-specific, the blood serum levels obtained using the respective composition with delayed release will inevitably fluctuate greatly from one substance to another.
  • the forms with delayed release can be used in the composition according to the invention, for blood serum levels in the order of magnitude of approximately 8 to approximately 20 ⁇ g / ml over time periods of approximately 4 to approximately 8 hours and more , for example over periods of up to about 6 hours after administration.
  • the preferred sustained release form of component b) is such that it gives the following approximate theophylline release characteristics under laboratory conditions:
  • the average theophylline release under the above conditions 1) after 1 hour preferably does not exceed approximately 30%, in particular approximately 25%.
  • Hourly theophylline release under the above conditions 1) during an 8 hour period varies within a range of about 4 to 20%, preferably about 5 to 15% / hour.
  • Such forms provide a maximum theophylline release of i) about 60%, preferably about 55% and ii) 100%, preferably about 90% to 95%, after i) 3 hours and ii) 8 hours under the standard conditions discussed above under 1. and 2. (All measurements are carried out at room temperature with stirring at 90 revolutions / minute. The pH value is expediently set after about 120 minutes.)
  • the preferred sustained release form for use in the composition according to the present invention is a theophylline retard pellet, as supplied by Klinge AG. is offered in the commercial preparation BRONCHORETARD. The production of a likewise preferred form with delayed release is described in Example la below.
  • components a) and b) will be present in the composition according to the invention in a ratio of about 1:50 to 500 parts by weight, preferably about 1: 100 to 500 parts by weight (a: b).
  • a special and preferred constituent of the composition according to the invention relates to components a) and b) in a ratio of approx. 1:50 to 350 parts by weight, in particular approx. 1: 100 to 300 parts by weight or approx. 1:50 to 300 parts by weight, in particular approx 1: 100, 200 or 300 parts by weight, for example approximately 1: 200 or 300 parts by weight.
  • compositions according to the invention comprise a unit dose form
  • the individual unit doses contain from about 1 to about 2 mg, preferably 1 mg, of component a).
  • Such unit doses appropriately contain at most about 500, preferably at most about 350, particularly preferably about 300 mg of component b).
  • preferred unit doses contain about 1 mg or about 2 mg (but especially about 1 mg) of component a) and from about 50 to about 500 mg, preferably from about 100 to about 350 mg, for example about 100, 150, 175, 200 or 300, in particular approximately 175, 200 or 300 mg of component b) which are intended for administration once to four times, in particular once or twice a day.
  • compositions are ⁇ eei.gnet for use in the treatment of all conditions for which a ketotifen therapy is usually used, as well as in conditions where bronchodilator activity is desired, for example in the treatment of active asthma or when triggering an asthma. Therapy. If a once-daily dosage is provided or bronchodilation is critical for the therapy, the proportions of component b) will generally be higher, for example in the case of unit dosage forms in the order of approximately 200 mg, or preferably 300 mg or more.
  • compositions according to the invention may contain as little as about 50 to 300 mg.
  • compositions according to the invention and in particular the synergistic interaction of ketotifene anti-asthmatic xanthines, for example theophylline, for example in relation to the protective effect, as discussed above, can be shown both in the clinic and in conventional animal models. Accordingly, the mutual synergistic interaction of ketotifen and theophylline at the transmitter level can be shown, for example, in relation to brochospasm caused by PAF, for example as described below:
  • Such animals are given medicinal products 5 minutes before (ketotifen or saline) or 1 minute before (aminophylline - the theophylline mixture as specifically described above - or saline) given a PAF injection. Inhibition is assessed by comparing the response after treatment with the response just before drug administration. The difference found between the two reactions can expediently be expressed as a percentage of the reaction immediately before the treatment with the active ingredient.
  • ketotifen In order to measure the synergism between ketotifen and aminophylline, the isobol technique is used as a strict test [Berenbaum, Clin.Exp.Immunol., 28, 1-18 (1977)]. Doses of ketotifen between 0.56 ⁇ g / kg and 18 ⁇ g / kg are used either alone or in combination with aminophylline in doses between 0.01 mg / kg and 0.32 mg / kg. Responses are determined in at least 5 animals for each dose or combination of doses, except for saline-treated animals (9) and animals containing 0.32 mg / kg aminophylline (10) or 1.8 ⁇ g / kg ketotifen (7) obtained if additional animals are used. A total of 86 animals are used for the study.
  • composition according to the invention can also be shown in clinical tests which are carried out, for example, as described below:
  • An examination is carried out using a group of 12 patients, male or female, with an age range of 16 to 65 years.
  • the selected patients show both seasonal and year-round chronic bronchial asthma (with reversible, allergic or mixed forms of bronchospasm) how anamnesis is determined with the help of skin tests or determination of allergen-specific IgE and, if necessary, confirmed by inhalation provocation.
  • Mild or moderately severe forms are characterized by mild or moderate obstruction of the bronchi with repeated determination of an infestation or permanent symptomatology.
  • the following imposition parameters are used: pregnancy, severe liver or kidney diseases, conditions following a myocardial infarction (not later than 6 months), diabetes mellitus that is difficult to control, gastrointestinal disorders that are related to influence absorption, metabolism or Elimination of test substance such as chronic diarrhea, malabsorption syndrome, etc., heartbeat disorders, gastric or intestinal ulcers, individuals known to be unreliable or physiologically unstable.
  • patients will only receive additional sympathomimetic or anti-cholinergic treatment if this is essential to avert asthma attacks.
  • another treatment for example with corticosteroids or antibiotics, is also permitted.
  • the type of such treatment, duration and the dose used are recorded. In the event that the patients are already receiving continuous bronchodilator, steroidal or theophylline therapy, this is gradually reduced only during the first 2 to 3 weeks of the trial.
  • All tablets are essentially identical in appearance, with tablets c) being offered in 2 sizes, the smaller size (for administration to individuals with ⁇ 50 kg) corresponding to the tablets containing 200 mg of theophylline, the larger (for administration to Individuals weighing more than 50 kg correspond to the other tablets containing 300 mg of theophylline.
  • each patient took 2 tablets daily (morning and evening) orally.
  • the duration of the examination is 6 months for each patient.
  • the clinical examination is carried out for each individual 2, 4, 6 and 8 weeks after the start of the examination and thereafter in a 4-week interval.
  • the following parameters are measured for each check:
  • results obtained during the first 4 to 6 weeks following the start of the tests with individually measured parameters, in particular the total resistance, the effectiveness in individuals who received ketotifen and theophylline in a fixed combination, show that this is greater than can be expected from studies on individuals receiving ketotifen or theophylline alone, ie that these are indicative of super-additive effectiveness.
  • the present invention also relates to a pharmaceutical composition for the treatment of asthma which also shows a super-additive or synergistic anti-asthmatic activity, in particular at the transmitter level, or which is a super-additive or synergistic preventive or prophylactic anti-asthmatic Efficacy shows, in particular at the transmitter level, for example as proven by a reduction in airway resistance, for example as a result of airway overreactivity, development of the mucous membrane, inflammation etc.
  • a composition contains a) ketotifen and b) an anti-asthmatic xanthine in a fixed combination (e.g. as discussed above).
  • the invention relates to a method for the treatment, in particular for the preventive or prophylactic treatment of asthma, in particular at the transmitter level or for reducing the airway resistance, for example as a consequence of airway overreactivity, development of the mucous membrane, inflammation etc., in particular during the preventive or prophylactic treatment of asthma: in an individual in need of such treatment, the method comprising the administration to such individuals of a pharmaceutical composition comprising a) ketotifen and b) an anti-asthmatic xanthine in a fixed combination (for example as described here) , or
  • the tablets obtained each weigh 630.00 mg and contain 300 mg of free theophylline and the equivalent of 1 mg of free ketotifen.
  • the theophylline release characteristics of the tablet samples as determined under standard laboratory conditions as described in Example 1 are as follows: Elapsed time% released theophylline
  • Ketotifen hydrogen fumarate 1 38 b) talc 0, 16 c) calcium hydrogen phosphate anhydrous 35, 26 d) corn starch 5, 26 e) dried corn starch 2, 6 f) magnesium stearate 0, 5
  • Hard gelatin capsules are produced analogously to Example 3, containing a tablet obtained according to Example 3a) and theophylline sustained release pellets from Klinge AG., As described in Example 3b) in the proportions listed below:
  • Theophylline pellets with a delayed release rate of the general type, described above in Example la), containing di theophylline granules as the core material and a coating, as described, are also new. Accordingly, another aspect of the present invention also relates to:
  • Theophylline in the form of a sustained release pellet containing granules consisting essentially of free theophylline as the pellet core material, provided with a pellet coating containing ethyl cellulose and hydroxypropyl methyl cellulose.
  • the coating is preferably applied as described, for example, in Example 1, in such a way that essentially all of the particles which contain the core material are coated individually.
  • the particles expediently contain the core material in accordance with the dimensional characteristics, as described, for the theophylline granules used as starting material in Example 1a).
  • the coating is expediently applied in such a way that the core material and the coating are present in the pellets obtained in a ratio of approximately 1: 0.5 to 0.2 parts by weight, preferably approximately 1: 0.1 parts by weight.
  • the pellets obtained preferably have the largest diameter of approximately 2.0 mm and the smallest diameter of approximately 0.3 mm.
  • about 55 to about 85%, preferably about 50 to about 80% of the pellets obtained have a diameter of> 0.71 mm.
  • no more than about 1.0%, preferably no more than about 0.5% of the pellets obtained have a diameter of> 1.4 mm and no more than about 15%, preferably no more than about 10 to 12% have a diameter of> 1.0 mm.
  • the ratio of hydroxypropylmethyl cellulose to ethyl cellulose in the applied coating is advantageously about 1: 6 to 14 parts by weight, preferably about 1: 8 to 12 parts by weight, more preferably about 1: 9 to 11 parts by weight, the coating advantageously also contains a plasticizer and di-n-butyl phthalate. If present, the plasticizer is present in a proportion of 8 to 15%, preferably approx. 12%, by weight based on the total coating material.
  • the invention further relates to:
  • a process for the production of theophylline in pellet form with a delayed release rate as indicated above under I., the process comprising spray coating a theophylline granulate with a coating mixture containing a methanolic solution of ethyl cellulose and hydroxypropyl methyl cellulose.
  • the method is expediently carried out using individual parameters and / or conditions, as described above in Example la).
  • the present invention also relates to:
  • a pharmaceutical composition containing a) ketotifen, preferably in the form of its hydrogen fumarate and b) theophylline in pellet form as stated above under I., in the form of a fixed combination, in particular a pharmaceutical composition, as stated above, containing a tablet or the like, wherein a) and b) are distributed substantially uniformly in the tablet mass or matrix.
  • the invention also relates to:
  • IVa a method of making a pharmaceutical composition as set out above which has improved efficacy in the treatment, particularly in the preventive or prophylactic treatment of asthma, or improved efficacy in reducing airway resistance, particularly during the preventive or prophylactic treatment of asthma, this method combining a) ketotifen preferably in the form of its hydrogen fumarate with b) an anti-asthmatic xanthine in a fixed combination as well
  • IVb a process for the preparation of a pharmaceutical composition as described under III. specified, the method consisting in that components a) and b) are brought into the form of a fixed combination, in particular by intimately mixing components a) and b) together with a solid, pharmaceutically acceptable diluent or carrier, in order to obtain a Produce mass, which is suitable for being pressed into tablets or the like and process this mass into tablets or similar forms.
  • Suitable theophylline release characteristics for the compositions as described in III above.
  • in tablets or other forms for example of the type described above in Examples 1 and 2, under laboratory conditions as described in Example 1 are the following:

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
PCT/CH1985/000120 1984-08-16 1985-08-06 Composition pharmaceutique WO1986001108A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CH3927/84-5 1984-08-16
CH392784 1984-08-16
CH438784 1984-09-14
CH4387/84-4 1984-09-14

Publications (1)

Publication Number Publication Date
WO1986001108A1 true WO1986001108A1 (fr) 1986-02-27

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PCT/CH1985/000120 WO1986001108A1 (fr) 1984-08-16 1985-08-06 Composition pharmaceutique

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AU (1) AU4617185A (enrdf_load_stackoverflow)
BE (1) BE903065A (enrdf_load_stackoverflow)
DE (1) DE3528481A1 (enrdf_load_stackoverflow)
DK (1) DK370085A (enrdf_load_stackoverflow)
FR (1) FR2569109A1 (enrdf_load_stackoverflow)
GB (1) GB2163957A (enrdf_load_stackoverflow)
GR (1) GR851988B (enrdf_load_stackoverflow)
HU (1) HUT40568A (enrdf_load_stackoverflow)
IL (1) IL76089A0 (enrdf_load_stackoverflow)
IT (1) IT1200102B (enrdf_load_stackoverflow)
LU (1) LU86044A1 (enrdf_load_stackoverflow)
NL (1) NL8502178A (enrdf_load_stackoverflow)
PT (1) PT80961B (enrdf_load_stackoverflow)
SE (1) SE8503771L (enrdf_load_stackoverflow)
WO (1) WO1986001108A1 (enrdf_load_stackoverflow)

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NL8701335A (nl) * 1986-06-21 1988-01-18 Sandoz Ag Orale farmaceutische preparaten.
GB2284761A (en) * 1993-12-03 1995-06-21 Euro Celtique Sa Prophylactic treatment of asthma
AR036797A1 (es) 2001-10-15 2004-10-06 Ferring Bv Un metodo para preparar una composicion farmaceutica que comprende acido 5-aminosalicilico para utilizar en el tratamiento de colitis ulcerosa y enfermedades de crohn
WO2004067006A1 (en) * 2003-01-27 2004-08-12 Pharmacia Corporation Combination of a pde iv inhibitor and a tnf-alpha antagonist
JP2007523664A (ja) 2003-04-23 2007-08-23 フェリング ベスローテン フェンノートシャップ 医薬組成物用サシェ
EP1547601A1 (en) * 2003-12-23 2005-06-29 Ferring B.V. Coating method
CN106913572B (zh) * 2017-04-06 2019-09-20 地奥集团成都药业股份有限公司 一种复方茶酮缓释片及其制备方法

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS51142543A (en) * 1975-05-20 1976-12-08 Sandoz Ag Improvement in organic compound

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS51142543A (en) * 1975-05-20 1976-12-08 Sandoz Ag Improvement in organic compound

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
Chemical Abstracts, vol. 101, no. 15, 8 October 1984, Columbus, Ohio (US) Bian, Rulian et al.: "Preliminary observation on the pharmacological effect of a new antiasthmatic agent, ketotifin", page 41, abstract 122799s; & Zhejiang Yike Daxue Xuebao 1982, 11 (5), 236-8, 260 (Ch) *
Chemical Abstracts, vol. 88, no. 5, 6 February 1978, Columbus, Ohio (US), page 252, abstract 41675j; & JP-A-51 142 543 (SANDOZ AG) 8 December 1976 *

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DK370085D0 (da) 1985-08-14
AU4617185A (en) 1986-02-20
BE903065A (fr) 1986-02-14
NL8502178A (nl) 1986-03-17
IL76089A0 (en) 1985-12-31
GR851988B (enrdf_load_stackoverflow) 1985-12-10
FR2569109A1 (fr) 1986-02-21
DE3528481A1 (de) 1986-02-27
PT80961A (en) 1985-09-01
SE8503771L (sv) 1986-02-17
GB8520189D0 (en) 1985-09-18
PT80961B (en) 1987-07-13
DK370085A (da) 1986-02-17
LU86044A1 (fr) 1986-02-18
IT1200102B (it) 1989-01-05
IT8548441A0 (it) 1985-08-02
HUT40568A (en) 1987-01-28
SE8503771D0 (sv) 1985-08-12
GB2163957A (en) 1986-03-12

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