JP2004231662A - Improved composition for control of smoking and method for producing the composition - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain a composition for control of smoking, in more details, reducing appetite of smoking, and to provide a method for producing the same. <P>SOLUTION: The compositions for the control of smoking comprises: (a) a xanthine oxidase inhibitor; (b) a phosphate or a compound capable of releasing phosphate on administration to a subject; and optionally (c) a sugar; and further optionally (d) one or more pharmaceutically acceptable carriers or excipients. The control of smoking is carried out by administering the composition to a subject having smoking habit and in need of such treatment. <P>COPYRIGHT: (C)2004,JPO&NCIPI

Description

The present invention relates to a composition for controlling smoking, in particular for reducing the need for smoking, and to a method for producing the same.

  It is widely accepted that smoking has significant implications for health risks. When comparing smokers to members of other populations, there is an increase in morbidity and mortality in all age groups. Smoking is associated with asthma, emphysema, and cancerous conditions such as the mouth, larynx, tongue, and lungs. According to Glynn and Sussman, many smokers believe that smoking harms their health, and despite the conviction of this crime, a relatively large percentage of Westerners or other groups continue to smoke. (Non-Patent Document 1). Approaches to smoking control, such as hypnosis, acupuncture, "naturopathic" and nicotine-based interventions, have almost all been unsuccessful. Chronic smokers generally find it very difficult to stop their habits.

In our pending application (U.S. Patent No. 6,038,059), we describe compositions and methods for controlling smoking. Quite surprisingly, we minimize the two different classes of compounds that, when combined, reduce the smoker's desire to smoke and thereby provide control over smoking It has been found that a composition can be prepared.
PCT / AU95 / 00621 S, M. Glynn and S. Sussmann, Hospital and Community Psychiatry, 41, 9, 1027-1028

  An object of the present invention is to provide a composition used for controlling smoking, more particularly for reducing the desire for smoking, and a method for producing the same.

  In a first aspect of the present invention, (a) a xanthine oxidase inhibitor, (b) a phosphate or a compound capable of releasing phosphate upon administration to a subject, and optionally (c) a sugar, and further optionally (D) A composition for smoking control comprising one or more pharmaceutically acceptable carriers or excipients.

  In another embodiment of the present invention, (a) a xanthine oxidase inhibitor, (b) a phosphate or a compound capable of releasing phosphate upon administration to a subject, and optionally (c) a sugar, and optionally a ( d) A method of controlling smoking comprising administering to a subject in need of such treatment a composition comprising one or more pharmaceutically acceptable carriers or excipients.

  In another aspect of the present invention, in the manufacture of a drug for controlling smoking, (a) a xanthine oxidase inhibitor, (b) a phosphate or a compound capable of releasing phosphate upon administration to a subject, and optionally (c) It relates to a method of using a composition comprising a sugar and, optionally, (d) one or more pharmaceutically acceptable carriers or excipients.

  In a further aspect of the invention, (a) a xanthine oxidase inhibitor, (b) a phosphate or a compound capable of releasing phosphate upon administration to a subject, and optionally (c) a sugar, and optionally a ( d) Provide a smoking control agent comprising one or more pharmaceutically acceptable carriers or excipients.

The compositions and methods of the present invention have surprisingly been found to control smoking. This is especially surprising, as it was previously considered by the present inventor that all of the components described in PCT / AU95 / 00621 were required for smoking control.
By controlling smoking, an individual may substantially reduce the number of cigarettes he or she may quit smoking. Various tests performed by chronic smokers described below show that the compositions of the present invention suppress the need and need for smoking.

Xanthine oxidase inhibitors regulate the activity of xanthine oxidase (including xanthine dehydrogenase and xanthine oxidoreductase) by various mechanisms (competitive inhibition (when the compound acts as an antagonist)), and by binding xanthine oxidase at or near the active site. Inhibits activity, alters the conformation of xanthine oxidase by binding outside the active site of the xanthine oxidase enzyme, generally, the binding or inactivation of free radical substances (agents) produced by xanthine oxidase, or other mechanisms. Including). Xanthine oxidase inhibitors are well known in the art. Examples of xanthine oxidase inhibitors include plant extracts from plants such as Eupatorium Purpureum (Gravel Root), allopurinol, oxypurinol, purpurogallin, and Trolox (e.g., Zeng and Wu, 1992, Cell. Biol., 70, 684-690).

One group of xanthine oxidase inhibitors are flavonoids (which may also be referred to as bioflavonoids) (eg, edited by Harborne et al., The Flavonoids, Academic Press, New York, 1975, Harborne et al., The Flavonoids, Advances in Research Since 1986). , 1994, Princemail et al., 1987, `` Ginkgo Biloba extract inhibits oxygen specles production generated by phorbol myristate acetate stimulated human leukocytes '', Experientia, February 15, 43 (2), 181-184, Frage et al. (1987), `` Flavonoids As antioxidants evaluated in vitro and in situ liver chemiluminescence, Biochem. Pharmacol., March 1, 36 (5), 717-720, Schmeda-Hirschmann et al., (1987), `` Preliminary pharmacological studies on Eugenia uniflora leaves: xanthine oxidase activity '', J. Ethnopharmacol., November 21 (2), 183-186, Zeng LH and Wu TW, (1992), `` Purpurogallin is a more powerful protector of kidney cells than Trolux and allopurinol '', Biochemistry and Cell Biology , 70, 604-709, Siggins FM, (1888), `` Analysis of the levels of Eupatorium Purpurem '', Am. J. of Pharm., 60, 121-122, Manger CC, (1984), `` Euparin '', Am J. of Pharm., 66, 120-124, Trimble H., 1890, "Eupatorium Purpurem", Am. J. of Pharm., February, 62, 73-80).

Flavonoids are a large group of plant secondary metabolites derived from flavan. The basic structure of flavonoids is flavanone (flavan-4-one), which is derived from the flavonoid derivatives flavonol (flavan-3-ol), flavones and flavonols. Anthocyanins and catechol are derived from flavans and should be considered as flavonoids for the purpose of the present invention (Concise Encyclopaedia of Chemistry, de Gruyter, 1994; see pages 77, 190 and 411-431 for details. ). Examples of anthocyanins, cyanine, pelargonine, delphin (delphin), idain (idaein), malvin (malvin), petunin (petunin), kerocyanin (keracyanin), mycocyanin (micocyanin), furasarin (frasarin), ぺ onin (paeonin), Enin, chyrsanthemin, and the like. These compounds can be hydrolyzed by acids and glycosidases to the corresponding aglycones (anthocyanins). The sugar residue can be linked to position 3 or 5 of the anthocyanin. Catechol tannins are a group of tannins whose monomer unit is flavan-3-ol (catechol) or flavan-3,4-diol. Catechol is 5,7,3 ', 4'-tetrahydroxyflavan-3-ol. The above compounds should be considered as flavonoids for the purpose of the present invention.

The most widespread flavonoids are flavones. Flavones are yellow pigments of the flavonoid group containing a flavone, isoflavone or flavonone skeleton. Flavones, for example, occur widely in nature as glycosides or esters of tannic acid, usually in flowers, trees and roots, and have long-term properties as described in The Flavonoids, Advances in Research Since 1986, Harborne et al., 1994 and the like. It can be easily extracted from these natural sources using well-known techniques that are well established. Examples of flavonoids include apigenin, chrysin, eupatorin, fisetin, genistein, hesperitin, kaempherol, luteolin, morin, myricetin and quercetin. Flavonoid compounds within the scope of the present invention and other xanthine oxidase inhibitors Eupatorium Purpureum (aka Gravel Root, Queen of the Meadow or known as Jo Pye Weed,), Eupatorium Coenobium ( known as an alias Agrimony), Eupatorium Fortun
ei (Peil lan or a related extract known as Peilan), which can be extracted from a wide variety of plant species, including Ginkgo Biloba. Examples of preferred compounds are eupalin and eupatorin, or plant extracts containing these substances. Euparin , including extracts from Eupatorium Purpurem, is commercially available from a number of suppliers, including Blackmores'"Gravel Root Extract" (Blackmores Pty, Balgowlah, New South Wales, Australia). Flavonoids can be provided as plant extracts prepared according to standard procedures such as alcohol extraction.

  Examples of additional flavonoids or bioflavonoids that can be used in the present invention include citrus bioflavonoids, vitamin P, vitamin P complex, rutin, bioflavonoids from orange peel, bioflavonoids from grapefruit peel, lemon Bioflavonoids, lime bioflavonoids, narigenin (narigenin), naringin (naringin), naringenis, delphinidin (delphinidin), phloretin (phloretin), cyanic (cyanic), catechin, morin, phlorizin, phloretin (phloretin), 3 -Hydroxyflavone, 3-deoxyflavonol, isorhamnetin, tricine, chrysoeriol, erlodictyon, techtrochrysin, silybin, taxifolin, pi Senburimu (pinocembrim), galangin (galangin), robinin (robinin), diosmetin (diosmetin), Kaemupuferido (kaempferide), include rhamnetin (rhamnetin) and 3-O-methyl catechin.

Xanthine oxidase inhibitors include plant extracts (eg, water and / or alcohol extracts) of plants such as Eupatorium Purpurem, which have xanthine oxidase inhibitory activity, common tea-derived extracts, and oak bark or chaff. Extract and the like.
Synthetically produced flavonoid compounds or analogs thereof, such as euparin, having xanthine oxidase inhibitory activity are within the scope of the present invention.

  Other xanthine oxidase inhibitors that can be used in the present invention include known plant extracts, such as modified tannins, or those that can exhibit xanthine oxidase inhibitory activity, common tea-derived extracts, and oak bark or gall berries. Extract. Examples of other xanthine oxidase inhibitors include purine analogs (caffeine, theobromine, theophylline, etofylline, etc.), quinazolines (including metacarone hydrochloride), triazines (1,2,3-triazine, 1,3 , 5-triazine, cyanuric acid, cyanuric chloride, and the like, pyrazaro (3,4-d) pyrimidine (such as allopurinol and oxypurinol), and benzocycloheptenone (such as purpurogallin).

  Xanthine oxidase (XO) inhibitory activity was measured using standard organisms such as those described in Biochem. Biophys. Acta., 1992, 1112 (2), 178-182, which are hereby incorporated by reference. Can be easily assessed by biological assays.

  Compounds that bind to or inactivate free radicals produced by xanthine oxidase should be considered inhibitors of xanthine oxidase. Such compounds include butylated hydroxyanisole, butylated hydroxytoluene, propyl gallate, sodium benzoate, pterin (FEBS Lett., 1992, 304, 2-3, 163-166), flavonoid compounds, superoxide dismutase , Iron-eliminating compounds such as desferrioxamine, plasma antioxidants such as glutathione, bilirubin, ubiquinone, and albumin; water-soluble antioxidants such as ascorbic acid; fat-soluble antioxidants such as tocipherol And heme-eliminating antioxidants such as salts of zinc, magnesium, chromium and manganese of haptoglobulin and aspartic acid.

  As noted above, xanthine oxidase inhibitors can be used, for example, as described in the techniques described in British Herbal Pharmacopeia, 1990, Volume 1, British Herbal Medicine Association, United Kingdom, and The Flavonoidds, Advances in Reseach Since 1986, Harborne et al., 1994. Plant / plant component extract produced according to various standard techniques.

  Examples of phosphates or compounds that can release phosphate (PO43-) when administered to a subject include phosphoric acid, orthophosphoric acid salts (depending on the number of hydrogen groups replaced, for example, sodium, magnesium, and potassium salts). Containing primary phosphate (dihydrogen phosphate), secondary phosphate (monohydrogen phosphate) or tertiary phosphate (such as magnesium phosphate, sodium phosphate and potassium phosphate), phosphoric acid C1 Organic esters, such as -10 esters, as well as herbal extracts that release phosphate or phosphorus when administered to human subjects. Phosphates should be considered as being included in the range of organophosphorus, including compounds including phytostigmine, minaprine, and eserin. Preferably, the compositions of the present invention include one or more of such substances. For example, in one aspect of the invention, the composition may include a compound that includes inorganic phosphorus, such as magnesium phosphate, and an organic phosphorus compound, such as phytostigmine.

  Optionally, the compositions of the present invention may include fructose, sucrose, or any other sugar (either a monosaccharide, disaccharide or polysaccharide). Such sugar components may promote uric acid production in humans. Examples of suitable sugars include glucose, fructose, galactose, xylose, arabinose, fucose, rhamnose, starch or other sugars including polymers. In particular, fructose is preferred.

  The compositions of the present invention comprise from about 0.1% to about 40% w / w, more particularly from about 10% to 25% w / w xanthine oxidase inhibitor, from about 0.2% to about 20%, more preferably from about 0.2% to about 20%. It may comprise 0.5% to about 5% w / w, more particularly about 0.5% to about 4% w / w phosphate or a compound capable of releasing phosphate. The balance of the composition can include pharmaceutically acceptable carriers or excipients described below. Optionally, the composition in an embodiment of the present invention further comprises from about 10% to about 50% w / w of sugar, more particularly from about 15% to about 40% w / w, and even more particularly from about 15% to about Includes an amount of about 30% w / w.

The compositions of the present invention may be administered orally, topically (including buccal and sublingual), parenteral (including subcutaneous, intramuscular, intravenous, intraperitoneal and intradermal), vaginal or rectal administration or implanted (eg, slowly) The use of releasing molecules). The compositions may conveniently be presented in unit dosage form and may be prepared by any of the methods well-known in the art of pharmacology.
Such methods include the step of bringing into association the main component with the carrier which constitutes one or more accessory ingredients. In general, the compositions are prepared by uniformly and intimately bringing into association the active ingredient with the liquid carrier or finely divided solid carrier or both, and then, if necessary, shaping the product.

  Depending on the rate of administration, the active ingredient may need to be coated with an agent to protect the active ingredient from the action of enzymes, acids and other natural conditions which may inactivate the ingredient.

  For oral administration, the pharmaceutical composition is in the form of tablets, lozenges, pills, troches, capsules, elixirs, powders, granules, aqueous solutions, suspensions, emulsions, syrups and tinctures obtain. Forms for slow release or delayed release may also be prepared, for example, in the form of coated particles, multilayer tablets or finely divided powders.

  Solid forms for oral administration may include pharmaceutically acceptable binders, sweeteners, disintegrants, diluents, flavors, coatings, preservatives, lubricants and / or time delay agents. Suitable binders include gum acacia, gelatin, corn starch, gum tragacanth, sodium alginate, carboxymethyl cellulose or polyethylene glycol. Suitable sweeteners include sucrose, lactose, glucose, aspartame or saccharin. Suitable disintegrants include corn starch, methylcellulose, polyvinylpyrrolidone, xanthan gum, bentonite, alginic acid or agar. Suitable diluents include lactose, sorbitol, mannitol, dextrose, kaolin, cellulose, calcium carbonate, calcium silicate or dicalcium phosphate. Suitable fragrances include peppermint oil, oil palm, cherry, orange, or raspberry scented oils. Suitable coatings include acrylic and / or methacrylic acid polymers or copolymers and / or their esters, waxes, fatty alcohols, zein, shellac or gluten. Suitable preservatives include sodium benzoate, vitamin E, α-tocopherol, ascorbic acid, methylparaben, propylparaben or sodium disulfate. Suitable lubricants include magnesium stearate, stearic acid, sodium oleate, sodium chloride or talc. Suitable time delay agents include glycerol monostearate or glycerol distearate.

  Liquid forms for oral administration can contain a liquid carrier in addition to the active ingredient. Suitable liquid carriers include water, oil (olive oil, peanut oil, sesame oil, sunflower oil, safflower oil, arachis oil, coconut oil, etc.), liquid paraffin, ethylene glycol, propylene glycol, polyethylene glycol, ethanol, propanol, isopropanol Glycerol, fatty alcohols, triglycerides or mixtures thereof.

  Suspensions for oral administration can further include dispersants and / or suspensions. Suitable suspending agents include sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, sodium alginate or cetyl alcohol. Suitable dispersants include polyoxyethylene esters of fatty acids such as lecithin, stearic acid, polyoxyethylene sorbitol mono or dioleate, stearate or laurate, polyoxyethylene sorbitan mono or dioleate, stearate or laurate, and the like. .

  Emulsions for oral administration may further comprise one or more emulsifiers. Suitable emulsifiers include the dispersing agents described above or natural gums such as gum acacia or tragacanth.

  For topical administration, the pharmaceutical composition may be in the form of a cream, ointment, gel, jelly, tincture, suspension or emulsion. Pharmaceutical compositions may include the pharmaceutically acceptable binders, diluents, disintegrants, preservatives, lubricants, dispersants, suspending agents and / or emulsifiers described above.

Pharmaceutical forms suitable for parenteral administration include sterile aqueous solutions (where water soluble) or dispersions and powders for the extemporaneous preparation of sterile injectable solutions or dispersion. Pharmaceutical forms must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. The solution or suspension may further include one or more buffers. Suitable buffers include sodium acetate, sodium citrate, sodium borate or sodium tartrate. Proper fluidity can be maintained, for example, by the use of a coating such as lectin, the maintenance of the required particle size when dispersed, and the use of surfactants. The action of microorganisms can be prevented by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thermelosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride. Absorption of the injectable compositions can be delayed, for example, by using a composition of absorption delaying agents.

  Sterile injectable solutions are prepared by mixing the required amount of active ingredient with a suitable solvent having the required other ingredients from those enumerated above, followed by sterile filtration.

Generally, dispersions are prepared by mixing the various sterilized active ingredients in a sterile vehicle which contains the main dispersion medium and the required other ingredients from those enumerated above.
In the case of sterile powders for the preparation of sterile injectable solutions, the preferred preparation methods are suction drying and lyophilization techniques, which result in a powder of the active ingredient and any further desired ingredients from the solution, which has been previously sterilized by filtration.

  For rectal administration, the active ingredient is suitably administered in the form of an enema or suppository. Suitable suppositories may be prepared by mixing the active ingredient with a non-inflammatory excipient which is solid at room temperature but which is soluble in the rectum. Suitable such materials are cocoa butter and polyethylene glycol. Suitable enemas may include agents that refer to the above described forms for topical administration.

  The above ingredients used to formulate the active ingredients into a suitable dosage form can be referred to collectively as carriers and excipients.

The compositions of the invention are preferably suitable for oral administration, more preferably as an aqueous solution. Examples of solutions of the invention may include (i) a water / ethanol flavonoid extract, eg, extracted from Eupatorium Purpureum species, (ii) an aqueous solution of a phosphate compound such as phosphoric acid, and (iii) a fragrance.

  In another embodiment, the composition may further include a sugar, such as fructose.

  In the method of the present invention, the active ingredients may be administered separately or as a composition comprising the active ingredients (ie, a xanthine oxidase inhibitor, a phosphate or a compound capable of releasing phosphate, and optionally a sugar). Without limiting the invention in general, a suitable dose of a xanthine oxidase inhibitor will be in the range of 0.5 mg to 10 mg / kg body weight, preferably 3 mg to 6 mg / kg body weight / day, more preferably 3 mg to 5 mg / kg body weight. kg body weight / day. Without limiting the invention in general, suitable dosage ranges for the phosphate or a compound capable of releasing phosphate are on the order of 0.01 mg to 0.5 mg / kg body weight / day, preferably 0.06 mg to 0 mg / kg body weight / day. 0.3 mg / kg body weight / day, more preferably in the range of 0.08 mg to 0.25 mg / kg body weight / day. When the saccharide component according to the optional embodiment of the present invention is contained, the saccharide such as fructose is contained in an amount of 0.75 mg to 50 mg / kg body weight, preferably 4.5 mg to 30 mg / kg body weight / day. , More preferably in the range of 6 mg to 25 mg / kg body weight / day.

  Each compound of the present invention, when in the form of a composition described herein, can be administered 1 to 10 times a day, more preferably 1 to 5 times a day, and at appropriate intervals and appropriate dosages. It can be administered at the level. Administration can be maintained for 1 to 10 weeks, preferably for at least 2 to 4 weeks.

  The compositions of the present invention may also include fatigue, chronic fatigue, concentration difficulties, mood disturbances, or `` asthenia '' or `` neurasthenia '' or `` post viral asthenia '' May be applied for the treatment of the general class of conditions described in Smokers may present with one or more of these conditions, which may be due to various metabolic instabilities. Such signs of instability can drive a strong urge to smoke. Treatment or amelioration of one or more of these conditions may reduce the urge or demand for smoking.

The present invention will now be described with reference to, but not limited to, examples.
(Example 1)
The following active water-soluble compositions were prepared.
A) 400 ml of ethanol extract of grass Gravel Root (1: 2 v / v)
Phosphate ion Phosphate or 10ml
10 g of calcium diphosphate
30ml fragrance
The above is adjusted to a total volume of 2 liters with water.
B) The composition of A), further comprising 1 kg of a thickening agent (glucose syrup).
C) The composition of A), further comprising 1 kg of fructose.
D) further comprising 1 kg of glucose syrup and 1 kg of fructose
Composition.
E) Compositions A) and D) when 2-20 g of allopurinol, oxypurinol, purprogalin or Trolox are used instead of the gravel root extract.

(Example 2)
A series of clinical trials have been conducted in Australia showing that the invention is effective in various aspects. Specific details are briefly described below.

A) Procedure Participants in this study were volunteers who smoked on average more than 30 cigarettes per day. Each study involved daily oral administration of the composition to participants and lasted 6 weeks. During the last two weeks of each test, no test or placebo composition was administered.

B) Composition The composition described in Example 1 was orally administered in a volume of 10 ml / day.

One of the trials was in the following treatment groups:
i) The first group to which the composition D of Example 1 was administered.
ii) a second group administered with a composition comprising:
-Ethanol extract of Gravel Root -Glucose syrup -Fragrance -Water Each of these compositions is present in the same amount as in Example 1.
iii) a third group administered with a composition comprising:
-Fructose-Phosphoric acid-Fragrance-Glucose syrup-Water Each of these compositions is present in the same amount as in Example 1.
iv) a fourth group administered with a composition comprising:
-Ethanol extract of Gravel Root-Glucose syrup-Fructose-Fragrance-Water Each of these compositions is present in the same amount as in Example 1.
v) Group 5 to which the composition A) of Example 1 was administered.
vi) Group 6 administered a composition comprising:
・ 30ml of fragrance
・ 1kg of glucose syrup
・ Make water 2 liters.

C) Results (Summary)
A small, transient placebo effect was noted in Group 6. There was no significant reduction in smoking during or after the study.
Large reductions in the proportion of participants smoking were observed in Groups 1 and 5. However, a small number (less than about 10%) of participants were refractory to treatment, which never diminished the efficacy of the present invention. In the other groups, there was no significant effect on smoking, meaning that the treatment was not effective.

The above detailed example is described below.
(First group)
XAA is a woman in his late thirties who smoked more than 15 cigarettes a day. She did not show a desire to smoke as a result of the treatment program.

(Second group)
XA is a 38-year-old man who smoked 25 cigarettes a day. The treatment course was not effective.
XB is a 46-year-old man who smokes 40 cigarettes a day. The treatment course was not effective.

(Group 3)
XC is a middle-aged man who smokes more than 30 cigarettes per day. The treatment course was not effective.

(Group 4)
XD is a 46-year-old man who smokes more than 30 cigarettes per day. The treatment course was not effective.

Group 5 XE is a 49-year-old man who smokes 15 cigarettes per day. As a result of his cool treatment, he stopped smoking.

  XF is a 45-year-old man who smokes more than 30 cigarettes per day. As a result of his treatment program, he no longer had a desire to smoke.

Claims (1)

In the manufacture of drugs for smoking control,
(a) Eupatorium Purpurem ethanol extract
(b) phosphate, phosphoric acid, salts of phosphoric acid or esters of phosphoric acid, and optionally
(c) sugar, and optionally
(d) A method of using a composition comprising one or more pharmaceutically acceptable carriers or excipients.