EP0756486A1 - Compositions pharmaceutiques contenant un principe actif solide, destinees a l'inhalation - Google Patents

Compositions pharmaceutiques contenant un principe actif solide, destinees a l'inhalation

Info

Publication number
EP0756486A1
EP0756486A1 EP95913275A EP95913275A EP0756486A1 EP 0756486 A1 EP0756486 A1 EP 0756486A1 EP 95913275 A EP95913275 A EP 95913275A EP 95913275 A EP95913275 A EP 95913275A EP 0756486 A1 EP0756486 A1 EP 0756486A1
Authority
EP
European Patent Office
Prior art keywords
active ingredient
pharmaceutical preparation
salt
salts
sodium chloride
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP95913275A
Other languages
German (de)
English (en)
Inventor
Peter John-National Heart & Lung Institute WILLS
Peter John-National Heart & Lung Institute COLE
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
National Heart and Lung Institute
Original Assignee
National Heart and Lung Institute
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 National Heart and Lung Institute filed Critical National Heart and Lung Institute
Publication of EP0756486A1 publication Critical patent/EP0756486A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/42—Phosphorus; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/02—Ammonia; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/04—Sulfur, selenium or tellurium; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/14—Alkali metal chlorides; Alkaline earth metal chlorides

Definitions

  • compositions containing a solid active Ingredient comprising a solid active Ingredient.
  • the present invention relates to a pharmaceutical preparation for use in the treatment of disorders having mucus retention as a symptom.
  • the invention is particularly concerned with, but not limited to, mucus retention in the lungs and airways.
  • respiratory mucus retention is a prominent symptom.
  • respiratory mucus In health, respiratory mucus is cleared unnoticed by the ciliary escalator, but in chronic bronchitis, bronchiectasis, and other conditions this mechanism fails to cleanse the lungs adequately, mucus is retained and usually becomes infected.
  • a patient with mucus retention is generally troubled with a productive cough and has a tendency to infections in the lungs and respiratory tract, including pneumonia and other serious conditions.
  • Normal mucus is present as a microscopic layer which coats the membranes of the respiratory system and it is consequently extremely difficult to obtain samples of normal mucus for study without using very invasive techniques. It is generally recognised that a person having enough mucus for the collection of a sample of mucus to be possible, without the use of such invasive techniques, is not in good health. In most cases it is not known exactly why mucus in patients suffering from mucus retention fails to be cleared by ciliary action. The general assumption is that the mucus is in some undefined way too "sticky” or "thick", but because normal mucus cannot be examined that assumption is speculative.
  • DNase Pulmozyme
  • Genentech a recombinant form of a natural human enzyme that degrades DNA, DNA often being one of the components of sputum that has accumulated in infected lungs. This liquifies sputum, making it easier to cough it up.
  • Aerosolized hypertonic sodium chloride solution has been shown in one study (D. Pavia et al, American Review of Respiratory Disease Vol 117, 1978, pl99) to aid clearance of mucus from the lungs of chronic bronchitis sufferers. It is not known by what mechanism that effect occurs. Hypertonic saline, inhaled from an ultrasonic nebulizer, has also been used as a diagnostic aid to encourage the production of a sputum sample for laboratory examination in persons who do not normally expectorate (R.F. Miller et al, The Lancet, vol 335, pll2) Again, the mechanism of action has been a matter for speculation.
  • the present invention provides a pharmaceutical preparation which comprises a solid active ingredient and is in a form suitable for administration of the solid active ingredient by inhalation, characterised in that the solid active ingredient is (i) a physiologically tolerable zwitterionic salt or
  • the present invention also provides a pharmaceutical preparation which comprises a solid active ingredient and is in a form suitable for administration of the solid active ingredient by inhalation, characterised in that the solid active ingredient comprises sodium chloride and one or more other active substances, for example, selected from (i) physiologically tolerable zwitterionic salts, (ii) physiologically tolerable metal, ammonium, amine and organic salts of inorganic and organic acids, and (iii) pharmaceutically active substances.
  • the solid active ingredient comprises sodium chloride and one or more other active substances, for example, selected from (i) physiologically tolerable zwitterionic salts, (ii) physiologically tolerable metal, ammonium, amine and organic salts of inorganic and organic acids, and (iii) pharmaceutically active substances.
  • Salts that are effective in improving mucus transportability include salts that are fully ionised in solution, for example, alkali, alkaline earth metal and ammonium salts of inorganic acids, and also salts that are only partly ionised in solution, for example, salts of organic acids, for example, carboxylic acids.
  • Zwitterionic salts for example, amino acids, for example, glycine, are also effective. It appears, however, that non-ionizable materials, for example, glucose, are not effective.
  • a salt to be used in a pharmaceutical preparation of the invention should generally be water-soluble.
  • the chosen salts should be physiologically tolerable and it is preferable that any salt administered in solid form should, on dissolution in an aqueous solvent, give a solution having an approximately physiological pH.
  • Salts which may be used according to the present invention include but are not limited to (i) physiologically tolerable zwitterionic salts, for example, amino acids, for example, glycine and valine; (ii) physiologically tolerable metal, ammonium, amine and organic salts of inorganic and organic acids and mixtures of two or more salts as defined in (i) and (ii) above. If a salt comprises an organic component, as cation or anion, that component should generally have a low molecular weight such that it can diffuse readily into the mucus, for example, it should have a molecular weight of about 150 or less, for example, about 100 daltons or less. The amine component of an amine salt may be substituted, if desired.
  • An organic acid is especially a carboxylic acid, for example, having from 2 to 6 carbon atoms, and may be substituted. Examples are acetic, propionic and butyric acid.
  • a salt may be an alkali metal, alkaline earth metal or transition metal salt, for example, a sodium, potassium, calcium, magnesium or ammonium salt.
  • a salt may be a chloride, sulphate, nitrate, phosphate, carbonate or bicarbonate salt, or a salt of a carboxylic acid having from two to six carbon atoms.
  • the active ingredient in a pharmaceutical preparation of the invention may comprise a mixture of salts having (a) cationic components selected from sodium, potassium, calcium, magnesium and ammonium ions and (b) anionic components selected from chloride, nitrate, sulphate, carbonate and bicarbonate ions.
  • Such a preparation may also comprise one or more amino acids.
  • sodium chloride may be the sole active ingredient or may be one of the active ingredients in a mixture of salts. It may be preferable to ensure that sodium chloride is the major component in a mixture of salts.
  • a mixture of salts comprising ions found at the airway surface for example, salts comprising sodium, calcium, magnesium, chloride, nitrate, sulphate and carbonate ions, is used as the active ingredient.
  • the various ions are preferably used in the relative proportions as present at the airway surface.
  • a pharmaceutically active substance that may be incorporated in a pharmaceutical preparation of the present invention may be any substance useful in the treatment of any pathological condition of the lungs or airways, for example, an antibiotic or antiinflammatory agent.
  • Production of pharmaceutical preparations and medicaments suitable for administration by inhalation may be carried out by methods known in the art. For example by microcrystallisation methods, for example, freeze drying or spray drying, or by comminution, for example, using grinding, milling or ultrasonic techniques followed by sieving or other particle selection techniques known in the art.
  • the particles may be coated or their surface characteristics modified.
  • compositions and/or delivery methods deliver the solid in spheroidal particulate form as this reduces any irritation and damage caused by the particles.
  • Additives may be included, for example, agents to stop adhesion or clumping of particles. Methods which may be employed include those described in GB1242211 for producing powders.
  • Spray drying allows the formation of fine powders of spherically shaped particles with mean sizes appropriate for pulmonary delivery.
  • One advantage of spray drying is that it is a single stage process which can be completely controlled by a single operator. It is a well known process which has been used successfully in many industries, including the pharmaceutical industry.
  • Particle sizes should generally be in the micron range to ensure that they are able to travel deep into the lungs.
  • the solid will be in a particulate form having an aerodynamic mass median particle size of ⁇ 10 ⁇ m, more preferably ⁇ 5 ⁇ m and most preferably of about 3 ⁇ m or less. It is generally regarded that the ideal size for deposition of particles in the peripheral airways is 0.8 to 5 ⁇ m. Ad- vantageously, the median particle size will fall within this range. Appropriately at least 70% and preferably 85 or 90 % of the particles comprising the active substance will be in the desired size range. Minimum particle size is less of a problem.
  • Solid pharmaceutical preparations and medicaments for administration by inhalation may be administered by the use of dry powder inhalers, advantageously, breath activated dry powder inhalers since with these inhalers it is not necessary for the patient to synchronise activation of the inhaler and inhalation.
  • dry powder inhalers are known, for example, the Spinhaler (trade name) , a dry powder aerosol device, (Fisons) and the Rotahaler (trade name) , which uses gelatin capsules of powder, (Glaxo) .
  • Such devices generally incorporate means for controlling the unit dose dispensed.
  • Inhalers that are known include but are not limited to those described in EP-A-488609, EP-A-495675, O92/10229, O92/10230, DE 4027390, DE 4027391 and EP 407028.
  • a solid pharmaceutical preparation of the present invention may be provided in a form suitable for use with a known inhaler, for example, in the form of hard gelatin capsules or a compressed disc.
  • the formulation may comprises a propellant and be in the form of an aerosol.
  • the salt may be dispersed as a powder or as drops of a suspension of the solid.
  • the aerosol will usually comprise a liquid propellant gas having a boiling point of below room temperature, and if desired, carriers such as liquid or solid, non-ionic or anionic surface-active agents and/or diluents.
  • the appropriate dose and frequency of treatment will be dependent on the symptoms and physical condition of the individual patient. Doses which provide in the range of 10 to 100 milligrams entering the lungs may be preferred. It will be appreciated that the use of dry powder inhalers and aerosols will allow patients to administer their own doses of medicament quickly, frequently and without the need for troublesome equipment and procedures as are experienced with nebulizers.
  • the invention further provides the use of sodium chloride in the manufacture of a medicament for administration of the sodium chloride in a solid form, for the treatment and/or the prevention of mucus retention, especially in the lungs and airways.
  • the sodium chloride may be used in combination with one or more other active substances, for example, selected from (i) physiologically tolerable zwitterionic salts, (ii) physiologically tolerable metal, ammonium, amine and organic salts of inorganic and organic acids, and (iii) pharmaceutically active substances.
  • active substances for example, selected from (i) physiologically tolerable zwitterionic salts, (ii) physiologically tolerable metal, ammonium, amine and organic salts of inorganic and organic acids, and (iii) pharmaceutically active substances.
  • the salts and mixtures thereof and other active substances are preferably as described above. In a mixture, it is generally preferred that sodium chloride is the major component.
  • a medicament is, for example, a pharmaceutical preparation as described above.
  • solid sodium chloride described above is generally for the treatment and/or prevention of mucus retention in the lungs and airways and in that case the medicament should be suitable for administration of the solid sodium chloride by inhalation.
  • the present invention also provides a pharmaceutical preparation which comprises an active ingredient in a form suitable for administration of the active ingredient by inhalation, characterised in that the active ingredient is (i) a physiologically tolerable zwitterionic salt or (ii) a physiologically tolerable metal, ammonium, amine or organic salt of an inorganic or organic acid or (iii) a mixture or two or more salts as defined in (i) and (ii) above, with the proviso that the active ingredient is not sodium chloride alone.
  • the active ingredient is (i) a physiologically tolerable zwitterionic salt or (ii) a physiologically tolerable metal, ammonium, amine or organic salt of an inorganic or organic acid or (iii) a mixture or two or more salts as defined in (i) and (ii) above, with the proviso that the active ingredient is not sodium chloride alone.
  • the present invention further provides a pharmaceutical preparation which comprises an active ingredient and is in a form suitable for administration of the active ingredient by inhalation, characterised in that the active ingredient comprises sodium chloride and one or more other active substances.
  • the other active substances are, for example, selected from (i) physiologically tolerable zwitterionic salts, (ii) physiologically tolerable metal, ammonium, amine and organic salts of inorganic and organic acids, and (iii) pharmaceutically active substances.
  • the present invention also provides the use of (i) a physiologically tolerable zwitterionic salt or (ii) a physiologically tolerable metal, ammonium, amine or organic salt of an inorganic or organic acid (with the exception of sodium chloride alone) , or (iii) a mixture or two or more salts as defined in (i) and (ii) above, in the manufacture of a medicament for the treatment and/or prevention of mucus retention.
  • the present invention further provides the use of sodium chloride and one or more other active substance in the manufacture of a medicament for the treatment and/or prevention of mucus retention.
  • the salts and other active substances to be used are generally as described for the pharmaceutical preparations of the present invention described above.
  • mixtures of salts, sodium chloride in admixture with other components, and individual salts other than sodium chloride alone may be presented for inhalation other than in solid form, for example, in the form of a solution or liquid suspension, for example, in a form suitable for administration by an atomizer or a nebulizer.
  • Such active ingredients may also be presented for inhalation in the form of an aerosol.
  • the aerosol may disperse the salt or mixture of salts in the form of drops of a solution or a suspension, including a liquid/liquid suspension.
  • Preparations in which the active ingredient is in solution may, if necessary, contain an additional solvent and/or a stabilizer.
  • Compressed air produced as required by means of a suitable compression and release device, may be used as the propellant.
  • the solution is preferably a strong solution, preferably having total salt concentration of at least 600 milliosmoles/litre.
  • the liquid is preferably of physiological pH, and may be buffered to maintain a physiological pH if necessary.
  • Suitable buffers include phosphates. The use of a buffer enables salts to be used that do not themselves give rise to solutions having a physiological pH i.e. the range of salts for use in liquid preparations is greater than that for solid preparations.
  • the present invention also provides a method for the treatment and/or prevention of mucus retention, which comprises administering, particularly by inhalation, a therapeutically effective dose of (i) a physiologically tolerable zwitterionic salt or (ii) a physiologically tolerable metal, ammonium, amine or organic salt of an inorganic or organic acid or (iii) a mixture or two or more salts as defined in (i) and (ii) above.
  • the method of the present invention includes the administration of sodium chloride in solid form only.
  • a solid preparation or a liquid preparation may be administered.
  • the various salts are preferably in the form of a pharmaceutical preparation of the invention.
  • Diseases in which mucus retention occurs include bronchitis, cystic fibrosis, asthma, bronchiectasis and sinusitis all of which may be treated with medicaments and pharmaceutical preparations according to the present invention.
  • the medicaments, pharmaceutical preparations, methods and uses according to the present invention are primarily concerned with the treatment and/or prevention of mucus retention in the lungs and airways it may also be possible to treat or prevent mucus retention in other locations, especially mucus retention on other ciliated epithelia, occurring in diseases such as cystic fibrosis with similar preparations. Such use is therefore part of the present invention.
  • the present invention may be used in the treatment of pre-existing mucus retention and it may also be used prophylactically to prevent mucus retention.
  • Prophylaxis is particularly useful for cystic fibrosis, which can be diagnosed at an early stage when the lungs are apparently normal and before clinical symptoms of bronchiectasis occur.
  • Prophylactic treatment according to the present invention should retard the development and the severity of bronchiectasis.
  • the present invention is in the field of human medicine, it may also be desirable to treat other mammals for mucus retention and the present invention therefore also includes uses of the described medicaments and preparations for the treatment of mammals other than humans and further includes preparations and medicaments as described above that are suitable for the treatment of non-human mammals.
  • the present invention also includes the use of a physiologically tolerable substance that on dissolution in an aqueous solvent is fully or partially ionized, or a mixture of two or more such substances, in the manufacture of a medicament for the treatment and/or the prevention of mucus retention.
  • the invention is particularly concerned with uses wherein the mucus retention affects the lungs and airways and the medicament is in a form suitable for administration by inhalation, and especially wherein the substance or mixture of substances is in solid form and the medicament is in a form suitable for administration of the substance or mixture of substances in solid form by inhalation.
  • the substances used are preferably those that, on dissolution in an aqueous solvent, give a solution having a substantially physiological pH.
  • the substance used or at least one of the substances used is preferably a salt.
  • the invention also includes the use of the salts described above (with the exception of sodium chloride alone) in the manufacture of other medicaments for the treatment and/or prophylaxis of mucus retention, for example, medicaments comprising the salts in solution or suspension for administration by inhalation.
  • medicaments comprising the salts in solution or suspension for administration by inhalation.
  • the following non-limiting Examples illustrate the invention.
  • the Examples relate to experiments carried out in vitro7 the teachings are directly applicable in vivo for example, to the treatment of humans and other animals, for example, as described in the specification.
  • Sputum samples were taken from patients and were then frozen and stored at -20 ⁇ C. When required the samples were thawed and either used in that form immediately or were incubated as described below or where mixed with test solutions. If mixed with a test solution then the sputum mixture was incubated.
  • the transportability of the sputum samples was measured by placing a portion of each sputum near the distal end of the tracheal explant and measuring the rate at which it moved proximally using a measuring-rod (ruler) and a watch.
  • the control used was bovine tracheal mucus which had accumulated at the proximal cut end of the trachea during the process of mucus depletion.
  • the control mucus was equilibrated in 300 milliosmolar phosphate buffered saline before use.
  • the transportability index of a sputum sample is its transport rate expressed as a percentage of that of bovine tracheal mucus.
  • each sample was divided into two aliquots of approximately 1ml. One aliquot was weighed and sodium chloride crystals were added to increase the sodium chloride concentration by 0.6% w/w. The samples were incubated overnight at 4° C, which allowed full diffusion of the added salt. The transportability of each sample was measured on bovine trachea.
  • G 4 61 H 9 35 mean 14 61
  • Example 2 Effect on transportability of incubating sputum with various mineral salts and glucose
  • Diammonium hydrogen phosphate 54 Dipotassium hydrogen phosphate 62
  • Example 4 Sputum from 11 patients with chronic bronchitis was collected and frozen. The samples were prepared following the method described in Example 1 and and were tested in salinated (solid sodium chloride) and untreated form as described in Example 1.
  • Sputum from 11 patients with cystic fibrosis was collected and frozen.
  • the samples were prepared following the method described in Example 1 and and were tested in salinated (solid sodium chloride) and untreated form as described in Example 1.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Inorganic Chemistry (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)
  • Medicinal Preparation (AREA)

Abstract

Préparations pharmaceutiques sous une forme appropriée à l'inhalation, comprenant un principe actif, généralement un solide, choisi parmi: (i) un sel zwittérionique tolérable sur le plan physiologique, ou (ii) un sel de métal, d'ammonium, d'amine ou un sel organique d'un acide inorganique ou organique, ou (iii) un mélange d'au moins deux sels choisis parmi (i) et (ii). On décrit également l'utilisation de ces principes actifs, notamment le chlorure de sodium, dans la fabrication de médicaments et dans des méthodes de traitement et/ou de prévention de la rétention du mucus.
EP95913275A 1994-04-22 1995-03-30 Compositions pharmaceutiques contenant un principe actif solide, destinees a l'inhalation Withdrawn EP0756486A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GB9408053 1994-04-22
GB9408053A GB9408053D0 (en) 1994-04-22 1994-04-22 Pharmaceutical preparation
PCT/GB1995/000743 WO1995028944A1 (fr) 1994-04-22 1995-03-30 Compositions pharmaceutiques contenant un principe actif solide, destinees a l'inhalation

Publications (1)

Publication Number Publication Date
EP0756486A1 true EP0756486A1 (fr) 1997-02-05

Family

ID=10753989

Family Applications (1)

Application Number Title Priority Date Filing Date
EP95913275A Withdrawn EP0756486A1 (fr) 1994-04-22 1995-03-30 Compositions pharmaceutiques contenant un principe actif solide, destinees a l'inhalation

Country Status (4)

Country Link
EP (1) EP0756486A1 (fr)
AU (1) AU2080695A (fr)
GB (1) GB9408053D0 (fr)
WO (1) WO1995028944A1 (fr)

Families Citing this family (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AUPM411494A0 (en) * 1994-02-25 1994-03-24 Central Sydney Area Health Service Method and device for the provocation of upper or lower airway narrowing and/or the induction of sputum
US5747002A (en) * 1995-04-05 1998-05-05 Genentech, Inc. Preparation of sodium chloride aerosol formulations
US6339075B1 (en) 1997-06-30 2002-01-15 The University Of British Columbia Use of dextran and other polysaccharides to improve mucus clearance
US20060165606A1 (en) 1997-09-29 2006-07-27 Nektar Therapeutics Pulmonary delivery particles comprising water insoluble or crystalline active agents
WO2001062264A2 (fr) * 2000-02-23 2001-08-30 The Procter & Gamble Company Procede d'halotherapie
US7871598B1 (en) 2000-05-10 2011-01-18 Novartis Ag Stable metal ion-lipid powdered pharmaceutical compositions for drug delivery and methods of use
CA2468958C (fr) 2001-12-19 2012-07-03 Nektar Therapeutics Administration pulmonaire d'aminoglycosides
WO2007101068A2 (fr) * 2006-02-22 2007-09-07 Puricore, Inc. Procédés de traitement de la mucoviscidose
MD4039C1 (ro) * 2009-11-05 2010-12-31 Институт Химии Академии Наук Молдовы Microsalină artificială de suprafaţă
MD4089C1 (ro) * 2009-11-18 2011-08-31 Институт Химии Академии Наук Молдовы Halocameră artificială de suprafaţă
MD4040C1 (ro) * 2009-12-09 2010-12-31 Институт Химии Академии Наук Молдовы Halocameră artificială de suprafaţă

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE4140689B4 (de) * 1991-12-10 2007-11-22 Boehringer Ingelheim Kg Inhalationspulver und Verfahren zu ihrer Herstellung
GB9208584D0 (en) * 1992-04-21 1992-06-03 Albasri Samir A I Effective & safe treatment to nausea and vomiting

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9528944A1 *

Also Published As

Publication number Publication date
AU2080695A (en) 1995-11-16
WO1995028944A1 (fr) 1995-11-02
GB9408053D0 (en) 1994-06-15

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