HUT75940A

HUT75940A - Pharmaceutical compositions containing a peptideleukotriene antagonist and an antihistamine for treating allergic rhinitis and such diseases

Info

Publication number: HUT75940A
Application number: HU9602786A
Authority: HU
Inventors: Egbert Dejong; Theodore J Torphy
Original assignee: Smithkline Beecham Corp
Priority date: 1994-04-12
Filing date: 1995-04-10
Publication date: 1997-05-28
Also published as: CZ295396A3; EP0755252A1; AP9500729A0; PL316850A1; NO964291D0; NO964291L; BR9507353A; HU9602786D0; ZA952932B; AP561A; GB9407335D0; JPH09511988A; CN1149828A; AU2381295A; WO1995027487A1; MA23503A1; IL113293A0; EP0755252A4

Description

EXAMPLE OF THE INVENTION The invention relates to e ... tlpüsü

for treating disease-induced diseases, in particular alberic rhinitis, wherein the diseases are dangerous to the patient administering such beteclates and an antihistamine. The present invention relates to the use of a peptidoleucotriene and an antihistamine in the manufacture of a medicament for the treatment of diseases caused by a type I immune response.

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The invention also encompasses pharmaceutical compositions for the treatment of diseases caused by mammalian type I immune responses comprising an effective amount of a peptidoleukotriene antagonist and an antihistamine in addition to a pharmaceutically acceptable carrier.

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SMITHKLINE BEECHAM CORPORATION, King of Prussia, PA, US

inventors:

TORPHY, Theodore, J. Bryn Mawr, PA, US

DeJONG, Egbert Bryn Mawr, PA, US

Date of announcement: 10.04.1995.

Priority: 12/04/1994 (9407335.0 GB)

International Application Number: PCT / US95 / 04376

International Publication Number: WO 95/27487

The present invention relates to a method of treating diseases caused by type I immune responses in mammals, including allergic rhinitis, pharmaceutical compositions for the treatment of such immune responses, and the use of a peptidoleukotriene antagonist and an antihistamine for the manufacture of such pharmaceutical compositions.

Slow Reacting Material for Anaphylaxis

Substance of Anaphylaxis; SRS-A is a highly effective bronchoconstrictor that is released from mast cells and basophils during the antigen test. The

SRS-A was previously proposed to be a primary mediator of human asthma. In addition to its powerful effects on the lung tissue, SRS-A also changes the permeability of the skin and can play a role in acute allergic skin reactions. In addition, SRS-A has been shown to reduce ventricular contraction and enhance cardiovascular effects of histamine.

The discovery of naturally occurring leukotrienes and their association with SRS-A greatly increased interest in SRS-A and other arachidonate metabolites. All SRS-A from mouse, rat, guinea pig, and human organism are characterized by being from leukotriene-C ₄ (LTC ₄ ), leukotriene-D ₄ (LTD ₄ ) and leukotriene-E ₄ ( LTE ₄ ).

Leukotrienes form a group of lipoxygenase-formed eukocanoids during arachidonic acid metabolism. These lipid derivatives are derived from LTA ₄ and have two types: (1) containing a sulfidopeptide side chain (LTC ₄ , LTD ₄ and LTE ₄ ); and (2) non-peptide (LTB ₄ ). Leukotrienes include a group of naturally occurring substances that are capable of contributing significantly to the pathogenesis of certain variants of inflammatory and aschemic disorders. Currently, intensive research is ongoing on the pathophysiological role of leukotrienes.

According to Left's summary [Left, AM, Biochemical Pharmacology, 35 (2), 123-127 (1986)], both peptide and non-peptidic leukotrienes exert microcirculatory effects that promote most of the capillary endothelial fluid in the vascular system types. through the membrane. LTB ₄ has significant chemotactic effects and contributes to the formation of mobile scavenger cells and to adherence to the endothelial membrane. LTC ₄ , LTD ₄ and LTE ₄ stimulate different muscle types. LTC ₄ and LTD _{4 are} effective bronchodilators and are an effective stimulant for vascular smooth muscle. This bronchodilator effect has been previously shown in the pulmonary, coronary, cerebral, renal and mesenteric vascular systems.

Leukotrienes play a role in a large number of pulmonary diseases. For LTC ₄ and LTD ₄ , these agents have been shown to be potent and selective, peripheral respiratory agonists more active than histamine [Drazen, JM et al., Proc. Nat'l. Acad.

Sci. USA, 77 (7), 4354-4358 (1980)]. It has also been proven that LTC ₄ and LTD ₄ in vitro increase mucosal release from the respiratory tract [Marom, Z. et.

- 4 al., Am. Respir. Dis., 126: 449-451 (1982)].

Leukotrienes have also been identified in nasal secretions of allergic subjects subjected to the in vivo specific antigen test. The degree of release of leukotrienes is proportional to the severity of characteristic allergic signs and symptoms [Creticos, PS et al., New England J. ofMed., 310 (25), 1626-1629 (1984)]. This suggests that an allergic rhiniti.sa leukotriene antagonist may be another use.

Antihistamines used in the present invention are Ηχ receptor antagonists. Other histamine receptors have also been identified, namely, the H ₂ and H ₃ receptors have been previously identified, but in the case of antagonists specific for the latter two, they have been found to exert their effects in different ways than the áló receptor antagonist compounds. In spite of this, the term antihistamine is generally used in connection with antagonists. For the sake of simplicity, the term "antihistamine" or the abbreviation "AH" is used herein in conjunction with ésben receptor antagonists only.

As in the past, histamine an receptor antagonists are primarily used to relieve the symptoms of hypersensitive reactions such as urticaria and angioedema, rhinitis and conjunctivitis, and pruritus associated with skin disorders. Others are used to treat nausea and vomiting and vertigo.

Previous use of antihistamines has been directed to the treatment of symptoms associated with rhinitis, especially allergic rhinitis.

In the treatment of allergic rhinitis, antihistamines act by blocking the function of histamine released from mast cells mainly during the initial phase of the allergic reaction. Although antihistamines can be used to treat nasal itching, sneezing, rhinorrhea and ocular symptoms such as conjunctivitis, they do not have an optimal effect on nasal congestion.

It has been found that, while using a non-sedative antihistamine, a peptidoleukotriene, such as LTC ₄ , LTD ₄ and LTE _4, provides an excellent method for treating rhinitis and related phenomena, and especially allergic rhinitis.

One object of the present invention is to provide a method for treating a disease caused by type I immune responses in a mammal, comprising administering to a patient suffering from such a disease or suffering from such a disease an amount of a peptidoleucotriene and an amount of an antihistamine which in combination is sufficient to treat the disease.

Another object of the present invention relates to the use of a peptidoleukotriene and an antihistamine for the manufacture of a medicament for the treatment of a disease caused by a type I immune response.

The method of the invention can be used as a prophylactic as well as for treating an existing condition.

The treatment method comprises the treatment of a type I immune response in a mammal. Such type I immune response refers to the interaction of an antigen with IgE, which results in an excessive reaction to the antigen, or such an interaction triggers an immune response. Such an excessive immune response may be induced by several antigenic substances from different sources. For example, a wide variety of plant and animal materials such as pens / hairs and pollen, as well as foods, powders, pharmaceuticals, and chemicals are known to cause abnormal reactions in mammals. These reactions can cause physiological changes that can lead to various diseases. Using the method of the invention, all of these diseases can be treated, including, but not limited to, allergic rhinitis and perennial rhinitis, atopic dermatitis, eczema, allergic conjunctivitis, systemic anaphylaxis, and hay fever. The foregoing lists only some of the diseases that can be caused by the IgE / antigen interaction; the list does not limit the use of the present invention.

The development of an allergic response can begin quite quickly after an allergic attaches to the IgE antibodies on mast cells. The formation of the bond induces the cell to release chemical substances that altogether produce the symptoms described by the concept of allergic rhinitis. There are two groups of released chemicals that cause these types of symptoms, namely histamine and peptidoleukotrienes, which are allergy-allergic

we call them mediators. For example, in the case of rhinitis, antihistamines relieve sneezing, rhinorrhea, and itching of the eyes, nose and throat. However, antihistamines are not particularly effective against nasal congestion, or if the amount of allergens is too high or if the allergens have a longer duration of action. In allergic rhinitis, which is a double respondent, histamine concentration in the early phase is proportional to the severity of sneezing and itching, while in the late phase, the concentration of peptidoleukotrienes is proportional to the severity of nasal congestion;

Nasal congestion is a symptom that can be triggered by the exogenous administration of leukotrienes.

The peptidoleukotriene (PTL) antagonists (PTLA) useful in the present invention are compounds that regulate the effect, production and release of peptidoleukotrienes, in particular those that regulate the former in LTC ₄ and LTD ₄ . This group of compounds include compounds that antagonize the LTC ₄ and LTD ₄ receptors, also known as such receptor antagonists, or compounds that, for example, inhibit the biosynthesis of peptidoleukotrienes: i) inhibit the substrate, e.g. availability of phospholipase A ₂ or coenzyme A independent transacylase (PLA ₂ inhibitors or CoA-IT inhibitors); ii) directly inhibit an enzyme (e.g., 5-LO inhibitors); or iii) inhibit the translocation / activation of an enzyme such as 5-LO activating protein (FLAP inhibitors). Those that • • · ·

Compounds that are competitive inhibitors or that bind irreversibly to a receptor also play a role in the present invention. Competitive binding LTC ₄ and LTD ₄ receptor antagonists are particularly valuable.

There are a number of clinically tested compounds for peptidoleukotriene antagonists that can be used in the present invention. Most or all of these antagonists are expected to be useful in the treatment procedures summarized below. For example, compounds reported as kc> receptor antagonists have been reported in Zileuton (Abbott Laboratories); Accolate, ZD 2138 and ZD 3523 (Zeneca); MK-476 (Merck);

BAY x-1005, BAY y-1015 and BAY x-7195 (Bayer); A78773 (Abbot

Laboratories); AS-35 (Tanabe); DS-4574 (Diiachi); SK&F 104353

SK&F 106203 and SB 205312 (SmithKline Beecham, plc); RG 12525 (Rhone-Poulenc Rorer); and CGP45715 and CGS 25019C (Ciba

Geigy). These compounds and their analogues are available from said manufacturers or can be prepared using the chemical methods disclosed in various published patent applications and patent disclosures describing the compounds. The foregoing short list only intended to illustrate some examples of compounds useful in the present invention; the list does not limit the scope or scope of the present invention.

Peptidoleukotriene receptor antagonists are most preferred. The most interesting peptidoleucotriene antagonist is 4-oxo-8 - {[4- (4-phenylbutoxy) benzoyl] amino} -2- (5 '· · · · · · · · · · · · · · · ····· · · · · · · · · · ·

- 9-tetrazolyl) -4H-1-benzopyran, and salts, isomers, polymorphs, etc. thereof. These compounds and their analogues are disclosed in U.S. Patent No. 4,780,469.

In the present invention, any antihistamin may be used until antihistaminic co-administration with a peptidoleukotriene antagonist maintains the native receptor antagonist activity. Antihistaminic compounds useful in the present invention are those which are non-sedative, but which retain their effect on the symptoms associated with rhinitis. In many antihistamines, central nervous system depression is common. Although this feature may be useful under certain therapeutic conditions, it is not considered to be a desirable effect in medical treatments where the purpose of treatment is to eliminate the phenomena that interfere with normal activity. Consequently, so-called non-sedative antihistamines have been developed. The compounds to be produced were primarily those which: i) are poorly penetrated through the blood / brain barrier, or ii) the peripheral histamine H! have higher selectivity or greater affinity for receptors than central nervous system histamine H1 receptors. Examples of this group of compounds include: acrivastine, astemizole, cetirizine, loratadine, terfenadine and carboxylic acid metabolite. One of the preferred antihistamines is loratadine. The exemplary compounds provided guidance • · · • · · ·

For the practitioner of the present invention, the characteristics of antihistamines within the scope of the so-called non-sedative antihistamines.

Known antihistamines may be obtained from commercial sources or prepared by known methods. Descriptions of the syntheses of antihistamines for human use can be found in the patent documents and in the literature. For more information on antihistamines for human use, see the following manuals: The Merck Index, 9th Edition,

Merck and Company, Rahway, New Jersey, USA; Cutting's Handbook of

Pharmacology, 6th Edition, Ed. TZ Czacky, MD, Appleton-Century-Crofts, New York, USA, 1979, Chapter 49: 538-550; as well as

Goodman and Gilman, The Pharmacological Basis, Therapeutics, 7th Ed.

Editors AG Gilman et al., 1985, Macmillan Publishing Co., New York, USA. Each of these references provides additional information on the pharmacology of the compounds and other relevant research in the area. As for the individual active ingredients, acrivastine is produced by Boroughs Wellcome. Number of Compound by Chemical Abstracts System (CAS): CAS-87848-99-5. Astemizole is manufactured by Janssen and the CAS number CAS-68844-77-9. Cetirizine can be obtained as the hydrochloride salt from Pfizer; this active substance has two CAS numbers: CAS-83881-52-1 and CAS-83881-51-0. Another Schering-Plow product, loratadine CAS-CAS-79794-75-5. The terfenadine (seldane) and carboxylic acid metabolite are Marion Merrell Dow • · • · ·

- 11 shakes. CAS Number: CAS-50679-08-8. Further information on these active ingredients can be obtained using the former CAS numbers from the Chemical Abstracts System database.

Since the combination of peptidoleukotriene antagonist and antihistamine is more effective in treating or alleviating the symptoms caused by the interaction of IgE / antigen than administering said compounds alone, a combination product is expected to contain smaller amounts of the two active ingredients than would be required during the usual administration.

Accordingly, the effective dose of antihistamine may be less than the dose that should be administered if the antihistamine is administered without a peptidoleukotriene antagonist. In combination with a peptidoleukotriene antagonist, the lower efficacy of the antihistamine dose is expected to be approximately half that used alone. Although it is not necessary to reduce the upper limit of the dosage range in accordance with the present invention, it should be noted that it is unnecessary to use a dose as high or as currently used for the highest dose of antihistamine alone. For example, loratadine is available in many countries in the form of tablets containing 10 mg of the active substance once a day. Terfenadine is available as a twice daily tablet of 60 mg.

Effective dose of peptidoleukotriene antagonist per day

- 12 about 10-500 mg / kg of body weight. The peptidoleukotriene antagonist is administered one to four times daily. In a preferred treatment method, the peptidoleukotriene antagonist is administered twice daily in the form of an oral dose of 75-450 mg.

The foregoing active ingredients may be combined in a single composition or in the form of separate preparations. In the preparation of the compositions containing the two active ingredients, any pharmaceutically acceptable carrier can be used until the compositions are sufficiently stable and acceptable to the patient. The most preferred formulation form is one of the solid or liquid dosage forms for oral administration.

In a preferred embodiment, the two active ingredients are combined in a single composition for simultaneous administration and use. However, the two active ingredients can also be formulated or administered separately, for example, in cases where one of the active ingredients is administered less than once in one day than the other. When the active ingredients are administered separately, care should be taken that the administration of the various active ingredients takes place within a relatively short period of time, e.g. within a few minutes. In addition, the dosage can be varied, for example, by using a higher amount of an active ingredient at a given time.

For example, in the most effective way, the treatment may be modified so that one of the active ingredients is administered at a higher dose in the morning than in the evening. If one of the compounds is customary

- use less than 13 days, this should be indicated in the dosing instructions. If an antihistamine, such as loratadine, is usually administered once a day, but the peptidoleukotriene antagonist is administered twice a day, two or three different formulations should be prepared and packaged together with an individual instructions for use.

Such compositions include tablets, capsules (hard or soft capsules), elixirs, syrups, suppositories, and the like, commonly used for the treatment of cold or flu. form. For example, in the case of tablets and capsules for oral administration, the active ingredients may be combined with any non-toxic oral, pharmaceutically acceptable carrier; such as, but not limited to, lactose, starch, sucrose, cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, ethyl alcohol (in liquid formulations), and the like. Additionally, if desired or desired, additional additives may be used. Examples of such binders are starch, gelatin, natural sugars, corn sweeteners, natural and synthetic rubbers such as acacia, sodium alginate, (carobixmethyl) cellulose, polyethylene glycol and waxes. Lubricants for use in such dosage forms include, but are not limited to, boric acid, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrants include, but are not limited to, starch, methylcellulose, agar, bentonite, guar gum, and the like. In that particular case

- 14 sweeteners, flavorings and preservatives can also be incorporated into the compositions.

In addition, the compositions may also be formulated as sustained release formulations that are capable of delivering one or more components at a controlled rate to optimize the therapeutic effect while minimizing undesirable side effects. Such sustained release formulations include layered tablets consisting of a layer of different disintegration rates, or delayed-release polymer matrices impregnated with the active ingredients and compressed into tablet form, or capsules containing such impregnated or encapsulated porous polymer matrices.

An example of a sustained release formulation is a partially or completely translucent soft gelatin capsule having a pharmaceutically acceptable liquid and beads inside; the pharmaceutically acceptable liquid and beads may partially fill the cavity of the soft capsule or be filled so that the beads fill the cavity completely and fill the space between the beads with the liquid. Such formulations are described, for example, in the patent application filed on June 18, 1993.

08/080851. and U.S. Patent Application Serial No. 08/089361, filed July 9, 1993; U.S. Pat. RH Blythe has pioneered the development of bead manufacturing processes

- 15 (U.S. Patent No. 2,738,303). At that location, Blythe described a pharmaceutical composition in unit dosage form which was made from extremely small seeds (sugar pellets), sieved, dropped into a syrup moistened with a syrup and then treated with a 80:20 dextrophenamine sulfate / calcium sulfate dihydrate mixture. after drying. Repeating this procedure repeatedly, the active ingredient is placed on the extremely small seeds; treated the material obtained with talc to form the core pellet. The pellets were then treated one or more times with a wax-fat coating solution to produce pellets having one or more layers of fat around the core pellet. In later developments, an osmotic wall was placed around the core pellet. In the formulations, the active ingredient dissolves in the granule wall forming material and then passes through the wall and is released into the external environment by the action of water. Such particles are disclosed, for example, in U.S. Patent 4,434,153. U.S. Patent No. 4,961,932 lists patent documents relating to small or small pills or dosage forms containing such pills.

Alternatively, the compositions may be formulated as pastilles, candies, and the like. also in the form of active substances dissolved or suspended in the matrix or in the form of beads. Such compositions may be opalescent, semi-transparent or transparent. Preferred compositions

In one of 16 forms, the beads are incorporated into a solid matrix forming material.

In another embodiment, the beads are filled into a hard shell gelatin coating.

A description of the processes for the preparation of the preparations described in the two preceding paragraphs is provided on 08 July 1993, 08/090387. U.S. Pat.

Claims

PATIENT INDIVIDUAL POINTS

A method of treating diseases caused by type I immune responses in a mammal, comprising administering to a patient suffering from such a disease or suffering from such diseases an amount of a peptidoleucotriene and an amount of an antihistamin that is sufficient in combination to treat the disease.

2. One peptidoleukotriene and one antihistamine are provided with a I.

for use in the manufacture of a medicament for the treatment of a disease caused by a type of immune response.

3. A pharmaceutical composition for use in the treatment of diseases caused by type I immune responses in a mammal, wherein the pharmaceutical composition comprises an effective amount of a peptidoleukotriene antagonist and an antihistamine in addition to a pharmaceutically acceptable carrier.

The proxy: