CA2391728A1 - Anti-oxidant inhalant and method - Google Patents
Anti-oxidant inhalant and method Download PDFInfo
- Publication number
- CA2391728A1 CA2391728A1 CA002391728A CA2391728A CA2391728A1 CA 2391728 A1 CA2391728 A1 CA 2391728A1 CA 002391728 A CA002391728 A CA 002391728A CA 2391728 A CA2391728 A CA 2391728A CA 2391728 A1 CA2391728 A1 CA 2391728A1
- Authority
- CA
- Canada
- Prior art keywords
- antioxidant
- effect
- bht
- inhalation
- cigarette
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
Classifications
-
- A—HUMAN NECESSITIES
- A24—TOBACCO; CIGARS; CIGARETTES; SIMULATED SMOKING DEVICES; SMOKERS' REQUISITES
- A24D—CIGARS; CIGARETTES; TOBACCO SMOKE FILTERS; MOUTHPIECES FOR CIGARS OR CIGARETTES; MANUFACTURE OF TOBACCO SMOKE FILTERS OR MOUTHPIECES
- A24D3/00—Tobacco smoke filters, e.g. filter-tips, filtering inserts; Filters specially adapted for simulated smoking devices; Mouthpieces for cigars or cigarettes
- A24D3/06—Use of materials for tobacco smoke filters
- A24D3/14—Use of materials for tobacco smoke filters of organic materials as additive
Landscapes
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
This invention described here is designed for ameliorative or prophylactic u se by smokers or others who are at high risk of developing environmental induce d lung disease. In one embodiment this involves a cigarette filter-type device (24) comprising a pharmaceutically acceptable high-effect antioxidant such a s BHT or BHA provided in an inhalable therapeutically effective amount, and a method of manufacture and use.
Description
ANTI-OXIDANT INHALANT AND METHOD
Field of the Invention The invention described here is designed for ameliorative or s prophylactic use by smokers or others who are at high risk of developing environmental induced lung disease. In one embodiment this involves a cigarette filter-type device comprising a pharmaceutically acceptable high-effect antioxidant such as BHT, propyl gallate and BHA provided in an inhalable therapeutically effective amount, and a method of manufacture to and use.
Background of the Invention Damage caused by environmental aerosols, tobacco and other smoking products is clearly established in the literature. Chronic smoking is 15 associated with a number of health problems including cardiovascular disease, lung cancer, and local damage to the lung tissue which eventually develops into chronic obstructive lung disease. The term chronic obstructive lung disease is to be broadly understood to encompass emphysema, pulmonary fibrosis and a number of other chronic lung ao diseases.
As many as 177,000 Americans were diagnosed with lung cancer in 1998. Of those, about 106,000 were men and 71,000 were women.
Unfortunately, lung cancer usually remains undiscovered until a tumor has grown large enough to compromise respiration or another physiological system, at which point the prognosis is poor. Experience indicates that only 1 out of 8 of patients diagnosed with primary lung cancer survives 5 years.
s Resources have been expended on developing new treatments for lung cancer. Abstinence counseling has been ineffective in reducing smoking among teenagers, and teenage smoking has been found to lead to lifelong addiction. Little effort has been directed toward preventing lung cancer in continuing smokers. The reality is that, despite the active to education campaign, 48,400,000 adults and 4,100,000 teenagers in the United States continue to smoke (1.1 billion smokers worldwide). In 1996, 487 billion cigarettes were consumed in the US.
Without being bound by any particular theory, it is believed that a malignancy results from a multi-step process; a cascade of events. Some 15 researchers believe that tumors evolve from a single cell that has mutated to become malignant. In some, if not all cases, several mutations must take place for a cell to become malignant.
In recent years, many researchers have described genetic abnormalities found in malignant cells. These genetic changes consist of ao several types of mutation. Some are point mutations that change some part of the reading frame of a gene. If present in the coding portion of a peptide, this type of mutation can produce an altered protein. Frequently, altered proteins fail to perform their customary physiological functions. In some instances this poses a health risk. In some instances, the altered protein is, itself, a health risk. Alternatively, a point mutation could alter the behavior of a non-coding region of the genetic material, affecting the control mechanisms that choreograph the timing of gene expression or the s quantity of material produced. Another type of mutation is a genetic translocation whereby two strands of DNA become displaced, such that a portion of part A crosses over to become affixed to part B. In a translocation event, a whole series of genes can shift to become subject to control elements that, in normal physiology, control an entirely different set to of genes. This can produce devastating physiological effects. For example, such effect may arise in genes whose normal function requires precise control that is lacking in the displaced condition. A third, related, type of mutation is an alteration in gene amplification, in which the number of copies of a gene is increased. This, too, can have adverse 15 consequences.
Appreciation and understanding of the complexity of this process is limited by an incomplete knowledge of the normal function of these genes whose function is implicated in the cascade that leads to malignancy. It does not appear that a single universal genetic alteration is present in all ao cancerous cells. Certain genes, such as p53, are implicated in a great number of cancers, but there are many malignant cells that do not appear to have any alteration in p53. Multiple possible paths which independently produce malignant cell. It appears that "oncogenes" (mutated forms of WO 01/10252 PCT/fJS00/21902 normal gene product) can cause healthy cells to become malignant when they are inserted into its DNA. Others, called "tumor suppressor genes"
are believed to act by preventing cells from uncontrolled proliferation.
These and other types of alterations may be required to convert a cell to s malignancy.
Tobacco smoke contains numerous compounds that are deposited in the lungs. As many as 3,000 different chemicals have been identified in tobacco smoke. It is believed that smoking associated disease are caused by these chemicals, acting alone or in concert with other chemicals. Some to of these compounds are known carcinogens of the class termed mutagens.
Mutagens are compounds which increase the rate of mutations in exposed cells. While most mutations are not associated with cancer, some are.
The accumulation of mutations in cells over time increases the chance that one cell will convert into a state of uncontrolled growth and become an i5 invasive tumor. A carcinogenic chemical agent may begin a process that will lead to a cancer in some cell, but there is no disease until the threshold of cellular conversion to uncontrolled replication is reached.
Some researchers believe the process by which the carcinogens that are in smoke cause mutations is by generation of free radicals that interfere ao with DNA-protein interactions which produce permanent changes in the DNA. An example of this class of carcinogens is the family of compounds called nitrosamines. Certain nitrosamines, for example, 4 - (N
nitrosoamino) - 4- (3 pyridyl) - 1 -butanone, have been reported to be carcinogenic, or procarcinogenic. By procarcinogenic it is meant that metabolites of the compounds are carcinogenic or of greater carcinogenicity than the unmetabolized compound. In some instances, free radicals increase the mutagenic activity of nitrosamines and other substances in s tobacco smoke.
Free radicals are species whose outermost electron is unpaired.
Often free radicals are associated with oxygen, as in an hydroxide or nitric oxide or superoxide, but they can involve other molecules as well. Usually free radicals are short lived and highly reactive. When proximate, releasing to the energy of a free radical dislocates interactions of proteins and nucleic acids in DNA in an active state such as DNA synthesis or repair, and thereby causes mutation. Superoxide is an OZ molecule that has an extra electron: OZ-, hydrogen peroxide is HZOZ and the hydroxyl radical is an OH
molecule that dissociated from water and is highly reactive: OH°.
i5 Oxygen free radicals exert their effect by binding to biological molecules such as lipids, proteins and DNA. One important reaction caused by oxygen free radicals is formation of peroxide intermediates in the unsaturated fatty acid moieties of cell membrane lipids. These oxidized intermediates can then propagate to interfere with the protein:DNA
2o interactions that leads to mutation, which can ultimately eventuate in conversion to malignancy.
Free radicals are ubiquitous and are normally part of many metabolic processes. Mammals produce natural anti-oxidants to neutralize free radicals. For example, the enzyme catalase converts hydroxide anion and hydrogen peroxide to water and oxygen. Superoxide dismutase is another enzyme that converts superoxide to H202. In addition to enzymes, there are small molecule anti-oxidants such as glutathione and alpha-tocopherol.
s Other potent anti-oxidants commonly used in the food industry include ("BHT") also termed 2, 6-bis( 1,1-dimethylethyl)-4-methyl-phenol or 2,6-di-tert-butyl-p-cresol, and butylated hydroxy anisole ("BHA") with the systematic name ( 1,1-dimethylethyl)-4-methoxy phenol, and propyl gallate with the systematic name 3,4,5-trihydroxy-benzoic acid, and propyl ester.
to Aspects of BHT are discussed in Witschi et al., "Metabolism and Pulmonary Toxicity of Butylated Hydroxytoluene (BHT)," Pharmac. Ther., Vol. 42, pp 89-1 13 (1989) the teachings of which are incorporated herein by reference.
One approach to reducing the long term effect of chronic exposure to 15 mutagens is regular treatment with anti-oxidants to interfere with free radicals before they cause damage. Dietary anti-oxidants are available in many forms, including food supplements and food preservatives.
It is the particular advantage of this present invention to apply an effective dose of high potency anti-oxidants topically to the lung epithelium ao where they directly act on the free radicals present in the lungs.
Another aspect of the present invention concerns retinoids.
Retinoids have also been considered in monodrug antineoplastic therapy both for the treatment of cancer and for cancer prevention. Retinoids are a family of isoprenoid compounds that include beta-carotene, vitamin A, retinal, retinoic acid, etc. Dietary beta-carotene is metabolized to produce two retinol molecules. Retinol is an essential vitamin. Vitamin A circulates in a protein complex called retinol binding protein. Retinol collects in cells s that have receptors for this complex, most notably epithelial cells. In the specialized cells of the retina, it is converted to the aldehyde form, retinal, the visual pigment of the eye. Vitamin A deficiency is associated with a number of effects, including night blindness, abnormal keratinazation of the skin, dry skin and conjunctiva) abnormalities.
to Retinoic acid is an intracellular signal molecule that acts directly on a nuclear receptor to catalyze the expression of a unique sequence of genes.
There are two families of currently identified retinoic acid receptors, RAR
and RXR. Two isomeric forms exist for the double bonds in the retinoid isoprene chain; cis and trans. Note that cis and trans double bonds can be 15 at various lications such as 13-cis and 9 cis etc. Retinoic acid promotes cellular differentiation and plays an important role in the timing of expression in embryonic development. It is known to be teratogenic in pregnant animals. 13-cis retinoic acid (isotretinoin) is effective topically in the management of acne through its direct action on keratinocytes. All-ao trans retinoic acid (tretinoin), isotretinoin and 9-cis retinoic acid have been shown to have antiproliferative effects on cultured leukemia cells, as have a number of synthetic analogs. The antiproliferative effect has been shown to have clinical utility in the management of cancer in certain settings when used as oral formulations.
Despite successes, other retinoid clinical trials have proven disappointing. For example, a recently published trial using a retinoic acid s derivative that, in laboratory tests was more potent than the natural compound, was ineffective in patients who were long term smokers. Kurie et al., "4-Hydroxyphenylretinamide in Reversal of Bronchial Metaplasia and Displasia In Smokers," Proceedings of ASCO 18:473a (1999) (American Society of Clinical Oncology, Atlanta, VA) found no significant effect from to an oral retinoid administration. Parthasarathy et al., "Aerosol delivery of liposomal all-trans-retinoic acid to the lungs," Cancer Chemotheraay Pharmacol 43(41:277:277-83 (1999) notes aerosol delivery of lipsosmal ATRA as an anti-inflammatory accompanying cancer chemotherapy.
15 Summary of the Invention Ingested dietary anti-oxidants distribute throughout the body upon ingestion and do not reach adequate levels in the lungs. A novel aspect of the present invention is in the combination of high effect, lipophilic antioxidants engaged with the lipid medium of the lungs to interdict the ao propagation of nuclear mutations. Without being bound by ant particular theory, hydrophilic anti-oxidants tend to clear more quickly than lipophilic antioxidants. In addition, hydrophilic antioxidants do not partition in lipids.
This reduces the efficacy of DNA protection afforded by hydrophilic antioxidants by reducing entry into the cell nucleus. In particular embodiments, high effect, lipophilic antioxidants are delivered in combination with an antiproliferative agent such as a retinoid.
This invention includes a cigarette filter-type device comprising a s pharmaceutically acceptable high-effect antioxidant, and particularly antioxidant present in an inhalable therapeutically effective amount. In particular embodiments antioxidant is present in at least about 0.2 to about 1.5 milligrams and particularly about 0.5 to 1 milligram. In some embodiments the device further comprises a pharmaceutically acceptable to volatile compound admixed with the antioxidant and or a therapeutically effective amount of a pharmaceutically acceptable retinoid such as all-trans retinoic acid or 13-cis retinoic acid.
Noted are high-effect antioxidants selected from the group comprising BHT, BHA or propyl gallate.
i5 Further included is a particular cigarette filter-type device, which comprises:
(a) an outer elongate cylinder of tobacco smoke filter material, (b) an inner elongate cylinder generally coextensive with the outer elongate cylinder of (a), and the inner elongate cylinder comprising high-effect antioxidant in ao powder form in inhalable therapeutically effective amount with the powder of averaged particle size of less than about 6 u, and in some instances less than about 2 u.
One specific cigarette filter-type device of this invention comprises an outer elongate cylinder of tobacco smoke filter material said device further comprising rupturable microcapsules comprising high-effect antioxidant, optionally in powder form. Noted is rupturable microcapsules s comprising high-effect antioxidant and optionally retinoids such as ATRA.
In some instances the microcapsules further comprise a pharmaceutically acceptable high-effect antioxidant solvent.
The invention yet further includes an aerosol device comprising a therapeutically effective amount of a pharmaceutically acceptable high-to effect antioxidant in diluent-propellant. Useful high-effect antioxidant is selected from the group comprising BHT, BHA or propyl gallate. Some aerosol devices are metered dose devices or pump type devices. These devices are usefully configured to deliver aerosol averaged particle sizes of less than about 6 u, and optionally particles of less than 2 u. A particular metered dose device uses BHT in an amount of at least about 300 mg in about 15 ml diluent-propellant. Also noted is BHT in an amount of at least about 30 mg/1 ml diluent-propellant.
This invention also includes a method of treating deep lung surfaces to provide an lipid peroxidation-mitigating surface by the step of inhaling at ao least about .5 mg of high-effect antioxidant, optionally in averaged particle sizes of about 6 microns ("p") or less including about 2 p or less. In one embodiment the method is accomplished by means of a cigarette filter-type device. In such method the high-effect antioxidant is selected from the group comprising BHT, BHA or propyl gallate. Alternatively the method is by means of an aerosol device. In practicing the method in one embodiment it is contemplated that at least about 15% of a subject's alveolar surface is treated with at least about 12 nanograms/m2.
s This invention further includes a method of creating a lipid peroxidation-reductive deep lung surface by the process of inhaling at least about .5 mg of high-effect antioxidant such as BHT, BHA or propyl gallate and at least about 1 mg retinoid, wherein said antioxidant and retinoid of averaged particle sizes of about 6p or less. In one example inhalation is by to means of a cigarette filter-type device, optionally co-timely, coordinated or coincident with inhalation of tobacco smoke.
Brief Description of the Drawings Fig 1. is a diagrammatic representation of a cigarette filter-type device attached to a cigarette.
15 Fig 2. is a diagrammatic representation of a cigarette filter-type device attached to a cigarette.
Fig 3. is a diagrammatic representation of a cigarette filter-type device with rupturable microcapsules.
Fig. 4. is a diagrammatic representation of a metered dose inhaler.
ao Fig. 5. is a diagrammatic representation of a pump type inhaler.
Detailed Description of the Invention This invention will be better understood with reference to the following definitions:
A. "Therapeutically effective amount" as to high-effect antioxidant administered on a daily basis shall mean at least about 0.5 mg per s day. For particular antioxidants, BHT, propyl gallate or BHA about 0.5 to about 10 mg and in a particular embodiment about 0.5 to about 1.5 mg, and particularly about 1 mg are therapeutically effective, but further noting about 1.5 mg to about 3 mg, and further up to about 5 mg.
to It is to be understood that therapeutically effective amount doses are also conveniently administered as divided doses on a "per cigarette" basis such as by placing antioxidant in a cigarette. As to inhaled smoke or an air/smoke mixture, about 1 ng of antioxidant /cc of inhaled smoke (including particulates) is therapeutic, with particular reference to about 15 100 to about 400 ng/cc.
In a multiple use cigarette filter, anticipating at least about 5 cigarettes being smoked daily from about .5 to about 2 ng/cc of inhaled smoke are therapeutically effective doses.
A cigarette filter type device which contains from about 0.1 to about ao 10 mg of high effect antioxidant is therapeutically effective. This range has a breadth, in part, due to the variability by which the antioxidant will mobilize from different filter materials, their compaction and the airflow during smoking.
As to an aerosol or pump type inhaler a delivered dose of about .5 to about 1.5 mg, and particularly about 1 mg is therapeutically effective. In a metered-dose inhaler a therapeutically effective amount is about 1 mg in a vapor or aerosol volume of from about 0.01 cc to about 0.2 cc. In a s nebulizer providing about 1 to about 5 cc of aerosol, a concentration of antioxidant of from about 0.2 to about 1 mg/cc is therapeutically effective.
In one embodiment from about 1 to about 5 cc is the volume of liquid put in the nebulizer. That volume is dispersed in the air by the nebulizer.
Typically the pressure unit produces 3 to 10 liters per minute, and runs for l0 3 to 15 minutes. In this example, this volume of air is about 20 to 80 liters.
B. "Deep lung" shall mean the ends of the bronchial tree, in the region called the respiratory zone, where the bronchial walls are open to exchange of gases.
C. High-Effect Antioxidant including BHT, BHA, propyl gallate, 15 anthocyanins shall mean that the general class of antioxidants displays at least about twice the anti-oxidant effect measured over time as alpha-tocopherol. In one embodiment of such a test, a standard vial of unsaturated phopspholipid and alpha -tocopherol are maintained at 37°C. By visual inspection the phospholipid material ao will turn brown in about 1 month. An equimolar amount of BHT or BHA or other high-effect anti-oxidant will keep a standardized amount of unsaturated phopspholipid from browning for at least twice as long.
WO 01/10252 PCT/fJS00/21902 Alternatively, free radical scavenging activities can be determined by a number of methods. Reference is made to Maulik G, et al., "Evaluation of antioxidant effectiveness of a few herbal plants," Free Radic Res Aug;27(2):221-8 (1997), the teachings of which are incorporated herein by s reference. One method of determining free radical scavenging is by chemiluminescence. Peroxyl radical is generated from 2,2'-azobis(2-amidinopropane) dihydrochloride (AAPH), superoxide radical (02-) from xanthine/xanthine oxidase (X0) and hydroxyl radical (OH) from Xanthine/XO/FeCl3/ EDTA. In addition, 02- and OH. scavenging activities to are determined by cytochrome C reduction and deoxyribose oxidation methods, respectively.
There are also many pharmaceutically acceptable high-effect anti-oxidants including plant extracts, water soluble anti-oxidants include vitamin C, sorbates, citric acid, thioesters and other sulfur reducing agents, i5 such as methionine, taurine, cysteine and glutathione. Lipophilic anti-oxidants include both natural and synthetic compositions. The carotenoids and tocopherols are of lesser effect. Another category of high-effect antioxidant is the isoflavone derivatives, such as Bachanin A. There are also phenols/0-methyl phenols including BHA, BHT, propyl gallate, 2o tertiary butyl hydroquinone, curcumin, eugenol, and ferulic acid. Also noted are salen-metal complexes such as those described in US 5,696,109 to Malfroy et al., the teachings of which are incorporated herein by reference.
D. "Aerosol device" shall be broadly understood to encompass pressurized and non-pressurized (spray) devices either of which may include spacers, and electrohydrodynamic devices. These devices include metered-dose inhalers, atomizers, piezo electric aerosol s generators, powder blowers or powder insufflators, vaporizers and nebulizers. A number of aerosol devices are described in Pharmaceutical Dosage Forms and Drua Delivery stems, Ansel et al., Sixth Ed. (Williams & Wilkins, Media Penn., 1995) as well as Ranucci et al, "Effect of Actuator Design on Metered-Dose Inhaler to Plume Particle Size" Pharmacology Technoloq_y 16(31:84-92, ( 1992), the teachings of which are incorporated herein by reference.
In practice pressurized aerosol devices are pressurized from about 25 to about 55 pounds per square inch gauge (psig). This invention is not to be limited by the device used to provide inhalable high effect antioxidants.
15 Of the many suitable devices, mention is made of pump inhalers, metered-dose inhalers, and electrohydrodynamic aerosol generators and other devices are also conveniently employed with enhancers such as spacers and the like. Note is made of the metered dose inhalers marked under the following names: Tidal InhalerT"' from Fisons, AzmacortT"" from Rhone-ao Poulenc Rorer, BecloventT"" and FloventT"~ from Glaxo Wellcome AiromirT""
from 3M Healthcare, and dry powder inhalers such as Pulmicort TurbohalerT"" from Astra and Severent DiskkhalerT"" from Glaxo Wellcome.
Also noted are electrohydrodynamic aerosol devices such as are described in US 5,91 15,377, US 5,813,614 and US 5,655,517 the teachings of which are incorporated herein by reference. Aerosol devices are also employed with diluent-propellants which encompass respiratory aerosol delivery adjuncts including surface-active agents, solvents, propellants such s as liquified gas or a mixture of liquified gases (e.g., chloro-fluorocarbons, dichlorodifluromethane, dichlorotetrafluroethane, trichloromonofluroethane, octafluorocyclobutane), non liquified compressed gases /e.g., carbon dioxide, nitrogen, nitrous oxide) and diluents and solvent such as water and ethyl alcohol. Two- and three-phase systems are noted as well as to compressed gas.
Aerosols produced by pressurized metered dose inhalers generally conform to "log-normal" functions. Aerosols are produced by many devices including a piezo-electric device that provides an ultrasonic vibration and devices that deliver dry powder aerosols. Drug delivery i5 properties of log-normal functions are frequently characterized by mass mean aerodynamic diameter (MMAD) and geometric standard deviation (GSD) values. Note is made of Raabe, "Particle Size Analysis Utilizing Grouped Data and Log-Normal Distribution," J. Aerosol. Sci, 2:289-303 ( 1971 ), Martonen et al., "Deposition Patterns of Aerosolized Drugs Within ao Human Lungs: Effects of Ventilatory Parameters," Pharmaceutical Research, 10(6):871-878 (1993), and Martonen et al., "Use of Analytically Defined Estimates of Aerosol Respirable Fraction to Predict Lung Deposition Patterns," Pharmaceutical Research, 9(12):1634-1639 (1992), the teachings of which are incorporated herein by reference.
E. "Co-timely" shall mean administration of a high-effect antioxidant while tobacco smoke is being inspired.
s F. "Coordinated" refers to mean pre- and post- dosing via inhaler or the like. "Coordinated" in the practice of the present invention refers to administration of a high-effect antioxidant in a therapeutically effective amount within at least about 1 to 30, or about 60 to 120 minutes before/after smoking a tobacco cigarette, and particularly to about 5 minutes or less prior to cigarette smoking G. "Coincident" refers to a combination drug therapy with a retinoid and a high-effect antioxidant. Coincident means dosing comprising administration of a retinoid while a high-effect antioxidant is present in at least about a therapeutic amount on the lung surface (or "in i5 delivery" to the lung surface), and potentially in higher concentrations. In a preferred embodiment of coincident administration, both drugs are administered in a single aerosol.
H. "Cigarette filter-type device" shall mean a device affixed or affixable to the downstream end of a cigarette. In the usual case the 2o downstream end of a cigarette is the end nearer the mouth of a smoker, with the cigarette filter-type device being inserted directly into the lips or mouth of the smoker or via a cigarette holder. The term is broadly construed to include filter-type devices which include filamentous materials typically employed to remove tars and other substances from smoke, but also to include the addition of drugs, flavorant and the like to smoke even when no substance is removed from the smoke. Further the term contemplates such devices as s affixed to cigarettes when manufactured forming a single unit, such devices as provided after cigarette manufacture and affixed later such as when smoking the cigarette begins, and the device as inserted or contained within a cigarette holder, in which the cigarette is inserted prior to smoking the cigarette. Cigarette holders are to generally characterized as having mouthpieces, often similar to those found on pipes.
"Cigarette" is a term to be broadly understood to include smoked tobacco type devices such as typical paper wrapped cigarettes, as well as plant leaf or otherwise wrapped cigarettes, and further i5 including cigars, pipes, hookahs and the like. It is also understood to mean, generally, a reference to smoked tobacco containing items, but other smoke producing products for purposeful smoke inhalation such as marijuana are also contemplated within the term.
J. "Inhalable" is a term referencing the amount of drug within a filter ao that will be inhaled in at least about 500cc of inhaled air and or smoke in the process of smoking a cigarette.
K. "Retinoid" shall mean natural and synthetic derivatives of vitamin A
(retinol). Isotretinoin and tretinoin represent two naturally occurring isomers of retinoic acid. Many other synthetic analogs have also been studied, including etretinate. Tong, et al., WO 97/3974 "Use of Inhaled Retinoids in the Prevention of Cancer," the teachings of which are incorporated herein by reference. Without being bound s by any particular theory it is believed that retinoic acid activates receptors in cell nuclei, notably RAR and RXR receptors which can result in significant physiological changes. Such changes include anti-proliferative effects and/or differentiation. Other retinoids may require processing by elements in the cytosol before they become to active in changing the pattern of transcription.
Without being bound by any particular theory, it is believed that retinoids act by inducing differentiation. A variety of in vitro studies have demonstrated the specialized ability of retinoids to induce terminal differentiation and inhibit growth of several human leukemia cell lines and 15 bone marrow cultures obtained from patients with acute myelogenous leukemia. These studies and many others done in murine cell lines provide a scientific foundation for the in vivo use of retinoids to treat certain types of leukemia. Data suggest that retinoids induce growing cells to mature to become end-stage cells that are no longer capable of dividing.
ao This property has been tested in clinical trials. Clinical activity of retinoids has been demonstrated in many diverse premalignant conditions including squamous cell carcinomas of the skin, basal cell carcinomas, cutaneous T-cell lymphomas, and leukoplakia. Patients who have demonstrable premalignant lesions and are treated with retinoids are less likely to develop malignancies, compared to patients who were not treated with retinoids.
L. "Therapeutically effective" as to retinoid doses will vary with the s presenting condition and subject.
In practice, dosing followed by lung biopsy offers an empirical end point for retinoid dosing and is within the skill of the medical practitioner.
As a general guide, attention is drawn to doses of about .1 to about 20 mg total delivered retinoid dose and in a particular embodiment about 0.25 to to about 10 mg, and more particularly about .5 to about 5 mg, as well as from about 10 to about 15 mg.
Daily total retinoid dosages such ad ATRA of from about 0.1 to about 15 mg/day are contemplated. Particular reference is made to daily doses of up to about 6 mg.
15 It is to be understood that total daily doses are variable. Many factors including smoking or inhalation "style," amounts of therapeutic agent per cigarette, and the number of cigarettes smoked effect total daily dosage. It is contemplated that a health professional will monitor a subject for symptoms or indicia of hypervitaminosis or build up of therapeutic agent 2o and reduce (or increase) doses accordingly.
Representative Devices Fig 1 . is a diagrammatic representation of a cigarette filter-type device (4) attached to a tobacco containing segment (2) of a cigarette (10).
Tobacco is noted as (8) and a filamentous filter material is noted as (6). In some embodiments the high-effect antioxidant or anti-mutagen comprises a coating on the filter material or a powder intermingled with the filter material.
s Fig 2. is a diagrammatic representation of a cigarette filter-type device (24) attached to a tobacco containing segment (22) of a cigarette (20). Tobacco is noted as (28) and a filamentous filter material is noted as (26). An additional element of the cigarette filter-type device (24) is high-effect antioxidant in powder form (27) in carrying tube (23) in air or smoke to flow connection with abutting tobacco containing segment (22). Porous filter material plugs (21 ) contain the powder (27) in tube (23).
Fig 3. is a diagrammatic representation of a cigarette filter-type device (34) with rupturable microcapsules (38) containing high effect antioxidant and or anti-mutagens dispersed amidst filamentous filter (36).
15 A tobacco containing element is shown in phantom (32).
Fig. 4. is a diagrammatic representation of a metered dose inhaler (40). Holder (42) supports a pressurized container (46) comprising antioxidant and propellant in connection with metered delivery element (44). Upon downward pressure on the pressurized container (46) metered ao delivery element (44) delivers an aerosol mist directed through opening (48).
Fig. 5. is a diagrammatic representation of a pump type inhaler (50).
Container (52) holds a solution or suspension (54) comprising high effect antioxidant and solvent/carrier liquid propellant in connection with pump means (58) in connection with atomizer head (56).
Methodological Aspects Dosing smokers with appropriate amounts of high-effect antioxidant s requires particular attention. It is appreciated that in specific instances, dosing subjects with compromised respiration or lung elasticity or function will necessarily deviate from preferred ranges. In some instances, modified inspiratory regimens are required. With aerosolizing devices, multiple inhalations are required by certain individuals to dose bronchiole or alveolar to surfaces to a specific level. In some instances, positive pressure ventilation is required to introduce high-effect anti-oxidant into the lungs of compromised subjects or to introduce dosages in controlled amounts or to specific depths.
Smaller alveoli produce lung surfactant which coats the inside of the i5 sac, reducing surface tension and stabilizing them. Lung surfactant is a mixture of several apoproteins and phospholipids. It is produced by type 2 cells of the alveoli, and is secreted into the lumen. There is an active recycling process whereby surfactant is absorbed and its components reassembled into surfactant for secretion. This lining of surfactant is a 2o target for oxidative damage by inhaled free radicals. Lipid peroxides produced by oxidation can propagate the damage inside the cells lining the airways, sometimes causing mutations. The lining surfactant is also the target for lipophilic anti-oxidants. The surfactant provides a bed to sustain levels of high effect anti-oxidant in the milieu where they can maximize their benefit.
It is to be understood that in some subjects, often associated with respiratory pathologies, a physiological dead space is present distinct from s the anatomic dead space. Certain alveoli will be either over or under ventilated under "at rest" conditions. The volume of gas in non-perfused alveoli and any volume of air in the alveoli in excess of that necessary to arteriolize the blood in the alveolar capillaries is part of the dead space (non-equilibrating) gas volume. Without being bound by any particular theory, in to the instant invention it is thought that an anti-oxidant such as BHA or a combination of BHT and BHA will eliminate or neutralize some free radicals and reduce the mutation rate in the lungs. By reducing the overall mutation rate the user has a reduced incidence of or delayed development of lung cancer.
15 Delivery of the anti-mutagenic therapy of this invention is usefully in aerosol form. Aerosol form refers to the condition of the inspired drug upon exiting the aerosol device. It is contemplated that a spray in aerosol form encompasses aqueous and oleaginous droplets. In some embodiments aerosol form is a dry powder. In some embodiments the ao aerosol form begins as a dry powder and in some the aerosol begins as a droplet of drug and volatile carrier, wherein the carrier evaporates leaving a dry powder. In yet other forms, the spray is droplets containing drug particle or liposomes containing drug. Noted volatile carriers are lower alkyl alcohols such as ethanol and isobutanol. When used withing filter type devices volatile carriers are usefully contained in rupturable microcapsules Powders for inhaled administration are also contemplated. In some embodiments powders are dusted directly onto filter material. These may s be prepared by any of a number of methods well known in the art. By way of example, a useful preparation is similar to that for cromolyn sodium.
The therapeutic is compacted with lactose in particle size of about 30-60 p, while the cromolyn is from about 1 to about10 p. The capsule of lactose and drug is broken capsule and placed in inhaler a powder, e.g. SpinhalerT"' to from Fisons. Upon inhalation, the larger lactose particles do not proceed beyond the upper airways while the smaller drug particles are inspired into the deeper lung. Reference is made to Ranucci et al., "Phase Doppler Anemometry: A Technique for Determining Aerosol Plume-Particle Size and Velocity," Pharmaceutical TechnoloQV, 17:62-73 (1993) the teachings of 15 which are incorporated herein by reference.
In one embodiment, this invention comprises is a product that is inhaled to cover the surface of the lungs, and optionally accompanied by printed and pictorial instructions for use. Inhalation raises the levels of these nutritional and/or anti-oxidant supplements to an effective level in and zo on the target tissue. In a specific embodiment the drug is administered once a day from a device that is inexpensive to manufacture, and is discarded after a few uses.
A related aspect of the present invention is to employ the therapeutic agents of the persent invention in "smokeless" tobacco products such as snuff and chewing tobacco. In such instances the therapeutic effect as to the surface of the oral cavity is noted.
s One particular embodiment of the therapeutic device of the present invention comprises a means for delivery of a combination of an anti-oxidant and retinoid (e.g., retinoic) to the lungs of a subject. Attention is drawn to "at risk" subjects. Particularly "at risk" subjects are tobacco smokers, ex-smokers, subjects with long term exposure to such hazards as to asbestos and hay, as well as miners of coal, uranium, beryllium and the like.
Cigarette Filter-Type Devices Fibre- or filament-containing filters for cigarettes are well known. In one form of construction, the filter body consists of a tow of continuous i5 filaments, commonly cellulose acetate (acetate) filaments, arranged parallel to the long axis of the cigarette. In another form of construction, the filter body consists of pleated or fluted paper compressed into a cylinder. Such forms of construction contain a single filter element and may be called "mono" filters. Another form of construction is the so-called "dual" filter ao which contains two filter elements, for example a paper filter towards the interior and a tow filter towards the exterior of the cigarette. A further form of construction is the so-called "triple" filter, which resembles a dual filter except that a quantity of a third substance such as activated carbon is interposed between the two filter elements hereinbefore mentioned.
Attention is drawn to US 5,839,448 to Woodings, the teachings of which are incorporate herein by reference.
In some cigarette filter-type devices active or aromatic substances s are introduced from the device into the smoke inhaled from a cigarette in order to modify its taste or to confer additional properties. For example, U.S. Pat. No. 3,991,773 and U.S. Pat. No. 3,635,226 describe mechanisms for humidifying cigarette smoke by including rupturable capsules or micro-capsules filled with a liquid, within the filter of the to cigarette. The smoker obtains the humidification effect by squeezing the filter to rupture the capsules prior to smoking. In some instances, liquid incorporated in the capsules contains flavorings or a synthetic saliva solution, for example. U.S. Pat. No. 4,498,485 discloses the inclusion of interferon into the tobacco of a cigarette for administering it directly to the 15 lungs of the smoker. Note is made of US 5,472,002 to Covarrubias the teachings of which are incorporate herein by reference.
Example 1 A BHA mixture for application to the filter material is compounded as follows:
ao BHA 1 mg is dissolved in 1 cc of ethanol. The solution is applied to a conventional cellulose acetate cigarette filter and air dried. The filter is then affixed to the end of a tobacco cigarette.
Example 2 A 24 year old female smoker is provided with a filter cigarette of Example 1. She smokes the cigarette in her normal manner inhaling the tobacco smoke. In the course of smoking the cigarette she inhales at least s about .5 mg of BHA.
Example 3 A BHT mixture for application to the filter material is compounded as follows:
to BHT, 0.8mg is dissolved in .5 cc of ethanol. The solution is applied to a conventional cellulose acetate cigarette filter and air dried. The filter is then affixed to the end of a tobacco cigarette.
Examale 4 15 A 67 year old male smoker is provided with a filter cigarette of Example 3. He smokes the cigarette in his normal manner inhaling the tobacco smoke. In the course of smoking the cigarette he inhales at least about .4 mg of BHT.
2o Example 5 A BHT-ATRA mixture for application to the filter material is compounded as follows:
BHT 1 mg and .5 mg ATRA are dissolved in 1 cc of ethanol. The solution is applied to a conventional cellulose acetate cigarette filter and air dried. The filter is then affixed to the end of a tobacco cigarette.
s Example 6 A 35 year old male smoker is provided with the cigarette of Example 5. He smokes the cigarette in his normal manner inhaling the tobacco smoke. In the course of smoking the cigarette he inhales at least about .4 mg of BHT and at least about .2 mg ATRA.
to Example 7 A BHT-ATRA mixture for application to the filter material is compounded as follows:
BHT 1 mg and .5 mg ATRA are encapsulated in rupturable is microcapsules each containing about 0.1 mg of the mixture. The rupturable microcapsules are located in cigarette filter-type material and the filter affixed to a cigarette.
Example 8 ao An 18 year old male smoker is provided with the cigarette of Example 7. With thumb and forefinger pressure on the cigarette filter he ruptures the microcapsules within the filter and their contents is distributed within the filter material. Promptly thereafter he smokes the cigarette in his normal manner inhaling the tobacco smoke. In the course of smoking the cigarette he inhales at least about .5 mg of BHT and 0.4 mg of ATRA
creating an lipid peroxidation-reductive deep lung surface.
Example 9 s A BHT mixture for application to the filter material is compounded as follows:
BHT 1 mg is encapsulated in rupturable microcapsules each containing about 0.1 mg BHT. The rupturable microcapsules are located in cigarette filter-type material and the filter affixed to a cigarette.
to Example 10 A 35 year old male smoker is provided with the cigarette of Example 9. With thumb and forefinger pressure on the cigarette filter he ruptures the microcapsules within the filter and their contents is distributed within 15 the filter material. Promptly thereafter he smokes the cigarette in his normal manner inhaling the tobacco smoke. In the course of smoking the cigarette he inhales at least about .5 mg of BHT.
All publications mentioned herein above are hereby incorporated in their entirety by reference
Field of the Invention The invention described here is designed for ameliorative or s prophylactic use by smokers or others who are at high risk of developing environmental induced lung disease. In one embodiment this involves a cigarette filter-type device comprising a pharmaceutically acceptable high-effect antioxidant such as BHT, propyl gallate and BHA provided in an inhalable therapeutically effective amount, and a method of manufacture to and use.
Background of the Invention Damage caused by environmental aerosols, tobacco and other smoking products is clearly established in the literature. Chronic smoking is 15 associated with a number of health problems including cardiovascular disease, lung cancer, and local damage to the lung tissue which eventually develops into chronic obstructive lung disease. The term chronic obstructive lung disease is to be broadly understood to encompass emphysema, pulmonary fibrosis and a number of other chronic lung ao diseases.
As many as 177,000 Americans were diagnosed with lung cancer in 1998. Of those, about 106,000 were men and 71,000 were women.
Unfortunately, lung cancer usually remains undiscovered until a tumor has grown large enough to compromise respiration or another physiological system, at which point the prognosis is poor. Experience indicates that only 1 out of 8 of patients diagnosed with primary lung cancer survives 5 years.
s Resources have been expended on developing new treatments for lung cancer. Abstinence counseling has been ineffective in reducing smoking among teenagers, and teenage smoking has been found to lead to lifelong addiction. Little effort has been directed toward preventing lung cancer in continuing smokers. The reality is that, despite the active to education campaign, 48,400,000 adults and 4,100,000 teenagers in the United States continue to smoke (1.1 billion smokers worldwide). In 1996, 487 billion cigarettes were consumed in the US.
Without being bound by any particular theory, it is believed that a malignancy results from a multi-step process; a cascade of events. Some 15 researchers believe that tumors evolve from a single cell that has mutated to become malignant. In some, if not all cases, several mutations must take place for a cell to become malignant.
In recent years, many researchers have described genetic abnormalities found in malignant cells. These genetic changes consist of ao several types of mutation. Some are point mutations that change some part of the reading frame of a gene. If present in the coding portion of a peptide, this type of mutation can produce an altered protein. Frequently, altered proteins fail to perform their customary physiological functions. In some instances this poses a health risk. In some instances, the altered protein is, itself, a health risk. Alternatively, a point mutation could alter the behavior of a non-coding region of the genetic material, affecting the control mechanisms that choreograph the timing of gene expression or the s quantity of material produced. Another type of mutation is a genetic translocation whereby two strands of DNA become displaced, such that a portion of part A crosses over to become affixed to part B. In a translocation event, a whole series of genes can shift to become subject to control elements that, in normal physiology, control an entirely different set to of genes. This can produce devastating physiological effects. For example, such effect may arise in genes whose normal function requires precise control that is lacking in the displaced condition. A third, related, type of mutation is an alteration in gene amplification, in which the number of copies of a gene is increased. This, too, can have adverse 15 consequences.
Appreciation and understanding of the complexity of this process is limited by an incomplete knowledge of the normal function of these genes whose function is implicated in the cascade that leads to malignancy. It does not appear that a single universal genetic alteration is present in all ao cancerous cells. Certain genes, such as p53, are implicated in a great number of cancers, but there are many malignant cells that do not appear to have any alteration in p53. Multiple possible paths which independently produce malignant cell. It appears that "oncogenes" (mutated forms of WO 01/10252 PCT/fJS00/21902 normal gene product) can cause healthy cells to become malignant when they are inserted into its DNA. Others, called "tumor suppressor genes"
are believed to act by preventing cells from uncontrolled proliferation.
These and other types of alterations may be required to convert a cell to s malignancy.
Tobacco smoke contains numerous compounds that are deposited in the lungs. As many as 3,000 different chemicals have been identified in tobacco smoke. It is believed that smoking associated disease are caused by these chemicals, acting alone or in concert with other chemicals. Some to of these compounds are known carcinogens of the class termed mutagens.
Mutagens are compounds which increase the rate of mutations in exposed cells. While most mutations are not associated with cancer, some are.
The accumulation of mutations in cells over time increases the chance that one cell will convert into a state of uncontrolled growth and become an i5 invasive tumor. A carcinogenic chemical agent may begin a process that will lead to a cancer in some cell, but there is no disease until the threshold of cellular conversion to uncontrolled replication is reached.
Some researchers believe the process by which the carcinogens that are in smoke cause mutations is by generation of free radicals that interfere ao with DNA-protein interactions which produce permanent changes in the DNA. An example of this class of carcinogens is the family of compounds called nitrosamines. Certain nitrosamines, for example, 4 - (N
nitrosoamino) - 4- (3 pyridyl) - 1 -butanone, have been reported to be carcinogenic, or procarcinogenic. By procarcinogenic it is meant that metabolites of the compounds are carcinogenic or of greater carcinogenicity than the unmetabolized compound. In some instances, free radicals increase the mutagenic activity of nitrosamines and other substances in s tobacco smoke.
Free radicals are species whose outermost electron is unpaired.
Often free radicals are associated with oxygen, as in an hydroxide or nitric oxide or superoxide, but they can involve other molecules as well. Usually free radicals are short lived and highly reactive. When proximate, releasing to the energy of a free radical dislocates interactions of proteins and nucleic acids in DNA in an active state such as DNA synthesis or repair, and thereby causes mutation. Superoxide is an OZ molecule that has an extra electron: OZ-, hydrogen peroxide is HZOZ and the hydroxyl radical is an OH
molecule that dissociated from water and is highly reactive: OH°.
i5 Oxygen free radicals exert their effect by binding to biological molecules such as lipids, proteins and DNA. One important reaction caused by oxygen free radicals is formation of peroxide intermediates in the unsaturated fatty acid moieties of cell membrane lipids. These oxidized intermediates can then propagate to interfere with the protein:DNA
2o interactions that leads to mutation, which can ultimately eventuate in conversion to malignancy.
Free radicals are ubiquitous and are normally part of many metabolic processes. Mammals produce natural anti-oxidants to neutralize free radicals. For example, the enzyme catalase converts hydroxide anion and hydrogen peroxide to water and oxygen. Superoxide dismutase is another enzyme that converts superoxide to H202. In addition to enzymes, there are small molecule anti-oxidants such as glutathione and alpha-tocopherol.
s Other potent anti-oxidants commonly used in the food industry include ("BHT") also termed 2, 6-bis( 1,1-dimethylethyl)-4-methyl-phenol or 2,6-di-tert-butyl-p-cresol, and butylated hydroxy anisole ("BHA") with the systematic name ( 1,1-dimethylethyl)-4-methoxy phenol, and propyl gallate with the systematic name 3,4,5-trihydroxy-benzoic acid, and propyl ester.
to Aspects of BHT are discussed in Witschi et al., "Metabolism and Pulmonary Toxicity of Butylated Hydroxytoluene (BHT)," Pharmac. Ther., Vol. 42, pp 89-1 13 (1989) the teachings of which are incorporated herein by reference.
One approach to reducing the long term effect of chronic exposure to 15 mutagens is regular treatment with anti-oxidants to interfere with free radicals before they cause damage. Dietary anti-oxidants are available in many forms, including food supplements and food preservatives.
It is the particular advantage of this present invention to apply an effective dose of high potency anti-oxidants topically to the lung epithelium ao where they directly act on the free radicals present in the lungs.
Another aspect of the present invention concerns retinoids.
Retinoids have also been considered in monodrug antineoplastic therapy both for the treatment of cancer and for cancer prevention. Retinoids are a family of isoprenoid compounds that include beta-carotene, vitamin A, retinal, retinoic acid, etc. Dietary beta-carotene is metabolized to produce two retinol molecules. Retinol is an essential vitamin. Vitamin A circulates in a protein complex called retinol binding protein. Retinol collects in cells s that have receptors for this complex, most notably epithelial cells. In the specialized cells of the retina, it is converted to the aldehyde form, retinal, the visual pigment of the eye. Vitamin A deficiency is associated with a number of effects, including night blindness, abnormal keratinazation of the skin, dry skin and conjunctiva) abnormalities.
to Retinoic acid is an intracellular signal molecule that acts directly on a nuclear receptor to catalyze the expression of a unique sequence of genes.
There are two families of currently identified retinoic acid receptors, RAR
and RXR. Two isomeric forms exist for the double bonds in the retinoid isoprene chain; cis and trans. Note that cis and trans double bonds can be 15 at various lications such as 13-cis and 9 cis etc. Retinoic acid promotes cellular differentiation and plays an important role in the timing of expression in embryonic development. It is known to be teratogenic in pregnant animals. 13-cis retinoic acid (isotretinoin) is effective topically in the management of acne through its direct action on keratinocytes. All-ao trans retinoic acid (tretinoin), isotretinoin and 9-cis retinoic acid have been shown to have antiproliferative effects on cultured leukemia cells, as have a number of synthetic analogs. The antiproliferative effect has been shown to have clinical utility in the management of cancer in certain settings when used as oral formulations.
Despite successes, other retinoid clinical trials have proven disappointing. For example, a recently published trial using a retinoic acid s derivative that, in laboratory tests was more potent than the natural compound, was ineffective in patients who were long term smokers. Kurie et al., "4-Hydroxyphenylretinamide in Reversal of Bronchial Metaplasia and Displasia In Smokers," Proceedings of ASCO 18:473a (1999) (American Society of Clinical Oncology, Atlanta, VA) found no significant effect from to an oral retinoid administration. Parthasarathy et al., "Aerosol delivery of liposomal all-trans-retinoic acid to the lungs," Cancer Chemotheraay Pharmacol 43(41:277:277-83 (1999) notes aerosol delivery of lipsosmal ATRA as an anti-inflammatory accompanying cancer chemotherapy.
15 Summary of the Invention Ingested dietary anti-oxidants distribute throughout the body upon ingestion and do not reach adequate levels in the lungs. A novel aspect of the present invention is in the combination of high effect, lipophilic antioxidants engaged with the lipid medium of the lungs to interdict the ao propagation of nuclear mutations. Without being bound by ant particular theory, hydrophilic anti-oxidants tend to clear more quickly than lipophilic antioxidants. In addition, hydrophilic antioxidants do not partition in lipids.
This reduces the efficacy of DNA protection afforded by hydrophilic antioxidants by reducing entry into the cell nucleus. In particular embodiments, high effect, lipophilic antioxidants are delivered in combination with an antiproliferative agent such as a retinoid.
This invention includes a cigarette filter-type device comprising a s pharmaceutically acceptable high-effect antioxidant, and particularly antioxidant present in an inhalable therapeutically effective amount. In particular embodiments antioxidant is present in at least about 0.2 to about 1.5 milligrams and particularly about 0.5 to 1 milligram. In some embodiments the device further comprises a pharmaceutically acceptable to volatile compound admixed with the antioxidant and or a therapeutically effective amount of a pharmaceutically acceptable retinoid such as all-trans retinoic acid or 13-cis retinoic acid.
Noted are high-effect antioxidants selected from the group comprising BHT, BHA or propyl gallate.
i5 Further included is a particular cigarette filter-type device, which comprises:
(a) an outer elongate cylinder of tobacco smoke filter material, (b) an inner elongate cylinder generally coextensive with the outer elongate cylinder of (a), and the inner elongate cylinder comprising high-effect antioxidant in ao powder form in inhalable therapeutically effective amount with the powder of averaged particle size of less than about 6 u, and in some instances less than about 2 u.
One specific cigarette filter-type device of this invention comprises an outer elongate cylinder of tobacco smoke filter material said device further comprising rupturable microcapsules comprising high-effect antioxidant, optionally in powder form. Noted is rupturable microcapsules s comprising high-effect antioxidant and optionally retinoids such as ATRA.
In some instances the microcapsules further comprise a pharmaceutically acceptable high-effect antioxidant solvent.
The invention yet further includes an aerosol device comprising a therapeutically effective amount of a pharmaceutically acceptable high-to effect antioxidant in diluent-propellant. Useful high-effect antioxidant is selected from the group comprising BHT, BHA or propyl gallate. Some aerosol devices are metered dose devices or pump type devices. These devices are usefully configured to deliver aerosol averaged particle sizes of less than about 6 u, and optionally particles of less than 2 u. A particular metered dose device uses BHT in an amount of at least about 300 mg in about 15 ml diluent-propellant. Also noted is BHT in an amount of at least about 30 mg/1 ml diluent-propellant.
This invention also includes a method of treating deep lung surfaces to provide an lipid peroxidation-mitigating surface by the step of inhaling at ao least about .5 mg of high-effect antioxidant, optionally in averaged particle sizes of about 6 microns ("p") or less including about 2 p or less. In one embodiment the method is accomplished by means of a cigarette filter-type device. In such method the high-effect antioxidant is selected from the group comprising BHT, BHA or propyl gallate. Alternatively the method is by means of an aerosol device. In practicing the method in one embodiment it is contemplated that at least about 15% of a subject's alveolar surface is treated with at least about 12 nanograms/m2.
s This invention further includes a method of creating a lipid peroxidation-reductive deep lung surface by the process of inhaling at least about .5 mg of high-effect antioxidant such as BHT, BHA or propyl gallate and at least about 1 mg retinoid, wherein said antioxidant and retinoid of averaged particle sizes of about 6p or less. In one example inhalation is by to means of a cigarette filter-type device, optionally co-timely, coordinated or coincident with inhalation of tobacco smoke.
Brief Description of the Drawings Fig 1. is a diagrammatic representation of a cigarette filter-type device attached to a cigarette.
15 Fig 2. is a diagrammatic representation of a cigarette filter-type device attached to a cigarette.
Fig 3. is a diagrammatic representation of a cigarette filter-type device with rupturable microcapsules.
Fig. 4. is a diagrammatic representation of a metered dose inhaler.
ao Fig. 5. is a diagrammatic representation of a pump type inhaler.
Detailed Description of the Invention This invention will be better understood with reference to the following definitions:
A. "Therapeutically effective amount" as to high-effect antioxidant administered on a daily basis shall mean at least about 0.5 mg per s day. For particular antioxidants, BHT, propyl gallate or BHA about 0.5 to about 10 mg and in a particular embodiment about 0.5 to about 1.5 mg, and particularly about 1 mg are therapeutically effective, but further noting about 1.5 mg to about 3 mg, and further up to about 5 mg.
to It is to be understood that therapeutically effective amount doses are also conveniently administered as divided doses on a "per cigarette" basis such as by placing antioxidant in a cigarette. As to inhaled smoke or an air/smoke mixture, about 1 ng of antioxidant /cc of inhaled smoke (including particulates) is therapeutic, with particular reference to about 15 100 to about 400 ng/cc.
In a multiple use cigarette filter, anticipating at least about 5 cigarettes being smoked daily from about .5 to about 2 ng/cc of inhaled smoke are therapeutically effective doses.
A cigarette filter type device which contains from about 0.1 to about ao 10 mg of high effect antioxidant is therapeutically effective. This range has a breadth, in part, due to the variability by which the antioxidant will mobilize from different filter materials, their compaction and the airflow during smoking.
As to an aerosol or pump type inhaler a delivered dose of about .5 to about 1.5 mg, and particularly about 1 mg is therapeutically effective. In a metered-dose inhaler a therapeutically effective amount is about 1 mg in a vapor or aerosol volume of from about 0.01 cc to about 0.2 cc. In a s nebulizer providing about 1 to about 5 cc of aerosol, a concentration of antioxidant of from about 0.2 to about 1 mg/cc is therapeutically effective.
In one embodiment from about 1 to about 5 cc is the volume of liquid put in the nebulizer. That volume is dispersed in the air by the nebulizer.
Typically the pressure unit produces 3 to 10 liters per minute, and runs for l0 3 to 15 minutes. In this example, this volume of air is about 20 to 80 liters.
B. "Deep lung" shall mean the ends of the bronchial tree, in the region called the respiratory zone, where the bronchial walls are open to exchange of gases.
C. High-Effect Antioxidant including BHT, BHA, propyl gallate, 15 anthocyanins shall mean that the general class of antioxidants displays at least about twice the anti-oxidant effect measured over time as alpha-tocopherol. In one embodiment of such a test, a standard vial of unsaturated phopspholipid and alpha -tocopherol are maintained at 37°C. By visual inspection the phospholipid material ao will turn brown in about 1 month. An equimolar amount of BHT or BHA or other high-effect anti-oxidant will keep a standardized amount of unsaturated phopspholipid from browning for at least twice as long.
WO 01/10252 PCT/fJS00/21902 Alternatively, free radical scavenging activities can be determined by a number of methods. Reference is made to Maulik G, et al., "Evaluation of antioxidant effectiveness of a few herbal plants," Free Radic Res Aug;27(2):221-8 (1997), the teachings of which are incorporated herein by s reference. One method of determining free radical scavenging is by chemiluminescence. Peroxyl radical is generated from 2,2'-azobis(2-amidinopropane) dihydrochloride (AAPH), superoxide radical (02-) from xanthine/xanthine oxidase (X0) and hydroxyl radical (OH) from Xanthine/XO/FeCl3/ EDTA. In addition, 02- and OH. scavenging activities to are determined by cytochrome C reduction and deoxyribose oxidation methods, respectively.
There are also many pharmaceutically acceptable high-effect anti-oxidants including plant extracts, water soluble anti-oxidants include vitamin C, sorbates, citric acid, thioesters and other sulfur reducing agents, i5 such as methionine, taurine, cysteine and glutathione. Lipophilic anti-oxidants include both natural and synthetic compositions. The carotenoids and tocopherols are of lesser effect. Another category of high-effect antioxidant is the isoflavone derivatives, such as Bachanin A. There are also phenols/0-methyl phenols including BHA, BHT, propyl gallate, 2o tertiary butyl hydroquinone, curcumin, eugenol, and ferulic acid. Also noted are salen-metal complexes such as those described in US 5,696,109 to Malfroy et al., the teachings of which are incorporated herein by reference.
D. "Aerosol device" shall be broadly understood to encompass pressurized and non-pressurized (spray) devices either of which may include spacers, and electrohydrodynamic devices. These devices include metered-dose inhalers, atomizers, piezo electric aerosol s generators, powder blowers or powder insufflators, vaporizers and nebulizers. A number of aerosol devices are described in Pharmaceutical Dosage Forms and Drua Delivery stems, Ansel et al., Sixth Ed. (Williams & Wilkins, Media Penn., 1995) as well as Ranucci et al, "Effect of Actuator Design on Metered-Dose Inhaler to Plume Particle Size" Pharmacology Technoloq_y 16(31:84-92, ( 1992), the teachings of which are incorporated herein by reference.
In practice pressurized aerosol devices are pressurized from about 25 to about 55 pounds per square inch gauge (psig). This invention is not to be limited by the device used to provide inhalable high effect antioxidants.
15 Of the many suitable devices, mention is made of pump inhalers, metered-dose inhalers, and electrohydrodynamic aerosol generators and other devices are also conveniently employed with enhancers such as spacers and the like. Note is made of the metered dose inhalers marked under the following names: Tidal InhalerT"' from Fisons, AzmacortT"" from Rhone-ao Poulenc Rorer, BecloventT"" and FloventT"~ from Glaxo Wellcome AiromirT""
from 3M Healthcare, and dry powder inhalers such as Pulmicort TurbohalerT"" from Astra and Severent DiskkhalerT"" from Glaxo Wellcome.
Also noted are electrohydrodynamic aerosol devices such as are described in US 5,91 15,377, US 5,813,614 and US 5,655,517 the teachings of which are incorporated herein by reference. Aerosol devices are also employed with diluent-propellants which encompass respiratory aerosol delivery adjuncts including surface-active agents, solvents, propellants such s as liquified gas or a mixture of liquified gases (e.g., chloro-fluorocarbons, dichlorodifluromethane, dichlorotetrafluroethane, trichloromonofluroethane, octafluorocyclobutane), non liquified compressed gases /e.g., carbon dioxide, nitrogen, nitrous oxide) and diluents and solvent such as water and ethyl alcohol. Two- and three-phase systems are noted as well as to compressed gas.
Aerosols produced by pressurized metered dose inhalers generally conform to "log-normal" functions. Aerosols are produced by many devices including a piezo-electric device that provides an ultrasonic vibration and devices that deliver dry powder aerosols. Drug delivery i5 properties of log-normal functions are frequently characterized by mass mean aerodynamic diameter (MMAD) and geometric standard deviation (GSD) values. Note is made of Raabe, "Particle Size Analysis Utilizing Grouped Data and Log-Normal Distribution," J. Aerosol. Sci, 2:289-303 ( 1971 ), Martonen et al., "Deposition Patterns of Aerosolized Drugs Within ao Human Lungs: Effects of Ventilatory Parameters," Pharmaceutical Research, 10(6):871-878 (1993), and Martonen et al., "Use of Analytically Defined Estimates of Aerosol Respirable Fraction to Predict Lung Deposition Patterns," Pharmaceutical Research, 9(12):1634-1639 (1992), the teachings of which are incorporated herein by reference.
E. "Co-timely" shall mean administration of a high-effect antioxidant while tobacco smoke is being inspired.
s F. "Coordinated" refers to mean pre- and post- dosing via inhaler or the like. "Coordinated" in the practice of the present invention refers to administration of a high-effect antioxidant in a therapeutically effective amount within at least about 1 to 30, or about 60 to 120 minutes before/after smoking a tobacco cigarette, and particularly to about 5 minutes or less prior to cigarette smoking G. "Coincident" refers to a combination drug therapy with a retinoid and a high-effect antioxidant. Coincident means dosing comprising administration of a retinoid while a high-effect antioxidant is present in at least about a therapeutic amount on the lung surface (or "in i5 delivery" to the lung surface), and potentially in higher concentrations. In a preferred embodiment of coincident administration, both drugs are administered in a single aerosol.
H. "Cigarette filter-type device" shall mean a device affixed or affixable to the downstream end of a cigarette. In the usual case the 2o downstream end of a cigarette is the end nearer the mouth of a smoker, with the cigarette filter-type device being inserted directly into the lips or mouth of the smoker or via a cigarette holder. The term is broadly construed to include filter-type devices which include filamentous materials typically employed to remove tars and other substances from smoke, but also to include the addition of drugs, flavorant and the like to smoke even when no substance is removed from the smoke. Further the term contemplates such devices as s affixed to cigarettes when manufactured forming a single unit, such devices as provided after cigarette manufacture and affixed later such as when smoking the cigarette begins, and the device as inserted or contained within a cigarette holder, in which the cigarette is inserted prior to smoking the cigarette. Cigarette holders are to generally characterized as having mouthpieces, often similar to those found on pipes.
"Cigarette" is a term to be broadly understood to include smoked tobacco type devices such as typical paper wrapped cigarettes, as well as plant leaf or otherwise wrapped cigarettes, and further i5 including cigars, pipes, hookahs and the like. It is also understood to mean, generally, a reference to smoked tobacco containing items, but other smoke producing products for purposeful smoke inhalation such as marijuana are also contemplated within the term.
J. "Inhalable" is a term referencing the amount of drug within a filter ao that will be inhaled in at least about 500cc of inhaled air and or smoke in the process of smoking a cigarette.
K. "Retinoid" shall mean natural and synthetic derivatives of vitamin A
(retinol). Isotretinoin and tretinoin represent two naturally occurring isomers of retinoic acid. Many other synthetic analogs have also been studied, including etretinate. Tong, et al., WO 97/3974 "Use of Inhaled Retinoids in the Prevention of Cancer," the teachings of which are incorporated herein by reference. Without being bound s by any particular theory it is believed that retinoic acid activates receptors in cell nuclei, notably RAR and RXR receptors which can result in significant physiological changes. Such changes include anti-proliferative effects and/or differentiation. Other retinoids may require processing by elements in the cytosol before they become to active in changing the pattern of transcription.
Without being bound by any particular theory, it is believed that retinoids act by inducing differentiation. A variety of in vitro studies have demonstrated the specialized ability of retinoids to induce terminal differentiation and inhibit growth of several human leukemia cell lines and 15 bone marrow cultures obtained from patients with acute myelogenous leukemia. These studies and many others done in murine cell lines provide a scientific foundation for the in vivo use of retinoids to treat certain types of leukemia. Data suggest that retinoids induce growing cells to mature to become end-stage cells that are no longer capable of dividing.
ao This property has been tested in clinical trials. Clinical activity of retinoids has been demonstrated in many diverse premalignant conditions including squamous cell carcinomas of the skin, basal cell carcinomas, cutaneous T-cell lymphomas, and leukoplakia. Patients who have demonstrable premalignant lesions and are treated with retinoids are less likely to develop malignancies, compared to patients who were not treated with retinoids.
L. "Therapeutically effective" as to retinoid doses will vary with the s presenting condition and subject.
In practice, dosing followed by lung biopsy offers an empirical end point for retinoid dosing and is within the skill of the medical practitioner.
As a general guide, attention is drawn to doses of about .1 to about 20 mg total delivered retinoid dose and in a particular embodiment about 0.25 to to about 10 mg, and more particularly about .5 to about 5 mg, as well as from about 10 to about 15 mg.
Daily total retinoid dosages such ad ATRA of from about 0.1 to about 15 mg/day are contemplated. Particular reference is made to daily doses of up to about 6 mg.
15 It is to be understood that total daily doses are variable. Many factors including smoking or inhalation "style," amounts of therapeutic agent per cigarette, and the number of cigarettes smoked effect total daily dosage. It is contemplated that a health professional will monitor a subject for symptoms or indicia of hypervitaminosis or build up of therapeutic agent 2o and reduce (or increase) doses accordingly.
Representative Devices Fig 1 . is a diagrammatic representation of a cigarette filter-type device (4) attached to a tobacco containing segment (2) of a cigarette (10).
Tobacco is noted as (8) and a filamentous filter material is noted as (6). In some embodiments the high-effect antioxidant or anti-mutagen comprises a coating on the filter material or a powder intermingled with the filter material.
s Fig 2. is a diagrammatic representation of a cigarette filter-type device (24) attached to a tobacco containing segment (22) of a cigarette (20). Tobacco is noted as (28) and a filamentous filter material is noted as (26). An additional element of the cigarette filter-type device (24) is high-effect antioxidant in powder form (27) in carrying tube (23) in air or smoke to flow connection with abutting tobacco containing segment (22). Porous filter material plugs (21 ) contain the powder (27) in tube (23).
Fig 3. is a diagrammatic representation of a cigarette filter-type device (34) with rupturable microcapsules (38) containing high effect antioxidant and or anti-mutagens dispersed amidst filamentous filter (36).
15 A tobacco containing element is shown in phantom (32).
Fig. 4. is a diagrammatic representation of a metered dose inhaler (40). Holder (42) supports a pressurized container (46) comprising antioxidant and propellant in connection with metered delivery element (44). Upon downward pressure on the pressurized container (46) metered ao delivery element (44) delivers an aerosol mist directed through opening (48).
Fig. 5. is a diagrammatic representation of a pump type inhaler (50).
Container (52) holds a solution or suspension (54) comprising high effect antioxidant and solvent/carrier liquid propellant in connection with pump means (58) in connection with atomizer head (56).
Methodological Aspects Dosing smokers with appropriate amounts of high-effect antioxidant s requires particular attention. It is appreciated that in specific instances, dosing subjects with compromised respiration or lung elasticity or function will necessarily deviate from preferred ranges. In some instances, modified inspiratory regimens are required. With aerosolizing devices, multiple inhalations are required by certain individuals to dose bronchiole or alveolar to surfaces to a specific level. In some instances, positive pressure ventilation is required to introduce high-effect anti-oxidant into the lungs of compromised subjects or to introduce dosages in controlled amounts or to specific depths.
Smaller alveoli produce lung surfactant which coats the inside of the i5 sac, reducing surface tension and stabilizing them. Lung surfactant is a mixture of several apoproteins and phospholipids. It is produced by type 2 cells of the alveoli, and is secreted into the lumen. There is an active recycling process whereby surfactant is absorbed and its components reassembled into surfactant for secretion. This lining of surfactant is a 2o target for oxidative damage by inhaled free radicals. Lipid peroxides produced by oxidation can propagate the damage inside the cells lining the airways, sometimes causing mutations. The lining surfactant is also the target for lipophilic anti-oxidants. The surfactant provides a bed to sustain levels of high effect anti-oxidant in the milieu where they can maximize their benefit.
It is to be understood that in some subjects, often associated with respiratory pathologies, a physiological dead space is present distinct from s the anatomic dead space. Certain alveoli will be either over or under ventilated under "at rest" conditions. The volume of gas in non-perfused alveoli and any volume of air in the alveoli in excess of that necessary to arteriolize the blood in the alveolar capillaries is part of the dead space (non-equilibrating) gas volume. Without being bound by any particular theory, in to the instant invention it is thought that an anti-oxidant such as BHA or a combination of BHT and BHA will eliminate or neutralize some free radicals and reduce the mutation rate in the lungs. By reducing the overall mutation rate the user has a reduced incidence of or delayed development of lung cancer.
15 Delivery of the anti-mutagenic therapy of this invention is usefully in aerosol form. Aerosol form refers to the condition of the inspired drug upon exiting the aerosol device. It is contemplated that a spray in aerosol form encompasses aqueous and oleaginous droplets. In some embodiments aerosol form is a dry powder. In some embodiments the ao aerosol form begins as a dry powder and in some the aerosol begins as a droplet of drug and volatile carrier, wherein the carrier evaporates leaving a dry powder. In yet other forms, the spray is droplets containing drug particle or liposomes containing drug. Noted volatile carriers are lower alkyl alcohols such as ethanol and isobutanol. When used withing filter type devices volatile carriers are usefully contained in rupturable microcapsules Powders for inhaled administration are also contemplated. In some embodiments powders are dusted directly onto filter material. These may s be prepared by any of a number of methods well known in the art. By way of example, a useful preparation is similar to that for cromolyn sodium.
The therapeutic is compacted with lactose in particle size of about 30-60 p, while the cromolyn is from about 1 to about10 p. The capsule of lactose and drug is broken capsule and placed in inhaler a powder, e.g. SpinhalerT"' to from Fisons. Upon inhalation, the larger lactose particles do not proceed beyond the upper airways while the smaller drug particles are inspired into the deeper lung. Reference is made to Ranucci et al., "Phase Doppler Anemometry: A Technique for Determining Aerosol Plume-Particle Size and Velocity," Pharmaceutical TechnoloQV, 17:62-73 (1993) the teachings of 15 which are incorporated herein by reference.
In one embodiment, this invention comprises is a product that is inhaled to cover the surface of the lungs, and optionally accompanied by printed and pictorial instructions for use. Inhalation raises the levels of these nutritional and/or anti-oxidant supplements to an effective level in and zo on the target tissue. In a specific embodiment the drug is administered once a day from a device that is inexpensive to manufacture, and is discarded after a few uses.
A related aspect of the present invention is to employ the therapeutic agents of the persent invention in "smokeless" tobacco products such as snuff and chewing tobacco. In such instances the therapeutic effect as to the surface of the oral cavity is noted.
s One particular embodiment of the therapeutic device of the present invention comprises a means for delivery of a combination of an anti-oxidant and retinoid (e.g., retinoic) to the lungs of a subject. Attention is drawn to "at risk" subjects. Particularly "at risk" subjects are tobacco smokers, ex-smokers, subjects with long term exposure to such hazards as to asbestos and hay, as well as miners of coal, uranium, beryllium and the like.
Cigarette Filter-Type Devices Fibre- or filament-containing filters for cigarettes are well known. In one form of construction, the filter body consists of a tow of continuous i5 filaments, commonly cellulose acetate (acetate) filaments, arranged parallel to the long axis of the cigarette. In another form of construction, the filter body consists of pleated or fluted paper compressed into a cylinder. Such forms of construction contain a single filter element and may be called "mono" filters. Another form of construction is the so-called "dual" filter ao which contains two filter elements, for example a paper filter towards the interior and a tow filter towards the exterior of the cigarette. A further form of construction is the so-called "triple" filter, which resembles a dual filter except that a quantity of a third substance such as activated carbon is interposed between the two filter elements hereinbefore mentioned.
Attention is drawn to US 5,839,448 to Woodings, the teachings of which are incorporate herein by reference.
In some cigarette filter-type devices active or aromatic substances s are introduced from the device into the smoke inhaled from a cigarette in order to modify its taste or to confer additional properties. For example, U.S. Pat. No. 3,991,773 and U.S. Pat. No. 3,635,226 describe mechanisms for humidifying cigarette smoke by including rupturable capsules or micro-capsules filled with a liquid, within the filter of the to cigarette. The smoker obtains the humidification effect by squeezing the filter to rupture the capsules prior to smoking. In some instances, liquid incorporated in the capsules contains flavorings or a synthetic saliva solution, for example. U.S. Pat. No. 4,498,485 discloses the inclusion of interferon into the tobacco of a cigarette for administering it directly to the 15 lungs of the smoker. Note is made of US 5,472,002 to Covarrubias the teachings of which are incorporate herein by reference.
Example 1 A BHA mixture for application to the filter material is compounded as follows:
ao BHA 1 mg is dissolved in 1 cc of ethanol. The solution is applied to a conventional cellulose acetate cigarette filter and air dried. The filter is then affixed to the end of a tobacco cigarette.
Example 2 A 24 year old female smoker is provided with a filter cigarette of Example 1. She smokes the cigarette in her normal manner inhaling the tobacco smoke. In the course of smoking the cigarette she inhales at least s about .5 mg of BHA.
Example 3 A BHT mixture for application to the filter material is compounded as follows:
to BHT, 0.8mg is dissolved in .5 cc of ethanol. The solution is applied to a conventional cellulose acetate cigarette filter and air dried. The filter is then affixed to the end of a tobacco cigarette.
Examale 4 15 A 67 year old male smoker is provided with a filter cigarette of Example 3. He smokes the cigarette in his normal manner inhaling the tobacco smoke. In the course of smoking the cigarette he inhales at least about .4 mg of BHT.
2o Example 5 A BHT-ATRA mixture for application to the filter material is compounded as follows:
BHT 1 mg and .5 mg ATRA are dissolved in 1 cc of ethanol. The solution is applied to a conventional cellulose acetate cigarette filter and air dried. The filter is then affixed to the end of a tobacco cigarette.
s Example 6 A 35 year old male smoker is provided with the cigarette of Example 5. He smokes the cigarette in his normal manner inhaling the tobacco smoke. In the course of smoking the cigarette he inhales at least about .4 mg of BHT and at least about .2 mg ATRA.
to Example 7 A BHT-ATRA mixture for application to the filter material is compounded as follows:
BHT 1 mg and .5 mg ATRA are encapsulated in rupturable is microcapsules each containing about 0.1 mg of the mixture. The rupturable microcapsules are located in cigarette filter-type material and the filter affixed to a cigarette.
Example 8 ao An 18 year old male smoker is provided with the cigarette of Example 7. With thumb and forefinger pressure on the cigarette filter he ruptures the microcapsules within the filter and their contents is distributed within the filter material. Promptly thereafter he smokes the cigarette in his normal manner inhaling the tobacco smoke. In the course of smoking the cigarette he inhales at least about .5 mg of BHT and 0.4 mg of ATRA
creating an lipid peroxidation-reductive deep lung surface.
Example 9 s A BHT mixture for application to the filter material is compounded as follows:
BHT 1 mg is encapsulated in rupturable microcapsules each containing about 0.1 mg BHT. The rupturable microcapsules are located in cigarette filter-type material and the filter affixed to a cigarette.
to Example 10 A 35 year old male smoker is provided with the cigarette of Example 9. With thumb and forefinger pressure on the cigarette filter he ruptures the microcapsules within the filter and their contents is distributed within 15 the filter material. Promptly thereafter he smokes the cigarette in his normal manner inhaling the tobacco smoke. In the course of smoking the cigarette he inhales at least about .5 mg of BHT.
All publications mentioned herein above are hereby incorporated in their entirety by reference
Claims
Claims 1. A cigarette filter-type device comprising a pharmaceutically acceptable high-effect antioxidant.
2, The device of Claim 1 wherein said antioxidant is present in an inhalable therapeutically effective amount.
3. The device of Claim 1 wherein said antioxidant is present in at least about 0.2 to about 1 gram.
4. The device of Claim 1 wherein further comprising a pharmaceutically acceptable volatile compound admixed with said antioxidant.
5. The device of Claim 1 wherein said high-effect antioxidant is selected from the group comprising BHT, BHA or propyl gallate.
6. A cigarette filter-type device, which comprises:
(a) an outer elongate cylinder of tobacco smoke filter material, (b) an inner elongate cylinder generally coextensive with the outer elongate cylinder of (a), said inner elongate cylinder comprising high-effect antioxidant in powder form in inhalable therapeutically effective amount, and (c) said powder of averaged particle size of less than about 6 u.
7. The device of Claim 6 wherein said high-effect antioxidant is selected from the group comprising BHT, BHA or propyl gallate.
8. A cigarette filter-type device, which comprises an outer elongate cylinder of tobacco smoke filter material said device further comprising rupturable microcapsules comprising high-effect antioxidant.
9. The high-effect antioxidant of Claim 8 in powder form.
10. Rupturable microcapsules comprising high-effect antioxidant 11. The microcapsules of Claim 11 further comprising a pharmaceutically acceptable high-effect antioxidant solvent.
12. An aerosol device comprising a therapeutically effective amount of a pharmaceutically acceptable high-effect antioxidant in diluent-propellant.
13. The device of Claim 12 wherein said high-effect antioxidant is selected from the group comprising BHT, BHA or propyl gallate.
14. The device of Claim 12 wherein said device is a metered dose device.
15. The device of Claim 12 wherein said device is a pump-type device 16. The device of Claim 1 further comprising a therapeutically effective amount of a pharmaceutically acceptable retinoid.
17. The device of Claim 16 wherein the retinoid is all-transretinoic acid or 13-cis retinoic acid.
18. A method of treating deep lung surfaces to provide an lipid peroxidation-mitigating surface by the step of inhaling at least about .5 mg of high-effect antioxidant.
19. The method of Claim 18 wherein said antioxidant is in averaged particle sizes of about 6 µ or less.
20. The method of Claim 18 wherein inhalation is by means of a cigarette filter-type device.
21. The method of Claim 18 wherein said high-effect antioxidant is selected from the group comprising BHT, BHA or propyl gallate.
23. The method of Claim 18 wherein inhalation is by means of an aerosol device.
24. The method of Claim 18 wherein at least about 15% of said alveolar surface is treated with at least about 12 nanograms/m2.
25. A method of creating an lipid peroxidation-reductive deep lung surface by the process of inhaling at least about .5 mg of high-effect antioxidant and at least about .1 mg retinoid, wherein said antioxidant and retinoid of averaged particle sizes of about 6 µ or less.
26. The method of Claim 25 wherein said high-effect antioxidant is selected from the group comprising BHT, BHA or propyl gallate.
27. The method of Claim 18 wherein inhalation is by means of a cigarette filter-type device.
28. The method of Claim 18 wherein said high-effect antioxidant is selected from the group comprising BHT, BHA or propyl gallate.
29. The method of Claim 27 wherein said inhalation is co-timely with inhalation of tobacco smoke.
30. The method of Claim 27 wherein said inhalation is coordinated with inhalation of tobacco smoke.
31. The method of Claim 27 wherein said inhalation is coincident with inhalation of tobacco smoke.
2, The device of Claim 1 wherein said antioxidant is present in an inhalable therapeutically effective amount.
3. The device of Claim 1 wherein said antioxidant is present in at least about 0.2 to about 1 gram.
4. The device of Claim 1 wherein further comprising a pharmaceutically acceptable volatile compound admixed with said antioxidant.
5. The device of Claim 1 wherein said high-effect antioxidant is selected from the group comprising BHT, BHA or propyl gallate.
6. A cigarette filter-type device, which comprises:
(a) an outer elongate cylinder of tobacco smoke filter material, (b) an inner elongate cylinder generally coextensive with the outer elongate cylinder of (a), said inner elongate cylinder comprising high-effect antioxidant in powder form in inhalable therapeutically effective amount, and (c) said powder of averaged particle size of less than about 6 u.
7. The device of Claim 6 wherein said high-effect antioxidant is selected from the group comprising BHT, BHA or propyl gallate.
8. A cigarette filter-type device, which comprises an outer elongate cylinder of tobacco smoke filter material said device further comprising rupturable microcapsules comprising high-effect antioxidant.
9. The high-effect antioxidant of Claim 8 in powder form.
10. Rupturable microcapsules comprising high-effect antioxidant 11. The microcapsules of Claim 11 further comprising a pharmaceutically acceptable high-effect antioxidant solvent.
12. An aerosol device comprising a therapeutically effective amount of a pharmaceutically acceptable high-effect antioxidant in diluent-propellant.
13. The device of Claim 12 wherein said high-effect antioxidant is selected from the group comprising BHT, BHA or propyl gallate.
14. The device of Claim 12 wherein said device is a metered dose device.
15. The device of Claim 12 wherein said device is a pump-type device 16. The device of Claim 1 further comprising a therapeutically effective amount of a pharmaceutically acceptable retinoid.
17. The device of Claim 16 wherein the retinoid is all-transretinoic acid or 13-cis retinoic acid.
18. A method of treating deep lung surfaces to provide an lipid peroxidation-mitigating surface by the step of inhaling at least about .5 mg of high-effect antioxidant.
19. The method of Claim 18 wherein said antioxidant is in averaged particle sizes of about 6 µ or less.
20. The method of Claim 18 wherein inhalation is by means of a cigarette filter-type device.
21. The method of Claim 18 wherein said high-effect antioxidant is selected from the group comprising BHT, BHA or propyl gallate.
23. The method of Claim 18 wherein inhalation is by means of an aerosol device.
24. The method of Claim 18 wherein at least about 15% of said alveolar surface is treated with at least about 12 nanograms/m2.
25. A method of creating an lipid peroxidation-reductive deep lung surface by the process of inhaling at least about .5 mg of high-effect antioxidant and at least about .1 mg retinoid, wherein said antioxidant and retinoid of averaged particle sizes of about 6 µ or less.
26. The method of Claim 25 wherein said high-effect antioxidant is selected from the group comprising BHT, BHA or propyl gallate.
27. The method of Claim 18 wherein inhalation is by means of a cigarette filter-type device.
28. The method of Claim 18 wherein said high-effect antioxidant is selected from the group comprising BHT, BHA or propyl gallate.
29. The method of Claim 27 wherein said inhalation is co-timely with inhalation of tobacco smoke.
30. The method of Claim 27 wherein said inhalation is coordinated with inhalation of tobacco smoke.
31. The method of Claim 27 wherein said inhalation is coincident with inhalation of tobacco smoke.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US14838899P | 1999-08-11 | 1999-08-11 | |
| US60/148,388 | 1999-08-11 | ||
| US63508700A | 2000-08-08 | 2000-08-08 | |
| US09/635,087 | 2000-08-08 | ||
| PCT/US2000/021902 WO2001010252A1 (en) | 1999-08-11 | 2000-08-10 | Anti-oxidant inhalant and method |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2391728A1 true CA2391728A1 (en) | 2001-02-15 |
Family
ID=26845812
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002391728A Abandoned CA2391728A1 (en) | 1999-08-11 | 2000-08-10 | Anti-oxidant inhalant and method |
Country Status (3)
| Country | Link |
|---|---|
| EP (1) | EP1239745A1 (en) |
| CA (1) | CA2391728A1 (en) |
| WO (1) | WO2001010252A1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2779765C2 (en) * | 2018-04-25 | 2022-09-13 | Филип Моррис Продактс С.А. | Ventilation for hookah device |
| US11800894B2 (en) | 2018-04-25 | 2023-10-31 | Philip Morris Products S.A. | Ventilation for shisha device |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1263420B1 (en) * | 2000-03-07 | 2005-09-07 | Battelle Memorial Institute | Retinoid formulations for aerosolization and inhalation |
| DE10137827A1 (en) * | 2001-08-02 | 2003-02-27 | Peter Marcinowski | Complex antioxidant preparation |
| ZA200901679B (en) | 2009-03-09 | 2015-08-26 | Tobacco Res And Development Institute (Pty) Ltd | Apparatus for introducing objects into filter rod material |
| ZA201008663B (en) | 2010-12-01 | 2014-08-27 | Tobacco Res And Dev Inst (Pty) Ltd | Feed mechanism |
| CN104720106A (en) * | 2015-01-28 | 2015-06-24 | 湖南中烟工业有限责任公司 | Application of harm-reduction function material in preparing cigarette function filter tip |
| CN106072761A (en) * | 2016-08-05 | 2016-11-09 | 福建中烟工业有限责任公司 | A kind of method reducing the peculiar N content of nitrosamines of Nicotiana tabacum L. in cigarette mainstream flue gas |
| CN107981408B (en) * | 2017-12-20 | 2020-05-22 | 江西中烟工业有限责任公司 | Novel tobacco shred expanding agent and application thereof |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5308874A (en) * | 1992-06-26 | 1994-05-03 | Vyrex Corporation | Airborne protectants against oxidative tissue damage |
| US5662934A (en) * | 1993-01-05 | 1997-09-02 | Najarian; Thomas | Compositions and methods for lowering cholesterol while maintaining antioxidant levels |
| US5829449A (en) * | 1997-09-19 | 1998-11-03 | Thione International, Inc. | Smoking products containing antioxidants |
| US5922346A (en) * | 1997-12-01 | 1999-07-13 | Thione International, Inc. | Antioxidant preparation |
-
2000
- 2000-08-10 CA CA002391728A patent/CA2391728A1/en not_active Abandoned
- 2000-08-10 WO PCT/US2000/021902 patent/WO2001010252A1/en not_active Application Discontinuation
- 2000-08-10 EP EP00955439A patent/EP1239745A1/en not_active Withdrawn
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2779765C2 (en) * | 2018-04-25 | 2022-09-13 | Филип Моррис Продактс С.А. | Ventilation for hookah device |
| US11800894B2 (en) | 2018-04-25 | 2023-10-31 | Philip Morris Products S.A. | Ventilation for shisha device |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2001010252A1 (en) | 2001-02-15 |
| EP1239745A1 (en) | 2002-09-18 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| RU2680422C2 (en) | Flavoured nicotine powder inhaler | |
| RU2734847C2 (en) | Inhalation system for nicotine | |
| US5906811A (en) | Intra-oral antioxidant preparations | |
| JP2021169005A (en) | Nicotine powder delivery system | |
| Witschi | Successful and not so successful chemoprevention of tobacco smoke-induced lung tumors | |
| JP7356430B2 (en) | dry powder inhaler | |
| RU2720573C2 (en) | Capsule with nicotine particles | |
| JP7183191B2 (en) | Inhaler article with obstructed airflow element | |
| US20200281870A1 (en) | Composition and use thereof | |
| CA2391728A1 (en) | Anti-oxidant inhalant and method | |
| JP2019524061A (en) | Nicotine particle delivery consumables | |
| JP2023113755A (en) | flavored nicotine powder | |
| US20120012123A1 (en) | Compositions, articles and methods for preventing or reducing tobacco-associated damage | |
| EP0003064A2 (en) | Method for introducing analogs of vitamin A into the respiratory tract of a cigarette smoker | |
| WO2020160667A1 (en) | Nicotine aerosol formulation | |
| Alshareef et al. | Toxicology of commonly found ingredients in e-cigarettes: a brief review | |
| RU2784423C2 (en) | Dry powder inhaler and inhaler system | |
| JP7352471B2 (en) | nicotine powder consumables articles | |
| Maddu | What is e-Cigarette and Associated Health Risks | |
| ATILGAN | NEGATIVE EFFECTS OF CANNABIS ON ORAL TISSUES | |
| MXPA00000097A (en) | Intra-oral antioxidant preparations |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Discontinued |