TW574037B - Nicotine addiction treatment - Google Patents

Description

The present invention relates to pharmaceutical compositions for tobacco addiction and nicotine addiction, and methods for treating patients using these compositions, which can reduce the effects of nicotine withdrawal and improve the results of other smoking cessation treatments. Each ingredient disclosed in the pharmaceutical composition has a unique mechanism of action, and the combination drug provides unexpected and superior advantages over existing therapies when administered simultaneously. Background of the Delight Nicotine addiction represents the most important preventable disease and cause of death in our society, and more than 40,000 people die each year. One in five Americans now smokes, which represents 50 million smokers in the United States alone. Half of all smokers will die from diseases directly related to tobacco use, and many smokers will suffer from significant morbidity. About 15 million smokers try to quit each year, but only 1 million of them have successfully quit. Tail nicotine addiction and nicotine addiction to cure pruritus Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs Much evidence supports the notion that people continue to smoke because of the nicotine's reinforcing effect. Related findings include that smokers who have previously been deprived of cigarettes or given a centrally acting nicotine antagonist will be allowed to choose higher nicotine concentrations when the nicotine content of each cigarette is allowed to be controlled. In addition, under certain conditions, smokers and animals will inject their own nicotine. The beneficial psychopharmacological effects of nicotine are diverse. It includes sedation, weight loss, reduced irritability, reduced cravings for cigarettes and other tobacco products, increased alertness, and increased cognitive ability. -4- This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) ) 574037 A7 __B7 _ 5. Description of the invention (2) (Please read the precautions on the back before filling this page). These effects include some degree of withdrawal symptoms that can be considered as a negative reinforcement of nicotine. However, some effects (such as increased attention) have been demonstrated in non-dependent animals (Rose, 1996 Rev. Med. 47: 493). Nicotine, which is inhaled in tobacco smoke, is quickly absorbed within seconds and enters the pulmonary circulation to the brain. One cigarette provides 5-30 ng / ml of nicotine in venous blood (Rose, 1996). The metabolic half-life of nicotine is about two hours, and cotinine is its main metabolite. Other nicotine delivery mechanisms, such as snuff, pipe, and Xuesu, have the same effect in the bloodstream. Nicotine is a potent psychoactive drug that activates the same brain pathways as cocaine and other psychostimulants to produce drug-related tolerance and withdrawal effects. Among smokers, the rapid onset of the central nervous system's effects of nicotine and the short half-life lead to rapid development of tolerance and provide an optimal environment for nicotine dependence. The Intellectual Property Bureau of the Ministry of Economic Affairs, the Consumer Cooperative, has printed several drug therapies Proven to quit smoking, including nicotine replacement therapies (NRTs). This nicotine replacement therapy is supplied in the form of chewing gum, transdermal absorption patches, nasal sprays, and inhalants. The first FDA-approved drug to provide nicotine replacement was Nicorette® (nicotine polacrilex), a prescription for chewing gum containing two milligrams (then four milligrams) of nicotine per tablet. This chewing gum is delivered through the mouth after chewing to deliver nicotine. Drug treatment with fenicotin is a recently developed treatment for nicotine addiction. Possible reagents include nicotine blockade therapy, which affects the size of the serum. The paper standard is applicable to the Chinese National Standard (CNS) A4 (210X297 mm) 574037 A7 B7. 5. Description of the invention (3) s ^ rdtonergic neurotransmission drugs, Anti-depressant tree, anti-scorching agent, clonidine, and airway sensory replacement (Rose, 1996; and Cinciripini ei α / ·, 1998 Oncology 12: 249-256). Nicotine blockade (also referred to as a nicotine receptor antagonist) uses compounds that occupy nicotine receptors to attenuate the positive reinforcement from tobacco use (reward) (Clarke, 1991 Br. J. Addict. 86: 501-505). B. Antidepressants and anxiolytics Antidepressants are often used to treat the withdrawal symptoms of nicotine. One such anxiolytic is bupropion. Wellbutrin® is the trade name for butylamine acetone salt (butylamine acetone HC1), an antidepressant produced by Glaxo Wellcome. A slow-release formulation of bupropion HC1 Wellbutrin SR® is also used in the treatment of depression. Glaxo Wellcome also has Food and Drug Administration (FDA) approval to sell a slow-release prescription for amphetamine HC1 as an aid to smoking cessation treatment. Glaxo Wellcome is selling the product under the trade name Zyban®. Zyban® can be used alone or in combination with a nicotine transdermal absorption system (NTS). The mechanism of action of bupropion is unknown, but it is thought to affect neurotransmitters. In particular, methamphetamine is believed to be neurochemically addicted to nicotine by increasing dopamine levels in the mesolimbic system and affecting ortho adrenergic neurons in the locus ceruleus portion of the brain. effect. Because dopamine is associated with the positive reinforcing effects of addictive substances such as nicotine, inhibition of orthopinephrine reuptake is expected to lead to a reduction in withdrawal symptoms [The Medical Letter 39:77 (Aug. 15, 1997)]. Another successful use is doxepin, an antidepressant that is discontinued from smoking treatment. The antipruritic pan and its pharmaceutically acceptable fluorescein salts were originally used as anti-; _______ -6 -__ This paper size applies the Chinese National Standard (CNS) Α4 ^ grid (210 X 297 mm) 'β. ---- -„--- LI_l — (Please read the precautions on the back before filling out this page) Order P. Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 574037 A7 __B7__ V. Description of the invention (4) (Please read the back Please fill in this page again for your attention) v 忧 # 剂 (ΤΪΪΕ MERCK INDEX, # 3425: 539). In addition, anti-anxiety agents that were used by Kang Sui to stop smoking treatment include imipramine (Nunn-Thompson et al .9 1989 Clin. Pharm. 8: 710-720) and Deying Min (Diana ei β / ·, 1990 Am. J. Physiol. 259: H1718-H1729). Anxiolytics have also been used to treat nicotine withdrawal .Anxiolytics counteract mild anxiety symptoms that occur during smoking cessation or alcohol treatment or other substance abuse treatments. The anxiolytic agent isovaleramide has been suggested for use in abstinence (Balandrin e / a / ·, WO 94/28888). Quit smoking has also been combined with antidepressants and anxiolytics ( Glazer, U.S. Patent No. 4,788,189) 〇 C. Nicotine Receptor Antagonist Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs

Another class of smoking cessation drugs is nicotine receptor antagonists, which are used to block nicotine receptors (Rose et al., 1997 Psychopharmacology 130: 28-40) ^ Evidence suggests that C6 (nerve A nicotine antagonist of the type (cholinoceptor) of nicotine to aid abstinence (Clarke, 1987 Psychopharmacology 92: 135-143). In addition, there are nicotine receptors that nicotine antagonists can act on. A nicotine receptor antagonist, mecamylamine and its pharmaceutically acceptable salts, have been studied in animals and humans as a possible smoking cessation drug treatment because it helps quit smoking in animals and humans. (Tennant ei α / ·, 1984 NIDA Res. Monogr. 55: 291-297). Tetramethyl camphoramine was patented in 1985 and sold as an antihypertensive drug. Inversine® is tetramethyl camphoramine hydrogen chloride (HCl) (Pfister, US Patent No. 2,831,027; THE paper) The scale is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) 574037 A7 B7 V. Description of the invention (5) MERCK INDEX # 5654: 9㈣) 9 Tetramethyl camphoramine hydrogen chloride has been shown to work in a nicotine-dependent environment. Hinders the physical, behavioral, and strengthening effects of many nicotine. Tetramethylcamantamine HC1 has been shown to promote smoking cessation when used in combination with the nicotine transdermal absorption system (NTS) (Rose e / α /., 1994 Clin · Pharmacology & Therapeutics 56: 86; Levin et aL , US Patent Nos. J, 574,052 and 5,316,759). In a double-blind clinical trial, nicotine was treated with a skin patch to treat Lele 'with or without the addition of tetramethylpyrrolidamine [two times a day, 5 times each time] Milligrams (5 mg / bid)], the continuous smoking cessation rate observed in the test group given the combination of tetramethylcamantamine-nicotine patch was higher than that observed in the test group given only the transdermal absorption patch It is three times higher. In addition, the efficacy of the test group given by the combination of tetramethylcamantamine-nicotine patch continued, but the withdrawal rate of the test group only given NTS decreased 4 times after 12 months. The other tetramethyl The effect of the combination of camphoramine-nicotine patch is to significantly reduce the craving, negative effects and appetite of cigarettes (Rose W α / ·, 1994) ο Therefore, because of drugs such as tetramethyl camphoramine or its pharmaceutically acceptable Salt competes for the same receptors as nicotine, because They help to improve existing smoking cessation treatment. Tetramethylene camphoramine is a central and peripheral nicotine antagonist and can allow people treated with tetramethyl camphoramine to require higher doses of nicotine compared to only Treatment with peripheral nicotine antagonists [such as trimethaphan] (Perkins ei a /, "Effects of Central and Peripheral Nicotinic Blockage on Human Nicotine Discrimination," Psychopharm. Prew). Stimulating effects of both cytisine and guacurine ____________ -8 -___ This paper size is applicable to China National Standard (CNS) A4 (210X297 mm) ------, --- L-- -(Please read the precautions on the back before filling out this page) Order printed by the Intellectual Property Bureau of the Ministry of Economy ’s Consumer Cooperatives printed 574037 A7 B7 V. Description of the invention (6) Fruits, which are all incorporated into the neuron ’s nicotine receptor (Chandler Say, 1997 Psvchopharmacology 129: 257-264) ° (Please read the notes on the back before filling out this page) Additional nicotine antagonists include hexametho di (trimethylamine) (hexametho nium) (Wotring et al., 1995 Neuroscience 67: 293-300), dihydro-beta-erythroidine (Stolerman et al., 1997 Psvchopharmacology 129: 390-397), d-tube arrows D-tubocurarine (Wotring α / ·, 1995), 1,2,2,6,6-pempidine (Rapier ei α / ·, 1990 L Neurochem. 54: 937-945) , Chloroisodamine, chlorisondamine (Caggiula et aL, 1995 Psvchopharmacology 122: 301-306), erysodine (Decker ei a / ·, 1995 Eur. J. Pharmacol. 280: 7980) and Sanmei He issued trimethaphan camsylate (Hisayama et aL, 1988 Br · J. Pharmacol · 95: 465-472) ° Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs Some nicotine antagonists have been tested in combination with other substances Effects on mean arterial blood pressure and sympathetic nerve activity in the kidney. Two nicotine receptor antagonists, pentolinium and hexamethylene di (trimethylamine), have been tested for their ability to regulate blood pressure in combination with benextramine, desipramine, and prazosin (Martin 1997 J. Auton. Pharmacol. 17: 249-259). However, the combination of nicotine antagonists with antidepressants or anxiolytics has not been indicated for smoking cessation treatment or other substance addiction treatments. D. Cocaine addiction treatment Cocaine addiction has been treated with certain medications used to quit smoking, which is used as a method to reduce the symptoms of coca test withdrawal. 'For example, to remove Fanmin ___________ -9- __ Λ degree of this paper applies Chinese National Standard (CNS) A4 specification (210 X 297 mm) 574037 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs A7 B7 5. Invention Description (7), Amantadine (amaiitadin Ridge and Moyin Ding (Bromocriptine) drug forensics has been shown in preliminary studies to minimize coca withdrawal symptoms (Hall et al. 9 1990 Pharmacotherapy 10: 47-65; and Kosten et aL, 1991 NIDA Res. Monogr. 105 : 510-511). Combination of desensitization and amantadine can help abstinence of opium and cocaine (Oliveto α /., 1995 L Abuse Treat. 12: 423-428) o Summary of the invention The invention is related to the use Pharmaceutical composition for treating tobacco addiction and nicotine addiction, which can be used for reducing nicotine withdrawal symptoms or promoting smoking cessation. A preferred composition comprises a therapeutically effective nicotine receptor antagonist and an antidepressant or an antianxiety Agent And it does not have a nicotine supplement. The intended pharmaceutical composition may be a mixture of several main ingredients administered in a single unit (such as a single lozenge or capsule) or in individual units (such as two capsules). The antidepressant intended for use in the pharmaceutical composition of the present invention may be amphetamine or a pharmaceutically acceptable salt thereof, or an antipruritic pan or a pharmaceutically acceptable salt thereof. In addition, it is expected to interact with a nicotine antagonist Combined anxiolytics include analgesic pan, deyumin, clomipramine, imipramine, nortriptyline, amitriptyline, protriptyline, trimipramine, fluoxetine, fluvoxamine, paroxetine, sertraline, phenelzine, tranylcypromine, amoxapine, maprotiline, trazodone, venlafaxine, mirtazapine and their pharmaceutically acceptable salts or Optical isomers. It is also expected to be used in the present invention in combination with a gadolinin antagonist to make __________- JO: __ applicable to this paper standard National Standard (CNS) A4 (210X297 mm) (Read the precautions on the back before filling this page) 574037 A7 B7 V. Description of the invention (8) The pharmaceutically acceptable salts of butylamine acetone are: Butyl phenyl meat is self-gasifying argon (HC1). The amount of bupropion, or a pharmaceutically acceptable salt thereof, administered with a nicotine receptor antagonist is formulated to provide a dose of about 50 mg to 300 mg per day. A pharmaceutically acceptable salt of an antipruritic pan combined with a nicotine antagonist is expected to be used in the present invention is antipruritic hydrogen gas (HC1p is further expected to be administered with a nicotine receptor antagonist The amount of an antipruritic pan or a pharmaceutically acceptable salt thereof is a dosage formulated to provide an analgesic pan of about 10 mg to 300 mg per day. The entire daily dose can be given in several doses (eg, 1 to 6 rotators) β is also expected to be a nicotine acceptor antagonist of the pharmaceutical composition. The component of the nicotine acceptor is tetramethyl camphoramine and its pharmaceutically acceptable salts and optical isomers. A pharmaceutically acceptable salt is tetramethylcamantamine gasified argon (HC1). In addition, it is expected that tetramethylcamphoramine or a pharmaceutically acceptable agent is administered with an antidepressant or an anxiolytic agent. The amount of salt received is formulated to provide a dose of about 1 mg to 25 mg per day. The present invention additionally relates to an anxiolytic agent, buspirone, or a pharmaceutically acceptable salt thereof, in combination with a nicotine receptor antagonist. Used. Buspirone It is expected that hydrogen chloride (HC1) will be used in combination with a mononicotine receptor antagonist. The present invention also relates to the use of buspirone or a pharmaceutically acceptable salt thereof administered with a mononicotine receptor antagonist is formulated to provide A dose of about 5 mg to 60 mg per day. It is preferred to use a nicotine receptor antagonist in a dose of about 1 to 25 mg of tetramethyl per dose administered in combination with about 5 to 10 mg of butrospirone (HC1) per tablet. Linalmine (HC1). These doses can be given in 1 to 6 tablets per day. Excluding __ _ 11- This paper size applies to China National Standards (CNS) A4 specifications (210X297 mm) n * ϋϋ i-ιϋ ι_ · ϋ «ιϋ —1» -1 > 1_ 1_11 I (Please read the notes on the back before filling out this page) Order printed by the Intellectual Property Bureau Staff Consumer Cooperatives of the Ministry of Economic Affairs 574037 A7 B7 V. Description of the Invention (9) It is expected to be used in combination with a nicotine antagonist for smoking_Pant table anxiolytics include hydroxyzine or meprobamate 〇 The present invention also provides Nicotine antagonists Compositions other than camphoramine and a primary anxiolytic or primary antidepressant. The nicotine antagonists include central nicotine antagonists, central and peripheral nicotine antagonists, and peripheral nicotine antagonists. Nicotine is expected to be indicated Antagonists include tetramethylcamantamine, amantadine, 1,2,2,6,6-pentamethylpiperidine, dihydro-7? -Etinolide, hexamethylenyl bis (trimethylamine), Erythrimidine, qi isoinduramin, trimeta camphor sulfonate, toxotoxin gaseous, cardiotoxin, and their pharmaceutically acceptable salts or their optical isomers. Related to a method of treating tobacco addiction or nicotine addiction, which can reduce nicotine withdrawal symptoms or promote smoking cessation, comprises administering to a patient any one of the aforementioned pharmaceutical compositions. The present invention further relates to a method for treating tobacco addiction or nicotine addiction, which can reduce the symptoms of nicotine withdrawal or promote smoking cessation, and comprises the additional step of administering a previously disclosed pharmaceutical composition in combination with nicotine replacement or supplementation therapy. This nicotine percutaneous absorption patch is the expected nicotine replacement therapy. It is further expected that the described pharmaceutical composition can be administered to treat cocaine addiction to improve cocaine withdrawal symptoms and that it can be used to treat alcohol addiction and improve the effects associated with alcohol withdrawal. The method and dose of delivery can be similar to that suggested for treating nicotine addiction. It is better to have a detailed explanation with It's example.) This paper size applies the Chinese National Standard (CNS) A4 specification (21〇297mm. (Please read the precautions on the back before filling this page)

-、 1T Printed by Consumer Affairs Bureau of Intellectual Property Bureau, Ministry of Economic Affairs 12. 574037 A7 B7

V. Description of the invention (J-. · 〆 '... I · Overview:' ... "-: c Although the over-the-counter nicotine replacement therapy is dominant in the market, its effectiveness in preventing the recurrence of nicotine-dependent patients and Not as large as non-nicotine dependent pharmacological substances such as amphetamine acetone HC1. The success rate of nicotine gum is less than 10% in 12 months and the nicotine percutaneous absorption patch is only 10-30% in 12 months (Rose ei α / ·, 1994 Therefore, identifying substances with a low failure rate is the goal of the industry and smokers who want to quit addictive habits. The present invention includes a method of treating tobacco addiction and nicotine addiction 'which can reduce nicotine withdrawal ) And can improve the results of other smoking cessation treatments, and it also provides long-term smoking cessation maintenance treatment. The present invention also includes related pharmaceutical compositions, which are administered in a therapeutically effective amount to treat patients. Special drug combinations, For example, an anxiolytic agent combined with a nicotine receptor antagonist is disclosed. In addition, a pharmaceutical composition of an antidepressant combined with a nicotine receptor antagonist is also expected The preferred nicotine receptor antagonists are those that are both central and peripheral nicotine antagonists (such as tetramethyl camphoramine) or a central nicotine synergist (agonist). Second-best nicotine receptor antagonists These are only peripheral nicotine antagonists. These compositions are also expected to be used in the treatment of coca addiction and its associated withdrawal effects, and alcohol dependence and its associated withdrawal effects. II. Detailed description of an example In the pharmaceutical composition of the present invention for treating tobacco addiction and reducing withdrawal symptoms associated with discontinuation of tobacco use, it preferably includes the following combinations: _; _ -13- This paper size applies the Chinese National Standard (CNS) A4 specification ( 210X297 mm) (Please read the precautions on the back before filling out this page), ιτ printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 574037 A7 B7 printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs Tetramethylammonium amine or a pharmaceutically acceptable salt of methyl cinnamylamine such as tetramethyl linalmine amine hydrogen chloride (HC1) and butylamine acetone Or a pharmaceutically acceptable butylamine phenylacetone salt such as butylamine phenylacetone hydrogen chloride (HC1) (2) tetramethyl camphoramine or a pharmaceutically acceptable tetramethyl camphoramine salt such as tetramethyl camphoramine HC1 and buspirone or a pharmaceutically acceptable buspirone salt such as buspirone hydrogen gas (HC1); (3) tetramethyl camphoramine or a pharmaceutically acceptable tetramethyl camphoramine salt, such as Tetramethyl camphoramine HC1 and antipruritic pan or a pharmaceutically acceptable antipruritic pan salt such as antipruritic hydrogen gas (HC1); and (4) a nicotine receptor antagonist and an anxiolytic or Anxiolytics. Existing antidepressants or anxiolytics (also referred to as anxiolytics), as indicated below, and nicotine antagonists such as tetramethylsalantamine are discussed for other uses of these substances. These patents describe the pharmaceutical composition and its pharmacologically acceptable salt derivatives, a method of making the medicament, and a method of using the same. Although high-dose ranges are expected for the [Nicotine Receptor Antagonist-Antidepressant] and [Nicotine Receptor Antagonist-Anxiolytic] composition, each drug is due to the unexpected benefits of this combination therapy The preferred dose may fall in the low to medium range. This lower dose will reduce the incidence of side effects and adverse reactions. Tetramethyl camphoramine was originally used as an anti-hypertensive J & L pressure drug, but may also act as a nicotine receptor antagonist. U.S. Patent No. 2,831,027 describes the synthesis of tetramethylcamantamine. The tetramethyl camphoramine salt and tetramethyl camphor __; _ -14- (Please read the precautions on the back before filling out this page), ιτ -f This paper size applies Chinese National Standard (CNS) A4 specifications ( 210X297 mm) 574037 Printed by A7 _B7__ of the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs. 5. Description of the invention (j alkane according to HC1; the chemical formula is CnHuClN. Tetramethyl 丨 yl camphor M Youqizhai 'rate: upper or physiological Acceptable salts (such as tetramethyl camphoramine HC1) and its optical isomers are contemplated by the present invention in combination with an anxiolytic or antidepressant to treat tobacco addiction and nicotine addiction, and improve nicotine withdrawal Action, combination with nicotine replacement therapy (NRTs), and treatment of cocaine addiction and alcohol dependence. Nicotine antagonists that are expected to be combined with an anxiolytic or antidepressant-in addition to tetramethylcamantamine-contain dihydro- Dot-Erythrobine [ie dihydro-iS-erythroidine; 3 cold-1,6-didehydro-14; 17-diargon-3-methoxy-16 (15H) -oxetia 15-15 Ketones; 12,13-dihydrogen-2,7,13,14-tetra-argon- «Erythromydine] (Ding! 1ug 1 ^ ug 11 (: 1 (: 1 \ 0ugyou, # 3 158: 500; 1989); tubertoxin chloride [also known as 7 ', 12'-dihydro-6,6-dimethoxy-2,2', 2 * -trisyltubocuraranium gasification gasification hydrogen ] (THE MERCK INDEX, # 9717: 1542, 1989); d-tubulin toxin (Wotring et α / ·, 1995); amantadine (also known as tricyclic [3.3.1.13'7] dec-1-amine; 1 -Amantadine; 1-Amine Fundantane; 1-Amine diamantane; 1-Amine Tricyclic [3.3. L: l3,7] decane) (THE MERCK INDEX # 380: 60, 1989); 1, 2 , 2,6,6-Pentamethylpiperidine (i.e. l, 2,2,6,6-pentamethylpiperidine) (THE MERCK INDEX # 7022: 1120, 1989); Erythramidine [related to dihydro-beta-erythroidine For erythrine bioassay, see Decker et α / ·, 1995; and Singh ei α / ·, 1969 Experientia 25: 785]; qi isoalpha bow ^ amine [ie chlorisdondamie chloride; 4,5,6,7 · Tetragas-2,3-dihydro_2-methyl-2- [trimethylammonium] ethyl] -2H-isoinduryl digaside; 4,5,6,7-tetrachloro-2 -(2-2 methylaminoethyl) -2-methylisoinduryl diazide methyl chloride] (THE MERCK INDEX # 2101: 324- — — — ^ __ This paper size applies to Chinese national standards ( CNS) M specifications (2 丨 〇X 297 mm) (Please read the notes on the back before filling out this page) 574037 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs A7 B7_V. Description of the invention (j 325, i9S9) # 然 甲 olefinr 基 二 （三Fluorenylamine is also known as hexamethyl-1,6-hexanediammonium; hexamethylenebis (trimethylammonium)] (THE MERCK INDEX # 4609: 741, 1989); and Smetafa Camphor sulfonate [also known as decahydro-2-oxo-1,3-bis (phenylmethyl) thieno [1 ', 2': 1,2]] thieno [3,4] imidazole-5_ 鏺Salt] (THE MERCK INDEX # 9621: 1527, 1989). Pharmaceutical salts of these compounds are also expected to be used in the treatment of smoking cessation. An example of the use of a nicotine antagonist other than tetramethylsalantylamine is amantadine HC1 and butylamine acetone, where about 150 to 300 mg of butylamine acetone is common with about 50 to 150 mg of amantadine HC1 Administer medicines to stop smoking and other conditions that involve withdrawal symptoms. The invention also relates to the use of an antidepressant such as amphetamine in combination with a nicotine receptor antagonist. U.S. Patent No. 3,819,706 and U.S. Patent No. 3,885,046 describe the synthesis of amphetamine. Many different forms of amphetamine have been used to treat men and women's psychotic dysfunction, reduce cholesterol levels, treat attention deficit disorder (ADD), and inhibit animal's prolactin ( (prolactin) levels, treatment of anxiety, tardive dyskinesia for mammals, and overcoming mental alertness from drinking. Patents containing the aforementioned method of using amphetamine are disclosed in U.S. Patent Nos. 4,507,323, 4,438,138, 4,435,449, 4,347,257, 3,885,046, 4,425,363, and 4,393,078, respectively. One pharmaceutically acceptable salt of butylamine acetone is butylamine acetone hydrogen gas (HC1), which is sold under the trade names Wellbatrin® and Wellbutrin® and has the chemical formula CUH19C12N0. Another anti--16 drug that is expected to be administered as a nicotine receptor antagonist-This paper size applies to the Chinese National Standard (CNS), 8 ^^ (21〇'297mm) (Please read the precautions on the back before Fill out this page),?! 574037 A7 B7 V. Description of the invention (j (please read the precautions on the back before filling this page) Depressant is an antipruritic pan or: its pharmaceutically acceptable salts. Meyer et al. Nos. 3,438,981 and 3,420,851 describe the synthesis, pharmaceutical composition, and use of the antipruritic pan. The chemical formula of the antipruritic pan is C19H21NO. A pharmaceutically acceptable salt of the antipruritic pan is the antipruritic pan Hen, which has the chemical formula C19H22C1N0. Named Adapin®, Aponal②, Curatii ^, Novoxapin®, Quitaxon®, and Sinequan®. Antipruritic pans and pharmaceutically or physiologically acceptable salts have been used as antidepressants or antipruritic agents (THE MERCK INDEX, # 3425: 539 ) Dosage. As expected for use in the present invention, Painkiller and a nicotine receptor antagonist are administered to treat tobacco addiction and the effects of nicotine addiction, mitigate the effects of nicotine withdrawal, and be used in other smoking These pharmaceutical compositions can also be used to treat cocaine addiction or alcohol dependence. Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, antidepressants that are also expected to be administered with nicotine receptor antagonists include: amitriptylixie (daily 100-30 mg), Qilinpai Feining (200-250 mg per day), deyumin (100-300 mg per day), imipramine (100-300 mg per day), nortriptil (50- 200 mg), protriptyline (20-60 mg per day), trimipramine (100-300 mg per day), fluoxetine (10-80 mg per day), fluoxamine (100-300 mg per day), paroxetine (20-50 mg per day), setraline (50-200 g per day) 葩 (45-90 g per day), aniline (20-50 mg per day), amoxapine (200-600 mg per day), horseshoe spirit (150-200 g per day) , Ketazolone (200-600 mg per day), nefazodone (300-600 mg per day), venlafaxine (75-375 mg per day), and mirtazapine (15-45 mg per day); and their pharmaceutically acceptable salts and optical isomorphs体 物。 The Contains a nicotine receptor antagonist and the above-mentioned anti -_______ 'J2s_ a paper size applicable to the Chinese National Standard (CNS) A4 specifications (210X297 public ^ one 574037 A7 B7 V. Description of the invention (j melanin pharmaceutical composition The preferred dosage range will likely be in the low-to-medium dosage range recommended for each medicament. In addition to antidepressants, anxiolytics can also be administered with nicotine receptor antagonists, either as mixtures or separately. One anticipated anxiolytic agent is buspirone and its pharmaceutically acceptable salts, such as buspirone HC1. U.S. Patent Nos. 3,717,634 and 4,182,763 describe the synthesis, pharmaceutical composition, and use of buspirone as a primary anxiolytic agent. The chemical formula of buspirone is C ^ H ^ NsO2. Its synthesis is described in US Patent No. 3,717,634. Buspirone and its pharmaceutically acceptable salts, such as Buspirone HC1, act as a non-benzodiazepine anti-anxiety agent and 5-hydroxytryptamine (5-HT). Receptor synergy (THE MERCK INDEX, # 1493: 539). The chemical formula of dibutyl helix g ^ jHCl is C21H32C1N502, which is sold under the trade names BeSpai: ㊣, Buspar®, Buspinol㊣, Censpar®, Lucelan②, and Travin®. Other non-benzodiazepines anxiolytics are also expected to be combined with a nicotine receptor antagonist to treat smoking termination. Additional anxiolytics include hydroxyethoxypiperazine (50-400 mg per day) and meprobamay (400-1600 mg per day). Due to the simultaneous administration of a nicotine antagonist, the preferred dosage range of the pharmaceutical composition can be in the recommended low to medium dosage range. This low dose reduces the risk of adverse side effects. A preferred embodiment of the present invention comprises a dosage formulation that delivers about 1 mg of tetramethylcamantamine HC1 to about 25 mg of tetramethylcamantamine HC1 and about 50 mg of butylamine acetone HC1 to 300 mg of butylamine per day. Pharmaceutical composition of amine acetone HC1. A more preferred embodiment is that a pharmaceutical composition contains a dose formulated to deliver about 1 mg of tetramethylcamantamine HC1 to about 10 mg of tetramethyl hydrazine per day. ________- 18- This paper applies Chinese National Standards (CNS) A4% grid (210X297 mm) (Please read the notes on the back before filling out this page) Order printed by the Employees ’Cooperatives of the Intellectual Property Bureau of the Ministry of Economy 574037 A7 B7 Printed by the Employees’ Cooperatives of the Intellectual Property Bureau of the Ministry of Economy 16) Roasted Ammonium Hem Suction ~: The agent Fenzhi is for rotation: about 50 mg butylamine phenylpropionate to 300 mg butylamine acetone HC1. The preferred embodiment comprises a dosage formulation that delivers about 1 mg of tetramethylcamantamine HC1 to about 5 mg of tetramethylcamantamine HC1 and about 50 mg of butylamine acetone HC1 to 300 mg of butylamine acetone HC1 per day. . These prescriptions can be given once a day as one pill or several pills, up to about six prescription units (eg, tablets or capsules) per day. The recommended maximum recommended daily doses of tetramethyl camphoramine HC1 and butylamine acetone HC1 are 25 mg and 300 mg, respectively. On the other hand, another contemplated embodiment is a pharmaceutical composition formulated to release a main component over a period of time. The pharmaceutical composition is also expected to be used to treat coca addiction, withdrawal symptoms associated with coca addiction, alcohol dependence, and its associated withdrawal effects. Another preferred embodiment is bustorone HC1 (Buspar®, Mead Johnson) in combination with tetramethyl camphoramine HC1 to treat tobacco addiction, nicotine addiction, reduce the side effects of nicotine withdrawal, improve long-term withdrawal or enhancement of smoking Nicotine replacement therapy. The pharmaceutical composition preferably comprises a dose of about 5 to 10 mg of buspirone HC1 per day and a dose of about 1 to 25 mg of tetramethylcamantamine HC1 per day. These prescriptions can be given once a day as one pill or several pills, up to about six prescription units (eg, tablets or capsules) per day. The recommended maximum recommended daily doses of buspirone HC1 and tetramethylcameramine HC1 are generally 60 mg and 25 mg, respectively. Another contemplated embodiment is a pharmaceutical pasta formulation that releases the main component over a period of time. This would include a formulation containing a dose of about 5 milligrams a day of buspirone HC1 and a dose of about 25 milligrams a day of tetramethylsalkanamine HC1, and a formula containing a dose of about 10 milligrams a day of buspione HC1 and about 1 Prescription of a mg dose of tetramethylcamantamine HC1. According to the recommended dosage range here ------19- (Please read the precautions on the back before filling this page)

、 1T f This paper is A degree applicable to Chinese National Standard (CNS) M specification (210X297 mm) 574037 A7 _____B7 V. Description of the invention (17) (Please read the notes on the back before filling this page) Encircle other possible combinations It will be obvious to a person familiar with the art. These prescriptions are also considered for the treatment of cocaine addiction-related withdrawal effects and alcohol dependence and its associated withdrawal effects. Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs. Another preferred embodiment using a nicotine acceptor antagonist in combination with an anti-proliferative agent is a pharmaceutical composition comprising itan HC1 in combination with tetracameramine HC1. The intended pharmaceutical composition comprises a dose of antipruritic pan HC1 in a dose of about 10 to 300 mg per day and a dose of about 1 to 25 μg of tetramethyl camphoramine HC1 in one dose, which can be administered separately (for example, each Each drug is dispensed in separate capsules or lozenges) or given in a unit such as a lozenge or capsule. These prescriptions can be given once a day as a pill or several pills, up to six prescription units per day (such as tablets or capsules). A more preferred prescription contains one dose of antipruritic pan HC1 at a dose of about 10 to 150 mg per day and one dose of tetramethylcameramine HC1 at a dose of about 1 to 25 mg per day. The best prescription consists of a dose of 5 mg of tetramethylammonium HC1 and a dose of about 75 g of antipruritic pan HC1, administered twice daily. On the other hand, another contemplated embodiment is one in which the pharmaceutical composition releases the main component over a period of time. This includes a prescription containing an antipruritic pan HC1 at a dose of about 50 mg per day and a tetramethyl stick burning fecHCl at a dose of about 25 mg per day. Other possible combinations will be apparent to a person skilled in the art from the dosage ranges suggested herein. The recommended maximum recommended daily doses of tetramethylsalanylamine HC1 and antipruritic HC1 are generally 25 mg and 300 mg, respectively. The pharmaceutical composition is also expected to be used for the treatment of cocaine addiction, withdrawal effects related to cocaine addiction, alcohol dependence and its associated withdrawal effects. The expected combination of the previously discussed pharmaceutical compositions can be formulated as oral, parenteral, rectal or oral, medicinal, or as a _ ________- 20 -___ This paper size applies to Chinese National Standards (CNS) A4 specification (2ΐ〇χ297) 574037 A7 _ '— B7 · V. Description of the invention (j (please read the precautions on the back before filling this page) It is suitable for the general adult through the injection of poor form by Weng Ruming To treat tobacco addiction and nicotine addiction, to treat the effects of tobacco and nicotine nicotine withdrawal, to improve long-term smoking cessation or to enhance smoking cessation treatments (such as nicotine replacement therapy, such as nicotine percutaneous absorption patches or Nicolette €) gum. The pharmaceutical composition may be further formulated using more than one pharmaceutically acceptable carrier and excipient. The drug can be administered in a single unit or as two or more independent drugs. Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs For the purpose of oral administration, the disclosed pharmaceutical composition may be in the form of tablets or capsules prepared in a conventional manner, which may be mixed with pharmaceutically acceptable excipients such as adhesives [ For example, pregelatinise (j) corn bactericide, polyvinylpyrrolidone or hydroxypropylfluorenyl cellulose; fillers (such as lactose, microcrystalline cellulose, or linolenic acid); lubricants (lubricant ) (Such as magnesium stearate, talc or silica); disintegrating agents [such as potato starch or sodium starch glycolate] or wetting agents (such as sodium lauryl sulfate); slip Glidants; artificial or natural flavors and sweeteners; artificial or natural colors or dyes; and solubilizers. The pharmaceutical composition may additionally be formulated to be released in a time-release manner The main ingredients are known in the art and are discussed in US Pat. Nos. 4,690,825 and 5,055,300. The tablets can be film-coated in a manner well known in the art. Oral liquid formulations can In the form of a solution, syrup or suspension 'or they may be dry products brewed with water or other solvents before use. The liquid formulations can be formulated using conventional methods with pharmaceutically acceptable additives, such as Suspensions (such as sorbitol syrup, methylcellulose, or argonized edible fat); emulsifiers (such as egg fat or _- ______) This paper size applies to China National Standard (CNS) A4 (210X297 mm) 'Cold — 574037 A7 ____ B7 V. Description of the invention (j Acacia gum); non-aqueous agents (for example, various oils, petroleum esters, ethanol burns, preservatives (for example, methyl or ethyl P-hydroxybenzoic acid or sorbic acid) And artificial or natural pigments and / or sweeteners. For oral administration, the composition may take the form of lozenges or lozenges formulated in a conventional manner. The active compounds may be formulated for injection Parenteral administration, which includes the use of known catheterization techniques or plaques. Prescriptions for injections can appear in unit dosage forms such as ampules Or in a multi-dose container with a preservative added. The composition may take the form of, for example, a suspension, solution or emulsion in an oil or water vehicle, and it may contain prescription agents such as suspensions, stabilizers and And / or a dispersing agent. In addition, the main ingredient may be in the form of a powder which can be infused with an appropriate solvent (eg, sterile pyrogen-free water) before use. The active compound may also be formulated as a rectal composition such as an anal suppository or retention enema. For example, it contains a conventional drug-containing base (such as cocoa butter or other glycerin S). For intranasal or inhaled administration, the active compound can be conveniently delivered in the form of a solution or suspension, which can be The patient is extruded or drawn from a pump spray container or a mist spray from a pressurized container or sprayer-using a suitable propellant (e.g. difluorodifluoromethane, trichloromethane) Halothane, difluorotetrafluoroethane, carbon dioxide or other suitable gas). In the case of a pressurized mist spray, the dosage unit can be determined by providing a valve that delivers a certain amount. The pressurized container or sprayer may contain a solution or suspension of the active compound. The capsules and cartridges used in inhalers or insufflators can be formulated to contain an active compound and a suitable -------- -22-_ ____ — This paper size applies to Chinese National Standard (CNS) A4 specifications (21 〇χ297mm) (Please read the notes on the back before filling this page) Order printed by the Intellectual Property Bureau of the Ministry of Economic Affairs, printed by the Consumer Cooperative 574037 A7 B7 V. Description of the invention (20) Combined powders such as milk seed or Tibetan powder y powder mixture. Without further description, those skilled in the art will be able to make and use the compounds of the present invention and implement the methods claimed by the present invention using the previous description and the following illustrative examples. In addition, all of the aforementioned pharmaceutical compositions-including a nicotine receptor antagonist and an antidepressant or anxiolytic drug for the treatment of nicotine dependence and smoking cessation-can be combined with a nicotine replacement therapy (such as a nicotine percutaneous absorption patch) use. These compositions and methods of administration are also expected to treat cocaine addiction and alcohol dependence. Subsequent practical examples therefore specifically point out the preferred embodiments of the present invention and should not be construed as the remaining limitations of this disclosure. Other common structures will be apparent to those skilled in the art. EXAMPLES Example 1 A prescription contains about 10 mg of tetramethylsalanylamine and about 50 mg of butylamine acetone combined into a single lozenge or capsule, and it is administered orally at a daily frequency of Between one and six ingots. Example 2 A prescription contains about 10 mg of tetramethyl camphoramine and about 150 mg of butylamine acetone combined into a single lozenge or capsule, and it is administered orally at a frequency of one to six per day Between the ingots. Example 3 A prescription contains about 5 mg of tetramethyl camphoramine and about 50 mg of butylamphetamine combined into a single lozenge or capsule, and it is administered orally at a frequency of one to six tablets per day between. Example 4 _ ____- 23- This paper is suitable for Ningguo National Standard (CNS) (210X297 public director) (Please read the precautions on the back before filling out this page) See also: Ordering the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs Printed 574037 V. Description of the invention (21) The prescription contains about 5 mg of tetramethyl camphoramine and about 15 mg of butylamine acetone combined into a single lozenge or capsule, and it is administered orally The dosing frequency is between one and six tablets per day. Example 5 The prescription contains about 25 亳 g of tetramethyl camphoramine and about 300 亳 g of amphetamine combined into a single lozenge or capsule, and it is administered orally in one dose. This dose is expected to be administered as a pharmaceutical composition that releases the main component over a period of time (eg, 24 hours). Example 6 One 2.5 mg of tetramethylcamphoramine lozenge and one 150 mg of butylamine acetone lozenge twice daily (in the morning and evening). Example 7 Other antidepressants, such as, but not limited to, antipruritic pan HC1 (Sinequan®, Pfizer), can also be used in combination with tetramethylcamantamine. A dose of about 10 to 15 mg of antipruritic pan HC1 can be administered in combination with a dose of about 1 to 25 mg of tetramethylcamantamine HC1. These doses can be prescribed in several smaller units during the day. Given during the course (eg one to six capsules). Example 7-An anxiolytic agent for persimmon with perylene and anti-scorching agent persimmon _ HC1 (Buspar®, Mead Johnson), a 5-hydroxytryptamine (5-HT) synergist Proven to overcome nicotine-associated withdrawal symptoms and improve short-term smoking cessation. The drug, as well as other anxiolytics, can be used in combination with tetramethylcamantamine HC1 to improve long-term self-smoking withdrawal. A dose of about 5 to 10 mg of buspirone (please read the notes on the back before filling this page) Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs

— ----- | 、 Order ------ 4— ——.- IK — ^-I Φ -24- 574037 V. Description of the invention (22) HC1 can be used with the agent about] to 25 亳A gram of tetramethyl camphoramine IX alpha was combined to shake. It includes a dose of 5 mg of buspirone HC1 in combination with a dose of about 25 mg of tetramethyl camphoramine HC1, and a dose of about 10 mg of buspirone HC1 in a dose of about 1 mg of tetramethylcamantamine HC1 is used in combination. These doses can be administered twice daily (in the morning and evening), but they can also be administered more or less frequently as needed. Based on the dosage range suggested here, other possible combinations will be apparent to a person skilled in the art. (Please read the notes on the back before filling out this page) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs -25. This paper size applies to China National Standard (CNS) A4 (210X297 mm) 574037 A7 B7 Intellectual Property of the Ministry of Economic Affairs Printed by the Bureau ’s Consumer Cooperatives 5. Description of Invention (23), References ^ This application is also incorporated in its entirety into US Provisional Application 60 / 060,794 filed on October 3, 1997. Subsequent references, as well as all the papers, textbooks, and patents mentioned before and after, are hereby incorporated into this case as reference materials. AW Peck, US Patent No. 4,393,078 (1983) BM Bloom et al. 9 US Patent No. 3,420,851 (1969) Balandrin et al. 9 WO 94/28888 Bupropion HC1, THE MERCK INDEX Eleventh Edition # 1488 (1989): 228 Bupropion (Zyban®) for Smoking Cessation, The Medical Letter 39 (1007): 77 (Aug.15, Buspirone, THE MERCK INDEX Eleventh Edition # 1493 (1989): 229 Caggiula et al., 1995 Psychopharmacology 122: 301-306 Casten et al. 9 US Patent No. 4,182,763 (1980) Chandler et al. 9 1997 Psychopharmacology 129: 257-264 Cinciripini et aL, 1998 Oncology 12: 249-256 Clarke, 1991 Br. J. Addict. 86: 501-505 Clarke, 1987 Psychopharmacology 92: 135-143 Decker et of., 1995 Ear; J: PhaimacoL 280: 79-89--Diana et al, 1990 Am. J. Physiol. 259: H1718-H1729) Doxepin, THE MERCK INDEX Eleventh Edition # 3425 (1989): 539 Glazer, US Patent No. 4,788,189 Gupta, US Patent No. 5,055,300 (1991) Hall et al. 9 1990 Pharmacotherapy 10: 47-65 Hisayama et al. 9 1988 Br. J. Pharmacol. 95: 465 -472 Kosten et al., 1991 NIDA Res Monogr 105: 510-51 1 Martin 1997 J. Auton. Pharmacol. 17: 249-259 Mecamylamine HC1, THE MERCK INDEX Eleventh Edition # 5654 (1989): 905 Mehta, US Patent No. 3,819,706 (1974)) -26- (Please read the note on the back first (Please fill in this page for matters) • Φ

、 1T t This paper size is applicable to China National Standard (CNS) A4 specification (210X 297mm) 574037 A7 B7 V. Description of invention (焱

Mehta, US, Pateni NoJ, 885,046 (1975) _; THE MERCK INDEX # 380: 60 (1989) THE MERCK INDEX # 2101: 324-325 (1989) THE MERCK INDEX # 3158: 500 (1989) THE MERCK INDEX # 4609 : 741 (1989) THE MERCK INDEX # 7022: 1120 (1989) THE MERCK INDEX # 9621: 1527 (1989) THE MERCK INDEX, # 9717: 1542 (1989)

Nunn-Thompson et ai9 1989 Clin. Pharm. 8: 710-720

Oliveto et aL, 1995 J. Suhst. Abuse Treat. 12: 423-428

Perkins et aL, nEffects of Central and Peripheral Nicotinic Blockage on Human Nicotine Discrimination, f, Psychopharm. In press

Pfister, U.S. Patent No. 2,831,027 (1958)

Rapier et al. 9 1990 J. Neurochem. 54: 937-945

Rose, "Nicotine addiction and treatment, " 1996 Annu. Rev. Med. 47: 493

Rose et al ·, "Mecamylamine combined with nicotine skin patch facilitates smoking cessation beyond nicotine patch treatment alone, " 1994 Clin. Pharmacology & Therapeutics · 56: 86-99 (1994)

Rose et al. 9 1997 Psychopharmacology 130: 28-40 Singh et aL, 1969 Experientia 25: 785 Stach, U.S. Patent No. 3,438,981 (1969)

Stern, U.S. Patent No. 4,507,323 (1985)

Stern, U.S. Patent No. 4,425,363 (1984)

Stern, U.S. Patent No. 4,435,449 (1984)

Stern, U.S. Patent No. 4,438,138 (1984)

Stern, U.S. Patent No. 4,347,257 (1982)

Stolerman et al. 9 1997 Psychopharmacology 129: 390-397 Tennan et al. 9 1984 NIDA Res Monogr 55: 291-297 Won, U.S. Patent No. 4,690,825 (1987)

Wotring et al. 9 1995 Neuroscience 67: 293-300 Wu et al. 9 US Patent No. 3,717,634 (1973) 30 ____- 27J; __ This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm)- ---- · --- r --- — (Please read the notes on the back before filling in this page) Order printed by the Intellectual Property Bureau's Consumer Cooperatives

Claims (1)

574037 8 8 8 8 A B c D Sixth, the scope of patent application * No. 088 104264 patent reexamination application application scope amendment date of revision · · April 1992 · a kind of treatment for tobacco addiction or nicotine fistula, reducing nicotine withdrawal symptoms or can promote smoking cessation A pharmaceutical composition comprising tetramethylcamantamine, a pharmaceutically acceptable salt thereof, or an optical isomer thereof, and butylamine acetone, a pharmaceutically acceptable salt thereof, or an optical isomer thereof A therapeutically effective combination, wherein the butylamine acetone-based formula delivers a dose of about 50 to about 250 mg per day. 2. A pharmaceutical composition according to item 1 of the application, wherein the pharmaceutically acceptable salt of butylaminophenone is butylaminophenone HC1. 3. The pharmaceutical composition according to item 1 of the application, wherein the pharmaceutically acceptable salt of tetramethylcinnamylamine is tetramethylcamantamine HC1. 4. The pharmaceutical composition according to the scope of application for patent, wherein the bupropion or its pharmaceutically acceptable salt formula is to deliver a dose of about 50 to 200 mg per day. 5. The pharmaceutical composition according to item 1 of the application, wherein the methamphetamine or a pharmaceutically acceptable salt thereof is formulated to deliver a dose of about 50 to milligrams per day. 6. The pharmaceutical composition according to item 1 of the patent application scope, wherein the tetramethyl camphoramine or a pharmaceutically acceptable salt formula thereof delivers a dose of about i to 25 <,: · 'mg per day. 7. The pharmaceutical composition according to item 6 of the application, wherein the tetramethyl camphoramine has a pharmaceutically acceptable salt formula that delivers a dose of about 10 to 10 mg per day. 8. The pharmaceutical composition according to item 1 of the scope of patent application, which further comprises a range of -28-574037 A B c D. Patent Application ~ Nicotine replacement therapeutic agent. 9. The pharmaceutical composition according to item 8 of the application, wherein the nicotine replacement therapeutic agent is a nicotine percutaneous absorption patch. 10 · The pharmaceutical composition according to item 1 of the scope of patent application, which is administered orally, parenterally, rectally, orally, or by inhalation or blowing. -29- This paper size applies to China National Standard (CNS) 8-4 (210 X297 mm) binding line