(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(19) World Intellectual Property Organization
`International Bureau
`
`1111111111111111 IIIIII IIIII IIII I II Ill lllll lllll lllll lllll llll 1111111111111111111
`
`(43) International Publication Date
`20 June 2002 (20.06.2002)
`
`PCT
`
`(10) International Publication Number
`WO 02/47689 A2
`
`(51) International Patent Classification 7:
`
`A61K31/495
`
`[BE/BE]; Avenue de la Foret de Soignes, 232, B-1640
`Rhode Saint Genese (BE).
`
`(21) International Application Number:
`
`PCT/EP0l/13232
`
`(22) International Filing Date:
`15 November 2001 (15.11.2001)
`
`(25) Filing Language:
`
`(26) Publication Language:
`
`English
`
`English
`
`(30) Priority Data:
`00127600.5
`01107022.4
`
`15 December 2000 (15.12.2000) EP
`21 March 2001 (21.03.2001) EP
`
`(71) Applicant (for all designated States except US): UCB,
`S.A. [BE/BE]; Allee de la Recherche, 60, B-1070 Brux(cid:173)
`elles (BE).
`
`(71) Applicant (for US only): CLAUS - BURSENS, Shirley
`(legal representative of the deceased inventor) [BE/BE];
`Kinkhoom, 22, B-8301 Heist (BE).
`
`(72) Inventor: BURSENS, William (deceased).
`
`(74) Agent: LECHIEN, Monique; UCB, S.A., Intellectual
`Property Department, Allee de la Recherche, 60, B-1070
`Brussels (BE).
`
`(81) Designated States (national): AE, AG, AL, AM, AT, AU,
`AZ, BA, BB, BG, BR, BY, BZ, CA, CH, CN, CO, CR, CU,
`CZ, DE, DK, DM, DZ, EC, EE, ES, Fl, GB, GD, GE, GH,
`GM, HR, HU, ID, TL, IN, IS, JP, KE, KG, KP, KR, KZ, LC,
`LK, LR, LS, lT, LU, LV, MA, MD, MG, MK, MN, MW,
`MX, MZ, NO, NZ, PH, PL, PT, RO, RU, SD, SE, SG, SI,
`SK, SL, TJ, TM, TR, TT, TZ, UA, UG, US, UZ, VN, YU,
`ZA, ZW.
`
`(84) Designated States (regional): ARIPO patent (GH, GM,
`KE, LS, MW, MZ, SD, SL, SZ, TZ, UG, ZM, ZW),
`Eurasian patent (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM),
`European patent (AT, BE, CH, CY, DE, DK, ES, Fl, FR,
`GB, GR, IE, IT, LU, MC, NL, PT, SE, TR), OAPI patent
`(BF, BJ, CF, CG, CT, CM, GA, GN, GQ, GW, ML, MR,
`NE, SN, TD, TG).
`
`Published:
`without international search report and to be republished
`upon receipt of that report
`
`(72) Inventors; and
`DE
`(75) Inventors/Applicants
`only):
`US
`(for
`LONGUEVILLE, Marc
`rue du
`[BE/BE]; Vieille
`Moulin, 83, B-1180 Uccle (BE). UYLENBROECK, Luc
`
`For two-letter codes and other abbreviations, refer to the "Guid(cid:173)
`ance Notes on Codes and Abbreviations" appearing at the begin(cid:173)
`ning of each regular issue of the PCT Gazette.
`
`!!!!!!!
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`= 0 (57) Abstract: The present invention relates to the use of a compound selected from efletirizine, cetirizine or an individual optical
`(54) Title: A METHOD FOR PREVENTING URTICARIA
`> isomer of cetirizine or a pharmaceutically acceptable salt of any of these for the preparation of a medicament intended for preventing,
`
`;;-,- or delaying the onset of, an urticaria attack in a patient.
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`UCB Biopharma SPRL (IPR2019-00400)
`Exhibit 2002
`Page 1
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`WO 02/47689
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`PCT/EP0l/13232
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`A Method for Preventing Urticaria
`
`5
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`The present invention relates to a method for preventing, or delaying the onset
`of urticaria attack with a compound selected from efletirizine, cetirizine, or an
`individual optical isomer of cetirizine or a pharmaceutically acceptable salt of any of
`these.
`The present invention relates to a method for preventing, or delaying the onset of
`primary urticaria with a compound selected from efletirizine, cetirizine or an individual
`optical isomer of cetirizine or a pharmaceutically acceptable salt of any of these.
`Urticaria is an inflammatory disease characterized by erythematous, itchy
`edematous and whealing lesions of the skin or mucous membranes. Individual wheals
`may be as small as 1-2 mm in diameter, but they can reach several centimeters. Acute
`urticaria has been defined as episodes lasting for less than 12 weeks particularly 6-12
`weeks, chronic urticaria has been defined as episodes lasting beyond 12 weeks.
`Different types of urticaria are described such as, but not limited to, acute
`idiopathic, chronic idiopathic, IgE-mediated , pseudo-allergic, serum-sickness,
`contact, hereditary angioedema, acquired C 1 inhibitor deficiency and physical as well
`as urticaria vasculitis.
`The onset of urticaria attack can be defined as a new flare up of urticaria in a
`patient, who had already experienced urticaria. Rash or flare up means that an
`urticaria lesion is already present. The onset of primary urticaria can be defined as the
`first urticaria attack during a patient's life or an attack at a time when the patient did
`not otherwise show any presence of urticaria; in this latter case, no urticaria lesions
`are present at the time of onset.
`The term "cetirizine" as used herein refers to 2-(2-[4-(4-
`chlorophenyl)phenylmethyl]- l-piperazinyl]ethoxy]acetic acid.
`The term "individual optical isomer of cetirizine" as used herein refers to the
`levorotatory and the dextrorotatary enantiomers of cetirizine. More precisely, it refers
`to the active substance comprising at least 90% by weight, preferably at least 95% by
`30 weight, of one individual optical isomer of cetirizine and at most 10% by weight,
`preferably at most 5% by weight, of the other individual optical isomer of cetirizine.
`The dextrorotatory enantiomer of cetirizine is also known as levocetirizine and in the
`form of its dihydrochloride salt is levorotatory. Each individual optical isomer may be
`obtained by conventional means, i.e., resolution from the corresponding racemic
`35 mixture or by asymmetric synthesis.
`Processes for preparing cetirizine, an individual optical isomer thereof or a
`pharmaceutically acceptable salt thereof have been described in European Patent No.
`EP 0 058 146 Bl, Great Britain Patents Nos. 2.225.320 and 2.225.321, United States
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`Patent No. 5,478,941, published European Patent Application Nos. EP 0 601 028 Al
`and EP 0 801 064 Al and published International Patent Application No. WO
`97 /37982.
`The term "efletirizine" as used herein refers to 2-[2-[4-(bis(4-
`fluorophenyl)methyl)-1-piperazinyl)ethoxy)acetic acid.
`1\vo pseudopolymorphic crystalline forms of efletirizine dihydrochloride,
`namely anhydrous efletirizine dihydrochloride and efletirizine dihydrochloride
`monohydrate are described in the European patent No. 1 034 171.
`Processes for preparing efletirizine or a pharmaceutically acceptable salt
`thereof have been described in European Patent 1 034 1 71, and in the international
`patent application WO 97 /37982.
`Unless otherwise mentioned, the invention concerns all forms of efletirizine and
`cetirizine and pharmaceutically acceptable salts thereof.
`Antihistamines are also known for the symptomatic treatment of urticaria and
`other skin disorders in which histamine plays a role (J. Allergy Clin. Immunol., 1995,
`95, 759-64).
`However, there remains a need for therapeutic methods and pharmaceutical
`compositions which prevent, or delay the onset of, urticaria attack and/or primary
`urticaria particularly in infants and/or young children, one of the major groups at risk
`of developing the disease, because of the relative immaturity of their immune systems
`and their physiological barriers to allergens.
`A first purpose of the invention therefore concerns the primary prevention of
`primary urticaria.
`A second purpose of the invention is the prevention of urticaria attacks in high
`risk patients, such as patients who have already suffered from urticaria attacks.
`A third purpose of the invention is the prevention of primary urticaria in
`children and particularly in atopic children or children with a direct relative family
`history of atopy.
`A fourth purpose of the invention is the prevention of urticaria attacks in
`children suffering from atopic dermatitis and/or with a direct relative family history of
`atopy.
`
`A fifth purpose of the invention is the prevention of acute urticaria attacks.
`The present invention is based on the unexpected finding that administration
`of efletirizine, cetirizine or an individual optical isomer of cetirizine or a
`pharmaceutically acceptable salt of any of these prevents urticaria attacks especially
`in infants.
`The present invention therefore concerns the use of a compound selected from
`efletirizine, cetirizine or an individual optical isomer of cetirizine or a pharmaceutically
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`acceptable salt of any of these for the preparation of a medicament intended for
`preventing, or delaying the onset of, an urticaria attack in a patient.
`The present invention further concerns the use of a compound selected from
`efletirizine, cetirizine or an individual optical isomer of cetirizine or a pharmaceutically
`acceptable salt of any of these for the preparation of a medicament intended for
`preventing, or delaying the onset of, primary urticaria in a patient. the said
`medicament being administered to the patient prophylactically prior to the onset of the
`urticaria.
`The present invention further concerns the use of a compound selected from
`efletirizine, cetirizine or an individual optical isomer of cetirizine or a pharmaceutically
`acceptable salt of any of these for the preparation of a medicament intended for
`preventing, or delaying the onset of, acute urticaria in a patient.
`The present invention further concerns the use of a compound selected from
`efletirizine, cetirizine or an individual optical isomer of cetirizine or a pharmaceutically
`acceptable salt of any of these for the preparation of a medicament intended for
`preventing, or delaying the occurrence or re-occurrence of urticaria in a patient.
`In addition the present invention concerns a method for preventing or delaying
`the onset of urticaria attack which comprises administering to a patient a
`therapeutically effective amount of a compound selected from efletirizine, cetirizine or
`an individual optical isomer of cetirizine or a pharmaceutically acceptable salt of any
`of these.
`The present invention also concerns the use of a compound selected from
`efletirizine, cetirizine or an individual optical isomer of cetirizine or a pharmaceutically
`acceptable salt of any of these for the preparation of a medicament intended for
`preventing, or delaying the onset of, urticaria.
`In accordance with the invention the selected compound is administered to the
`patient prior to the onset of the urticaria attack or the primary urticaria (e.g. before
`any biological or clinical symptoms of urticaria disease occur (primary prevention) or
`after biological signs of sensitization to an allergen but before the onset of symptoms of
`an urticaria attack (secondary prevention)).
`The present invention also concerns the use of the selected compound for the
`preparation of a medicament intended for preventing the onset of primary urticaria in
`a patient. the said medicament being administered to the patient prophylactically after
`a resolved urticaria attack in order to prevent the re-occurrence of the disease .
`It has been shown that the effect of cetirizine in urticaria is two-fold: firstly
`cetirizine prevents the occurrence of acute urticaria and secondly when acute urticaria
`occurs the patients, especially children. treated with cetirizine have fewer episodes of
`acute urticaria than non-treated patients.
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`The term "pharmaceutically acceptable salts" as used herein refers not only to
`addition salts with pharmaceutically acceptable non~toxic organic and inorganic acids,
`such as acetic, citric, maleic, succinic, ascorbic, hydrochloric, hydrobromic, sulfuric,
`and phosphoric acids and the like, but also to metal salts (for example sodium or
`potassium salts) or ammonium salts, the amine salts and the amino acid salts.
`Accordingly efletirizine and cetirizine may each be employed as the free acid or in the
`form of a pharmaceutically acceptable salt. The best results have been obtained with
`the dihydrochloride salt.
`By patient, is to be understood adults, infants and children, in particular
`young children. Generally, the patients most benefiting from treatment in accordance
`with the invention are infants or children aged 1 week to 10 years, preferably aged 6
`months to 5 years, and more preferably 10 months to 5 years. The best results have
`been obtained with patients aged 1 to 3.5 years.
`Preferably patients treated in accordance with the invention are those not
`currently affected by urticaria disease and most preferably, those who have never been
`affected thereby.
`A therapeutically effective amount of a compound selected from efletirizine,
`cetirizine or an individual optical isomer of cetirizine or a pharmaceutically acceptable
`salt of any of these is used to prevent, or delay onset of, an urticaria attack and/or
`primary urticaria. The dosage employed will depend essentially on the specific method
`of administration and on the purpose of the prophylaxis. The size of the individual
`doses and the administration program can best be determined based on an individual
`assessment of the relevant case. The methods required to determine the relevant
`factors are familiar to the expert.
`A preferred daily dosage for use in accordance with the invention is from about
`0,0005 mg to about 2 mg of the selected compound, per kg of body weight per patient.·
`A particularly preferred daily dosage is from about 0,005 to about 2 mg per kg of body
`weight per patient. The best results are obtained with a daily dosage from about 0,05
`to 1 mg per kg of body weight per patient, preferably 0,5 mg. The dosage may be
`administered once per day of treatment, or divided into smaller dosages, for examples
`1 to 4 times a day, and preferably 1 to 3 times a day, and administered over about a
`24 hours time period to reach a total given dosage. Best results are obtained with
`administration twice a day in two equal doses per day or once a day in retarded release
`form. The exact dosages in which the compositions are administrated can vary
`according to the type of use, the mode of use, the requirements of the patient, as
`determined by a skilled practitioner. The exact dosage for a patient may be specifically
`adapted by a skilled practitioner, in view of the severity of the condition, the specific
`formulation used, and other drugs which may be involved.
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`Pharmaceutical compositions used according to the present invention may be
`administered by any conventional means. The routes of administration include
`intradermal, transdermal, slow release administration, intramuscular, oral and
`intranasal routes, fast release. dry syrup. Any other convenient route or form of
`administration can be used, for example absorption through epithelial or
`mucocutaneous linings.
`The pharmaceutical forms according to the present invention may be prepared
`according to conventional methods used by pharmacists. The forms can be
`administered together with other components or biologically active agents,
`pharmaceutically acceptable surfactants, excipients, carriers, diluents and vehicles.
`The pharmaceutical compositions of the invention may include any
`conventional therapeutically inert carrier. The pharmaceutical compositions can
`contain inert as well as pharmacodynamically active additives. Liquid compositions
`can for example take the form of a sterile solution which is miscible with water.
`Furthermore. substances conventionally used as preserving, stabilizing, moisture(cid:173)
`retaining, and emulsifying agents as well as substances such as salts for varying the
`osmotic pressure, substances for varying pH such as buffers, and other additives can
`also be present. If desired an antioxidant can be included in the pharmaceutical
`compositions. Pharmaceutical acceptable excipients or carriers for compositions
`include saline, buffered saline, dextrose or water. Compositions may also comprise
`specific stabilizing agents such as sugars, including mannose and mannitol. Carrier
`substances and diluents can be organic or inorganic substances, for example water,
`gelatine, lactose, starch, magnesium stearate, talc, gum arabic, polyalkylene glycol
`and the like. A prerequisite is that all adjuvants and substances used in the
`25 manufacture of the pharmaceutical compositions are nontoxic.
`Pharmaceutical compositions can also be administered by spray inhalation.
`Any conventional pharmaceutical composition for spray inhalation administration may
`be used. Another preferred mode of administration is by aerosol.
`The pharmaceutical composition of the invention can also be formulated for
`topical application. The composition for topical application can be in the form of an
`aqueous solution, lotion or jelly, an oily solution or suspension or a fatty or emulsion
`ointment.
`The pharmaceutical composition of the invention can also be used for slow
`prolonged release with a transdermal therapeutic system in polymer matrix or with an
`appropriate formulation for oral slow release.
`The pharmaceutical compositions according to the present invention may also
`be administered orally or rectally. They may also be administered by nasal instillation
`(aerosols) or in the form of unguents or creams. The pharmaceutical compositions
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`which can be used for oral administration may be solid or liquid, for example, in the
`form of uncoated or coated tablets, pills, dragees, gelatine capsules, solutions, syrups
`and the like. For administration by the rectal route, the compositions containing the
`compounds of the present invention are generally used in the form of suppositories.
`The pharmaceutical forms. such as tablets. drops, suppositories and the like,
`are prepared by conventional pharmaceutical methods. The compounds of the present
`invention are mixed with a solid or liquid, non-toxic and pharmaceutically acceptable
`carrier and possibly also mixed with a dispersing agent. a disintegration agent, a
`stabilizing agent and the like. If appropriate, it is also possible to add preservatives,
`sweeteners, coloring agents and the like.
`Preferably. the pharmaceutical composition of the invention is administered in
`traditional form for oral administration. such as film coated tablets, lozenges, dragees.
`and oral liquid preparation such as syrup.
`Best results are obtained with an oral dosage form, in particular liquid
`formulations. For example, patients can receive 2 doses of 0,25 mg/kg (total daily
`dose: 0,50 mg/kg/day) of an oral solution of cetirizine 10 mg/ml per day; one ml of
`the solution contains 20 drops and one drop of cetirizine solution contains 0.5 mg.
`As an example of a composition according to the present invention, the
`following formulation of a syrup (oral drops) is preferred: cetirizine dihydrochloride.
`20 methyl- and propylparaben. saccharinum, and purified water.
`As an example of a composition according to the present invention, the
`following formulation of a film coated tablet is preferred: cetirizine dihydrochloride,
`magnesium stearate, cellulose, lactose and silicon dioxide.
`Pharmaceutical compositions of the invention are useful prophylactically.
`25 These compositions can delay or prevent the onset of urticaria attack or delay or
`prevent the onset of urticaria itself.
`The method of the invention is believed particularly suited for use in atopic
`patients. By atopic patient. is understood a patient predisposed to development of
`diseases associated with excessive IgE antibody formation.
`Another advantage of the invention resides in the ability of the treatment to
`prevent the onset of urticaria disease, in particular in atopic children, and also in
`atopic children suffering from atopic dermatitis. Specifically the patients are atopic
`children suffering from atopic dermatitis and with a positive family history of atopy.
`For example. early treatment with cetirizine dihydrochloride (initiated between 1 and 2
`years of age) decreased from 16 % in the placebo group to 6 % in the treated group the
`number of children suffering from atopic dermatitis and with a direct relative family
`history of atopy, who had experienced one or more urticaria episode. Another
`advantage of the invention resides in the ability of the treatment to prevent acute
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`urticaria and reduce the number of episodes per child subsequent to its urticaria
`initiation.
`The pharmaceutical composition of the invention may be used to prevent the
`onset of primary urticaria in patients considered to be at high risk of developing the
`disease.
`The invention is further defined by reference to the following example.
`Example
`Study on the effect of long-term treatment with the H1 -receptor antagonist
`cetirizine in the prevention of urticaria in young children with atopic dermatitis.
`Th~ study had a prospective, double-blind, parallel-group, placebo-controlled
`design, 817 children with atopic dermatitis but no asthma or other systemic disorder,
`who were 12-24 months old at study entry and had at least one allergic parent or
`sibling, were randomized. The cetirizine dose of 0.25 mg/kg twice daily, or placebo
`solution similar in appearance, was administered as drops with breakfast and with the
`evening meal every day for 18 months. After treatment with cetirizine or placebo was
`discontinued, the study continued in a double-blind manner for an additional 6
`months.
`Throughout the study, the child's primary caregiver recorded all symptoms,
`events and medications administered on a diary card, weekly when the child was well,
`and daily when the child was having symptoms. At 9 regularly scheduled visits : before
`treatment with cetirizine or placebo, at 1, 3, 6, 9, 12, 15, and 18 months during
`treatment, and at 24 months (6 months after discontinuation of the study treatment),
`the information recorded in the diary cards was reviewed and validated with the
`investigator and entered on the case record fon:n. Before data analysis, the description
`of the symptom or event was transcribed verbatim from the case record forms and
`classified according to World Health Organization terminology. Symptoms or events
`with different WHO preferred terms or different dates of onset were counted as
`different events. A symptom or event was counted as urticaria when hives, or areas of
`skin swelling, redness and itching distinct from the child's atopic dermatitis, were
`reported. The urticaria was considered to be associated with infection if sore throat.
`pharyngitis, tonsillitis, "cold", upper respiratory tract infection, ear infection, vomiting,
`diarrhea, gastroenteritis, fever, "flu", or "virus" were reported concurrently with the
`hives, or within the time frame of 7 days before, or 7 days after the hives appeared.
`The Frequency of children with urticaria was compared in the two treatment
`groups using the Fisher exact test. Use of medications in addition to study medication
`was compared in the two treatment groups using the x2 test.
`During the 18-month treatment phase, only 23 of the 399 children treated with
`cetirizine (5.8 %), had one or more urticaria! episodes, in contrast to 64 of the 396
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`children (16.2 %) treated with placebo (p<0.001). Also, the children treated with
`cetirizine had fewer episodes of urticaria per child. During the 6-month follow-up
`phase. there was no difference with regard to the number of episodes of urticaria in
`the children previously treated with cetirizine and those previously treated with
`placebo.
`During the 18-month treatment phase with cetirizine or placebo. the child's
`personal physician, while not encouraged to prescribe additional H1 receptor
`antagonists. was allowed to do so if necessary. Fewer children treated with cetirizine
`(138 of 399, 34.6 %) received additional oral prescription or non-prescription Hi-
`antagonists in comparison to those treated with placebo (164 of 396. 41.4 %, p=
`0.047).
`In this study. a relatively high cetirizine dose. approximately twice that
`recommended world wide for use in children age 2-6 years, was administered. Despite
`this, cetirizine was free from adverse effects, including central nervous system and
`cardiovascular system effects. The rationale for twice-daily dosing was that in very
`young children, cetirizine has a shorter terminal elimination half life and a shorter
`duration of action as assessed by suppression of the histamine-induced wheal and
`flare in the skin than it does in older children and adults.
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`CLAIMS
`
`1. The use of a compound selected from efletirizine, cetirizine or an individual optical
`isomer of cetirizine or a pharmaceutically acceptable salt of any of these for the
`preparation of a medicament intended for preventing, or delaying the onset of. an
`urticaria attack in a patient.
`2. The use of a compound selected from efletirizine, cetirizine or an individual optical
`isomer of cetirizine or a pharmaceutically acceptable salt of any of these for the
`preparation of a medicament intended for preventing. or delaying the onset of,
`primary urticaria in a patient.
`3. The use of a compound selected from efletirizine, cetirizine or an individual optical
`isomer of cetirizine or a pharmaceutically acceptable salt of any of these for the
`preparation of a medicament intended for preventing, or delaying the onset of,
`acute urticaria in a patient.
`4. The use of a compound selected from efletirizine, cetirizine or an individual optical
`isomer of cetirizine or a pharmaceutically acceptable salt of any of these for the
`preparation of a medicament intended for preventing, or delaying the occurrence or
`re-occurrence of urticaria in a patient.
`5. Use according to claim 1, 2, 3 or 4. wherein the selected compound is the cetirizine
`dihydrochloride.
`6. Use according to claim 1, 2, 3, 4 or 5, wherein the patient is an infant or a child.
`7. Use according to claim 6. wherein the patient is aged 1 to 3,5 years.
`8. Use according to any one of claims 1 to 7, which comprises administering a daily
`dosage from about 0,0005 mg to about 2 mg of cetirizine or individual optical
`isomer of cetirizine or pharmaceutically acceptable salt of these, per kg of body
`weight per patient.
`9. Use according to any one of claims 1 to 8, wherein the patient is an atopic patient.
`10. Use according to claim 9, wherein the patient suffers from atopic dermatitis or has
`a direct family history of atopy.
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`UCB Biopharma SPRL (IPR2019-00400)
`Exhibit 2002
`Page 10
`
`