WO1998051300A1 - Traitement d'etats allergiques - Google Patents

Traitement d'etats allergiques Download PDF

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Publication number
WO1998051300A1
WO1998051300A1 PCT/GB1998/001353 GB9801353W WO9851300A1 WO 1998051300 A1 WO1998051300 A1 WO 1998051300A1 GB 9801353 W GB9801353 W GB 9801353W WO 9851300 A1 WO9851300 A1 WO 9851300A1
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WO
WIPO (PCT)
Prior art keywords
microgranules
composition according
patient
chromone
coating
Prior art date
Application number
PCT/GB1998/001353
Other languages
English (en)
Inventor
Alexander James Wigmore
Original Assignee
Hewlett Healthcare Limited
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 Hewlett Healthcare Limited filed Critical Hewlett Healthcare Limited
Priority to AU73462/98A priority Critical patent/AU7346298A/en
Publication of WO1998051300A1 publication Critical patent/WO1998051300A1/fr

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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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1658—Proteins, e.g. albumin, gelatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose

Definitions

  • the present invention relates to the treatment of allergic conditions, in particular allergic conditions which relate to the nature of the food or drink consumed by the patient.
  • Allergy to ingested substances can manifest itself in a wide range of symptoms affecting any organ in the body. Commonly it affects particularly the gastrointestinal tract, the skin, the lung, the nose and the central nervous system. Allergic reactions to ingested substances affecting these organs can manifest themselves as abdominal pain, abdominal bloating, disturbance of bowel function, vomiting, rashes, skin irritation, wheezing and shortness of breath, nasal running and nasal blockage, headache and behavioural changes.
  • the cardiovascular and respiratory systems can be compromised giving anaphylactic shock and in some cases death.
  • chromones such as sodium cromoglycate are effective in treating these various allergic conditions providing that they are formulated in a particular manner and/or provided that the patient is first selected according to a specific criterion.
  • a first aspect of the invention provides an oral drug delivery composition
  • a chromone characterised in that the chromone is made bioavailable in the small intestine following human oral administration.
  • a composition wherein the composition comprises microgranules of up to 1.5 mm diameter, each microgranule having an enteric coating.
  • the chromone is preferably sodium cromoglycate or nedocromil sodium. References to sodium cromoglycate hereafter refer to the class of chromones as well as to the individual compound.
  • the current "Nalcrom" formulation of sodium cromoglycate consists of a powder which is either taken by the patient as a solution (ie after dissolving the powder in water) or presented in a gelatin capsule which dissolves in the stomach.
  • the various Fisons patent specifications concerning sodium cromoglycate list a vast number of theoretical formulations of the drug, practically none of which have been put into effect.
  • GB 1 423 985 discloses an enteric coated composition intended to make the drug available "at an appropriate part of the gastro-intestinal tract" (unspecified)
  • GB 1 549 229 discloses a gelatin capsule containing granules of the drug, for oral use in the treatment of allergic conditions.
  • the previously proposed gelatin capsules of sodium cromoglycate are, we believe, of low bioavailability because the sodium salt of the drug is converted in the acidic conditions of the stomach into insoluble and inactive cromoglycic acid. Although, in the alkaline medium of the duodenum, the cromoglycic acid will convert back to a salt, this is unlikely to be the sodium salt and is more likely to be an insoluble and inactive salt such as a calcium salt.
  • the enteric-coated formulations which have been proposed previously, at least on paper, similarly may be of low bioavailability because the sodium cromoglycate is released into the duodenum in a lump, rather than being dispersed evenly throughout the food material passing through the small intestine. We consider it to be desirable for the drug to be applied evenly and consistently across the whole surface area of the mucosa in the small intestine prior to and at the same time as the intestine is exposed to the food which is causing the allergy.
  • a second aspect of the invention is a composition as in the first aspect of the invention, wherein the composition comprises microgranules of up to 1.5 mm diameter which are packaged in a hard or soft capsule, which capsule has an enteric coating.
  • microgranules may be produced as described in Example 1 and put into a gelatin capsule (for example, a capsule which consists essentially of gelatin) which is then enteric coated, for example as described below.
  • a gelatin capsule for example, a capsule which consists essentially of gelatin
  • Suitable capsules are well known to those skilled in the art.
  • the capsules should not be such that they may pass through the small intestine or even the whole gastrointestinal tract substantially intact.
  • the capsules may be such that if they were used without the enteric coating they may release their contents in the stomach.
  • the capsules and enteric coating are chosen such that maximum disintegration of the coated capsules occurs within the small intestine (duodenum, jejunum, ileum).
  • drug is made bioavailable from the duodenum onwards.
  • Suitable coatings which may be used in the capsules of the invention are discussed below. It will be appreciated that the microgranules may, but do not necessarily, each have an enteric coating. It is preferred in this embodiment that each microgranule does not have an enteric coating.
  • the microgranules in the formulation of the present invention have a size of 25-250 ⁇ m, 25 to 500 ⁇ m or 200 to HOO ⁇ m. Microgranules at the smaller end of these ranges (about 25 to 250 ⁇ m) may be classed as granules, whereas microgranules at the larger end of the ranges (for example, about 200 to 1100 ⁇ m) may be referred to as pellets (which may be melt or wet-formed, as described below).
  • a drug can be made "bioavailable", for example, either as a result of the coating disintegrating or as a result of the coating becoming porous.
  • at least 25 % , 50% , 75 % or 90% of the drug in the formulation has been taken up by the gut wall before the formulation reaches the large intestine, hence within the approximately 3 to 5 hours after the formulation has left the stomach.
  • the composition is such as to prevent release of the sodium cromoglycate from said microgranule/pellet in gastric fluids, but to permit release of the sodium cromoglycate from said microgranule/pellet in intestinal fluids at a rate allowing treatment of the part of the small intestine, ie at a rate corresponding to a release time of 10 minutes to 10 hours or 1 to 10 hours, preferably 10 minutes to 5 hours or 1 to 5 hours, said rate being measured in vitro as a dissolution rate of said unit in simulated gastric and intestinal fluids, when measured in a flow through cell (eg Sotax Dissotest CE6, equipped with 12 mm cells) at 8 ml/min and 37°C.
  • a flow through cell eg Sotax Dissotest CE6, equipped with 12 mm cells
  • At least 90% , preferably 100% of the total sodium cromoglycate is released within two hours in simulated intestinal fluid (eg USP, pH 7.5, without enzymes) in said assembly.
  • simulated intestinal fluid eg USP, pH 7.5, without enzymes
  • This may be pH triggered release, not matrix release.
  • Two particular ways in which the drug can be made bioavailable at differing times, and therefore differing locations of the small intestine as the contents pass through the intestine, are to coat the microgranules/pellets with differing thicknesses of the same enteric coating or to use differing enteric coating materials which dissolve at differing pH's. This may provide a non-pareil formulation. Both formulations take advantage of the fact that the pH of the contents of the intestine gradually rises as the contents pass from the stomach into and through the small intestine. Suitable enteric coatings are known in the art and are discussed in more detail below.
  • microgranules/pellets may be taken orally as a suspension in a liquid (for example reconstituted as a suspension in a liquid at the time of use), preferably with food, or they may be packaged in capsules, for example of gelatin, which make the preparation easy to swallow but which disintegrate in the stomach, thus helping to mix the microgranules/pellets evenly with food.
  • a liquid for example reconstituted as a suspension in a liquid at the time of use
  • capsules for example of gelatin, which make the preparation easy to swallow but which disintegrate in the stomach, thus helping to mix the microgranules/pellets evenly with food.
  • a second aspect of the invention provides a method of treating a patient for an allergic condition by orally administering sodium cromoglycate, characterised in that the patient has first been tested for serum IgE level and has been found to have a total level of at least 150 iu/ml.
  • Suitable IgE tests include an in vitro total IgE test and an in vitro specific IgE test, for example the UniCAP Total (or Specific) IgE tests sold by Pharmacia & Upjohn, which use the Allergen ImmunoCAPs as the allergen reagent.
  • IgE tests include an in vitro total IgE test and an in vitro specific IgE test, for example the UniCAP Total (or Specific) IgE tests sold by Pharmacia & Upjohn, which use the Allergen ImmunoCAPs as the allergen reagent.
  • a patient is selected for therapy according to whether their total serum IgE level is above 150 iu/ml. They may be tested immediately before therapy, or reference may be made to earlier test results.
  • the pathophysiology of food allergy and food allergic disease is unknown but we consider that the primary defect in a number of patients is an allergic inflammatory reaction in the mucosa of small intestine caused by a reaction between specific substances in the food and specific IgE antibodies to that food produced by the patient. This allergic inflammatory reaction may cause symptoms itself but commonly does not. We consider that it results in an alteration in gut permeability allowing increased absorption of a number of substances, including those substances to which the patient is allergic.
  • the primary mode of action of orally administered sodium cromoglycate in the treatment of food allergy is to reduce the severity of the IgE-mediated allergic inflammatory reaction in the mucosa of the small intestine and therefore prevent the increased absorption of allergic substances.
  • the severity of the allergic reaction in the secondary target organs is related to the amount of allergen reaching the organ, this effect of the drug will be to reduce the severity of the allergic reaction in the secondary target organ.
  • the present invention therefore provides a long-term treatment with oral sodium cromoglycate, based not only on its ability to reduce the consequences of the acute antigen/IgE antibody reaction but also the overall sensitivity by reducing the local synthesis of IgE antibody. This will initially be seen in the reduction in locally measured IgE antibody and ultimately in the amount of IgE antibody measured systemically, that is in the blood as Total Serum IgE.
  • the basis of an aspect of this invention is that the efficacy of oral sodium cromoglycate in the treatment of food allergic conditions will be increased by selecting patients who have clear evidence of an IgE mediated disease and whose clinical response is associated with a reduction in imtially local and subsequently systemic levels of IgE antibody and secondly by increasing the bioavailability of the drug with a formulation that maximises the concentration of the drug in the secretions of the small intestine.
  • microgranules/pellets used in the formulation of the present invention may be made by known techniques. Hence, they can be prepared by coating non-pareil seeds with the sodium cromoglycate or by forming a core comprising sodium cromoglycate dispersed therein. Suitable binding agents which may be used in forming such a core are known in the art.
  • the excipients used to prepare the seeds may comprise one or more of pharmaceutically acceptable materials, eg sugar, starch, microcrystalline cellulose, waxes and polymeric binding agents, such as those listed below.
  • the first layer on the non-pareil seeds may comprise the sodium cromoglycate and a water-soluble or water-insoluble polymer which acts both as binder for the sodium cromoglycate and as a rate-limiting layer for release of the sodium cromoglycate.
  • Such polymers may be selected from cellulose derivatives, vinyl polymers and other high molecular polymer derivatives or synthetic polymers such as methylcellulose, hydroxypropylcellulose , hydroxypropylmethylcellulose , ethylcellulose , cellulose acetate, polyvinyl pyrrolidone, polyvidone acetate, polyvinyl acetate, acrylic polymers and copolymers, polymethacrylates and ethylene-vinyl acetate copolymer or a combination thereof.
  • Preferred film-forming polymers are ethylcellulose or copolymers of acrylic and methacrylic acid esters (Eudragit NE, Eudragit RL, Eudragit RS) in aqueous dispersion form
  • the optionally first rate-limiting layer on the seeds with homogeneously distributed sodium cromoglycate may comprise a water insoluble polymer or a mixture of water insoluble polymers or a mixture of water soluble and water insoluble polymers mentioned above.
  • the polymers used to coat the core (for example in the absence of a first layer as described above) or used in a second layer may be selected from the group of anionic carboxylic polymers suitable for pharmaceutical purposes and being soluble only with difficulty at a low pH but being soluble at a higher pH, the pH limit for solubility being in the interval of pH 4 to pH 7.5, said group comprising cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropylmethylcellulose phthalate, polyvinyl acetate phthalate and acrylic acid polymers eg partly esterified methacrylic acid polymers such as Eudragit L, Eudragit L100-55 and
  • Eudragit S These polymers may be used alone or in combination with each other or in combination with water insoluble polymers mentioned before. Preferred polymers are the Eudragits in aqueous dispersion form.
  • the anionic carboxylic polymer may comprise 25 to 100% of the total polymer content.
  • the coatings may optionally comprise other pharmaceutically acceptable materials which improve the properties of the film-forming polymers such as plasticizers, anti-adhesives, surfactants, and diffusion- accelerating or diffusion-retarding substances.
  • plasticizers comprise phthalic acid esters, triacetin, dibutylsebacate, monoglycerides, citric acid esters and polyethyleneglycols.
  • Preferred plasticizers are acetyltributyl citrate and triethyl citrate.
  • Suitable antiadhesives comprise talc and metal stearates.
  • the amount of the first coating applied on the units is normally in the range between 0.5% and 30% by weight, preferably between 1 % and 15% . This amount includes in the relevant case the weight of the sodium cromoglycate as well.
  • the amount of the second coating applied on the units is normally in the range between 1 % and 50% by weight, preferably between 2% and 25% , calculated on the weight of the coated units.
  • the amount of coating (which may be one or two coatings) applied on the units may be in the range between 1 and 50% or 5 % and 60% by weight, preferably between 5% and 50% or 2% to 25% , calculated on the weight of the coated units. The remainder constitutes the weight of the seed or core.
  • the above percentages refer to the coating as a percentage of the final weight of the units after coating.
  • the amount of the coating may be in the range between 5 and 120% , preferably between 5 and 100% , more preferably between 5 and 50% by weight of the weight of the seed or core or active ingredient.
  • sodium cromoglycate powder (in which 90% of the particles may have a diameter of less than 30 ⁇ m) is spray granulated in a fluid bed dryer in combination with water and HPMC to agglomerate the particles into larger particles, which may be cores for coating.
  • the latter are then enteric coated in a fluid bed coater and can then be filled into capsules, compressed into tablets or filled into unit- dose sachets, the contents of which may be suspended in a liquid at a suitable pH immediately prior to use and drunk by the patient.
  • the sodium cromoglycate can be mixed with a melt binder such as polyethylene glycol, heated to its melting point in a high shear mixer and cooled. This produces rather larger particles of about 200 ⁇ m, or 200 to 1100 ⁇ m, which are then enteric coated, or packaged and then enteric coated, and presented as the desired oral dosage form as above.
  • the sodium cromoglycate may be mixed and granulated with an aqueous binder system in a high shear mixer to produce substantially spherical granules and then dried in a fluid bed drier.
  • larger particles of between 200 and 1100 ⁇ m may be produced and then either packaged and enteric coated, or enteric coated.
  • composition of the coating should be optimised to maximise disintegration of the coating within the small intestine (duodenum, jejunum, ileum) and to minimise the possibility of the coated microgranules/pellets passing through the small intestine, or even the whole gastrointestinal tract, intact.
  • drug is made bioavailable from the duodenum onwards.
  • any coating can be used which ensures that the microgranules or capsules do not break up and release the drug until they are in the small intestine.
  • the coating may be one which is pH-sensitive, redox-sensitive or sensitive to particular enzymes or bacteria, such that the coating only dissolves or finishes dissolving in the small intestine. Thus, the microgranules or capsules will not release the drug until they are in the small intestine.
  • the amount of the coating will typically be in the range of 4-20% w/w on dry granules, or 5 to 120% w/w of the weight of the dry granules before the coating is applied.
  • the amount of the particular coating used will be chosen according to the mechanism by which the coating is dissolved. Suitable amounts of coating for a capsule are well known to those skilled in the art.
  • Preferred coating materials are those which dissolve at a pH of 5 or above, for example pH 5.5 to 7.5, such as polyacids having a pK a of 3 to 5. The coatings therefore only begin to dissolve when they have left the stomach and entered the small intestine.
  • a coating can be made from a variety of polymers such as cellulose acetate trimellitate (CAT), hydroxypropylmethyl cellulose phthalate (HPMCP), polyvinyl acetate phthalate (PNAP), cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), carboxymethyl ethylcellulose (CMEC) and shellac as described by Healy in his article
  • PVAP is preferred to CAP or
  • Eudragits L, S, "L and S” and LD are anionic copolymers of methacrylic acid and methylmethacrylate and are generally suitable.
  • Eudragit L100 50% free carboxyl groups
  • S100 (30% free carboxy groups) may be used.
  • Eudragit L100-55 is especially suitable and is obtained from L30 D-55 by spray-drying. It has equal amounts of methacrylic acid and ethyl acrylate and about 50% free carboxyl groups.
  • microgranules can also be given a sustained or controlled release property, for example with waxes or silicone elastomers, especially by using melt granulation techniques.
  • a chelator of heavy metal ions such as EDTA
  • the chelating agent should be included in the microgranules but, alternatively, it can be mixed with the microgranules.
  • Suitable dosage regimes include the following.
  • An initial daily dose of 1 mg to 2 g, preferably 100-1000 mg, more preferably about 200-800 mg, still more preferably about 300 to 500 mg is given in, for example, two divided doses spaced 12 hours apart. This may be increased at intervals of, say, 1-3 weeks, to a maximum of 1000-5000 mg daily.
  • a typical maximum daily dose is 4000 mg or 100 mg/kg/day (whichever is the greater).
  • Formulation A2 (for a larger and stronger granule)
  • Formulation B %. for 1000 g of granule
  • Formulation Al , A2 or A3 is sprayed through a two fluid nozzle placed above the fluidised bed, using atomizing air at approx 2 bar, to produce granules.
  • the rate used is approx 27 g/min and therefore the time taken to spray 1167 g of solution is approx 44 minutes.
  • Sodium Cromoglycate for example 100 or 200 mg per capsule, is weighed into hard gelatin capsules, and the capsules sealed and enteric coated in a fluidised spray coater or rotary coating pan.
  • the atomizing air pressure is approx 3 bar.
  • the bed of granules is preheated to a temperature of approx 36 °C (inlet air temperature of 60 °C used) before spraying commences.
  • the coating solution (Formulation B) is sprayed onto the granules at an approx rate of 18 g/min using atomizing air pressure of approx 3 bar and therefore the time taken to spray 1065 g of solution is approx 60 mins (1 hour).
  • the temperature of the granules gradually drops and by the end has reached approx 25 °C.
  • the bed is allowed to heat up to approx 40 °C before stopping the process to allow the coat to dry. Total process time including drying is approx IV2 hours (90 mins). In nearly all cases/batches produced to date the yields have been very good at 100% .
  • coated granules are filled into capsules for the final dosage form.
  • An alternative method involves the use of high shear mixer technology using a melt granulation technique.
  • Stage one - this process involves mixing SCG with a melt binder such as PEG under ambient conditions.
  • the mixture is then heated to the melt point of the binder (approx 60 °C) in a high shear mixer and mixed intensely to produce a round particle of approximate size 200 to 500 ⁇ m, and then cooled.
  • Stage two - these particles are then enteric-coated in a fluid bed spray coater (obtainable from Aeromatic-Fielder Ltd, Hampshire, UK) with AQOAT (Shin-Etsu) or one of the other commercially available coatings such as a CAP (FMC), CAT (Eastman Kodak), PVAP (Colorcon), or a Eudragit (Rohm Pharma).
  • a fluid bed spray coater obtainable from Aeromatic-Fielder Ltd, Hampshire, UK
  • AQOAT Shin-Etsu
  • one of the other commercially available coatings such as a CAP (FMC), CAT (Eastman Kodak), PVAP (Colorcon), or a Eudragit (Rohm Pharma).
  • Stage three - these coated particles may then be used to produce a variety of oral dosage forms such as capsules to be swallowed, or tablets to be swallowed, or filled into unit-dose sachets the contents of which may be suspended in a liquid of suitable pH immediately prior to use and drunk, or partially filled into bottles to which a suitable diluent is added, by the pharmacist immediately prior to it being dispensed, and drank.
  • oral dosage forms such as capsules to be swallowed, or tablets to be swallowed, or filled into unit-dose sachets the contents of which may be suspended in a liquid of suitable pH immediately prior to use and drunk, or partially filled into bottles to which a suitable diluent is added, by the pharmacist immediately prior to it being dispensed, and drank.
  • Patients with symptoms of food allergy or chronic disease such as irritable bowel syndrome, rhinitis, asthma, conjunctivitis, atopic dermatitis, urticaria, migraine, eczema or hyperactivity in which allergy to foods has been shown to be a causative factor are investigated for total serum IgE levels by the Pharmacia & Upjohn UniCAP Total IgE Test, and preferably also investigated for sensitivity to food or drink by the Pharmacia & Upjohn UniCAP Specific IgE Test and/or skin prick tests to ingested allergens. If total serum IgE levels are above 150 iu/ml or if a skin prick test or UniCAP Specific IgE test is positive the patient should be considered for treatment with the formulation of the invention.
  • Patients may initially experience a worsening of symptoms. This is a positive sign that the medication is having an effect. In these patients the dosage should be reduced to half for 1 week before being increased again.
  • an anticholinergic drug such as dicyclomine hydrochloride or propantheline bromide may be administered concurrently for the first week.
  • Serum IgE measurements should continue to be taken at monthly intervals for 6 months, 3 monthly for a further 6 months and 6 monthly thereafter.
  • a maintained reduction in levels will indicate a reduction in sensitivity to the ingested allergens and symptomatic improvement in the condition. It is important that patients continue to take their medication even though their symptoms are absent or significantly improved. If they do not, their IgE levels will begin to increase again and when they start the medication again it will take time for the IgE levels and therefore the symptoms to subside - but patients will not wait and will conclude that the medication is ineffective.

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Abstract

Selon cette invention, il a été découvert que le cromoglycate de sodium administré par la voie orale était efficace dans le traitement d'états allergiques tels que l'asthme, des allergies alimentaires générales, la recto-colite hémorragique, l'eczéma atopique, l'urticaire chronique et le syndrome du côlon irritable et ce, s'il est présenté sous forme de microgranules à délitement entérique individuel ou de microgranules enrobées d'une capsule à délitement entérique et/ou si les patients sont sélectionnés sur la base d'un taux de IgE total sérique d'au minimum 150 iu/ml.
PCT/GB1998/001353 1997-05-10 1998-05-11 Traitement d'etats allergiques WO1998051300A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU73462/98A AU7346298A (en) 1997-05-10 1998-05-11 Treatment of allergic conditions

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9709451.0 1997-05-10
GBGB9709451.0A GB9709451D0 (en) 1997-05-10 1997-05-10 Treatment of allergic conditions

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Publication Number Publication Date
WO1998051300A1 true WO1998051300A1 (fr) 1998-11-19

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GB (1) GB9709451D0 (fr)
WO (1) WO1998051300A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000027392A1 (fr) * 1998-11-11 2000-05-18 Hewlett Healthcare Limited Formulation entero-soluble de chromones

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1423985A (en) * 1972-02-15 1976-02-04 Fisons Ltd Pharmaceutical compositions containing bischromonyloxy compounds
GB1549229A (en) * 1976-09-23 1979-08-01 Fisons Ltd High density sodium cromoglycate
GB1569612A (en) * 1977-01-13 1980-06-18 Fisons Ltd Disodium cromoglycate pellets or granules
WO1985000015A1 (fr) * 1983-06-15 1985-01-03 Pharmacia Ab Preparation orale contenant de l'allergene et procede d'immunotherapie intestinale

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1423985A (en) * 1972-02-15 1976-02-04 Fisons Ltd Pharmaceutical compositions containing bischromonyloxy compounds
GB1549229A (en) * 1976-09-23 1979-08-01 Fisons Ltd High density sodium cromoglycate
GB1569612A (en) * 1977-01-13 1980-06-18 Fisons Ltd Disodium cromoglycate pellets or granules
WO1985000015A1 (fr) * 1983-06-15 1985-01-03 Pharmacia Ab Preparation orale contenant de l'allergene et procede d'immunotherapie intestinale

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000027392A1 (fr) * 1998-11-11 2000-05-18 Hewlett Healthcare Limited Formulation entero-soluble de chromones
US7258872B1 (en) 1998-11-11 2007-08-21 Thornton & Ross Limited Chromone enteric release formulation

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Publication number Publication date
AU7346298A (en) 1998-12-08
GB9709451D0 (en) 1997-07-02

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