HK1148697B - Method and means for obtaining bronchorelaxation - Google Patents

Description

Method and means for obtaining bronchorelaxation

Technical Field

The present invention relates to a method and means for obtaining bronchorelaxation in the airways of a human or animal. The invention also relates to methods and pharmaceutical compositions for treating chronic obstructive pulmonary disease and asthma and methods of their use.

Background

Chronic Obstructive Pulmonary Disease (COPD) and asthma are important causes of morbidity, mortality, and medical costs worldwide. In many western countries, the prevalence of COPD is estimated to exceed 10% of the population (Mannino and Buist, 2007). In the united states, COPD accounts for 980 ten thousand as a major cause of discharge and an additional 3750 ten thousand as a minor cause of discharge from 1979 to 2001. COPD is estimated to cause more than 80,000 deaths annually in the united states. It is estimated that the total national cost of COPD in the united states in 2003 is $ 321 billion.

Currently, about 3 hundred million people worldwide suffer from asthma. Most in industrialized countries, the asthma prevalence in these countries is about 10% in adults and close to 20% in children. In the uk, the rate of emergency admission in the early 21 st century is 10/100,000 per year for adults and 100/100,000 per year for young children (Anderson et al, 2007). Asthma causes 1,200 deaths each year in the uk alone. The financial burden on asthma patients amounts to about $ 3000 billion per year in different western countries.

COPD is associated with smoking and is characterized by a gradual decline in airway inflammation and lung function. Frequently, patients experience repeated episodes of cough, sputum production and wheezing, and pneumonia, often several times per winter. Airway obstruction is usually irreversible, meaning that it continues despite treatment with corticosteroids and β 2-agonists. Due to the progression of the disease over many years, airway obstruction can become severe, leading to severe dyspnea during exercise and rest and ultimately to lung failure. At this stage, a lung function test by spirometry usually reveals a loss of lung volume of 50% or more. Other severe symptoms such as weight loss, depression and heart disease also often occur during this period. The risk of death for these patients is high. The only established drug therapy for these patients is the anticholinergic, which produces only a small effect. Steroids and bronchodilators have little beneficial effect.

Asthma is characterized by chronic inflammation and bronchial hyperreactivity in the airways with irreversible airway obstruction. In contrast to COPD, asthma can often be treated with steroids and bronchodilators. However, even with the maximum treatment, 10% of asthmatic patients have severe symptoms. There is also an overlap of COPD and asthma, often making it difficult to obtain an exact diagnosis (Chang & mosenigar, 2007).

COPD in horses (also known as equine dyspnea, equine asthma, alveolar emphysema and equine asthma) is characterized by inflammation in the airways. It can be made of dusty or moldy hay, matDust and mold in the layers, or pollen, dust and other irritants in the environment, but the cause is often unknown. Horses show symptoms like coughing, increased breathing, strong breathing and yellow nasal discharge. The severity of these symptoms ranges from mild to severe, with The horses appearing without semen production, dyspnea, and The appearance of muscle "camouflaging" along The horse's body from The point of double exhalation (The Columbia Encyclopedia, 2007). COPD in horses is frequently treated with β 2-agonists, but the bronchodilatory effects caused by these drugs are weak: (K. and Ingvast-Larson, C.1999).

There have also been reports of obstructive pulmonary disease (primarily asthma) in other animals such as cats and dogs. Like humans, these animals suffer from airway obstruction when the bronchi fill with mucus and spasm begins (bronchoconstriction). This is more common in cats than in dogs, particularly in the siamese cat and himalayan cat species (animalhosptials-USA, 2007).

Clearly, there are many individuals suffering from COPD and asthma who are in urgent need to better treat their disease.

US 6,063,363 discloses a method of treating upper respiratory tract infections with potassium salts including potassium iodide and potassium bromide. The potassium salt is introduced into the lungs and/or nasal region and/or oral cavity as a liquid solution, nasal spray, or the like. However, this effect on upper respiratory tract infections is said to be caused by potassium cation saturation of cells and tissues involved in upper respiratory tract infections. The anion of the administered salt is not important in the treatment. Furthermore, US 6,063,363 discloses a treatment for infections but not bronchoconstriction.

WO 00/36915 discloses a method of treating chronic obstructive airways diseases by administering to the afflicted airway surface a compound active in osmotically pressure, such as a salt (including potassium iodide and potassium bromide), a sugar alcohol or an organic permeant. Compounds active in osmotically are administered to the airway in order to increase the volume of liquid on the airway surface. No bronchorelaxing effect was reported.

The use of iodine-containing nasal solutions for the treatment of nasal congestion caused by, for example, the common cold, influenza or sinusitis is disclosed in US 6,696,041 and US 6,171,611. The two disclosed nasal solutions containing iodine may also contain various salts, including sodium iodide. US 6,171,611 also discloses aqueous mouthwash solutions comprising iodine and iodine salts, including potassium iodide and sodium iodide.

U.S. patent nos. 5,910,318 and 5,955,101 disclose starch-iodine pharmaceutical formulations for the preparation of capsules and tablets. The pharmaceutical formulation is suitable for administration to patients suffering from iodine deficiency, in particular breast dysplasia, breast cancer, endometriosis, premenstrual syndrome, ovarian cysts and radiation disorders. In this formulation, iodine complexes with amylose-containing starch to form triiodide ions or polyiodide ions (I)₅ ^--I₁₁ ^-). After alpha-amylase hydrolyzes starch, iodine is released in the upper small intestine. Since the triiodide ion cannot exist in uncomplexed form, I₂Is released.

Iodine poisoning may be a problem when large amounts of iodine are administered to the human body. Iodotoxicity manifests itself through other symptoms including thyroiditis, goiter, hypothyroidism and hyperthyroidism. It has been suggested that some individuals can tolerate very high levels of iodine without significant side effects, and that iodine intakes of less than or equal to 1,000 mg/day may be safe for most people, but may have adverse effects in some individuals (Pennington, 1990). Administration of hydrobromide, specifically sodium bromide, to animals suffering from iodotoxic effects helps to reverse symptoms (Baker et al, 2003). Sodium bromide is well tolerated by humans and has been found to have a non-effective dose of 4 mg/kg body weight (van Gelderen et al, 1993).

Activated carbon is used in medical applications to treat intoxication and oral overdose of various drugs. Activated carbon has a very large surface area; 1 g of surface area of 300-²(GreenwoodEt al, 1984). The impregnated activated carbon is a carbonaceous adsorbent (carbonaceous sorbent) having chemicals finely distributed on its inner surface. This impregnation optimizes the existing properties of the activated carbon, giving a synergistic effect between the chemicals and the carbon (jaceau technologies-activated carbon GmbH, germany). Iodinated activated carbon has been used for many years to bind heavy metals in gases.

Object of the Invention

It is an object of the present invention to provide methods and means for bronchorelaxation of the lungs of a human or animal affected by airway obstruction.

It is another object of the invention to provide a method for bronchorelaxation in a human or animal suffering from chronic obstructive pulmonary disease.

It is a further object of the present invention to provide a method for producing bronchorelaxation in a human or animal suffering from asthma.

It is a further object of the present invention to provide a pharmaceutical composition for bronchorelaxation of lungs of a human or animal affected by airway obstruction and uses thereof.

It is another object of the present invention to provide a pharmaceutical composition for bronchorelaxation in a human or animal suffering from chronic obstructive pulmonary disease and use thereof.

It is another object of the present invention to provide a pharmaceutical composition for producing bronchorelaxation in a human or animal suffering from asthma and use thereof.

Other objects of the present invention will become apparent from the following summary, preferred embodiments and appended claims.

Disclosure of Invention

According to the present invention, there is disclosed a method of producing bronchorelaxation of a lung of a human or animal affected by airway obstruction, the method comprising administering to the intestine of said human or animalAdministering a pharmacologically effective amount of elemental iodine (I) on activated charcoal₂)。

In the present specification, the term iodine refers to elemental iodine I₂The term iodine on activated carbon refers to iodinated activated carbon.

According to the present invention, there is also disclosed a method of producing bronchorelaxation in the lungs of a human or animal suffering from Chronic Obstructive Pulmonary Disease (COPD) and/or asthma, which method comprises administering to the intestine of said human or animal a pharmacologically effective amount of iodine on activated charcoal.

Furthermore, according to the present invention, a pharmaceutical composition comprising iodine on activated charcoal for use in the method of the present invention is disclosed.

Preferred modes of administration of the pharmaceutical compositions of the invention are tablets, tablets with disintegrants, capsules which disintegrate faster in the stomach (such as gelatin capsules and pullulan capsules), wherein the tablets and capsules comprise iodine on activated carbon and optionally comprise a hydrobromide salt and optionally flavourings, colours, preservatives, sweetener adjuvants.

Preferred iodine concentrations are 1-10% w/w of the activated carbon, in particular 2-8% w/w of the activated carbon, most preferably 3-7% w/w of the activated carbon.

Preferred daily doses of iodine for administration to humans in the form of pharmaceutical compositions of the present invention are from 5 mg to 5,000 mg, specifically from 25 mg to 1,000 mg, most preferably from 50 mg to 250 mg.

A preferred daily dose of iodine administered to an animal in the form of a pharmaceutical composition of the invention is from 0.07 to 70 mg/kg body weight, specifically from 0.35 to 15 mg/kg body weight, most preferably from 0.7 to 3.5 mg/kg body weight.

Preferred dosages of activated carbon for administration to a human are from 0.10 grams to 100 grams per day, specifically from 0.50 grams to 20 grams per day, most preferably from 1 gram to 5 grams per day.

Preferred daily doses of activated charcoal administered to an animal are from 1.5 mg/kg to 1,400 mg/kg body weight, specifically from 7 mg/kg to 285 mg/kg body weight, most preferably from 14 mg/kg to 70 mg/kg body weight.

According to a first preferred aspect of the invention, iodinated activated charcoal is administered to the intestine of a human or animal in need of bronchorelaxation in a pharmaceutically acceptable form, in particular in the form of a tablet or capsule comprising elemental iodine on activated charcoal.

According to a second preferred aspect of the invention, the iodinated activated carbon is administered to the intestine of a human or animal in the form of a tablet, wherein the tablet comprises a disintegrant for fast release of the tablet contents in the stomach.

According to a third preferred aspect of the invention, iodinated activated carbon is administered to the intestine of humans or animals in the form of capsules, wherein the capsule shell comprises gelatin or amylopectin for rapid release of the capsule contents.

According to a fourth preferred aspect of the invention, a hydrobromide salt is co-administered with iodinated activated charcoal to a human or animal in need of bronchorelaxation in order to minimize the risk of iodine poisoning.

Preferred hydrobromides are sodium bromide, potassium bromide, magnesium bromide, lithium bromide, ammonium bromide and calcium bromide.

The preferred concentration of the hydrobromide salt to be co-administered is 0.5-5% w/w of the iodinated activated carbon.

We will now describe the invention in more detail by referring to preferred but non-limiting embodiments.

Description of the preferred embodiments of the invention

Example 1 administration of iodine on activated charcoal

One male caucasian, born 1935, had smoked everyday for many years, but smoking ceased about 10 years ago. The decision to stop smoking is made due to the increasing problems from the airways and the recurrent episodes of pneumonia and airway obstruction. These symptoms are usually treated with antibiotics, steroids and bronchodilators. COPD diagnosis was first suggested in month 6 of 2000.

After that, airway symptoms increase greatly, with cough episodes and exercise-induced dyspnea lasting up to one month. The spirometric evaluation several years later showed a forced respiration volume (FEV) within one second₁) 1.44 liters, corresponding to 49.7% of his reference value, and a maximum respiratory flow (PEF) of 282 liters/min, corresponding to 60.1% of his reference value.

Over the next few months, despite the maximum treatment with anticholinergics, steroids and bronchodilators, the situation continues to worsen with loss of appetite, weight loss and severe dyspnea during rest. Now, the patient feels desperate and asks how long he can still live.

The severity of the condition prompted patients to look for alternative therapies. When ingested, contains about 5% by weight iodine (I)₂) In the form of activated carbon rods (1 x 5 mm) (Sigma-Aldrich, Inc.) the patient experienced immediate relief of airway obstruction and dyspnea. After a few days of twice daily intake of 1-2 g of iodinated activated charcoal suspended in yoghurt (equivalent to 50-100 mg iodine intake twice daily), a drastic increase in lung function and energy occurs and dyspnea is completely eliminated. The production of sputum is also greatly reduced. A subjective improvement was confirmed by repeated spirometry evaluation several months later (FEV)₁2.79 l corresponding to 97.1% of his reference value and PEF 427 l/min corresponding to 92.5% of his reference value).

Patients continue to take the composition on a regular basis for more than a year and still experience substantial benefit. Temporary cessation of ingestion for several days results in the reproduction of many symptoms. However, once uptake of iodinated activated carbon was restored, they disappeared quickly. The patient can live a normal life now, can engage in gardening, ride a bicycle, and even play badminton occasionally.

To test the bronchorelaxing effect of activated charcoal without iodine addition, the same patient ingested 5 grams of iodine-free activated charcoal (Medikol, Selena Fournier) for several days. However, no bronchorelaxing effect was observed, and the condition was rather worsened.

To figure out whether iodine itself has bronchodilatory properties, 50 milligrams of elemental iodine (Sigma-Aldrich, Inc.) placed in a gelatin capsule were ingested by the same patient for several days. However, no significant bronchorelaxing effect was observed.

Example 2. tablets containing iodine on activated charcoal.

Tablets containing iodine on activated carbon were pressed from 500 mg iodinated activated carbon (sigma-aldrich) mixed with 122 mg lactose monohydrate, 6 mg magnesium stearate and 122 mg sodium methylcellulose in a conventional tablet press to form 750 mg tablets containing about 25 mg iodine. Optionally, sodium bromide (0.5-5% w/w) may be added to the tableting mixture.

Example 3. tablets containing iodine on activated charcoal-for rapid release in the stomach.

In a conventional tablet press, a tablet containing iodine on activated charcoal for rapid release of the drug contents in the stomach is pressed out from 500 mg of iodinated activated charcoal (sigma-aldrich) mixed with 108 mg lactose monohydrate, 6 mg magnesium stearate, 16 mg croscarmellose sodium and 120 mg methylcellulose sodium, forming 750 mg tablets containing about 25 mg iodine. Optionally, sodium bromide (0.5-5% w/w) may be added to the tableting mixture.

Example 4. capsules containing iodine and sodium bromide on activated charcoal.

Capsules containing iodine and sodium bromide on activated charcoal were prepared by mixing 350 mg of iodinated activated charcoal (sigma-aldrich) with 5 mg of sodium bromide. Gelatin capsules were filled with the mixture on a conventional capsule filling machine to form capsules containing about 17 mg of iodine.

Example 5. capsules containing iodine and sodium bromide on activated charcoal-for rapid release in the stomach.

Capsules containing iodine and sodium bromide on activated charcoal were prepared by mixing 350 mg of iodinated activated charcoal (sigma-aldrich) with 5 mg of sodium bromide. The pullulan capsules were filled with the mixture on a conventional encapsulation machine to form capsules containing about 17 mg iodine.

Example 6 adsorption of Hg dissolved in water with activated carbon.

An aqueous solution of metallic Hg was prepared by placing a drop of mercury in a 250 ml beaker, adding 150 ml of distilled water and stirring at 40 ℃ for 1 hour. 100 ml of this aqueous phase was poured into another 250 ml beaker and a 30 ml sample was removed. Iodinated activated carbon (0.7 g) was added to the aqueous phase and the suspension was stirred at 40 ℃; samples were taken at 30 minutes and 60 minutes (30 ml each). The samples were filtered and placed in glass tubes equipped with polypropylene stoppers, and 2% nitric acid (0.6 ml) was added to each sample and sent for analysis. Hg2+, mg/ml: 0.075 before addition of iodine on charcoal; 0.0055 30 minutes after addition of iodine on charcoal; at 60 minutes after addition of iodine on charcoal, it was < 0.0001. Thus, 99.9% Hg (0) was removed from the solution by contacting 1 g of iodinated activated carbon per 100 ml of water for 1 hour.

Reference to the literature

Global burden of Mannino, d.m. and Buist, s.a.copd: risk factors, prevalence and future trends (Gobal garden of COPD: risk factors, prevalence, and future trees.) Lancet 2007370: 765-73.

50years of asthma Anderson, r.h., Ramyani, g., Strachan, d.p. and Limb, e.s.: 1955 British Trend of 2004 (50years of Asthma: UK threads from 1955 to 2004.) Thorax 200762: 85-90.

Chang, j. and Mosenifar, z. Clinical Practice distinguishes COPD from Asthma (differential COPD from Asthma in Clinical Practice.) Journal of intensive care Medicine (Journal of intensive care Medicine) 200722: 300-309.

K. And Ingvast-Larson, C.Beta 2-aginster vid handling av COPDSvensk1999 51(1)：13-16。

Columbia Encyclopedia (The Columbia Encyclopedia), 6 th edition, Columbia University Press, USA, http:// www.encyclopedia.com/doc/1 El-heights.html, 11/19 th year 2007.

Animal Hospital (animal Hospitals) -USA, http:// www.animalhospitals-usa.com/logs/asthma.html, 11/19 days 2007.

Pennington, J.A. Iodine Toxicity report Review (A Review of Iodine Toxicity Reports.) Journal of the American dietary Association (Journal of the American dietary Association)199090 (11): 1571-81.

Baker, d.h., Parr, t.h. and augspur, n.r. Bromine supplementation reversible chicken Oral iodointoxication (Oral Iodine toxicities in chicken Can Be Reversed by complementary Bromine) Journal of Nutrition handbook (Journal of Nutrition) 2003133: 2309-2312.

van Gelderen, c.e., Savelkoul, t.j., Blom, j.l., van Dokkum, w. and Kroes, r. non-effective dose of Sodium Bromide in healthy Volunteers (The No-effect Level of Sodium Bromide in health Volunteers) Human & Experimental Toxicology (Human & Experimental Toxicology)199312 (1): 9-14.

Greenwood, n.n. and Earnshaw, a. Chemistry of the Elements Pergamon press, 1984.

Jiabao Tech-activated carbon GmbH (carbon Tech-Aktivkohlen GmbH) Franz-Ficher-Weg 61, D-45307 Germany.

Claims (23)

1. Use of elemental iodine on activated charcoal in the manufacture of a medicament for bronchorelaxation of a human or animal airway affected by obstruction.

2. Use of elemental iodine on activated carbon for the manufacture of a medicament for bronchorelaxation in a human or animal suffering from chronic obstructive pulmonary disease.

3. Use of elemental iodine on activated charcoal for the manufacture of a medicament for producing bronchorelaxation in a human or animal suffering from asthma.

4. The use according to any one of claims 1 to 3, wherein the medicament is in the form of a tablet.

5. The use according to any one of claims 1 to 3, wherein the medicament is in the form of a tablet comprising a disintegrant for rapid release of the tablet contents in the stomach.

6. The use according to any one of claims 1 to 3, wherein the medicament is in the form of a capsule.

7. The use according to any one of claims 1 to 3, wherein the medicament is in the form of a gelatin capsule.

8. Use according to any one of claims 1 to 3, wherein the medicament is in the form of a pullulan capsule.

9. Use according to any one of claims 1 to 3, wherein the amount of elemental iodine is from 1% to 10% w/w of the activated carbon.

10. Use according to any one of claims 1 to 3, wherein the amount of elemental iodine is from 2% to 8% w/w of the activated carbon.

11. Use according to any one of claims 1 to 3, wherein the amount of elemental iodine is from 3% to 7% w/w of the activated carbon.

12. The use of any one of claims 1-3, wherein the daily dose of elemental iodine administered to a human is from 5 mg to 5,000 mg.

13. The use of any one of claims 1-3, wherein the daily dose of elemental iodine administered to a human is from 25 mg to 1,000 mg.

14. The use of any one of claims 1 to 3, wherein the daily dose of elemental iodine administered to a human is from 50 mg to 250 mg.

15. The use of any one of claims 1 to 3 wherein the daily dose of elemental iodine administered to an animal is from 0.07 mg/kg to 70 mg/kg of body weight of said animal.

16. The use of any one of claims 1 to 3 wherein the daily dose of elemental iodine administered to an animal is from 0.35 mg/kg to 15 mg/kg of body weight of said animal.

17. The use of any one of claims 1 to 3 wherein the daily dose of elemental iodine administered to an animal is from 0.7 mg/kg to 3.5 mg/kg of body weight of said animal.

18. The use of any one of claims 1 to 3, wherein the daily dose of activated carbon administered to a human is from 0.10 grams to 100 grams.

19. The use of any one of claims 1 to 3, wherein the daily dose of activated carbon administered to a human is from 0.50 grams to 20 grams.

20. The use of any one of claims 1 to 3, wherein the daily dose of activated carbon administered to a human is from 1 gram to 5 grams.

21. The use of any one of claims 1-3, wherein the daily dose of activated carbon administered to the animal is from 1.5 mg/kg to 1,400 mg/kg body weight.

22. The use of any one of claims 1 to 3, wherein the daily dose of activated charcoal administered to the animal is from 7 mg/kg to 285 mg/kg body weight.

23. The use of any one of claims 1 to 3, wherein the daily dose of activated charcoal administered to the animal is from 14 mg/kg to 70 mg/kg body weight.