KR20150087282A - Activated carbon comprising an adsorbed iodide salt in a method for treating chronic bronchitis - Google Patents

Abstract

The present invention provides an activated carbon comprising an adsorbed iodide salt selected from the group consisting of alkali metal iodide and alkaline iodide for use in a method of treating chronic bronchitis.

Description

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an active carbon containing an iodide salt adsorbed in a method for treating chronic bronchitis,

The present invention relates to the treatment of chronic bronchitis. In particular, the present invention aims to provide a use of activated carbon comprising an iodide salt adsorbed in a process for increasing sputum production and cough caused by chronic bronchitis.

Chronic bronchitis is characterized by an increase in coughing and sputum production for two consecutive years over three months a year. When bronchitis accompanies the species, it is called chronic obstructive pulmonary disease (COPD). The prevalence of chronic bronchitis has recently been found to be ~ 5-6% (Pahwa et al., J Occup Environ Med .

Chronic bronchitis is mainly caused by tobacco smoking, secondhand smoke, and air pollution, although other factors may also be important. The main objective in the treatment of chronic bronchitis is to maintain airway opening and proper function, to help remove mucus from the airway to prevent lung infection, and to prevent further disability. Notwithstanding the above, chronic bronchitis usually progresses to COPD, which is the fourth most common cause of death in the Western world.

Although nothing has been disclosed about treating chronic bronchitis of milder pathology, the airway obstruction caused by COPD, a chronic obstructive pulmonary disease, can be reduced by the administration of the mercuric conjugated conjugate "iodinated activated carbon " (WO 2009/067067).

However, one disadvantage of administering iodine impregnated activated carbon is that it contains a large amount of iodine, which can be harmful to humans. Another problem with using iodinated activated carbon as the drug is that the iodine element is highly reactive and therefore the conjugate can not be formulated into standard capsules or tablets.

Accordingly, there is a need for improved formulations for the treatment of chronic bronchitis.

It has thus been found that an improved formulation for the treatment of chronic bronchitis can be obtained by the subject matter of claim 1 of the present invention.

Thus, in a first aspect, the invention provides an activated carbon comprising an adsorbed iodide salt selected from the group consisting of alkali metal iodides and alkaline iodides for use in a method of treating chronic bronchitis.

As disclosed herein, the term "activated carbon" also includes "activated carbon. &Quot;

Typically this requires the example of which can be used in the present invention has iodide NaI, KI, MgI _2, CaI ₂ and. Preferably, KI is included as an adsorbed iodide as described above.

Preferably, the amount of adsorbed iodide salt is within the range of 0.25-10% (wt.), And preferably within the range of 0.5-5% (wt.).

Preferably, the activated carbon also comprises adsorbed pharmaceutically acceptable bromide salts, such as sodium bromide, potassium bromide, magnesium bromide, lithium bromide, ammonium bromide and / or calcium bromide. The amount of bromide salt can be in the range of 1-1,000% (wt.), Based on the weight of adsorbed iodide salt.

In a second aspect, the present invention provides the use of activated carbon comprising an adsorbed iodide salt according to the first aspect in a method of treating chronic bronchitis.

In an attempt to solve the problems mentioned in the above technical background section, it was investigated whether it is possible to impregnate activated carbon with a mercury-binding ability of activated carbon but with a smaller potential hazard to humans and a smaller reactivity. Surprisingly, the addition of potassium iodide showed a much more specific mercury binding capacity when compared to iodine impregnation. In fact, 1.6% KI impregnated activated carbon was found to bind as much mercury as 8% iodine impregnated activated carbon. In addition, activated carbon impregnated with potassium iodide can be placed in a standard capsule without the risk of any undesired side reactions between the capsule material and the active ingredient, in contrast to activated carbon impregnated with I ₂ .

Typically, the iodide salt impregnated activated carbon is administered to a pharmaceutical composition comprising said impregnated activated carbon together with a pharmaceutically acceptable excipient for the human or animal in need thereof. The choice of excipient is not critical, and the most commonly used acceptable excipients may be included in the pharmaceutical composition.

Preferably, the pharmaceutical composition is selected from the group consisting of aqueous suspensions, capsules, powders or tablets for the manufacture of oral suspensions. For example, when the activated carbon containing the adsorbed iodide salt is administered in tablet or capsule form, the activated carbon comprising the adsorbed iodide salt may be administered orally, non-toxic, pharmaceutically acceptable inert Carrier, such as ethanol, glycerol, water, and the like. Also, if desired or necessary, suitable binders, lubricants, disintegrants, and coloring agents may also be incorporated into the mixture. Suitable binders include, without limitation, starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, Sodium acetate, sodium chloride, and the like. Disintegrators include, without limitation, starch, methylcellulose, agar, bentonite, xanthan gum, and the like.

The pharmaceutical composition preferably also comprises a bile secretion stimulant. Typically, the bile secretion stimulant is fat.

The pharmaceutical composition should preferably be administered between two meal times, for example, 1 or 2 or 3 hours after one meal and at 1 or 2 or 3 hours or more before the meal. The composition should also be administered prior to breakfast.

In some embodiments, the particulate activated carbon loaded with the adsorbed alkali metal or alkaline earth metal iodide is packed in a soft or hard gelatin capsule, vegetable or pullulan capsule, or adsorbed alkali metal iodide or alkaline earth In the form of tablets formed from particulate activated carbon loaded with metal iodide and suitable pharmaceutically acceptable binders. Binders should be of a type that allows the tablet to disintegrate in the gastrointestinal tract. Suitable binders include chemically modified celluloses such as carboxymethylcellulose and polyvinylpyrrolidone. Since the nature of the carbon is fragile, only a slight squeeze should be used in forming the tablet to prevent carbon particles from breaking.

Preferably, a pharmaceutically effective amount of activated carbon loaded with an adsorbed alkali metal or alkaline earth metal iodide is administered daily, which may comprise 1-3 doses per day. However, administration may be intermittent and may include administration every 2 or 3 days or more than once per week.

Experimental Study :

Example 1: Preparation of activated carbon samples loaded with alkali metal iodide or alkaline earth metal iodide .

matter:

Activated carbon (Sigma C7606), potassium iodide (Sigma P7744), deionized water.

equipment:

Magnetic stirrer IKA RTC basic, oil bath, reflux condenser, balance XP-300 (Denver instruments), Pyrex glass flask (2 L), polymer-sealed magnetic rod, vacuum filter flask ), OOH filter paper (Whatman), laboratory drying oven TS80000, Thermaks.

Way:

In the adsorption experiment, 8.0 g KI was dissolved in 1 L water. Activated carbon (92 g) was added. The suspension was stirred at room temperature (21 - 23 [deg.] C) for 12 hours. The activated carbon product was isolated from the KI solution by filtration under reduced pressure and dried at 75 DEG C for 12 h. This gave a sample consisting of ~ 1.6% (wt.) KI impregnated active carbon. Example 1 was repeated using different amounts of activated carbon and KI to obtain activated carbon samples coated with another specific amount of KI. Measuring the amount of KI adsorbed on the activated carbon was performed by three methods: electrical conductivity method, gravimetric analysis and elemental analysis.

Example 2: Mercury absorption analysis of KI - impregnated activated carbon samples

matter:

KI impregnated carbon sample. Trizma, Sigma T1503-100G. Sodium chloride: Sigma, S988-500G. Potassium chloride: Fluka 60130-1000G. Deionized water. Hydrochloric acid: Sigma 84422-1L. Mercury (II) chloride 99.5% min., Alfa Aesar. Nitric acid: Sigma 30702, min 69%, puriss.

equipment:

Water tank with stirrer and thermostat RCT B (IKA: Germany). Magnetic stir bar. Bulk measuring glass flask, 500 ml. Round bottom glass flask with stopper, 1,000 ml, safety pipette, 25 ml. Filter paper 00H grade, diameter 150 mm, wattman.

Preparation of brine solution:

A buffer solution containing 0.01 M trizma, 140 mM NaCl, and 4 mM KCl was prepared and the pH was adjusted to 7.4 using HCl. The buffer was capped, preheated and stored at 37 < 0 > C.

Preparation of mercury (II) chloride stock solution (approximately 10 ^-3 M) Preparation:

About 0.027 g of HgCl ₂ was weighed on the analytical balance. The exact weight was recorded. HgCl ₂ was transferred to a 100 ml volumetric flask and diluted with deionized water to a concentration of 10 ^-3 M. [

Preparation of test solution containing mercury (II) chloride (10 ^-5 M)

HgCl ₂ a stock solution of 5 ml with an automatic pipette and added to 500 ml measuring flask. Preheated 37 ° C buffer was added to a maximum of 500 ml mark. The test solution was transferred to a 1,000 ml round bottom flask. The flask was capped and placed in a 37 ° C water bath.

Binding of mercury from test solution to KI loaded active carbon: 50 mg of activated carbon loaded with KI was added to the test solution containing 10 ^-5 M mercuric chloride (II), mercury in impregnated carbon Was agitated at 300 rpm for 30 min so that it could be adsorbed. Upon completion of adsorption, a 20 ml sample was recovered using a safety pipette and filtered. The 2% HNO ₃ was added and the samples analyzed in a brown bottle containing.

analysis:

Samples were analyzed by atomic fluorescence spectroscopy. The mercury (Hg) analysis results are reported in (mg / L).

result:

In this model, KI of 1.6% (wt.) Showed that the impregnated activated carbon was bound to 98% of the available HgCl ₂ .

Example 3. Preparation of iodinated activated carbon

Materials: Activated carbon (obtained from Sigma C7606): Meets USP test specifications. Iodine element (available from Sigma-Aldrich 03002); Meets USP inspection. Unmodified ethanol (available from Kemetyl); Meets USP and EP inspection specifications, water content <0.5%.

equipment:

500 ml of mixing cylinder, 500 ml of measuring cylinder, 50 ml of E-flask, 105 ml of Buchner funnel Duran diameter and stirrer motor with blade, RZR 1 (obtained from Heidolph) . Filter grade 00H (obtained from Munktell). Evaporation dish made from borosilicate glass.

Method: The amount of activated carbon, iodine and ethanol was calculated according to batch size. For a batch size of 50 g of iodinated carbon, 4.5 g of iodine, 45.5 g of activated carbon and 450 ml of ethanol were used. The activated carbon was suspended in a measuring cylinder, and 410 ml of ethanol and an iodine element were dissolved in an E-flask containing 40 ml of ethanol. Iodine was added and stirred for 2 min and allowed to attach to the carbon for 1 h. Thereafter, the iodized activated carbon was separated from the ethanol solution by filtration under reduced pressure, and dried at 150 DEG C for 5 hours. This yielded 9% (wt.) I ₂ impregnated iodinated activated carbon. The amount of iodine adsorbed by elemental analysis was measured.

Example 4. Further analysis of mercury absorption in activated carbon containing adsorbed potassium iodide and iodine

The experiment of Example 2 was repeated except that the amount of potassium iodide adsorbed on the activated carbon was varied. Similar to Example 2, mercury was present as HgCl ₂ dissolved in deionized water. The residual amount of dissolved mercury was measured by atomic fluorescence in the same manner as in Example 2. In addition, the results were compared with the results obtained for a similar amount of iodine adsorbed on activated carbon. Preparation of activated carbon samples loaded with different amounts of potassium iodide according to Example 1 was carried out. Although different amounts of iodine were used, activated carbon containing adsorbed iodine was prepared using the method of Example 3.

The results obtained provide the following:

KI end Imprinted  Activated carbon KI (%) in the impregnated solution On activated carbon
The adsorbed KI (% (wt.)) Mercury residue in solution
(mg / l) Mercury residue in solution
(% (wt.)) Pre-charcoal
Control mercury concentration 2.0 100 KI adsorbed
Activated carbon (%) 0 0 0.66 33 1.0 0.55 0.34 17 3.0 1.09 0.14 7 8.0 1.62 0.047 2

The above experiment was repeated using iodine instead of KI. The following results were obtained:

I ₂ end Imprinted  Activated carbon I ₂ (%) in impregnation solution On activated carbon
The adsorbed I ₂ (% (wt.)) Mercury residue in solution
(mg / l) Mercury residue in solution
(% (wt.)) Pre-charcoal
Control mercury concentration 20 100 I ₂ adsorbed
Activated carbon (%) 0 0 8 40 One One 7.8 39 3 3 5.3 26 8 8 0.78 3.9

Based on the results obtained, the following conclusions were drawn:

The dissolved I ₂ in the impregnated solution all adsorbed on activated carbon (even if the solution contained 8% (wt.)). Surprisingly, only 1.62% (wt.) Of activated carbon was adsorbed on activated carbon when exposed to a solution containing 8% (wt.) KI. However, as described above, a small amount of KI increased the mercury binding capacity of the activated carbon by more than 10 times, which was the same value as the mercury binding ability obtained when 8% I ₂ was adhered to activated carbon. This is unexpected and can be harmful to humans and animals when iodine is abundant, and is also very beneficial because KI is less reactive than iodine. Substitution with potassium iodide instead of iodine reduces the risk of toxic side effects in humans and animals significantly, with reduced pharmacological dosage forms used, such as the risk of unwanted reactions with components in capsules or tablets .

Example 5: Use of a charcoal is impregnated KI for the treatment of chronic bronchitis patients

A 60-year-old white man has experienced an increase in problems associated with prolonged cough and mucus production over the years. He was diagnosed with chronic bronchitis. He has been prescribed standard treatments including corticosteroids, anti-cholinergic agonists, beta 2-stimulants, and mucolytic, e.g., acetylcysteine. However, the treatment did not substantially reduce cough or mucus production.

Having chronic bronchitis considerably uncomfortable, he studied alternative methods to reduce the symptoms. During one month, when the active carbon of 1.6% KI in 300 vegetable capsules was administered at 300 mg / day, both cough and sputum production decreased significantly.

To make sure that this improvement was caused by activated charcoal, he took 300 mg of activated carbon without iodide for one month. However, as a result, coughing and sputum production again worsened to the original situation.

In order to clarify whether the improvement of chronic bronchitis by KI impregnated activated carbon was caused by iodide, he then added 10 mg daily for 1 month (this amount is the amount of iodide in KI impregnated activated carbon, 300 mg x 1.62% = significantly greater than 4.9 mg) of KI. This did not reduce cough or sputum production at all.

Finally, he again took 300 mg of activated charcoal impregnated with 1.6% KI in a 00 vegetable capsule for one month. Cough and sputum production again decreased significantly.

Potassium iodide has previously been used to treat chronic obstructive pulmonary disease (Bernecker, C. Intermittent therapy with potassium iodide in chronic obstructive disease of the airways, Acta Allergologica, 1969, 216-225). However, it was provided in much greater amounts (1.5 - 3 g and more). Ammonia treated potassium iodide mixture (150 - 300 mg per dose) was also used. Which is much more than ~ 5 mg / day used in the above example. In addition, none of the cough or sputum production was shown to improve when a capsule containing only KI was used in the above example. Therefore, it is considered essential to administer both KI and activated carbon at the same time in order to improve chronic bronchitis.

Claims (5)

An activated carbon comprising an adsorbed iodide salt selected from the group consisting of alkali metal iodides and alkaline earth iodides for use in a method for treating chronic bronchitis. The activated carbon of claim 1, wherein the amount of adsorbed iodide salt is in the range of 0.25-10% (wt.) And preferably in the range of 0.5-5% (wt.). The activated carbon according to any one of claims 1 to 2, wherein the adsorbed iodide is potassium iodide. 4. The process according to any one of claims 1 to 3, characterized in that the activated carbon is also a pharmaceutically acceptable bromide salt, for example sodium bromide, potassium bromide, lithium bromide, ammonium bromide and / or calcium bromide Active carbon. Use of activated carbon comprising an adsorbed iodide salt according to any one of claims 1 to 4 in a method for treating chronic bronchitis.