(cid:38)(cid:68)(cid:83)(cid:86)(cid:88)(cid:74)(cid:72)(cid:79)(cid:3)(cid:40)(cid:91)(cid:75)(cid:76)(cid:69)(cid:76)(cid:87)(cid:3)(cid:20)(cid:19)(cid:20)(cid:23)
`
`Page 1 of 24
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`Page 1 of 24
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`
`Formulated Ereparation and its use
`
`TITL 'o13o163
`
`se-
`
`The present invention is concerned with a novel formu-
`
`lated preparation containing an immunotherapeutically
`
`active amount of at least one allergen. The invention
`
`comprises also a method of treating allergic conditions
`
`by oral administration of the formulated preparation.
`
`Allergic disorders may arise when the body is exposed
`
`to foreign substances, for instance due to inhaling of
`
`such substances or due to their contacting the skin or
`
`'
`
`mucous membranes, or due to their reaching the body via
`the food ingested. Hypersensitivity reactions may
`occur, resulting from stimulation of immunological or
`other mechanisms.
`
`The term "allergen" is used here and subsequently to
`
`mean a substance which, when exposed to a mammal, will
`
`be able to mount an immune response resulting in
`
`antibodies of the IgE-class and which also will be able
`
`to trigger an allergic reaction when the mammal later
`
`on is exposed to the substance. Allergens are chemically
`
`a very heterogenous class of compounds and they may
`
`consist of protein, a lipid, a carbohydrate or a
`
`combination thereof such as a glycoprotein, a protec-
`
`glucan, a lipoprotein etc.
`
`Some compounds eliciting allergenic activity have to
`
`combine with biopolymers in vivo in order to mount the
`
`immune response or to trigger the allergic reaction in
`
`question.
`
`Among immunologically-based disorders, the most dramatic
`
`one is the so-called atopic or IgE mediated
`
`allergic reaction which in its most severe form may
`
`result in a so-called anaphylactic shock which is
`
`potentially fatal. This disorder is characterized by
`
`the presence of antibodies of the imunoglobulin E
`
`Page 2 of 24
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`Page 2 of 24
`
`
`
`01
`
`class (IgE) which are capable of binding just thatso-'63
`foreign substance (allergen) to which the individual is
`hypersensitive. These IgE antibodies moreover have the
`property of binding to the surface of certain cell
`types in the body. one such cell type is the mast cell
`which is present abundantly in the skin and in the
`mucosae of e.g.
`the nose, eyes,
`trachea and intestine.
`
`When IgE antibody coated mast cells are exposed to the
`allergen that had originally "raised" the antibody,
`the
`mast cells are stimulated to release so-called mediators.
`All these mediators, for example histamine, SRS-A
`tleucotrienes}, PAP {platelet activating factor) and a_
`number of chemotactic factors and enzymes, contribute
`to the typical allergic inflamation which is charac-
`terized by (i) an early phase starting immediately with
`edema, gontraction of smooth muscles and increased
`secretion, and (ii) a late phase with infiltration of
`
`phagocytic cells.
`
`There are different ways of alleviating an allergic
`condition. Two of these are utilized in accordance with
`
`the present invention, viz.:
`
`(1)
`
`Imunotherapy, also called hyposensitization,
`
`whereby the aforesaid stimulation of the maast
`cell may be prevented, probably due to a combined
`effect of developing immunological tolerance
`
`[inhibiting IgE antibody formation) and forming
`
`so-called blocking antibodies which belong to
`
`other classes of immunoglobulins.
`
`(2)
`
`Pharmacotherapy, by which allergic symptoms may be
`
`averted or mitigated. Averting of the symptoms may
`be obtained by means of mediator release inhibition
`(for instance by administration of antiallergic
`
`substances such as e.g. disodium cromoglycate
`
`{DSCG} or other substances which applied locally
`are apt to decrease or prevent mediator formation
`
`Page 3 of 24
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`Page 3 of 24
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`
`
`0130163
`
`or release, such as e.g. calcium antagonists,
`
`substances increasing the CAMP level or substances
`
`interfering with leucotriene synthesis). Mitigation
`
`of the symptoms may be obtained by inhibition of
`
`the effect of the mediators (for instance by
`
`administration of antihistamine or of antagonists
`
`to other mediators or of substances having opposite
`
`effects such as e.g. adrenergics, anticholinergics
`
`or xanthine derivatives).
`
`An antiallergic substance of the DSCG type is believed
`
`to locally affect the mast cell so as to inhibit
`
`release of histamine and other mediators of the immediate
`
`allergic reaction. To be effective the drug has to
`
`reach the mast cell prior to the exposure to allergen.
`
`Ever since the discovery of DSCG, attempts have been
`
`made to find other compounds inhibiting this reaction.
`
`Ketotiphene , for instance, has been said to be such a
`
`potential compound. But unfortunately, such potentially
`
`promising substances are very rarely as effective in
`
`actual fact as they have seemed to promise.
`
`The term 'antia1lergic substance“ is used here and
`
`subsequently to mean a substance inhibiting the
`
`allergen—induced allergic and inflammatory reaction.
`
`Consequently such "antiallergic substances“ should be
`
`understood to comprise substances inhibiting mediator
`
`release as well as substances neutralizing the mediators
`themselves.
`
`Immunotherapy means that an allergy patient is treated
`
`with small amounts of the allergen to which he is
`
`allergic, the purpose of this treatment being that the
`
`patient is to build up a defense or tolerance in action
`
`the next time he is exposed to that particular allergen.
`Thus
`the object is to prevent the allergen from
`
`binding to its specific IgE antibodies on the mast
`
`cell.
`
`In immunotherapy treatment,
`
`the patient is given
`
`Page 4 of 24
`
`Page 4 of 24
`
`
`
`0130163
`
`repeated administrations of {immunotherapeutically
`active amounts of} allergen to thereby build up his
`defense. However,
`the doses must not be so high as to
`give rise to an allergic reaction. It will therefore be
`appreciated that immunotherapy implies a precarious
`balancing between the administration of an effective
`
`Immunotherapy is normally carried out by means of
`subcutaneous injections of allergen. For certain food
`allergies it has, however, been suggested that the
`normal route of the allergen should be utilized,
`thus
`comprising oral administration and absorption in the
`stomach or intestine. It has been'suggested also,
`in
`this context, that the hyposensitizing treatment should
`be combined with DSCG administration.
`
`Thus in connection with food allergies oral hyposensitiz-
`ation combined with oral administration of DSCG has
`been previously known. The role of DSCG was believed to
`reside in exerting its effect locally in the digestive
`tract, i.e.
`in the zone where exposure to the allergen
`takes place. Tests have been carried out in which food
`allergy patients have been given 180 — 300 mg of DSCG
`for 3 — 10 days before allergenic challenge (La Houv.
`Presse Med. 3,
`[1979)r22, p. 1851 — 52). These tests
`have ultimately resulted in a proposal for an oral
`hyposensitizing method which is quite rudimentary and
`involves many disadvantages. The teachings of the
`reference are conducive to a hyposensitizing method in
`which exposure to the allergen and ingestion of DSCG
`take place at entirely different times. This is unpract—
`ical because the digestive functions of the stomach and
`intestine are apt to vary from individual to individual
`and at different occasions in one individual. Moreover
`it has been found to be difficult, with concomitant
`risks, to persuade participant indidividuals to re-
`peatedly ingest two different preparations at different
`
`Page 5 of 24
`
`Page 5 of 24
`
`
`
`5 —
`
`0130163
`
`occasions: it should be noted here that deviations from
`
`a strict dose administration schedule entrain the risk
`
`of an anaphylactic reaction. The obstacles of the prior
`
`art methods for oral and/or intestinal hyposensitization
`
`are mainly the same as for skin hyposensitization. Even
`
`in a very weak allergy there is always a risk for an
`
`anaphylactic reaction. Once adverse reactions have been
`
`initiated their further development is hard to control.
`
`Capsules containing allergen and intended for oral
`
`administration have also been described by Stickl, H.
`and by Stickl. H. conjointly with Kersher, G.
`(Fortschr.
`
`Med. 99 (1981), p. 1991 - 3, and 16th 98 (1980): P.
`343 — 46, respectively). However, unpublished results
`
`{Bjdrksten, B.) have shown that oral administration of
`
`allergen capsules may give rise to side effects in the
`
`form of diarrheas and other unpleasant phenomena. The
`
`work of both Bjdrksten and Stickl has been directed
`
`towards immunotherapy irrespective of whether or not
`
`the allergen is a foodstuff.
`
`Earlier on, attempts have been made also with so-called
`
`peroral hyposensitization. According to this method
`
`dilute solutions of the allergen have been placed under
`
`the patient's tongue. The method has been found to be
`
`virtually ineffective.
`
`From what has been said above it will be evident that
`
`there is a great need of novel formulated preparations
`and improved methods for non—parentera1 hyposensitization.
`
`Such preparations and such methods are provided by the
`
`present invention which is aimed at eliminating the
`aforesaid disadvantages inherent in the earlier methods
`
`and preparations. The greatest advantage provided by
`the invention is that the immunotherapeutic dose can
`
`now be increased considerably without any significant
`increase of the risk of provoking an anaphylactic
`
`reaction. The present invention will enable, for
`
`AL—HBfpb
`1984-05-28 (111
`Page 6 of 24
`
`Page 6 of 24
`
`
`
`6 .-
`
`0130163
`
`intestinal hyposensitization purposes, to administer
`the correct dose of the allergen preceded by a pro-
`tective dose of an antiallergic substance at the
`correct location with a predetermined time lag between
`delivery of the protective compound and the allergen.
`
`The formulated preparation according to the invention
`is characterized by being resistant to gastric juice
`and containing a therapeutically active amount of an
`antiallergic substance. The preparation is intended for
`oral administration, and in a preferred embodiment is
`characterized in that upon being administered it gives
`a delayed release of both the active amount of the
`antiallergic substance and the imunotherapeutically
`active amount of the allergen so that both of these are
`released, in the order as stated, when exposed to the
`action of intestinal juice while remaining unreleased
`under the action of gastric juice. By “resistant to
`gastric juice“ is meant that the preparation resists
`attack by gastric juice, so that a therapeutically
`active amount of both the allergen and the antiallergic
`substance can pass through the stomach and be released
`in the intestine. The concept of "resistance to gastric
`juice‘ is widely known and accepted, and this term has
`been in use for almost a century.
`
`The invention also comprises a method for intestinal
`immunotherapy treatment of allergies,
`in the first
`place IgE mediated allergies. According to this method
`a formulated preparation of the type as set forth above
`is administered orally to a patient who is allergic to
`the allergen in said preparation. The invention is in
`particular concerned with a method, and a preparation
`formulated therefore, which during intestinal
`immunotherapy will inhibit the allergic reaction,
`especially the immediate allergic reaction.
`
`The term “intestinal immunotherapy“ means that the
`treatment is carried out by causing the allergenic
`
`Page 7 of 24
`
`Page 7 of 24
`
`
`
`"7"
`
`0130163
`
`material to be delivered to and absorbed in the intestine.
`
`This type of hyposensitization is not restricted to the
`
`case where the allergen is one that is present in a
`
`foodstuff: also other allergens may be employed.
`
`The most
`
`important allergens to be used according to
`
`the invention are the so-called food allergens and
`
`inhalation allergens. This types of allergens are of
`
`proteinaceous nature having more than one antigenic
`
`determinant and a molecular weight of more than 2000
`
`daltons, either in itself or combined with body proteins.
`
`Examples of low molecular weight allergens are drugs,
`
`such as penicillin, and reactive chemicals. The pro-
`
`teinaceous allergens are mostly used in the form of
`
`extracts, which are derived from their natural sources.
`
`Common proteinaceous al1ergens_are found in dust,
`
`mites, plants, animals, fungi,
`
`insects and insect
`
`venoms,
`
`food etc.
`
`In the light of experience made to date,
`
`the most
`
`preferred antiallergic substance to be employed according
`
`to this invention is of the type which inhibits mediator
`
`release. Examples are disodium cromoglycate, homologues
`
`and analogues thereof, and other therapeutically active
`
`and pharmaceutically acceptable salts, esters or amides
`
`of the corresponding acids. The invention also covers
`
`substances which will be found later on to have the
`
`same effect as DSCG ("DSCG effect" 3 compounds of the
`
`DSCG—type are described in US Patent Specification No.
`
`3 419 578. They are called Bis—Chromonyl compounds and
`
`have the general structure:
`
`Page 8 of 24
`
`Page 8 of 24
`
`
`
`‘B '
`
`0130163
`
`and R are the same or
`6
`wherein R1: R2: R3: R4: R5
`lower alkyl,
`different and each is H or halogen,
`hydroxy,
`lower alkoxy, substituted lower alkyl or
`substituted lower alkoxy, and X is a saturated or
`unsaturated, substituted or unsubstituted, straight or
`branched polymethylene chain which may be interrupted
`by one or more carbocyclic rings or oxygen—containing
`heterocyclic rings, oxygen atoms or carbonyl groups.
`
`The advantages of the invention are in the first place
`derived from the fact that ti) the allergen and {ii}
`the antiallergic substance are administered in the form
`of one formulated preparation in which both (i) and
`(ii) are present. The invention'enab1es a therapeutically
`active amount of the antiallergic substance to be
`administered locally to the intestine. Local release of
`a therapeutically active amount of the antiallergic
`substance takes place within a well—defined period of
`time before the allergen becomes available for producing
`
`an anaphylactic response.
`
`The formulated preparation according to the present
`invention enables antiallergic substance to be relased
`as soon as it has reached the intestine; but also
`earlier. In this latter case, however, it is imperative
`that a therapeutically active amount of the substance
`still remains in the formulated drug preparation so
`that it can be released therefrom when the preparation
`reaches the intestine. Normally the antiallergic
`substance or most of it should be released within
`60 minutes after arrival of the formulated preparation
`in the intestine, and most preferably within 30 minutes.
`
`Page 9 of 24
`
`Page 9 of 24
`
`
`
`' 9 '
`
`0130163
`
`Allergen should not be released from the preparation
`
`before the latter has reached the intestine. The
`
`allergen release in the intestine may then start when
`
`an active amount of the antiallergic substance has been
`
`released and become effective. In actual practice the
`
`allergen should be released within 120 minutes after
`
`arrival of the preparation in the intestine, preferably
`
`within 30 minutes after the bulk of the antiallergic
`
`substance has been released from the preparation in the
`
`intestine. The dissolution rate is defined by the
`
`conditions prescribed for simulated intestinal juice in
`
`the US Pharamcopoea XX, p. 1105, and its third supple-
`
`ment p. 310 - 11.
`
`For each dosage unit of the formulated preparation,
`
`the
`
`total amount of allergen and the total amount of
`
`antiallergic substance may vary. The same applies to
`
`their proportions inter se. A substance having a low
`
`antiallergic effect can be combined with only small
`
`amounts of allergen. Highly potent allergens will
`
`require larger amounts of antiallergic substance. DSCG
`
`is regarded as being non—toxic in itself and so may be
`administered in unlimited amounts. other substances
`
`exhibiting an antiallergic effect may give rise to side
`
`reactions, and consequently each dosage unit may
`
`contain only small amounts of these active substances.
`
`It is important, however, that the amount of
`
`antiallergic substance per unit dose is always such in
`
`relation to the amount of allergen per unit dose that
`
`it will inhibit any potential allergic reaction in the
`
`intestine. To an average person skilled in the art it
`
`will be quite easy to ascertain the proper proportions
`
`and amounts that are acceptable. A point to be noted
`
`here is of course that a patient may become sick if
`
`proportions are chosen wrongly.
`
`As regards the volume of the dosage unit, its upper
`
`limit is set by that which can be swallowed. As a rule
`
`this means that each unit will always contain less than
`
`Page 10 of 24
`
`Page 10 of 24
`
`
`
`_ 10 -
`
`0130163
`
`500 mg of the antiallergic substance. The upper limit
`for the amount of allergen is set by the ability of the
`
`antiallergic substance to protect the patient from an
`
`anaphylactic reaction: usually the amount of allergen
`per dosage unit is from 1
`to 500 mg. In immunotherapy
`it is common practice to start with a low dose of
`allergen. After this and as the treatment is proceeding
`further, it is possible as a rule to increase the dose
`
`administered and consequently there may be a need of
`
`dosage units having different contents of allergen. A
`further corollary is that even in a single individual
`
`the imunotherapeutic amount for any given allergen may_
`
`differ in different stages of therapy. of course the
`
`immunotherapeutic dose is affected also by purification
`
`and enrichment, as well as in some cases chemical or
`
`physical modifications carried out for the purpose of
`increasing or decreasing the allergenicity of the
`
`allergenic material.
`
`when a plurality of different allergens are combined in
`a single formulated preparation due attention must be
`paid to their relative potencies and to such immunological
`cross reactivities as may sometimes occur.
`
`The preparations according to the invention may take
`various different pharmaceutical forms. Examples of
`
`two-layer
`advantageous forms are double-wall capsules,
`tablets and combinations thereof. Double-wall capsules
`
`may contain the allergen in their interior (core
`capsule, core) and contain the antiallergically active
`substance in the space between their walls [= in their
`
`envelope}. Two-layer tablets may contain the anti-
`allergically active substance in their outer layer l=
`envelope) and contain the allergen in their interior (=
`
`core). Capsule walls and/or layer surfaces may advan-
`tageously be coated with a film resistant to gastric
`juice or other film to thus become more resistant to
`gastric juice attack or acquire more well-defined and
`
`Page 11 of 24
`
`Page 11 of 24
`
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`_ 11 _
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`0130163
`
`predetermined release properties. Coating of the core
`
`will cause a delay in the release of the core contents.
`
`If a thicker coating is applied on the core the release
`
`of the allergen will be delayed still further in
`
`relation to the release oi the antiallergic substance.
`
`Other types of preparations,
`
`too, may be used, such as
`
`for instance tablets containing microcapsules with
`
`allergens spread in and surrounded by the substance
`
`having an antiallergic activity.
`
`In its broadest
`
`concept the invention comprises any and all forms for
`
`administration that give a delayed intestinal release
`
`of both the antiallergic substance and the allergen so
`
`that immunotherapy may proceed under the protection of
`
`the antiallergic substance.
`
`The formulated preparation according to the invention
`
`may contain both the allergen and the antiallergic
`
`substance together with pharmaceutically acceptable
`
`adjuvants, carriers and additives. All of these three
`
`types of additional ingredients are welleknown to
`
`persons skilled in the art. The allergen is usually
`
`employed as an extract in a freeze—dried form.
`
`Capsules and tablets which are resistant to gastric
`
`juice and have predetermined release properties in
`
`intestinal juice may be produced according to known
`
`techniques (“The Theory and Practice of Industrial
`
`Pharmacy“, Lachman L., Lieberman H.A. and Klanig J.L.,
`
`2nd edition Lea F. Febiger, Philadelphia, USA (1976),
`
`p. 321 — 465}. Capsules of suitable sizes are commer—
`
`cially available. They are usually composed of gelatin
`
`or other material that will be unaggressive in the
`
`digestive tract. Filled capsules and compressed tablets
`
`are rendered resistant to gastric juice by being coated
`
`with a film of resistant material. The material of the
`
`envelope or shell of the capsule will be a further
`
`factor contributing to determining the rate of dis-
`
`solution. One may thus choose, for example, a gelatin
`
`dissolving at the pH of the intestinal juice while
`
`Page 12 of 24
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`Page 12 of 24
`
`
`
`12
`
`0130163
`
`remaining undissolved at the pH of the gastric juice.
`In that case there will be less need to apply a coating
`of a film which is resistant to gastric juice.
`In cases
`where a coating is applied this will be done with the
`coating material dissolved in a volatile solvent.
`Materials that are resistant to gastric juice are
`commercially available from a multitude of commercial
`sources. Such materials may consist of e.g. non-toxic
`cellulose esters and synthetic polymers. The materials
`that are useful in the context of the present invention
`are capable of dissolving in intestinal juice having a
`pH higher than 3, preferably higher than 5, depending
`on where, i.e.
`in which intestinal region or zone,
`
`release is desired.
`
`the most
`In the light of experience made to date,
`preferred modality of the invention is an enteric
`coated formulation containing a proteinaceous allergen
`
`in combination with the antiallergic substance DSCG.
`
`The invention is not in any way limited to the forms of
`
`administration mentioned above, although capsules and
`
`tablets are currently being regarded as having certain
`practical advantages. The below examples are set forth
`for the purpose of illustrating the invention and
`should not be construed as limiting the scope thereof.
`
`Example 1: Double capsule resistant to gastric juice
`and containing an antiallergic substance as well as egg
`
`allergen
`
`Capsule
`
`10 g of powdered egg albumen were subjected to briguetting,
`trituration and screening to 20 mesh, whereupon the
`
`thus resultant particles were uniformly distributed
`
`(0.13 ml standard
`5
`into 100 gelatin capsules No.
`capsule from Parke-Davis, USA). Each capsule was sealed
`
`Page 13 of 24
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`Page 13 of 24
`
`
`
`- 13 -
`
`0130163
`
`and enclosed together with 100 mg disodium cromoglycate
`
`(DSCGJ
`
`in a gelatin capsule No.
`
`2
`
`(0.37 ml standard
`
`capsule from Parke-Davis, USA). The outer capsules were
`
`then sealed and pan coated with a gastric juice resistant
`
`film material;
`
`this was applied in the form of a
`
`solution corresponding to that set forth in Example 4
`
`(D).
`
`Simulated gastric juice (US Pharmacopoea XX p. 1105 and
`
`its supplement 3 p. 310 — 11} was employed for checking
`
`the gastric juice resistance of the double capsule
`
`obtained (2 h).
`
`In an analogous manner, double capsules were produced
`
`in which the DSCG was replaced by glucose.
`
`Components dissolved out
`
`The rate at which DSCG and egg albumen allergen were
`
`dissolved out was measured in a bath of intestinal
`
`juice in accordance with US Pharmacopoea xx p. 1105 and
`
`its supplement
`
`3 p. 310 - ll, with determination of
`
`changes in protein concentration and in the light
`
`absorption of the bath at 325 nm {DSCG]. Changes in
`
`protein concentration were determined according to the
`
`method of Bensadoun and Winstein, Analytical Biochemistry 70
`
`(1976), p 241. The changes, expressed as a function of
`
`time, are set forth in Table la below:
`
`Page 14 of 24
`
`Page 14 of 24
`
`
`
`Table la
`
`0130153
`
`Time, min.
`
`Release in intestinal juice! %
`
`DSCG
`0
`
`10
`
`26
`
`33.5
`
`52
`
`73
`
`87
`
`allergen
`D
`
`2
`
`4
`
`11
`
`19
`
`29
`
`40
`
`54
`
`62
`
`78
`
`Example 2
`
`A series of double blind tests was run on egg hypersensi-
`
`tive patients to verify the proper performance of the
`
`preparation in vivo, that is, to verify that allergen
`
`can thus be supplied to the patients without causing
`
`the local or general allergic reaction that would have
`
`followed upon traditional administration of a corresponding
`
`dose of the allergen.
`
`The patients were given capsules produced according to
`
`Example 1. These were either capsules containing egg
`
`albumen allergen together with DSCG or, respectively,
`
`capsules containing the egg albumen allergen but having
`
`the antiallergic agent replaced by glucose. The results
`
`are given in Table 2. The preparation of Example 1
`
`releases allergen at a time interval of 15 min.
`after DSCG release.
`
`[average]
`
`Page 15 of 24
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`Page 15 of 24
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`
`
`01 30163
`
`Clinical symptoms after administration
`of
`
`Formulated
`
`Control
`
`preparation [egg
`
`preparation
`
`albumen allergen
`
`[egg albumen al-
`
`Patient
`
`+ DSCG)
`
`lergen + glucose)
`
`no reaction
`
`vomiting
`
`abdominal pain
`
`no reaction
`
`(not done)
`
`It can be seen from these tests that by using combination
`
`capsules containing both the antiallergic substance and
`
`the allergen it is possible to reduce the risk of
`
`anaphylactic reactions occurring in the course of
`
`intestinal immunotherapy.
`
`Example 3: Double capsules resistant to gastric juice
`
`and containing antiallergic substance as well as
`
`timothy grass pollen allergen
`
`100 double capsules were produced in a manner similar
`
`to that of Example 1. Each capsule contained an inner
`
`capsule with 10 mg pollen of timothy grass (Phlemum
`
`pratense] and surrounded by 100 mg DSCG.
`
`Page 16 of 24
`
`Page 16 of 24
`
`
`
`- 15 -
`
`061 63
`The antiallergic substance and allergen were digglfae
`out in a manner analogous to Example 1. Also as in
`Example 1, DSCG was measured as the change in final
`absorption at 325 nm. The changes occurring in the
`allergen activity of the bath {activity of timothy
`grass pollen} were measured by EAST inhibition,
`(Yman
`et al., Develop. biol. Stand. 29 (1975). p. 151 - 165},
`as modified according to Schrbder and Yman,
`(Allergy 35
`(1980), p 234 — 236). It will be seen from Table 3 how
`the antiallergic and allergen substances were dissolved
`
`out successively.
`
`Table 3
`
`Release of DSCG and timothy grass pollen allergen from
`
`double capsule
`
`____________________._______________.____________________.__
`
`Release in intestinal juice, %
`
`DSCG
`
`allergen,
`
`Phleum Eratense
`
`Page17of24
`
`Page 17 of 24
`
`
`
`- 17 -
`
`Q130163
`Example 4: Antiallergic substance and allergen in
`
`double tablet
`
`(compressed dragée] resistant to gastric
`
`juice
`
`Ingredients per tablet produced:
`
`A.
`
`Core
`
`-
`
`1 tablet
`
`Powdered egg albumen {grade P:26 from
`
`Kallhergs Industri AB, Tfireboda, Sweden)
`
`Avicel® (Ph 102, microcrystalline cellulose,
`
`FML International, Cork, Ireland, see also
`
`Merck Index 8th edition, Merck Co. Inc.,
`
`Rahway, USA (1976) p. 246]
`
`Aerosilfi (silica particles, 2 nm,
`
`from
`
`Degussa, Federal Republic of Germany)
`
`Magnesium stearate
`
`Envelope
`
`Disodium cromoglycate (DSCG)
`
`Avicel®
`
`Aerosilfi
`
`Magnesium stearate
`
`Gastric juice resistant film, core
`
`Eudragitfl L100 {esters of polymeth-
`
`acrylic acid, Rfihm E Haas Gmbfl,
`
`Darmstadt, Germany]
`
`*Ethano1 99.5 %
`
`*Acetone
`
`Citroflex 40 (softener, Pfizer, USA)
`
`Propylene glycol
`
`Page 18 of 24
`
`Page 18 of 24
`
`
`
`.-13...
`
`D. Gastric juice resistant film.
`
`compressed dragée
`
`Eudragitfi L100
`
`*Ethanol 99.5 %
`
`*Acetone
`
`Citroflex 43
`
`Propylene glycol
`
`mg
`
`mg
`
`mg
`
`mg
`
`ng
`
`evaporates and will not be present in the final product.
`
`100 core tablets were prepared by introducing the item
`
`(A) materials into a mixer and mixing them homogeneously.
`Brilliant Blue was added as a marker to permit observation
`
`of allergen release from the tablet. The mixture was
`
`then compressed to tablets, and these were pan coated
`
`with a solution according to {C} above, whereby they
`
`were coated with a gastric juice resistant film.
`
`The materials according to item (B) were introduced
`
`into a mixer and mixed homogeneously. Then the core
`
`tablet as produced beforehand was coated with an
`
`envelope of this mixture,
`
`the coating procedure being
`
`performed in a known per se manner by means of so-called
`
`compression coating. The resulting envelope was then
`
`to
`pan coated with the solution according to item (D)
`thus form an outer film that was resistant to gastric
`
`juice.
`
`The tablets were shown to be gastric juice resistant,
`
`and the manner in which the substances were dissolved
`
`out was studied. All this was done by means of techniques
`
`analogues to those of Examples 1 and 3. The results are
`
`set forth in Table 4.
`
`Page 19 of 24
`
`Page 19 of 24
`
`
`
`Tflfle4
`
`0130163
`
`DSCG and allergen (Brilliant Blue) dissolved out from
`
`gastric juice resistant double tablet in intestinal
`juice at 37 °c
`
`% dissolved out
`
`allergen measured
`
`Time, minutes
`
`DSCG
`
`as Brilliant Blue
`
`Page 20 of 24
`
`Page 20 of 24
`
`
`
`_ 23 _
`
`C L A I M S
`
`0130163
`
`1.
`
`A formulated preparation to be used for oral
`administration and containing an immunotherapeuti-
`
`cally active amount of at least one allergen,
`c h a r a c t e r i z e d
`by being resistant to
`gastric juice and containing in addition to
`allergen a therapeutically active amount of an
`
`antiallergic substance.
`
`A preparation according to claim 1 which upon
`being administered gives a delayed release of both
`said active amount of antiallergic substance and
`said imunotherapeutic amount of allergen in a
`manner such that said two amounts are released in
`the said order under the action of intestinal
`juice but not under the action of gastric juice.
`
`A preparation according to claim 2 which is
`composed of one or more inner cores containing the
`allergen and of an outer envelope which surrounds
`and confines the core or cores of the preparation
`
`and contains said antiallergic substance.
`
`A preparation according to claim 3 in which said
`envelope is coated with a gastric juice resistant
`film.
`
`A preparation according to claim 3 in which each
`core is coated with a gastric juice resistant
`
`film.
`
`A preparation according to claim 3 in the form of
`
`a capsule or tablet.
`
`A preparation according to any of claims 1 - 5 in
`which said antiallergic substance is an inhibitor
`
`for mediator release.
`
`Page21of24
`
`Page 21 of 24
`
`
`
`8.
`
`A preparation according to claim 1
`
`from whflii figidsa
`
`active amount of antiallergic substance and said
`
`immunotherapeutic amount of allergen are released
`
`within 60 and 120 minutes respectively under the
`
`action of intestinal juice.
`
`A method for intestinal immunotherapy treatment of
`
`IgE mediated allergy by oral administration of an
`
`immunotherapeutic amount of at least one allergen,
`
`c h a r a c t e r i 2 e d
`
`by administering a
`
`formulated preparation which is resistant to
`
`gastric juice and which in addition to allergen
`
`contains a therapeutically active amount of an
`
`antiallergic substance.
`
`Page 22 of 24
`
`Page 22 of 24
`
`
`
`0130163
`
`M‘-‘nllcalion number
`
`Ep 848501904
`
`A 51 K 39
`
`/35
`A 61 K 31/35
`
`TECHNICAL FIELDS
`3E-AFICHED (Int. Cl. '1
`
`A 61 K
`
`DOCUMENTS CONSIDERED TO BE RELEVANT
`
`etsnav Editor Middleton E.
`'
`'
`St. Louis
`tax 3. 5.5.: "flromolyn
`KINBSLEY P.J,
`sodium (sodium cromoglycate) and drugs
`with similar activities“. pages £81 to
`498
`
`1973
`
`* Page &B6, "Food allergy" and page dB?
`“Hyposensitization"*
`
`US—A—& 152 ¢flB IFISUNS LTD)
`
`*Example 1*
`
`PRAXIS PNEUMUIDGIE, vol. 33, 1979, pages
`302-306, STUTTGART;
`E.A. STEMMANN et al:"0rale Hyposensibi1—
`iserung bei Kindern".
`
`*The W hole document“
`
`___
`
`INCOMPLETESEAHCH
`
`The Search Division oonaiders that the nreseritlfiuropean patent applrcatipn does not comply with
`the provisions 0! the European Patent Convenleon to such an extent that it 15' not possible to carry
`out a ITIBI ningtul search into the state of the art on the basis ol some ol the claims.
`Claims searched completely:
`.1 -3
`Claims searched incompletely:
`9 [artn
`Blairnsnotsearched:
`Reason tor the timnation ol the search-
`
`)
`
`Method for treatment of the human
`
`or animal body by surgery or therapy
`(See article 52 ffl) of the European
`Patent Convention}.
`
`Place ot aearch
`
`Dale ot completion ot the search
`
`Examiner
`
`.I.
`GUSTAFSSUN
`: theory or principle underlylng the invention
`: earlier patent document. but published on. or
`after the tlling date
`: document cited in the application
`: document clted [or other reasons
`
`": mé}§i'Be'i'6t'tHé 'eii}i'{é'i$'§i'Eiii'iiiiiI'I}I'EEi}é§j3bfiHiri'5
`document
`
`1U-U9-193a
`_
`. __.
`CATEGORY OF CITED DOCUMENTS
`
`: particularly relevant it taken alone
`: particularly relevant tl combined with another
`document ol the same category
`:
`technological background
`non-written disclosure
`intermediate document
`
`XY AOP
`
`GPOForm1505.1M.fl’
`
`Page 23 of 24
`
`0 omce
`
`European patent PARTIAL EU ROPEAN SEARCH REPORT
`
`which under Rule45 ofthe European PatentConvention
`
`shall be considered. for the purposes at subsequent
`proceedings. as the European search report
`
`Page 23 of 24
`
`
`
`0130163
`Applicaiion number
`
`B4BS019D.fi
`
`TECHNICAL FIELDS
`SEARCH ED llnl. C|.=]
`
`°"“°
`
`PARTIALEUROPEAN semenREPORT
`9)) E‘"°"°““ P“‘°“‘
`DOCUMENTS CONSIDERED TO BE RELEVANT
`W passage!
`THE MAST CELL, its rple in health
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