WO2010148262A1 - Treatment of acute pulmonary inflammation induced by cigarette smoking - Google Patents

Abstract

A cigarette being impregnated with corticosteroid is used to treat pulmonary inflammation, The active ingredient could be impregnated in the tobacco, paper, the filter - or any combination thereof.

Description

Treatment of Acute Pulmonary Inflammation Induced by Cigarette Smoking

RELATED APPLICATIONS

This application claims the priority of U S Provisional Patent Appl Ser No 61/187,895, filed on June 17, 2009

FIELD OF THE INVENTION

The invention relates to the field of drug delivery, more specifically to a cigarette that is impregnated with a corticosteroid thus allowing for passive and therefore automatic delivery of a required dose of anti-inflammatory medication to a smoker's lungs

BACKGROUND OF THE INVENTION

Cigarette smoke is known to cause lung cancer, Chronic Obstructive Pulmonary Disease (COPD) and cardiovascuiar disease As shown in Figure 1 It is believed that the common etiologic pathway for cigarette smoke induced lung cancer and COPD is pulmonary inflammation

Several decades of clinical experience and clinical trials in the treatment of both childhood and adult asthma have demonstrated that the regular use of inhaled corticosteroids can safely control and reverse pulmonary inflammation

In addition, as quoted below, initial data supports the use of inhaled corticosteroids in the chemoprevention of both COPD and lung cancer

Among a group of mostly older male veterans suffering from chronic obstructive pulmonary disease (COPD), an illness that offers a greater susceptibility to lung cancer, researchers found that regular use of high dose inhaled corticosteroids (!CS) lowered the risk of developing lung cancer

The results for this study appear in the first issue for April 2007 of the American Journal of Respiratory and Critical Care Medicine, published by the American Thoracic Society

David H Au, M D , M S , of the Veterans Administration Puget Sound Health Care System in Seattle, along with five associates found that among 10,474 patients with COPD, 517 were considered regular users of ICS

Among users of more than 1 ,200 micrograms of ICS per day, the relative risk for lung cancer was lowered to 0 39 For users of less than 1 ,200 micrograms per day, the relative risk was 1 13 (A relative risk of 1 means there is no difference in risk between two groups )

Over the next four years, the researchers found that among a total of 9,957 nonusers of ICS, 402 developed lung cancer For 298 users of ICS at a level below 1 ,200 micrograms per day, 16 developed lung cancer Among 219 patients who used over 1 ,200 micrograms per day, five developed lung cancer

"Lung cancer is the most common cause of cancer-refated death in the United States and accounts for more deaths each year than breast, prostate and colon- rectal cancer combined," said Dr Au "Studies such as the Lung Health Study have demonstrated that the most common cause of death among subjects with COPD is lung cancer "

In 2004, more than 11 million U S adults were estimated to suffer from COPD, which results from chronic bronchitis and emphysema, two inflammatory lung diseases that frequently co-exist and interfere with normal breathing Smoking is the primary cause of COPD "Tobacco smoke is a we 11- recognized stimulant of systemic and local inflammation and the roie of inflammation in the causal pathway for both lung cancer and COPD has been suggested," said Dr Au .

The researchers noted that ICS have been shown in prospective studies to suppress systemic markers of inflammation such as C-reactive protein and to reduce airway inflammation.

They hypothesized that higher doses of ICS among the male veterans reduced such factors as local airway inflammation, celt turnover, and the propagation of genetic errors Consequently, these effects couid lead to a subsequent reduction in lung cancer risk

In an editorial on the research in the same issue of the journal, York E Miller, M D , of the Denver Veterans Affairs Medical Center, and Robert L Keith, M D , of the University of Colorado Cancer Center, Denver, wrote:

"Although the data at present are certainly not definitive, inhaled corticosteroids deserve further consideration for lung cancer chemoprevention. Adequately powered, prospective, controlled trials with prolonged follow-up to capture effects on a carcinogenic process that progresses over years will ultimately be needed to determine efficacy If these could be designed to capture outcomes of interest relevant to both lung cancer and COPD, joint funding by the National Cancer Institute and the National Heart Lung Blood institute would then be desirable "

Prior art methods of administering an inhaled corticosteroid requires the continual use by the patient of either a metered dose spray inhaler, a metered dry powder inhaler, or a nebulizer These methods of corticosteroid dosage require continual, active patient intervention and are therefore only likely to be utilized by those highly motivated patients who already have established symptomatic disease SUMMARY OF THE INVENTION

This invention discloses the passive administration of inhaled corticosteroids by impregnation of the pharmaceutical agent into the filter of a cigarette or other smoking device Alternatively, corticosteroid is added with a proper solvent to tobacco or cigarette paper, or both, to create a drug-delivery device The dosage of added drug may be less than therapeutic doses or in accordance with therapeutic doses When a smoker ignites the cigarette, the temperature thereof will reach a sufficient temperature to vaporize the active ingredient. The active ingredient is drawn into a smoker's lungs when the cigarette is smoked

Corticosteroid could be added to any smoking device A "smoking device" herein, refers to any device in which a user inhales a dosage of nicotine, typically, but not necessarily as a result of combustion with tobacco, Smoking devices include, but are not limited to, cigarettes, cigars, pipes, hookahs, nicotine vaporizing devices, electronic cigarettes and the like Any such device wherein a measured dosage of anti-inflammatory drug is provided, such that when a user draws on the smoking device, anti-inflammatory drug is introduced into his/her lung is contemplated by the current invention Anti-inflammatory drug may be mixed with smoke or vapor - as the case may be, when drawn into the user's lungs

The invention has several fundamental advantages over the prior art

As the first passive method of administering a controlled dosage of an inhaled corticosteroid, the drug will be provided to those most likely to require it regardless of the presence of symptoms or their motivation to actively take the required medication As such, inhaied corticosteroids can now be utilized effectively as both a therapy for established pulmonary inflammation and more importantly for chemoprevention of cigarette smoke induced COPD and lung cancer

The degree of cigarette smoke induced pulmonary inflammation found in the patient is correiated with the number of cigarettes smoked each day The disclosed invention automatically provides a dosage of anti-inflammatory corticosteroid that is correctly correlated for this factor Since the known measured dose of the anti-inflammatory is included in each cigarette the more cigarettes the individual smokes the more of the anti-inflammatory drug he or she will automaticaliy receive

It is also important that the anti-inflammatory pharmaceutical be transmitted to the precise depth and location of lung tissue that is impacted by the inflammation inducing cigarette smoke This factor is an additional impediment to effective anti-inflammatory dosing using prior art active methods of administering inhaled corticosteroids Even if the patient will be motivated enough to remember to inhale their medicine regularly, they will often inhale their cigarette far more deeply than they will inhale their metered dose inhaler Since in the present invention the anti-inflammatory pharmaceutical is an automatic component of the same cigarette smoke that is causing the inflammation it is also automatically and passively applied to the exact lung tissue where it is required

BRIEF DESCRIPTION OF THE DRAWINGS

Fig 1 shows a schematic representation of the pathways leading from smoking to COPD and lung cancer

Fig 2 shows bottom, side and top views of a cigarette

Fig 3 shows front and side views of a cigarette filter having channels disposed therein, according to an embodiment of the invention

Fig 4 shows a side view of a filter having two segments, according to an embodiment of the invention DETAILED DESCRIPTION OF THE INVENTION

Embodiments of the present invention will now be described However, the description herein of the invention is not intended to limit the scope of the invention It will be understood that various modifications of the present description of the invention are possible without departing from the spirit of the invention Also, features described herein may be omitted, additional features may be included, and/or features described herein may be combined in a manner different from the specific combinations recited herein, ali without departing from the spirit of the invention

Referring to Fig 2, in a preferred embodiment a cigarette is treated with an anti-inflammatory corticosteroid, such as but not limited to, any one of the following:

1 beclomethasone dipropionate

2 budesonide

3 flunisolide

4 fluticasone propionate

5 triamcinolone acetonide

In a preferred embodiment, any of the above active ingredient is dissolved in a solvent at a desired concentration The tobacco is then immersed in the solution, withdrawn therefrom and then allowed to dry The tobacco 12 (showing through the top of the cigarette), as such, becomes impregnated with active ingredient, and is then used in a cigarette in a normal manner Additionally, or alternatively, the cigarette paper 14 is soaked in the above-described solution, such that it too becomes impregnated with active ingredient In another embodiment, the filter 16 (showing through the bottom end of a cigarette) of a cigarette is soaked in the above-described solution - thereby becoming impregnated with active ingredient.

Possible solvents to be used to dissolve the active ingredient include dimethyl sulfoxide (DMSO), dimethylformamide (DMF), methanol, ethanol or hot water

The combustion temperature of a cigarette during smoking is 600-750C This temperature is sufficient to vaporize at least a portion of active ingredient Once vaporized, it is delivered into a smoker's lungs mixed in the smoke he/she inhales,

Fluticasone propionate is one preferred corticosteroid as it is the most active corticosteroid for delivery via inhalation The relevant physical properties of Fluticasone propionate are:

1 room temp, appearance - white powder

2, melting point 272C

3. solubility - insol. in water, soluble in DMSO, DMF; slightly sol, in methanol or ethanol

4 surface tension 48 dynes/cm

5 flash pt 298C

6 boiling point 568C at 760 mm Hg

7 vapor pressure 2 79E-15 mm Hg at 25C

The maximum smoke temperature in the cigarette filter at a puff volume of 40- 100ml is 65-75C with a less than 55mm cigarette length.

In the above example of Fluticasone propionate, the vapor pressure of the active ingredient is 2 79E-15 mm Hg at 25C (i e room temperature) However, as the vapor pressure rises with heat, more active ingredient goes into the gas phase Vapor pressure increase also will impact active ingredient impregnated in the filter As the vapor pressure increases, more active ingredient will disassociate from the filter

In another embodiment of the invention, an anti-inflammatory inhalation corticosteroid such as any of:

1 beclomethasone dipropionate

2 budesonide

3 flunisolide

4 fluticasone propionate

5 triamcinolone acetonide

is added into a cigarette filter 16

in this embodiment, any of the above-mentioned particulate corticosteroid, is powder-coated or spray coated onto a cigarette filter Most preferably, the filter is so treated early in the manufacture thereof - while the fibers are not yet tightly bundled (e g while the filter materials are arranged as a tow - or even before) This allows for maximum acceptance of particulate corticosteroid

Particle cohesive forces are minimized or efiminated by using, for example, 50 meg microfine solids in 12 5 mg of 1-10 micrometer microfine lactose particles

Cigarette inhalation air velocity for a therapeutic dose is 60 L / min for 2 sec

In one embodiment of the invention, and as shown in Fig 3, a filter comprising particulate corticosteroid is provided with narrow channels 18 that open on the outside face 17 of the filter 16 and extend into the filter This allows for more access to particulate active ingredient that is trapped in the fibers thereof

In another embodiment of the invention, as shown in Fig 4, a filter comprises two segments A first segment 20 abuts and is continuous with the tobacco-containing portion 22 and the second segment 24 is the end that is the bottom end of the cigarette and the part that is introduced into a smoker's lips The first segment 20 comprises tightly bound filaments, whereas the second segment 24 comprises loosely bound filaments The second segment 24 is treated (for example, sprayed coated) with particulate active ingredient In this manner, the segment that is closest to the tobacco serves as a customary filter - blocking small tobacco pieces and other additives However, the second segment 24, which contains loosely associated fibers allows for particulate active ingredient to readily disassociate when a smoker draws on the filter

Amount of corticosteroid per cigarette may vary according to different embodiments of the invention For example, if a medicated cigarette is to be used strictly as a prophylactic device, a very low dosage per cigarette may be warranted

On the other hand, a person who is known to present with pulmonary inflammation may use the medicated cigarette to control, or as treatment for, such inflammation Such a smoker may require a higher dose of corticosteroid, so as to adequately treat the established inflammation

Using the example of a fluticasone propionate, the following are examples of possible dosage according to embodiments of the invention As shown, fluticasone propionate could be introduced into cigarettes at low, medium or high dosages In a low dosage cigarette, as little as 3 meg of fluticasone propionate is introduced into a cigarette If a smoker were to smoke a pack of cigarettes in a day (assuming that all active ingredient is inhaled), the maximum active ingredient that he/she will inhale is 60 meg - which is well below the recommended low dose for fluticasone propionate The medium dose cigarette comprises a dose of 15 meg If a smoker were to smoke a pack a day, the maximum amount of active ingredient inhaled is 300 meg, which is in the mid- range of the recommended dose for fluticasone propionate Finally, the high dose cigarette contains 30 meg of active ingredient If one were to smoke a pack of high-dose cigarettes in a day, the maximum inhaled dose would be 600 meg - which is in the high range of the recommended dose for fluticasone propionate

DOSAGE [meg]

LOW MEDIUM HIGH total daily 60 300 600 based on one box smoked mcg/cigarette 3 15 30 meg/box 60 300 600

It will be understood by those of ordinary skill in the art that corticosteroid need not be impregnated in the structures of a conventional cigarette Rather, in embodiments of the invention corticosteroid could be placed in a designated dosage chamber, such that it will be drawn into a user's lungs when he/she inhales on the smoking device

In an alternate embodiment, the corticosteroid can be added (in solvent solution, as described above) to the nicotine containing solution used in an electronic cigarette, also known as an e-cigarette or personal vaporizer An e- cigarette is a battery-powered device that provides inhaled doses of nicotine by way of a vaporized solution In this embodiment, the anti-infiammatory is automatically vaporized along with the nicotine and flavor and inhaled together with these components,

Having described this invention with regard to specific embodiments, it is to be understood that the description is not meant as a limitation since further modifications and variations may be apparent or may suggest themselves to those skilled in the art. It is intended that the present application cover all such modifications and variation as fall within the scope of the appended claims

Claims

What is Claimed is:

1 A smoking device, comprising: nicotine; and a measure dose of anti-inflammatory drug

2 The smoking device of Claim 1 , wherein said anti-inflammatory corticosteroid is selected from the group consisting of beclomethasone dipropionate, budesonide, flunisolide, fluticasone propionate, triamcinolone acetonide

The smoking device of Claim 1 , wherein said anti-inflammatory corticosteroid is combined with a solvent

The smoking device of Claim 1 , comprising a cigarette comprising tobacco and a filter, wherein said filter comprises particulate antiinflammatory drug

The smoking device of Claim 1 , wherein said smoking device comprises a cigarette, said cigarette comprising tobacco and a filter, wherein said filter comprises particulate anti-inflammatory drug

The smoking device of Claim 1 , wherein said smoking device comprises a cigarette, said cigarette comprising tobacco and a filter, wherein said tobacco is impregnated with anti-inflammatory drug

The smoking device of Claim 6, wherein said filter comprises channels disposed therein

The smoking device of Claim 6, wherein said filter comprises two segments, a first of said segments being continuous with a tobacco- containing portion of a cigarette and a second of said segments comprising the bottom end of cigarette

The smoking device of Claim 1 , further comprising a dosage chamber disposed in said device, said dosage chamber containing antiinflammatory drug

A method of treating pulmonary inflammation, said method comprising the steps of: impregnating tobacco or a filter with an anti-inflammatory corticosteroid; introducing said impregnated tobacco or said filter into a cigarette; igniting said cigarette; and inhaling smoke comprising vaporized active ingredient