Method and composition for treating asthma

 

(57) Abstract:

The invention relates to medicine, in particular to pulmonology and Allergology and for the treatment of a patient suffering from antigen-induced asthma, and reduced hyperresponsiveness of the Airways. The method includes intrabronchial introduction the indicated patient a pharmaceutical composition, containing in each dose of from 0.05 to 1.0 mg ultrametabolism heparins having an average molecular weight of 3000 daltons or less, per 1 kg body weight of the patient. Well established pharmaceutical composition for inhalation for use in a new method of treatment. The method provides a reduction of bronchoconstriction while reducing complications of treatment. 3 S. and 31 C. p. F.-ly, 11 ill. , 7 PL.

This application covers the material included in the bid 377066, filed in the U.S. Patent Office on June 23, 1995.

This invention relates to methods and compositions to prevent and reverse the development of symptoms and symptoms of asthma.

Chronic asthma can be regarded primarily as an inflammatory disease involving bronchospasm-IOM. The degree of reactivity and narrowing of the bronchi in response to a stimulus in individuals, traditionnaly respiratory tract. It can be also observed swelling of the mucous membrane, bronchial obstruction with mucus and hypersecretion; the lung parenchyma is normal. The narrowing of the Airways may undergo reverse development spontaneously or under the influence of treatment. The immune response of type 1 (immediate) can play an important role in the development of asthma in children and many adults; however, if the disease starts in adulthood, to identify allergic factors can be difficult. Exposure to cold air, exercise, and other aggravating factors may also be a factor causing asthma.

The most common symptoms of asthma are shortness of breath and feelings of tightness in the chest; that there are also stercorosus breathing, shortness of breath and cough. Usually there is a decrease in lung function more obstructive than restrictive type. Often asymptomatic periods alternating with attacks.

Among the known factors that cause asthma, attention is more focused on allergens and exercise. Both of these factors are powerful, stichomythia in vivo stimuli; physical activity is of great importance in everyday life of each patient with asthma, in t the e only.

The main goals of drug treatment of asthma are prevention of bronchospasm and long-term control of bronchial reactivity. Because neither the patient nor the doctor usually can't predict when it will happen bronchospasm, patients with episodic and/or exclusively seasonal attacks may require continuous therapy.

As bronchodilatory agents use of beta-agonists; they stimulate the beta2-adrenergic receptors, increase content vnutrikletochnogo camp and can inhibit the release of mediators of mast cells. Other suitable drugs include theophylline and related drugs xantinove series, which cause bronchodilatation through unknown mechanisms; bickerman, kromolin that prevent the release of mediators and inhibit neuronal reflexes of the respiratory tract, as well as corticosteroids, which primarily reduce inflammation and swelling. To relieve bronchospasm can anticholinergic drugs that block the parasympathetic cholinergic impulses at the level of receptors. Antihistamines in some cases prevent or cropped to allergologic histamine is only one of many mediators.

Modern medicines used for treatment of allergic asthma, have several disadvantages. In General, the known agents have a relatively short duration of action and can be partially or completely ineffective if applied after antigen provocation has already taken place. Moreover, because of the serious side effects associated with the use of such agents, as agonists of the beta2-adrenoreceptor and corticosteroids, therapeutic interval the safety of these agents is relatively narrow and the patients who receive them, require careful monitoring.

Bronchial reactivity (or hypersensitivity of the respiratory tract) is a hallmark of asthma and is closely linked with the previous inflammation of the Airways. Deterioration of asthma and airway inflammation is associated with increased bronchial hyperresponsiveness, which can be called as antigenic and panthenyl stimuli. Agonists of beta2-adrenergic receptors are powerful agents for the treatment of bronchospasm, but they do not affect the inflammation of the Airways or bronchial reactivity. Constant use only agencystatement beta2-adrenergic receptors. Currently, corticosteroids are the only available effective agents that reduce bronchial reactivity. Although inhaled corticosteroids are relatively safe for adult patients with asthma, these agents possess a huge amount of toxicity in children, including the suppression of adrenal function, as well as reduced bone density and growth retardation. Thus, the search for safe and effective agents that would reduce bronchial reactivity, continues.

In the past few years, it was found that heparin administered intrabronchial, can be an effective inhibitor of bronchospasm and bronchoconstriction and, therefore, is a valuable agent for the prevention of asthma (see , for example, Ahmed et al. New Eng. J. Med. , 329: 90-95, 1993; Ahmed, Resp. Drug Deliv. , 1V: 55 to 63, 1994). It was found that low molecular weight heparins, such as heparin with an average molecular weight of 4,000 to 5,000 daltons, effectively prevent induced antigen bronchoconstriction; these low molecular weight heparins also demonstrate a significantly lower anticoagulant activity compared to commercial heparin, which is a VC is A).

While it was found that different heparins suitable as preventive agents if they are introduced to the antigen provocation, however they previously were described as ineffective in changing bronchoconstricting reactions and hyperresponsiveness of the Airways in the introduction after antigen provocation (Ahmed et al. J. Appl. Physiol. , 76: 893-901, 1994).

The aim of the present invention is to provide a method and compositions for the treatment of asthma induced by antigen, and bronchial hyperresponsiveness, which would not have the disadvantages described in the previous level.

Another objective of the present invention is to provide a method and compositions for the treatment of asthma, which would be effective to prevent and reverse the development of manifestations of asthma attack.

Another objective of the present invention is to provide a method and compositions that would be highly effective for the reduction of specific and nonspecific bronchial hyperresponsiveness even when administered to the patient after antigen provocation.

Pursuing these and other objectives which will become clear from the further description, the present invention includes a method to lichenplanus pharmaceutical composition, including from about 0.05 to 1.0 mg ultrametabolism heparins per kilogram body of the patient in each dose. The introduction of these heparins can be an urgent therapy after antigen provocation or long-term therapy to suppress bronchial hyperresponsiveness.

Ultramicrobacteria heparins used in the present invention have an average molecular weight of less than 3,000 daltons, and may exhibit low anticoagulant activity, or to have almost no activity at all. New inhalation compositions are in the form of liquid or powder spray or aerosol compositions containing the appropriate concentration ultrametabolism heparins.

Fig. 1 is a diagram illustrating the effect of pre-treatment inhalation ultrametabolism heparin (CY222) in various doses on antigen-induced acute bronchoconstriction in sheep with allergies. Data are presented as antigen-induced mean standard deviation% change SLS preliminary treatment CY222 without it.

CRL = specific pulmonary resistance

+ = significantly different from the antigenic controls (p<0,0 is amolecular heparin (CY216) on antigen-induced acute bronchoconstriction in sheep with allergies. Data are presented as antigen-induced mean standard deviation% change SLS preliminary treatment CY216 without it.

Fig. 3 is a diagram illustrating the effect of pretreatment with inhaled heparin with an average molecular weight (Fragmin - Fragmin) on antigen-induced acute bronchoconstriction in sheep with allergies. Data are presented as antigen-induced mean standard deviation% change SLS with prior treatment with Fragmin without it.

Fig. 4 is a diagram illustrating the effect of pre-treatment inhaled ultra-low-molecular heparin (CY222) on antigen-induced hypersensitivity of the respiratory tract in sheep with Allergy. Data are presented as potentising medium CKO PD4in percent from baseline values with pre-treatment CY222 without it.

PD4= cumulativa provoking dose carbachol enhancing SLS up to 400% of the original values.

+ = significantly different from the antigen alone (p<0,05).4in percent from baseline values with pre-treatment CY216 without it.

Fig. 6 is a diagram illustrating the effect of pretreatment with inhaled heparin with an average molecular weight (Fragmin - Fragmin) antigonadotropin hypersensitivity of the respiratory tract in sheep with allergies. Data are presented as potentising average RMSE PD4in percent from baseline values with pre-treatment with Fragmin without it.

Fig. 7 is a graph illustrating the comparative protective effects inhalation CY222, CY216 and Fragmin on antigen-induced acute bronchoconstrictor reaction (OBR) in sheep with allergies. Data are presented as potentional average RMSE% protection against antigen-induced ARR. Thick horizontal stripes represent IT.

+ = significantly different from Fragmin (p<0,05)

+ = significantly different from baseline values (p<0,05)

Fig. 11 is a diagram illustrating the effect of Fragmin on antigen-induced hypersensitivity of the respiratory tract during its introduction in the form of an aerosol immediately after antigen provocation.

Heparin, sulfated mucopolysaccharide, is synthesized in the fat cells in the form of proteoglycan and in excess is present in the lungs of various animals. Heparin is not a specific compound with a constant molecular weight, but is in fact a heterogeneous mixture in varying degrees sulfated polysaccharide chains composed of repeating fragments of D-glucosamine and either L-iduronovoy, or D-glucoronosyl acid. Average molecular entire heparin isolated from animal tissues, ranges approximately from 6000 to 30000 daltons.

Pharmacologically heparin is known primarily as an anticoagulant. This activity of the heparin Italy the agent of activated coagulation factors and preventing the conversion of prothrombin to thrombin. Large amounts of heparin can inactivate thrombin and earlier coagulation factors, preventing the conversion of fibrinogen to fibrin.

The anticoagulant activity of heparin is associated with its molecular weight polysaccharide fragments; low molecular weight components or fragments (e.g., fragments with a molecular weight of less than 6,000 daltons) have moderate and low antithrombin and hemorrhagic effect. Similarly, low molecular weight heparins, isolated from animal tissues, have reduced the anticoagulant properties because they consist mainly of low molecular weight fragments or fractions.

Commercial heparin, which is mainly derived from the lungs of cattle or intestinal mucosa of pigs, has an average molecular weight of about 15000-17500 Dalton.

It is shown that heparin acts as a specific receptor blocker IP3and inhibits mediated IP3the release of calcium. We have previously hypothesized that heparin can block receptors IP3in fat cells and thus preventing the transmission of signals can modulate mast cell degranulation and release preparations is heparin may reduce allergic bronchoconstriction sheep, to prevent asthma caused by physical stress, as well as to inhibit the release of histamine mast cells induced by anti-IgE. Found that inhaled heparin in doses of up to 1000 units per kg has no effect on the partial thromboplastin time (THU), which implies the absence of anticoagulant effect.

It was reported that low molecular weight heparin (average molecular weight about 4500 daltons), which have a reduced activity against APTT were effective in terms of prevention of antigen-induced acute bronchoconstriction reaction (ARR) and bronchial hyperresponsiveness, also called hypersensitivity of the respiratory tract (PPD), in animal studies. However, as will be discussed and illustrated in more detail below, neither commercial heparin or low molecular weight or average molecular weight heparins, even with very low anticoagulant activity, ineffective in terms of improving PPD after antigen provocation. These incidents clearly demonstrate only a preventive warning effect, but is of no value in the treatment of provoked by antigen asthma attack.

In the us, which are effective inhibitors of anaphylaxis respiratory tract, but also highly effective in the reduction of PPD, even if they are introduced after antigen provocation. Long-term regular use WNMG also reduces PPD, and, therefore, UNMH can be used for long-term therapy of asthma is caused by specific (i.e., antigenic), and nonspecific factors.

Accordingly, the present invention includes a method of treating a patient suffering from antigen-induced asthma, which has been exposed to the antigen that caused the asthma, the method includes intrabronchial introduction to the patient a pharmaceutical composition containing from about 0.05 to 1.0 mg of one or more fractions UNMH per kilogram of body weight of the patient per dose specified composition and preferably from about of 0.075 to 0.75 mg/kg dose. For the purposes of this application UNMH can be defined as the fraction of heparin with an average molecular weight of 3000 daltons or less. OMG having an average molecular weight 2500 daltons or less, can be even more effective when used in the method of the present invention. Each faction UNMH may include disaccharides, trisaccharide, tetrasaccharide and/or pentasaccharide, as well as molecules with longer chain.

The present invention also includes a long introduction UNMH patients suffering from asthma, to reduce and suppress PPD. The concept of "long introduction" in this document means the introduction WNMG-containing compositions at least once a day for at least ten consecutive days. Long-term administration of a composition containing about 0.05-1.0 mg/kg per dose, and preferably about of 0.075-0.75 mg/kg per dose, can continue indefinitely to provide therapy, the majority of PPD, at least comparable with therapy corpiration heparins in other biological systems, for example, as inhibitors of cell growth, it was found that all factions OMG that are active and can be used in the present invention for the treatment of patients suffering from asthma, are N-sulfated, N-desulfation faction ineffective.

Inhalation composition UNMH used in the present invention may include liquid or powder compositions containing UNMH and easy to spray and intrabronchial introduction, or aerosol composition introduced by aerosol container, releasing a metered amount of the composition.

Suitable liquid compositions include UNMH in water, pharmaceutically acceptable for inhalation of solvent, such as isotonic saline or bacteriostatic water. These solutions imposed by a pump or dosing spray device, triggered by pressure, or by using any other known device, which when inhaled ensure delivery of the desired dose of liquid composition into the lungs of the patient.

Suitable powder compositions include, for example, powder of heparin, thoroughly mixed with lacto is ut be entered using an aerosol dispensing device or be placed in a breakable capsule, which the patient may be inserted into the device, making this capsule and blowing the powder out a steady stream suitable for inhalation.

Aerosol compositions for use in this method usually include fluorinated alcamovia propellants, surfactants and co-solvents and can be placed in an aluminum or other conventional aerosol containers, which are then closed with a suitable metering valve and pump pressure of the propellant.

The total concentration of the fractions UNMH in any medium, suitable for use in accordance with the present invention should be sufficiently high to provide the desired dose of from about 0.05 to 1.0 mg OMG/kg. for example, if aspatial introduces 4 ml per dose, concentration UNMH in the solution if the patient weighs 75 kg, should be approximately 1.0 to 20.0 mg/ml

Specialists in the field of pharmacy is clear that there are many known methods and devices for introducing a precisely metered doses intrabronchial drugs and to regulate the right dosage according to the weight of the patient and the severity of his condition. Moreover, there are many known liquid,ia. The present invention is not limited to any specific inert fillers, solvents or carriers, as well as any specific methods or apparatus or intrabronchial introduction.

Composition OMG described herein provide highly effective treatment of antigen-induced asthma even after antigen provocation.

To demonstrate the unexpected superiority of fractions OMG compared to the more high-molecular weight heparins in the treatment of antigen-induced asthma after antigen provocation, experiments were conducted comparing the effect of different types of heparin in sheep with allergies, both before and after antigen provocation. A detailed description of these experiments and the obtained results are produced in the following examples and figures.

The following examples illustrate the method of the present invention and showing its effectiveness, are not intended to enumerate specific materials, procedures or regimens that only and should be used for the practical implementation of the present invention.

Example 1

The introduction of episkeptomai used sixteen sheep with allergies, have documented only acute bronchoconstrictive reaction to an antigen Ascaris suum. Sheep were intubated nasotracheally tube with cuff and measured pulmonary resistance to airflow (LS) using the technique of balloon esophageal catheter, while the volume of gas in the chest was measured using plethysmography combined body. Data were expressed specific drugs (CRL defined as a drug in relation to the volume of gas in the chest (Abgg).

The reactivity of the Airways

To assess airway responsiveness was drawn curves, the cumulative dose - response to inhaled carbachol by measuring the CRL before and after inhalation of saline solution containing buffer, and after each introduction of the 10 inputs of increasing concentrations of carbachol (0,25, 0,5, 1,0, 2.0 and 4.0% (weight/volume) solution). The airway reactivity was measured by determination of the cumulative provocative dose (PD4) carbachol (in units of inhalation), which increased the CRL to 400% of the original values. One inhalation was defined as one inhalation of 1% solution of carbachol.

Heparin fractions

In the experiment comparing the effectiveness of different heparin materials, administered ovzay heparin (CY216, Sanofi) and one heparin with an average molecular weight (Fragmin, Kabivitrum, Stockholm, Sweden). Molecular weight and other characteristics of these* heparin fractions are presented in table 1.

As shown in the table, UNMH used in this experiment, not only had a molecular weight of less than 3000, but additionally about 88% of the heparin chains included in this fraction had a molecular weight of less than 2500.

The Protocol of the experiment

Studies of the respiratory tract

For each animal was determined by the reactivity of the Airways (PD4), and then on different days of the experiment the sheep were subjected to antigen provocation antigen Askaris suum. Was measured CRL prior to and immediately after the provocation, and then every hour up to 2 hours, up until the value of the CRL is not returned to the original value. Then measured the amount of PD4after provocation. This Protocol was repeated after at least 14 days after pre-treatment CY222, CY216 and Fragmin in the form of an aerosol at doses of 0.31 in, 0,62, of 1.25, 2.5 and 5.0 mg/kg

Data analysis

Data were expressed as (a) the average RMSE% change CRL; (b) PD4as % of original values; (C) % protection from acute bronchoconstrictive reaction (ARR) and (d) % protection is dwarfling treatment examinees drugs on ARR and PPD are presented in tables 2-6 and graphically depicted in Fig. 1-8.

These data indicate that pre-treatment CY222 and CY216 and Fragmin in the form of aerosols weakened antigen-induced acute bronchoconstrictor reaction dose-dependent manner; the minimum effective dose amounted to 0.62 mg/kg, 1.25 mg/kg and 2.5 mg/kg, respectively.

Pre-treatment CY222, CY216 and Fragmin in the form of aerosols weakened antigen-induced PPD dose-dependent manner, the minimum effective dose amounted to 0.62 mg/kg, 1.25 mg/kg and 5.0 mg/kg, respectively.

Comparative analysis of drugs revealed an inverse Association between protective effects and molecular weight heparin fractions. Fraction OMG, CY222, proved to be the most effective agent that has been shown significant inhibition of antigen-induced bronchoconstriction and PPD at a dose of 0.6 mg/kg, while CY216 and Fragmin at this dose was ineffective. Average group values of EID50for CY222, CY216 and Fragmin against allergic bronchoconstriction 0.5, 1.3 and 1.8 mg/kg, respectively. The corresponding average group values of EID50for CY222, CY216 and Fragmin against PPD was of 0.51, a 2.5 and 4.7 mg/kg

Example 2

To in example 1, with the exception of the following: (a) three heparin product, administered to experimental animals, was CY222, commercial heparin (molecular weight of about 15000 daltons) and Fragmin; and (b) heparin was administered to animals in the form of an aerosol immediately after antigen provocation. Experimental data are presented in table 7 and plotted in Fig. 9-11.

As can be seen from table 7 and Fig. 9-11, inhalation CY222 entered after antigen provocation, significantly changed in experimental animals potentional PPD, restored the levels of PPD to the initial values and higher. This effect was not observed when using commercial heparin or Fragmin, in which the introduction of these heparins after antigen provocation did not lead to improvements in PPD.

Thus, it is shown that the generated methods and compositions reaching different objectives of the present invention and are well adapted to meet the requirements for practical application.

Since various possible embodiments of the above invention and as various changes in the above embodiments, it should be understood that all the material description is 2">

Claimed as new and claiming the protection of the patent certificate set forth in the following claims.

1. A method of treating a patient suffering from antigen-induced asthma, which had been subjected to provocation caused the asthma antigen, including intrabronchial introduction to the patient a pharmaceutical composition containing from 0.05 to 1.0 mg ultrametabolism heparins (UNMH) per 1 kg of body weight of the patient in each dose; these UNMH have an average molecular weight of 3000 daltons or less.

2. The method according to p. 1 which includes UNMH have an average molecular weight of 2500 daltons or less.

3. The method according to p. 1, in which the specified composition contains from of 0.075 to 0.75 mg OMG/kg per dose.

4. The method according to p. 1, in which each dose is administered in the form of a composition containing from 1.0 to 20.0 mg UMNG 1 ml of the composition.

5. The method according to p. 1 which includes UNMH have little or no anticoagulant activity.

6. The method according to p. 1, in which each of these UNMH includes disaccharides, trisaccharide, tetrasaccharide or pentasaccharide.

7. The method according to p. 1, in which the specified composition includes a solution UNMH in an aqueous pharmaceutically acceptable the first solution or bacteriostatic water.

9. The method according to p. 7, in which the above composition is administered using a pump or spray device is triggered when the compression.

10. The method according to p. 7, in which the specified composition further includes an aerosol propellant and injected using an aerosol dispensing inhaler.

11. The method according to p. 1, in which the specified composition comprises powdered drug UNMH mixed with inert powders acceptable for intrabronchial introduction.

12. The method according to p. 11, in which the specified inert powder is lactose.

13. The method according to p. 11, in which the above composition is administered using an aerosol dispensing device.

14. The method according to p. 11, in which the above composition is introduced from the breaking of the capsules.

15. A method of treating a patient suffering from asthma, to reduce and suppress hyperresponsiveness of the Airways, including long intrabronchial introduction the indicated patient a pharmaceutical composition containing from 0.05 to 1.0 mg ultrametabolism heparins (UNMH) per 1 kg of body weight of the patient in each dose; these UNMH have an average molecular weight of 3000 daltons or less.

16. The method according to p. 15, in the cat the m specified composition contains from of 0.075 to 0.75 mg OMG/kg per dose.

18. The method according to p. 15, in which the daily dosage is administered in the form of a composition containing from 1.0 to 20.0 mg OMG/ml.

19. The method according to p. 15, in which these UNMH have little or no anticoagulant activity.

20. The method according to p. 15, in which each of these UNMH includes disaccharides, trisaccharide, tetrasaccharide or pentasaccharide.

21. Pharmaceutical composition for treating a patient suffering from antigen-induced asthma, comprising from 0.05 to 1.0 mg UNMH per 1 kg of body weight of the patient in each dose in a pharmaceutically acceptable for inhalation media, these UNMH have an average molecular weight of 3000 daltons or less.

22. The composition according to p. 21, in which the mentioned UNMH have an average molecular weight of 2500 daltons or less.

23. The composition according to p. 21, which includes the from of 0.075 to 0.75 mg OMG/kg per dose.

24. The composition according to p. 21, in which each dose is presented in the form of a solution containing from 1.0 to 20.0 mg UMG/ml.

25. The composition according to p. 21, in which the mentioned UNMH have little or no anticoagulant activity.

26. The composition according to p. 21, in which each of these UNMH includes disaccharides, trisaccharide, tetrasaccharide or pentangle inhalation media.

28. The composition according to p. 27, in which the specified carrier is isotonic saline or bacteriostatic water.

29. The composition according to p. 27, which is convenient for administration by a pump or spray device is triggered when the compression.

30. The composition according to p. 27, which further includes an aerosol propellant and convenient for administration using aerosol dispensing inhaler.

31. The composition according to p. 27, which includes a powdered drug UNMH mixed with inert powders acceptable for intrabronchial introduction.

32. The composition according to p. 31 in which the specified inert powder is lactose.

33. The composition according to p. 31, which is entered using the aerosol dispensing device.

34. The composition according to p. 31, which is entered from the breaking of the capsules.

 

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