WO2021249578A2 - 预防治疗哮喘或慢阻肺或过敏性疾病等的药物 - Google Patents
预防治疗哮喘或慢阻肺或过敏性疾病等的药物 Download PDFInfo
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- WO2021249578A2 WO2021249578A2 PCT/CN2021/111365 CN2021111365W WO2021249578A2 WO 2021249578 A2 WO2021249578 A2 WO 2021249578A2 CN 2021111365 W CN2021111365 W CN 2021111365W WO 2021249578 A2 WO2021249578 A2 WO 2021249578A2
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- WIPO (PCT)
- Prior art keywords
- aspirin
- pharmaceutically acceptable
- point
- salicylate
- salicylic acid
- Prior art date
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- KHPCPRHQVVSZAH-UHFFFAOYSA-N trans-cinnamyl beta-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OCC=CC1=CC=CC=C1 KHPCPRHQVVSZAH-UHFFFAOYSA-N 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 239000003029 tricyclic antidepressant agent Substances 0.000 description 1
- FQCQGOZEWWPOKI-UHFFFAOYSA-K trisalicylate-choline Chemical compound [Mg+2].C[N+](C)(C)CCO.OC1=CC=CC=C1C([O-])=O.OC1=CC=CC=C1C([O-])=O.OC1=CC=CC=C1C([O-])=O FQCQGOZEWWPOKI-UHFFFAOYSA-K 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/60—Salicylic acid; Derivatives thereof
- A61K31/612—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid
- A61K31/616—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid by carboxylic acids, e.g. acetylsalicylic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/60—Salicylic acid; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/08—Bronchodilators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
Definitions
- the present invention relates to the field of medical treatment and medicine, in particular to the provision of aspirin and its derivatives in providing medicines for the prevention or treatment or amelioration of diseases in mammals or humans caused by asthma or chronic obstructive pulmonary disease or bronchitis and allergic diseases. application.
- Allergic rhinitis which is characterized by paroxysmal nasal itching, sneezing, runny nose, and nasal congestion, is one of the more difficult diseases in clinical treatment. Its incidence is high, about 1% to 5% in China, and there are 38% of them. Patients with allergic rhinitis can further develop into more serious diseases such as bronchial asthma.
- Allergic diseases are allergic diseases. Allergic diseases have become a global public health problem. The increasing incidence rate has attracted global attention. It not only affects the quality of life of patients, but even threatens the lives of patients, and its common pathogenesis It is the body's specific Ig E-mediated or cell-mediated immune response to common inhaled or food allergens. Allergic rhinitis (allergic rhinitis), also known as allergic rhinitis, is the release of IgE-mediated mediators (mainly histamine) after exposure to allergens by atopic individuals, and has a variety of immunologically active cells and cytokines, etc.
- IgE-mediated mediators mainly histamine
- Participating chronic inflammatory disease of the nasal mucosa is characterized by nasal itching, sneezing, hypersecretion, and swelling of the nasal mucosa.
- a small number of patients may also experience shortness of breath and asthma.
- the disease is often divided into perennial allergic rhinitis and seasonal allergic rhinitis, the latter is also called "hay fever".
- Allergic rhinitis is a common and frequently-occurring disease in otolaryngology, accounting for about 40% of all nasal diseases. Although allergic rhinitis is not a serious disease, allergic rhinitis can occur at any age, but it is more common in young adults and can occur throughout the year.
- Hay fever is a type I allergy caused by pollen allergens and is the main representative of seasonal asthma.
- pollen allergy has become a seasonal epidemic, and its incidence is quite high. For example, in the United States, more than 2 out of every 100 people suffer from hay fever, and about 6 million people in Japan are affected by pollen. The incidence of hay fever in the population is about 1%.
- the clinical manifestations of hay fever allergies include continuous sneezing, a lot of nasal discharge and itching, nasal congestion, headache, and watering, just like acute infectious rhinitis when you have a bad cold.
- Antihistamine H 1 receptor drugs are mainly used for the treatment of urticaria, allergic dermatitis, allergic rhinitis and other diseases, but the treatment course is longer, only to control the symptoms, and when there is an inducement, it may occur again.
- Rhinitis is an inflammatory disease of the nasal cavity, which is an inflammation of the nasal mucosa caused by viruses, bacteria, allergens, various physical and chemical factors, and certain systemic diseases.
- Chronic rhinitis rhinitis is chronic inflammation of the nasal mucosa and submucosa, accompanied by different degrees of dysfunction, lasting for several months or recurring inflammation, prolonged non-healing, and often no clear pathogenic microbial infection.
- Chronic rhinitis can be divided into chronic simple rhinitis according to its pathology and dysfunction.
- Asthma symptoms are caused by genetic factors as well as allergens. Allergens include
- Dust mites are the most common and most harmful indoor allergens, and they are also an important cause of asthma worldwide. Dust mites are found in secretions such as fur, saliva, urine and feces. Fungi are also one of the allergens that exist in indoor air, especially in dark, humid and poorly ventilated places. Pollen is the most common outdoor allergen that causes asthma attacks.
- Occupational allergens common allergens include grain flour, flour, wood, feed, tea, coffee beans, silkworms, pigeons, mushrooms, antibiotics (penicillins, cephalosporins), rosin, reactive dyes, persulfuric acid Salt, ethylenediamine, etc.
- Drugs Aspirin, propranolol (Propranolol) and some non-corticosteroid anti-inflammatory drugs are the main allergens of asthma caused by drugs.
- the first choice is to inhale the glucocorticoid beclomethasone dipropionate (beclomethasone dipropionate powder spray, beclomethasone dipropionate inhalation powder spray, beclomethasone dipropionate aerosol, Beclomethasone propionate inhalation aerosol, beclomethasone dipropionate nasal aerosol) or budesonide (BUD, budesonide inhalation aerosol, budesonide suspension for inhalation) and fluticasone (FP), etc.
- beclomethasone dipropionate powder spray beclomethasone dipropionate inhalation powder spray
- beclomethasone dipropionate aerosol Beclomethasone propionate inhalation aerosol
- beclomethasone dipropionate nasal aerosol or budesonide
- FP fluticasone
- Inhaled glucocorticoids can also cause dose-related decrease in bone density and bone loss, side effects such as local fungal infections such as candidal stomatitis and pharyngitis. Mild throat irritation, coughing, and hoarseness are inhaled sugars. Another important local complication of corticosteroids is about 30%. Rapid or delayed allergic reactions, including skin rash, contact dermatitis, urticaria, angioedema, and bronchospasm; mental symptoms such as nervousness, restlessness, depression, and behavioral disorders.
- the adverse reactions of ⁇ 2 receptor agonists include arrhythmia, skeletal muscle tremor, hypokalemia, runny nose, cough, headache, sore throat, nausea, muscle cramps, elevated blood pressure, etc., and thiazide diuretics, glucocorticoids
- Combination of xanthine derivatives may increase the occurrence of hypokalemia; combined use with methyldopa can cause severe acute hypotension; combined use with monoamine oxidase inhibitors and tricyclic antidepressants may increase ⁇ 2
- the effect of receptor agonists on the cardiovascular system can aggravate arrhythmia; when combined with digitalis, it can increase the risk of inducing tachycardia.
- COPD chronic obstructive pulmonary disease
- the main symptoms are prolonged cough, sputum, wheezing, and shortness of breath, which will gradually weaken the patient’s respiratory function. It includes chronic bronchitis, bronchial asthma, and chronic obstructive pulmonary.
- Emphysema chronic pulmonary heart disease.
- COPD has progressive and irreversible characteristics. The clinical manifestations are long-term repeated coughing, sputum production and wheezing, which will evolve into pulmonary heart disease over time, and eventually may involve all systems of the body. It is characterized by incompletely reversible airflow restriction.
- the prevalence rate of the disease is relatively high in the elderly. It is the third most common chronic disease in China after hypertension and diabetes.
- the mortality rate can be as high as 20-30% within 5 years.
- the treatment drugs for COPD are usually as follows: 1. Bronchodilators, used to relieve symptoms and improve airway resistance, including ⁇ -receptor agonists, anticholinergic drugs, and theophylline drugs; 2. Expectorant Drugs for chronic obstructive pulmonary obstructive pulmonary patients with long-term difficulty in expectoration or thick sputum; 3. Anti-inflammatory drugs for respiratory inflammation, including antibiotics, glucocorticoids, etc.; 4. Antioxidant drugs, such as N-acetyl Cysteine, etc.; 5. Antibacterial drugs, used for COPD patients with complications such as respiratory tract infection or pneumonia. The above-mentioned drugs cannot solve the fundamental problem, and most patients need drug treatment on a daily basis.
- Salicylic acid and aspirin have been used for a century and become one of the three classic drugs in the history of medicine. So far, it is still the most widely used antipyretic, analgesic and anti-inflammatory drug in the world, as well as a standard preparation for comparing and evaluating other drugs. It has an anti-thrombotic effect in the body. It can inhibit the release reaction of platelets and inhibit platelet aggregation, which is related to the reduction of TXA2 production. It is clinically used to prevent the onset of cardiovascular and cerebrovascular diseases.
- the antipyretic and analgesic dose of aspirin is usually 0.3-0.6g once, 3 times a day, if necessary, once every 4 hours; the anti-rheumatic dose is 3-5g a day (acute rheumatic fever can be up to 7-8g) , Oral in 4 times.
- the current dosage and usage of arginine aspirin intramuscular injection: 1g each time, 1 to 2 times a day, or according to the condition of the doctor as prescribed. Children: 10 ⁇ 25mg/kg body weight. Before use, add 0.9% isotonic saline to each bottle or add 2 ⁇ 4ml of sterile water for injection to dissolve and inject.
- lysine aspirin intramuscular or intravenous injection: 0.9 ⁇ 1.8g each time, 2 times a day. Children 10-25mg/kg body weight per day. Dissolve in 4ml water for injection or isotonic saline and inject. The dosages mentioned above are all very large.
- acetylsalicylic acid, salicylic acid or its salts can be used for asthma, it is also not known to be able to treat allergic diseases or allergic rhinitis or asthma or chronic obstructive pulmonary disease.
- aspirin can induce it.
- the patient has adverse reactions such as asthma or allergies.
- aspirin salicylate and pharmaceutically acceptable salts, double salts or prodrugs or pharmaceutically acceptable esters thereof cannot be used to prevent or treat asthma in humans or animals but cause asthma, urticaria or allergic reactions. There is no cure for allergic diseases or allergic rhinitis or asthma or chronic obstructive pulmonary disease.
- the present invention relates to the field of medical technology, and specifically provides applications for the prevention or treatment of mammals or humans caused by allergic diseases, asthma, chronic obstructive pulmonary disease, or bronchitis.
- bronchitis For a long time, under the usual route of administration, such as oral or intravenous or intramuscular injection, salicylic acid, salicylamine, acetylsalicylic acid, aspirin, arginine aspirin, lysine aspirin did not show allergies
- the present invention finds that under special circumstances, it unexpectedly exhibits therapeutic or preventive effects at lower doses than conventional oral or injection administration.
- acetylsalicylic acid, salicylic acid or its pharmaceutically acceptable salts, double salts or esters and their derivatives or pharmaceutical compositions containing any of them do not show Anti-allergic disease or asthma or chronic obstructive pulmonary disease or bronchitis, but the present invention has found that under special circumstances, it will exhibit anti-allergic disease or asthma or bronchitis.
- acetylsalicylic acid, salicylic acid or aspirin derivatives or their pharmaceutically acceptable salts, double salts, or pharmaceutical compositions containing any of them can be administered in a special acupoint mode Demonstrating the effect of anti-allergic disease or asthma or COPD or bronchitis disease, or changing the course of the disease, can prevent or treat or cure the above-mentioned related allergic diseases or diseases such as asthma or COPD or bronchitis.
- salicylic acid or aspirin derivatives or their prodrugs found that salicylic acid or aspirin derivatives or their prodrugs, pharmaceutically acceptable salts, double salts, solvates or their pharmaceutically acceptable esters or ethers or their pharmaceutically acceptable inclusion complexes
- Drugs, or medicinal compositions containing any of them show obvious therapeutic and preventive effects on allergic diseases, asthma, or chronic obstructive pulmonary or bronchitis, or change the course of the disease, It can prevent or treat or cure the above-mentioned related allergic diseases or diseases such as asthma or chronic obstructive pulmonary disease or bronchitis.
- the drug is selected from but not limited to salicylic acid or aspirin or aspirin derivatives or their prodrugs, pharmaceutically acceptable salts, double salts, solvates or their pharmaceutically acceptable amides or esters or ethers or their pharmaceutically acceptable Accepted clathrates, or pharmaceutical compositions containing any of them, and compositions with pharmaceutically acceptable excipients.
- Salicylic acid or aspirin derivatives are selected from but not limited to salicylamine, salicylic acid, pharmaceutically acceptable salts of aspirin (selected from but not limited to sodium, potassium, or magnesium, or amino acid, or organic ammonium salts, etc., And pharmaceutically acceptable pharmaceutical compositions or preparations containing them; inclusion compounds include urea, thiourea, and cyclodextrin inclusion compounds, and the cyclodextrins are selected from ⁇ -cyclodextrin, ⁇ -cyclodextrin, and ⁇ -Cyclodextrin, hydroxypropyl- ⁇ -cyclodextrin, sulfobutyl- ⁇ -cyclodextrin, etc.
- the medicine for treating and preventing human allergic diseases or asthma or chronic obstructive pulmonary or bronchitis is: the medicine is salicylic acid or aspirin or aspirin derivative or its prodrug, pharmaceutically acceptable salt, compound Salts, solvates or their pharmaceutically acceptable esters or ethers or their pharmaceutically acceptable clathrates, or pharmaceutical compositions containing any of them, salicylic acid or aspirin derivatives are selected from but not limited to Salicylamine, acetylsalicylic acid, salicylic acid, aspirin pharmaceutically acceptable salt, acetylsalicylic acid or sodium salicylate, salicylic acid L-arginine, salicylic acid arginine, salicylic acid L-histidine, salicylic acid L-lysine, salicylic acid DL-lysine, salicylic acid meglumine salt, salicylic acid ethylenediamine salt, acetylsalicylic acid or salicylic acid L- Citrulline, Acetylsal
- Salicylic acid arginine or acetylsalicylic acid, lysine, or salicylic acid or converted to acetylsalicylic acid or salicylic acid is based on the weight of the administration; the amount of liquid to be administered is usually selected from but not limited to 0.01-2.5ml/piece
- the acupuncture points are more preferably but not limited to 0.02-1.5 ml/acupuncture point, and more preferably the amount of liquid administered is 0.04-0.8 ml/acupuncture point.
- the above prevention or treatment can be administered alone or in combination with other drugs.
- the combined administration is selected from but not limited to vitamin C tablets or capsules or granules or injections, vitamin C sodium tablets or injections, snake gall and chuanbei Loquat Ointment, Chuanbei Loquat Ointment or Chuanbei Loquat Granules, Cough Loquat Granules, Orange Red Pills, Jizhi Syrup, Diamine Glycyrrhizinate Enteric-coated Tablets or Capsules, Compound Licorice Tablets, Yupingfeng Granules or Oral Liquid, Huoxiang Zhengqi Pills or Chinese traditional proprietary Chinese medicine preparations such as granules (according to the names and standards of the Chinese Pharmacopoeia or drug specifications), or antihistamines, nasal glucocorticoids and leukotriene receptor antagonists, bronchodilators including ⁇ -receptor agonists One or more of drugs, anticholinergic drugs, theophylline drugs, etc., the above including
- the medicine for treating and preventing human allergic diseases or asthma, chronic obstructive pulmonary or bronchitis and other diseases and its treatment method It is characterized by the administration of acupoints in the meridian system, and the acupoints are selected from but not limited to the meridian of the meridian system of traditional Chinese medicine.
- Or collaterals or twelve meridians, eight meridians of odd meridians, twelve meridians, twelve meridians, twelve skin parts, fifteen meridians, sunluo fuluo or full sun meridian, foot Taiyin spleen meridian or Ashi Acupoints or odd acupoints (Chinese Dictionary of Acupuncture and Moxibustion Points, Editor-in-Chief: Wang Shoudong, Publisher: China Medical Science and Technology Press, Beijing, 1999-07), selected from but not limited to Dazhui, Temple, Baihui, Yingxiang, Lung Shu, Futu, Zhongfu, Tiantu, Tianrong, Jingbailao, Tianxi, Tanzhong, Qihai, Backshu, Shenshu, Pishu, Gefang , Xuehai, Lieque, Chize, Taiyuan, Hegu, Fenglong, Yintang, Zusanli, Quchi, Fengchi, Tianshu,
- the frequency or interval of administration is selected from but not limited to 1-2 injections per day or every other day, and can also be selected from but not limited to once every 2-5 days or once every one to two weeks or once every 3 weeks or once every month Or 1 time/5 weeks or 1 time/6 weeks or 1 time/8 weeks or 1 time/9 weeks or 1 time/10 weeks or longer.
- Acupoint injection should be operated in accordance with the conventional requirements of acupoint injection.
- the injection administration in the present invention is operated according to the usual acupoint administration disinfection procedures, and sterile or sterilized syringes and needles should be used.
- the operating procedure select the appropriate syringe and needle according to the selected acupuncture points and the amount of medication. After the local skin is routinely disinfected, the needle is pierced into the subcutaneous tissue with a painless quick-introduction method. Aseptic operation is strictly followed to prevent infection. Generally, a needle is replaced for each injection point.
- the commercially available aspirin and its derivative injections are in large doses.
- the commercially available arginine aspirin for injection is produced by many companies (the production companies include Bayer, Hainan Lingkang Pharmaceutical, Ruiyang Pharmaceutical, Hainan General Kangli, Hope Pharmaceuticals, Gourd Baby Pharmaceuticals, etc.), lysine for injection (manufacturing companies include Bayer, Shanxi Pude Pharmaceuticals, Shenzhen Huayao Nrushing Pharmaceuticals, Chongqing Yaoyou, Fengyuan Tushan Pharmaceuticals, Hainan Meixilin Biology , Sichuan Meidakang Huakang, Hainan Lingkang Pharmaceutical, Ruiyang Pharmaceutical, Hainan General Kangli, Hope Pharmaceutical, etc.); in clinical practice, it is troublesome to only dilute and prepare about 1% content, or even lower content Trouble, aseptic operation conversion is very difficult, wasteful, wastes a lot of time, and easily contaminates when the dose is cross-used, which increases the unsafe factors
- the prescription specifications based on the weight of salicylic acid or aspirin are selected from but not limited to 3-50mg/bottle or bottle, more preferably from but not limited to 3-30mg/bottle or bottle, and more Preferably, but not limited to 5-25mg/bottle or tube.
- composition refers to a pharmaceutical composition, and the pharmaceutical composition may contain at least one pharmaceutically acceptable carrier or excipient.
- “Pharmaceutically acceptable excipient” as used herein refers to a pharmaceutically acceptable carrier or vehicle suitable for the administration of the compound provided herein, and includes any such carrier known to those skilled in the art as being suitable for a particular mode of administration .
- the physiological saline in the present invention usually refers to 0.9% physiological saline or about 0.9% physiological saline.
- Example 1-A Preparation of L-arginine aspirin powder injection (prescription specification 30mg/bottle, based on L-arginine containing aspirin)
- Prescription process Take 30.00g of sterile L-arginine aspirin and 3.00g of glycine, and dispense 30mg per bottle into 10ml sterile vials, stopper and press the cap to get it.
- Prescription process Aseptic lysine aspirin 50.00g, glycine 5.0g, each 0.050g aliquoted into 10ml sterile vials, stoppered and press the cap to get it.
- Example 1-C Preparation of salicylic acid DL-lysine injection (prescription specification 10mg/bottle, based on salicylic acid)
- Example 1-D Preparation of salicylic acid L-arginine injection (prescription: salicylic acid 15mg/bottle, based on salicylic acid)
- Example 1-G Preparation of salicylic acid lysine injection (prescription specification: salicylic acid 15mg/3ml/bottle)
- Example 1-J Preparation of aspirin L-arginine powder injection (prescription 60mg/bottle, based on aspirin L-arginine)
- Prescription process Take 6.00g of sterile aspirin L-arginine and 0.60g of glycine, divide 60mg per bottle into 10ml sterile vials, stopper and press the cap to get it.
- Prescription process Take 9.00g of sterile aspirin L-arginine and 0.90g of glycine, divide 90mg per bottle into 15ml sterile vials, stopper and press the cap to get it.
- Example 1-L Preparation of aspirin lysine injection (prescription 30mg/bottle, calculated as containing aspirin lysine)
- Example 1-M Preparation of aspirin lysine injection (prescription specification 60mg/bottle, calculated as containing aspirin lysine)
- Example 1-M Preparation of aspirin lysine injection (prescription specification 90mg/bottle, calculated as containing aspirin lysine)
- Prescription process Take 12.00g of sterile aspirin L-arginine and 0.90g of glycine, divide 120mg per bottle into 15ml sterile vials, stopper and press the cap to get it.
- Patient A is a 46-year-old male who has been suffering from seasonal hay fever for more than 6 years. He has been onset with pollen for several months each year. After contact with pollen, he develops symptoms such as nasal itching, sneezing, runny nose drops, and itchy eyes. Acupoint therapy is used. The patient’s Dazhui, Futu, Tiantu, and Feishu points were injected with L-arginine aspirin (1%) in physiological saline solution 0.5ml/time, qd, for 4 consecutive days, the next day itching, nasal itching, The symptoms such as sneezing, runny nose drops, and itchy eyes alleviated. On the third day, the symptoms disappeared and the body recovered. Within one month, despite contact with pollen again, no allergic symptoms appeared.
- Patient B a 15-year-old male, suffered from rhinitis and seasonal hay fever for 3 years. He suffered from pollen for several months every year. After contact with pollen, he developed nasal itching, sneezing, runny nose drops, and itchy eyes. He used acupoint therapy.
- Patient C is a 60-year-old male who has suffered from allergic rhinitis for 10 years. He often has symptoms such as nasal itching, sneezing, and runny nose. Acupoint therapy is used to inject the water prepared by the method of Example 1-G into the patient's Yingxiang point.
- Patient E is a 59-year-old male who has suffered from asthma for 15 years. He has irregular symptoms every week. After the onset, he needs to spray hormones or inhale ⁇ -agonists. The patient also suffers from hay fever. Using acupoint therapy, each Dazhui point, Futu point, Tiantu point, Feishu point, and Dingchuan point of the patient were injected with arginine aspirin (1%) of physiological saline solution 0.5m/time, qd, for 4 consecutive points After that, inject 0.4ml/time of the above solution into Dazhui, Tiantu, Feishu points, once every four days, for 5 consecutive administrations. During the treatment period and the following month, it was observed that there were many After the first contact with pollen, there was no attack of hay fever or allergic symptoms, and no attack of asthma.
- Patient F is a female, 47 years old, suffering from asthma for 4 years. She has irregular symptoms every week. After the onset, she needs to spray inhalation of hormones or inhalation of beta agonists. After contact with pollen, she develops nasal itching, sneezing, and runny nose drops. , And sudden onset of chest tightness, wheezing, dyspnea, and coughing symptoms. After inhaling beclomethasone dipropionate aerosol to control the symptoms, use acupoint therapy to treat each Dazhui point, Futu point, Tiantu point, and lung of the patient.
- the above solution was injected 0.5ml/time at Dazhui, Tiantu, Feishu points, once every five days, for 5 consecutive administrations, acupoint injection treatment During the period, other drugs were discontinued. During the treatment period and within one month after the drug was stopped, although he came into contact with pollen again, no allergic symptoms appeared. Within one month after the drug was stopped, there was no attack of asthma.
- Example 8 Prevention and treatment of chronic obstructive pulmonary disease
- Patient G Female, 55 years old, diagnosed with chronic obstructive pulmonary disease for 2 years, onset at night, with symptoms such as chest tightness, wheezing, dyspnea, coughing, etc., after the onset, nebulization of hormones or inhalation of ⁇ receptor agonist is required; acupoint therapy is used for the patient’s
- Each Dazhui point, Futu point, Tiantu point, Feishu point, Dingchuan point, Fengmen point were injected with arginine aspirin (1%) of physiological saline solution 0.5ml/time, qd, each hole is the most acupoint,
- the above-mentioned solution at Zusanli, Hegu, Chize, and Fenglong points were 0.2ml/time, qd, for 7 consecutive days.
- the patient felt comfortable breathing and warmed up all over the body.
- the patient felt relaxed and comfortable; after seven days, again Inject the above solution 0.3ml/time at Dazhui, Tiantu, Feishu, Dingchuan and Zusanli points, once every four days, for 10 consecutive administrations.
- the patient recovers physically. See chest tightness, wheezing, dyspnea, and coughing symptoms.
- Beclomethasone dipropionate or inhaled ⁇ receptor agonist using acupoint therapy, inject lysine into each Dazhui point, Futu point, Tiantu point, Feishu point, and Dingchuan point of the patient (1%) 0.5ml/time of physiological saline solution, qd, for 6 consecutive days, 0.2ml/time of the above solution for each of Zusanli, Tanzhong, Fenglong, Chize, and Pohu points, qd, for 6 consecutive days; Six days later, inject 0.3ml of the above solution into Dazhui, Tiantu, Feishu, Dingchuan, and Zusanli points, once every four days, for 6 consecutive administrations, during the treatment period and within one month after stopping the drug , Although there was exercise, there were no episodes of bronchitis and asthma.
- Patient I male, 23 years old, suffering from chronic rhinitis for 4 years, often feels nasal discomfort, nasal congestion is mild and severe, or bilateral long-term alternating nasal congestion, nasal congestion worsens in winter, night, and when cold, dizziness, etc.;
- Yingxiang, Bitong, Zusanli, and Chize points were injected with 0.2ml of physiological saline solution of lysine (1%) per time, qd, each Dazhui point and Fu
- the above-mentioned solution was injected 0.5ml/time at Tu, Tiantu, and Feishu points, qd, for 6 consecutive days. On the second day, the symptoms of nasal congestion and dizziness were alleviated.
- Example 12 Prevention and treatment of chronic obstructive pulmonary disease
- each Dazhui point, Futu point, Tiantu point, Feishu point, and Chize point of the patient were injected with arginine aspirin (1%) of physiological saline solution 0.5ml/time, qd, for 3 consecutive days, Then change to injection once every three days, three times in a row, after that, change to injection once every five days, 7 times in a row; on the first day, add the orange red pill in the instruction dose, and the big mi pill twice a day, twice a day, in a row.
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Abstract
本发明提供治疗和预防人或哺乳动物的过敏性疾病或哮喘或或慢阻肺或支气管炎疾病的等的药物或药物组合物的新用途和新方案,该药物为水杨酸或阿司匹林或其前药、或其药学上可接受的盐、复盐、溶剂化物或其药学上可接受的酯或醚或其药学上可接受的包合物,或含有它们中任何一种的药用组合物等,该药物可以经络系统的穴位给药等来实现治疗或预防。
Description
本发明涉及医疗医药领域,具体地说是提供阿司匹林及其衍生物在提供预防或治疗或改善在哮喘或慢阻肺或支气管炎及过敏性疾病等导致的哺乳动物或人患病的药物中的应用。
以发作性鼻痒、打喷嚏、流清涕和鼻塞为特征的变应性鼻炎是临床治疗比较棘手的疾病之一,其发病率高,国内约1%~5%,其中还有38%的变应性鼻炎病人可进一步发展为支气管哮喘等更为严重的疾病。
过敏性疾病即变态反应性疾病,过敏性疾病已成为全球性公共卫生问题,逐年升高的发病率已引起全球的关注,其不仅影响患者的生活质量,甚至威胁患者的生命,其共同发病机制是机体对常见的吸入性或食物性过敏原产生以特异性Ig E介导的或者细胞介导的免疫反应。变态反应性鼻炎(allergic rhinitis)又称变应性鼻炎,是特应性个体接触致敏原后由IgE介导的介质(主要是组胺)释放、并有多种免疫活性细胞和细胞因子等参与的鼻黏膜慢性炎症反应性疾病,以鼻痒、喷嚏、鼻分泌亢进、鼻黏膜肿胀等为主要特点,少数病人还可出现气急、气喘。本病临床常分为常年性变应性鼻炎和季节性变应性鼻炎,后者又称为“花粉症”。变应性鼻炎是耳鼻喉科的一种常见病、多发病,占全部鼻病的40%左右。虽然变应性鼻炎不是一种严重疾病,变应性鼻炎可发生于任何年龄,但以青壮年多见,一年四季均可发病,以秋冬季多见,影响病人的正常工作、学习以及工作效率,并且造成经济上的沉重负担,可诱发支气管哮喘、鼻窦炎、鼻息肉、中耳炎等,或与变应性结膜炎同时发生。
花给人以美的享受,但五颜六色的花粉却可使有过敏体质的人患过敏性鼻炎、哮喘等多种变态反应性疾病,典型的代表是花粉症。花粉症是由花粉过敏原引起的I型变态反应,是季节性哮喘的主要代表。在某些国家,花粉过敏成为季节性流行病,其发病率相当高。例如,在美国,每100人当中就有2人以上患有花粉症,日本约有600万人被花粉所累。花粉症在人群中的发病率大约为1% 左右。花粉过敏临床表现为连续打喷嚏、流大量清鼻涕和鼻痒、鼻塞、头痛、流泪,就像得了重感冒时的急性感染性鼻炎一样,因此常误诊为感冒,但花粉症患者同时伴有上腭、外耳道、鼻、眼等部 位奇痒,严重者可出现胸闷、憋气、哮喘等。
临床常用抗组胺H
1受体药物或激素,也研究并批准了新的治疗方法,如奥马珠单抗治疗哮喘和荨麻疹。抗组胺H
1受体药物主要用于荨麻疹、过敏性皮炎、过敏性鼻炎等疾病的治疗,但疗程较长,仅控制症状,有诱因时,或再次发作。
鼻炎即鼻腔炎性疾病,是病毒、细菌、变应原、各种理化因子以及某些全身性疾病引起的鼻腔黏膜的炎症。慢性鼻炎(Chronic
rhinitis)是鼻腔黏膜和黏膜下层的慢性炎症,且伴有不同程度的功能紊乱,持续数月或炎症反复发作,迁延不愈,常无明确的致病微生物感染。慢性鼻炎依其病理和功能紊乱程度,可分为慢性单纯性鼻炎(chronic
simple rhinitis)和慢性肥厚性鼻炎(chronic
hypertrophic rhinitis),二者病因相同,且后者多由前者发展而来,病理组织学上没有绝对的界限,常有过渡型存在。临床多以抗组胺药物、鼻用糖皮质激素和白三烯受体拮抗剂为主,譬如布地奈德鼻腔局部用药治疗等,有的患者口服盐酸西替利嗪片治疗,每日一次,两周为一疗程,需两疗程。
哮喘(asthma)为一种肺部疾病,其特征为可逆性气道阻塞,气道炎症和对多种刺激的气道反应性增高。哮喘的气道阻塞由联合因素所致,包括有:气道平滑肌痉挛、气道黏膜水肿、黏液分泌增加、气道壁细胞(尤其是嗜酸性细胞和淋巴细胞)浸润、气道上皮损伤和脱屑。
哮喘症状起因有遗传因素,也有变应原,变应原包括
1、室内外变应原:尘螨是最常见、危害最大的室内变应原,也是哮喘在世界范围内的重要发病原因。尘螨存在于皮毛、唾液、尿液与粪便等分泌物里。真菌亦是存在于室内空气中的变应原之一,特别是在阴暗、潮湿以及通风不良的地方。花粉是最常见的引起哮喘发作的室外变应原。
2、职业性变应原:常见的变应原有谷物粉、面粉、木材、饲料、茶、咖啡豆、家蚕、鸽子、蘑菇、抗生素(青霉素、头孢菌素)、松香、活性染料、过硫酸盐、乙二胺等。
3、药物:阿司匹林、普萘洛尔(心得安)和一些非皮质激素类抗炎药是药物所致哮喘的主要变应原。
目前,哮喘治疗的目标主要是急性期发作要达到完全缓解,缓解期的治疗主要是减少哮喘的发作,恢复正常肺功能,恢复正常的运动和活动,防止哮喘猝死。哮喘的治疗有相关的治疗策略。首先是长期的抗炎治疗。长期的抗炎治疗是治疗哮喘的基础,首选吸入糖皮质激素丙酸倍氯米松(丙酸倍氯米松粉雾剂、丙酸倍氯米松吸入粉雾剂、丙酸倍氯米松气雾剂、丙酸倍氯米松吸入气雾剂、丙酸倍氯米松鼻气雾剂)或布地奈德(BUD,布地奈德吸入气雾剂、吸入用布地奈德混悬液)和氟替卡松(FP)等;其次,急性期发作主要使用的是β受体激动剂,以缓解哮喘的支气管痉挛;如果吸入β受体激动剂效果不理想,哮喘不能够达到完全缓解,应该加用白三烯受体拮抗剂或者调整激素吸入剂量。如果是重度发作哮喘,需要入院治疗,会给予全身大剂量的激素治疗,待哮喘缓解、肺功能逐渐恢复正常,逐渐的转为吸入糖皮质激素和吸入β受体激动剂,以达到完全缓解。而吸入性糖皮质激素也可引起与剂量相关的骨密度下降和骨质丢失,念珠菌性口腔炎和咽喉炎等局部霉菌感染等副作用,轻度喉部刺激、咳嗽、声嘶是吸入性糖皮质激素的另一重要局部并发症,其发生率为30%左右。速发或迟发的过敏反应,包括皮疹、接触性皮炎、荨麻疹、血管神经性水肿和支气管痉挛;精神症状,如紧张、不安、抑郁和行为障碍等。而β2受体激动剂不良反应包括心律失常、骨骼肌震颤、低钾血症、流涕、咳嗽、头痛、咽喉痛、恶心、肌肉痉挛、血压升高等,与噻嗪类利尿剂、糖皮质激素、黄嘌呤衍生物合用,可能会增加低钾血症的发生;与甲基多巴合用,可引起严重的急性低血压反应;与单胺氧化酶抑制剂、三环类抗抑郁药合用,可能会增强β2受体激动剂对心血管系统的效应,加重心律失常;与洋地黄类合用,可加重其诱发心动过速的危险性。
慢阻肺(COPD),即慢性阻塞性肺疾病,主要症状为长时间咳嗽、咳痰、喘息、气促,会逐渐削弱患者的呼吸功能,它包括慢性支气管炎、支气管哮喘、慢性阻塞性肺气肿、慢性肺源性心脏病。慢阻肺具有进行性、不可逆特征。临床表现为长期反复咳嗽、咳痰和喘息,久而久之将演变成肺心病,最后可能累及全身各系统。以不完全可逆的气流受限为特点。该病中老年人群患病率较高,是仅次于高血压、糖尿病的中国第三大常见慢性病,当患者感到“胸闷、上不来气、胸口有东西压着”时已是中晚期,5年内死亡率可以高达20~30%。
慢阻肺的治疗药物通常如下:1、支气管舒张剂,用于缓解症状,改善气道的阻力,包括β-受体激动剂、抗胆碱能药物、茶碱类药物;2、祛痰的药物,用于慢阻肺患者长期存在咳痰困难或痰液粘稠时;3、抗炎药物,用于呼吸道炎症,包括抗生素、糖皮质激素等;4、抗氧化的药物,如N-乙酰半胱氨酸等;5、抗菌药物,用于慢阻肺患者在合并呼吸道感染或肺炎等并发症时。以上药物并不能解决根本问题,大多患者日常性需要药物治疗。
水杨酸和阿司匹林已应用百年,成为医药史上三大经典药物之一,至今它仍是世界上应用最广泛的解热、镇痛和抗炎药,也是作为比较和评价其他药物的标准制剂。在体内具有抗血栓的作用,它能抑制血小板的释放反应,抑制血小板的聚集,这与TXA2生成的减少有关。临床上用于预防心脑血管疾病的发作。
阿司匹林于1898年上市,近年来发现它还具有抗血小板凝聚的作用,于是重新引起了人们极大的兴趣。将阿司匹林及其他水杨酸衍生物与聚乙烯醇、醋酸纤维素等含羟基聚合物进行熔融酯化,使其高分子化,所得产物的抗炎性和解热止痛性比游离的阿司匹林更为长效。
阿司匹林精氨酸盐为乙酰水杨酸与精氨酸制成的可溶性盐,赖氨酸阿司匹林为阿司匹林和赖氨酸复盐,具有解热,镇痛及抗炎作用,与阿司匹林基本相同。适应症: 主要用于发热、头痛、神经痛、牙痛、肌肉痛及活动性风湿病、类风湿性关节炎、创伤及手术后疼痛。目前也无低剂量的制剂,阿司匹林类药物的胃肠道刺激大,较常见的有恶心、呕吐、上腹部不适或疼痛或胃溃疡,较易出现过敏反应,支气管痉挛性过敏反应,肾损害等,此外,尤其有发热及脱水者,阿司匹林类药物易出现毒性反应。急性发热性疾病,尤其是流感及水痘患儿应用该品,可能与发生瑞氏综合征(Reye’s syndrome)有关。
阿司匹林的解热、镇痛的剂量,通常一次0.3—0.6g,一日3次,必要时每4小时1次;抗风湿的剂量,一日3—5g(急性风湿热可用到7~8g),分 4次口服。精氨酸阿司匹林目前的用量用法:肌注:每次1g,每日1~2次,或依病情按医嘱用药。儿童:10~25mg/kg体重。临用时,每瓶内加入0.9%等渗盐水或加入灭菌注射用水2~4ml溶解后注入。赖氨酸阿司匹林目前的用量用法:肌注或静注:每次0.9~1.8g,每日2次。儿童1日10~25mg/kg体重。以4ml注射用水或等渗盐水溶解后注射。上述给药剂量都很大。
阿司匹林或精氨酸阿司匹林或赖氨酸阿司匹林适用症状
现有技术中不仅未公开乙酰水杨酸、水杨酸或其盐等可以用于哮喘,也未见能治疗过敏性疾病或变应性鼻炎或哮喘或慢阻肺,反而是阿司匹林反而可诱发患者哮喘或过敏等不良反应。目前阿司匹林水杨酸盐及药学上可接受的盐、复盐或前药或其药学上可接受的酯并不能用于预防或治疗人或动物的哮喘反而引起哮喘、荨麻疹或过敏反应,也未见能治疗过敏性疾病或变应性鼻炎或哮喘或慢阻肺等。尽管在常规大剂量和或通常给药途径下才仅能用于退热、镇痛、消炎、抗风湿、抗血栓等或改善症状等,却无法预防或治疗过敏性疾病或变应性鼻炎或哮喘或慢阻肺等,特别在低剂量或极低剂量下,公知现有技术是口服或静脉是无效的或无价值的或无可能的。
本发明涉及医药技术领域,具体地说是提供预防或治疗过敏性疾病或哮喘或慢阻肺或支气管炎等导致的哺乳动物或人的药物或治疗用途中的应用。长期以来,在通常的给药途径下,譬如口服或静脉或肌肉注射等下,水杨酸、水杨胺、乙酰水杨酸、阿司匹林、精氨酸阿司匹林、赖氨酸阿司匹林并未体现出过敏性疾病或哮喘或慢阻肺或支气管炎等作用,但本发明却发现在特殊情况下,在低于常规口服或注射给药剂量下,却出乎意料的表现出治疗或预防作用。本发明出乎意料的发现乙酰水杨酸、水杨酸或其药学上可接受的盐、复盐或其酯它们的衍生物 或含有它们中任何一种的药用组合物对并未体现出抗过敏性疾病或哮喘或慢阻肺或支气管炎等作用,但本发明却发现在特殊情况下,却会表现出抗过敏性疾病或哮喘或支气管炎作用。本发明出乎意料的发现乙酰水杨酸、水杨酸或阿司匹林衍生物 或其药学上可接受的盐、复盐或含有它们中任何一种的药用组合物在特殊的穴位给药方式下表现出抗过敏性疾病或哮喘或慢阻肺或支气管炎疾病作用,或改变疾病的进程,能够预防或治疗或治愈上述的相关过敏性疾病或哮喘或慢阻肺或支气管炎等的疾病。
更多的,本发明发现水杨酸或阿司匹林衍生物或其前药、药学上可接受的盐、复盐、溶剂化物或其药学上可接受的酯或醚或其药学上可接受的包合物,或含有它们中任何一种的药用组合物在特殊的给药方式下对过敏性疾病或哮喘或慢阻肺或支气管炎疾病表现出明显的治疗与预防作用,或改变疾病的进程,能够预防或治疗或治愈上述的相关过敏性疾病或哮喘或慢阻肺或支气管炎等疾病。
药物学上公知的前药原理是将已知有生物活性而又存在某些缺点(如: 生物利用度差、性质不稳定、作用时间短、有异味等。)的药物经结构修饰制成新药即前药,后者体外无活性,在体内分解释放出原药产生药效。与原药相比,前药保持或增强原药的药效,又克服原药的缺点。前药是药物分子的生物可逆的衍生物,在体内经酶或化学作用释放具有活性的原药,从而发挥预期的药理作用(李敏.前药设计原理及其临床应用[J].中国现代药物应用,2009,3(15):193-195.)。水杨酸或阿司匹林衍生物或其前药也是一样。
该药物选自但不仅限于水杨酸或阿司匹林或阿司匹林衍生物或其前药、药学上可接受的盐、复盐、溶剂化物或其药学上可接受的酰胺或酯或醚或其药学上可接受的包合物,或含有它们中任何一种的药用组合物,以及与药学上可接受的赋形剂的组合物。水杨酸或阿司匹林衍生物选自但不仅限于水杨胺、水杨酸、阿司匹林药学上可接受的盐(选自但不仅限于钠盐或钾盐或镁盐或氨基酸盐或有机铵盐等,以及含有其的药学上可接受的药物组合物或制剂等;包合物包括尿素、硫脲、环糊精包合物,环糊精选自α-环糊精,β-环糊精,γ-环糊精,羟丙基- β-环糊精,磺丁基- β-环糊精等中的一种或两种的混合物,其中优选羟丙基-β-环糊精等;包合物溶解于水中易释放药物,效果可预见(黄正佳,黄芳,谢雅.正交试验设计优化阿司匹林环糊精包合物的合成[J].化工时刊,2019,33(05):1-4.)。另外,还包括复方水杨酸钠注射液、水杨酸钠碘化钠注射液(10ml:水杨酸钠0.5g、碘化钠0.5g)、撒溴葡萄糖注射剂、复方柳安咖注射液等。
所述的治疗和预防人的过敏性疾病或哮喘或慢阻肺或支气管炎等疾病的药物为:该药物为水杨酸或阿司匹林衍生物或其前药、药学上可接受的盐、复盐、溶剂化物或其药学上可接受的酯或醚或其药学上可接受的包合物,或含有它们中任何一种的药用组合物,和药学上可接受的载体。所述的治疗和预防人的过敏性疾病或哮喘或慢阻肺或支气管炎等的药物为:该药物为水杨酸或阿司匹林或阿司匹林衍生物或其前药、药学上可接受的盐、复盐、溶剂化物或其药学上可接受的酯或醚或其药学上可接受的包合物,或含有它们中任何一种的药用组合物,水杨酸或阿司匹林衍生物选自但不仅限于水杨胺、乙酰水杨酸、水杨酸、阿司匹林药学上可接受的盐、乙酰水杨酸或水杨酸钠、水杨酸L-精氨酸、水杨酸精氨酸、水杨酸L-组氨酸、水杨酸L-赖氨酸、水杨酸DL-赖氨酸、水杨酸葡甲胺盐、水杨酸乙二胺盐、乙酰水杨酸或水杨酸L-瓜氨酸、乙酰水杨酸或水杨酸双异丙胺、水杨酸胆碱镁、乙酰水杨酸或水杨酸镁、水杨酸镁4水合物、水杨酸葡乙胺)、乙酰水杨胺、沙利芬saliphen、水杨酸萘酯、水杨丙磺酸、双水杨酯、最著酸、水杨吗啉、水杨胺、水杨各可酯、水杨酸甲酯、乙基水杨胺、阿司匹林L-精氨酸、D-精氨酸阿司匹林、精氨酸阿司匹林、赖氨酸阿司匹林、L-赖氨酸阿司匹林、D-赖氨酸阿司匹林、阿司匹林葡甲胺盐等。
所述的治疗和预防人的过敏性疾病或哮喘或慢阻肺或支气管炎等的药物为:该药物为水杨酸或阿司匹林衍生物 或其前药、药学上可接受的盐、复盐、溶剂化物或其药学上可接受的酯或醚或其药学上可接受的包合物,或含有它们中任何一种的药用组合物,以及与药学上可接受的赋形剂的组合物,其给药途径为穴位给药,小水针制剂可视剂量直接给药,粉针制剂可以生理盐水或无菌用水或葡萄糖水等中的一种或几种稀释后穴位给药,较优选以0.9%生理盐水或无菌用水或注射用水或5%或10%的葡萄糖水等稀释后穴位给药,可一个或多个穴位给药,给药剂量选自但不仅限于0.1-40mg/个穴位(可以换算为水杨酸或阿司匹林的重量计),较优选给药剂量为0.2-20mg/个穴位,更较优选给药剂量为0.3-10mg/个穴位,可以阿司匹林或乙酰水杨酸或乙酰水杨酸精氨酸或乙酰水杨酸赖氨酸或水杨酸或折算乙酰水杨酸或水杨酸为计给药重量;给药液体量通常选自但不仅限于0.01-2.5ml/个穴位,较优选自但不仅限于0.02-1.5ml/个穴位,更较优选给药液体量为0.04-0.8ml/个穴位。以上的预防或治疗可以是单独给药或与其它药物联合给药,联合给药,选自但不仅限于维生素C片或胶囊或颗粒剂或注射液、维生素C钠片或注射液、蛇胆川贝枇杷膏、川贝枇杷膏或川贝枇杷颗粒、止咳枇杷颗粒、橘红丸、急支糖浆、甘草酸二胺肠溶片或胶囊、复方甘草片、玉屏风颗粒或口服液、藿香正气丸或颗粒等中国传统的中成药制剂(按照中国药典或药品规范的名称及标准),或抗组胺药物、鼻用糖皮质激素和白三烯受体拮抗剂、支气管舒张剂包括β-受体激动剂、抗胆碱能药物、茶碱类药物等中的一种或多种,以上包括药学上可接受的药物剂型,联合抗生素或抗菌药给药可以用于合并细菌感染的疾病;上述药物的可以不同给药途径进行联合给药,或静脉注射或肌肉注射或口服或喷雾或吸入或外用或穴位注射等。
所述的治疗和预防人的过敏性疾病或哮喘或慢阻肺或支气管炎等疾病的药物及其治疗方法:以经络系统的穴位给药为特征,穴位选自但不仅限于中医的经络系统经脉或络脉或十二经脉、奇经八脉、十二经别、十二经筋、十二皮部、十五脉络、孙络浮络或足太阳经、足太阴脾经的穴位或阿是穴或奇穴(中国针灸穴位辞典,主编:王守东,出版社:中国医药科技出版社,北京,1999-07出版),选自但不仅限于大椎穴、太阳穴、百会穴、迎香穴、肺俞穴、扶突穴、中府穴、天突穴、天容穴、颈百劳穴、天溪穴、膻中穴、气海穴、背俞穴、肾俞穴、脾俞穴、膈腧穴、血海穴、列缺穴、尺泽穴、太渊穴、合谷穴、丰隆穴、印堂穴、足三里、曲池穴、风池穴、天枢穴、内庭穴、孔最穴、鱼际穴、膏肓穴、夹脊穴、膻中穴、外关穴、风门穴、尺泽穴、定喘穴、大抒穴、丰隆穴、阴陵穴、胸1-7夹脊、天府穴、百劳穴、魄户穴、孔最穴、支正穴、太溪穴、身柱穴、气户穴、云门穴、中府穴、隐白穴、期门穴、阿是穴或奇穴等中的一个或多个。在上述穴位或其临近可单点或左右两侧或多点注射给药。给药次数或间隔选自但不仅限于每日或隔日注射1-2次,亦可选自但不仅限于隔2-5日一次或一到两周一次或1次/3周或1次/月或1次/5周或1次/6周或1次/8周或1次/9周或1次/10周或更长。
穴位注射应按照穴位注射的常规要求操作,本发明中的注射给药均按通常的穴位给药消毒程序操作,应使用无菌或消毒的注射器和针头。根据使用药物的剂量大小及针刺的深度选用不同的注射器和针头。常用的注射器为1ml、2.5ml,操作程序:根据所选穴位及用药量的不同选择合适的注射器和针头。局部皮肤常规消毒后,用无痛快速进针法将针刺入皮下组织,严格遵守无菌操作、防止感染,一般每注射一个穴位换一个针头。
目前,市售的阿司匹林及衍生物注射剂都是大剂量的,譬如市售注射用精氨酸阿司匹林有多家公司生产(生产公司有拜耳、海南灵康制药、瑞阳制药、海南通用康力、荷普药业、葫芦娃药业等),注射用赖氨匹林(生产公司有拜耳、山西普德药业、深圳华药南方制药、重庆药友、丰原涂山制药、海南美好西林生物、四川美大康华康、海南灵康制药、瑞阳制药、海南通用康力、荷普药业等);临床实际操作中仅稀释制备约1%含量的很麻烦,或更低含量的更麻烦,无菌操作转换很困难,浪费也大,浪费大量时间,剂量大交叉使用时易污染等,增加临床用药的不安全因素,因此,需要制备其低剂量或小剂量的注射剂。
小剂量的水杨酸或阿司匹林及衍生物注射剂的制备方法,可以制备无菌粉针或冻干粉针或小水针或输液剂等。无菌粉针可以将无菌原料直接分装到西林瓶中,加塞压盖。冻干粉针的制备可将水杨酸或阿司匹林及衍生物或阿司匹林与精氨酸或赖氨酸或组氨酸或葡甲胺等在注射用水或和溶剂中或和助溶剂中溶解,可再加入适量的药学上可接受的抗氧剂、pH调节剂、赋形剂、助溶剂、或其它组分等,无菌过滤,分装,冷冻干燥、冷冻干燥后无菌分装、减压干燥后无菌分装、喷雾干燥后无菌分装,加塞,压盖,包装。小水针的制备可将水杨酸或阿司匹林及衍生物或阿司匹林与精氨酸或赖氨酸或组氨酸或葡甲胺等在注射用水或和溶剂中或和助溶剂中溶解,可再加入适量的药学上可接受的抗氧剂、pH调节剂、填充剂、助溶剂或其它药学上可接受的组分等,加注射用水定容,无菌过滤,定量灌封,灭菌,检验,包装。药用辅料及制剂可参见:《药用辅料手册》,化学工业出版社,2005年出版,作者 (美)舍斯基、(英)韦勒、郑俊民;《药用辅料应用技术》(第二版) 侯惠民等主编;上海医药工业研究院药物制剂部,药物制剂国家工程研究中心编著/2002年。
对于单个患者的临床用药,现有技术的阿司匹林或水杨酸的单支剂量规格太大,浪费太多,使用很不方便,本发明制备水杨酸或阿司匹林或其衍生物的注射剂,该药物为水杨酸或阿司匹林或其前药、药学上可接受的盐、复盐、溶剂化物或其药学上可接受的酯或醚或其药学上可接受的包合物,或含有它们中任何一种的药用组合物的相应低剂量的注射剂。对于本发明药物的注射剂,譬如注射用精氨酸阿司匹林、阿司匹林L-精氨酸、阿司匹林赖氨酸注射剂、注射用赖氨匹林、水杨酸葡甲胺注射剂、或水杨酸L-精氨酸注射剂等衍生物注射剂中,以折算为含水杨酸或阿司匹林重量处方规格选自但不仅限于3-50mg/瓶或支计,较优选自但不仅限于3-30mg/瓶或支,更较优选自但不仅限于5-25mg/瓶或支。
除了在实施例中以及另有指示时,说明书和权利要求书中所用的所有的数值应被理解为在所有的实例中以术语“约”进行修饰,因此,除非有相反的指示,本说明书和所附的权利要求书中所给出的数值参数是近似值,其可以根据通过本公开内容所寻求的所需要性质而改变,最起码地,并且不是意欲限制等同原则权利要求范围的应用,每个数值参数应考虑有效数字的数和常规四舍五入方法来解释。
虽然设定公开内容的宽范围的数值范围和参数是近似值。但是在具体实施例中所给出的数值被尽可能精确地报道,任意数值本质上包含某些由在它们各自的测试中发现的标准偏差所必然产生的误差。
需要指出的是,除非文中明确地另外说明,在本说明书和附加的权利要求中使用的单数形式“一个”、“一种”以及“该”包括指代物的复数形式,所以,例如。如果提及含有“一种化合物”的组合物时包括两种或多种化合物的混合物,另外需要注意的是,除非本文明确地另外说明,术语“或”通常包括“和/或”。
药物组合物,本文所用“药物组合物”是指药物的组合物,所述的药物组合物可以含有至少一种药学上可接受的载体或赋形剂。
本文所用“药学上可接受的赋形剂”是指适用于本文所偶提供的化合物给药的药用载体或溶媒,其包括本领域技术人员公知的适用于特定给药方式的任何此类载体。本发明中的生理盐水通常是指0.9%生理盐水或约0.9%生理盐水。
为了进一步了解本发明,下面结合实施例对本发明优选实施方案进行描述,但是应当理解,这些描述只是为进一步说明本发明的特征和优点,而不是对本发明权利要求的限制。
以下以具体实施例说明本发明的效果,但本发明的保护范围不受以下实施例的限制。
实施例1-A L-精氨酸阿司匹林粉针剂的制备(处方规格30mg/瓶,以L-精氨酸含阿司匹林计)
处方工艺:取无菌L-精氨酸阿司匹林30.00g,甘氨酸3.00g,按每瓶30mg分装于10ml无菌的西林瓶中,加塞,压盖即得。
实施例1-B 赖氨酸阿司匹林注射剂的制备(处方规格50mg/瓶,以含赖氨酸阿司匹林赖氨酸计)
处方工艺:无菌赖氨酸阿司匹林50.00g,甘氨酸5.0g,按每瓶0.050g分装于10ml无菌的西林瓶中,加塞,压盖即得。
实施例1-C 水杨酸DL-赖氨酸注射剂的制备(处方规格10mg/瓶,以含水杨酸计)
处方工艺:在洁净室中,称取药用水杨酸 40.0g,加DL-赖氨酸42.65g,EDTA钙钠1g,置于2升注射用水中,搅拌溶解,用适量的1mol/L氢氧化钠溶液或1mol/L盐酸溶液调节溶液pH值至约7.2左右,加入0.05%药用活性炭搅拌30分钟(重量体积比g/L),加注射用水定容至4升,过滤,0.22微孔滤膜过滤,按规格灌装于已灭菌的5ml西林瓶中,在-40℃预冻4小时,从-30℃~0℃升华干燥, 5℃~35℃再干燥6小时,35℃保温3小时,轧盖制得。
实施例1-D 水杨酸L-精氨酸注射剂的制备(处方:水杨酸15mg/瓶,以含水杨酸计)
在洁净室中,称取药用水杨酸 30.0g,L-精氨酸38.10g,EDTA钙钠1.0g,置于1.5升注射用水中,搅拌使溶,用适量的1mol/L氢氧化钠溶液和或1mol/L硫酸溶液调节溶液pH值至约7.2左右,加注射用水定容至2升,加入0.05%药用活性炭搅拌30分钟(重量体积比g/L),过滤,0.22微孔滤膜过滤,按体积分别灌装于已灭菌的10ml西林瓶中,在-40℃预冻4小时,从-30℃~0℃升华干燥, 5℃~35℃再干燥7小时,35℃保温3小时,轧盖制得。
实施例1-E 水杨酸葡甲胺注射剂的制备(处方规格10mg/瓶,以含水杨酸计)
处方工艺:在洁净室中,称取药用水杨酸 30.0g,药用葡甲胺42.62g,EDTA钙钠4水合物1.0g,置于2.2升注射用水中,搅拌溶解,用适量的1mol/L氢氧化钠溶液和或1mol/L盐酸溶液调节溶液pH值至约7.2左右,加注射用水至3升,加入0.05%药用活性炭(重量体积比g/L),搅拌30分钟,过滤,0.22微孔滤膜过滤,按体积分别灌装于已灭菌的10ml西林瓶中,在-40℃预冻4小时,从-30℃~0℃升华干燥, 5℃~35℃再干燥7小时,35℃保温3小时,轧盖制得。
实施例1-F 水杨酸L-赖氨酸小水针注射液的制备(处方规格:水杨酸6mg/3ml/支)
在洁净室中,称取药用水杨酸 3.00g,L-赖氨酸3.195g,置于1升注射用水中,搅拌溶解,加入EDTA钙钠4水合物3.0g,搅拌溶解,用适量的1mol/L氢氧化钠溶液和或1mol/L盐酸溶液调节溶液pH值至约7.3左右,加注射用水定容至1.5升,加入0.03%药用活性炭(重量体积比g/L),搅拌40分钟,过滤,0.22微孔滤膜过滤过滤两次,按体积分别灌封于已灭菌的安培瓶中,115℃灭菌30分钟,取出冷却至室温,灯检后即得。
实施例1-G 水杨酸赖氨酸注射液的制备(处方规格:水杨酸15mg/3ml/支)
在洁净室中,称取药用水杨酸 30.00g,赖氨酸31.95g,置于5升注射用水中,搅拌溶解,加入EDTA钙钠3.0g,搅拌溶解,用适量的1mol/L氢氧化钠溶液和或1mol/L盐酸溶液调节溶液pH值至约7.2左右,加注射用水定容至6升,加入0.04%药用活性炭(重量体积比g/L),搅拌35分钟,过滤,0.22微孔滤膜过滤两次,按体积分别灌封于已灭菌的安培瓶中,115℃灭菌30分钟,取出冷却至室温,灯检后即得。
实施例1-H 水杨酸L-精氨酸注射液的制备(处方规格:水杨酸11.68mg/3ml/支)
处方:药用水杨酸 11.68g,L-精氨酸14.80g,EDTA钙钠4水合物3.0g,1mol/L氢氧化钠溶液或1mol/L盐酸溶液 适量 加注射用水定容至3.0升
在洁净室中,称取处方量的药用水杨酸,L-精氨酸,EDTA钙钠4水合物,置于2升注射用水中,搅拌溶解,用适量的1mol/L氢氧化钠溶液和或1mol/L盐酸溶液调节溶液pH值至约7.0左右,加注射用水定容至3.0升,加入0.06%药用活性炭(重量体积比g/L),搅拌30分钟,过滤,0.22微孔滤膜过滤两次,按体积分别灌封于已灭菌的安培瓶中,115℃灭菌30分钟,取出冷却至室温,灯检后即得。
实施例1-I 水杨酸钠小水针注射液的制备(处方规格:水杨酸15mg/3ml/支)
处方:药用水杨酸 15.00g,维生素C 10g,EDTA钙钠4水合物3.0g,氢氧化钠 适量,注射用水加到3.0升
在洁净室中,称取处方量的药用水杨酸,维生素C,EDTA钙钠4水合物,氢氧化钠 适量,置于2.5升注射用水中,加适量的氢氧化钠,搅拌溶解,用适量的1mol/L氢氧化钠溶液或1mol/L盐酸溶液调节溶液pH值至约7.2左右,加注射用水定容至3.0升,加入为0.01%药用活性炭(重量体积比g/L),搅拌25分钟,过滤,0.22微孔滤膜过滤两次,按体积分别灌封于已灭菌的安培瓶中,115℃灭菌30分钟,取出冷却至室温,灯检后即得。
实施例1-J 阿司匹林L-精氨酸粉针剂的制备(处方60mg/瓶,以含阿司匹林L-精氨酸计)
处方工艺:取无菌阿司匹林L-精氨酸6.00g,甘氨酸0.60g,按每瓶60mg分装于10ml无菌的西林瓶中,加塞,压盖即得。
实施例1-K 阿司匹林L-精氨酸粉针剂的制备(处方90mg/瓶,以含阿司匹林L-精氨酸计)
处方工艺:取无菌阿司匹林L-精氨酸9.00g,甘氨酸0.90g,按每瓶90mg分装于15ml无菌的西林瓶中,加塞,压盖即得。
实施例1-L 阿司匹林赖氨酸注射剂的制备(处方30mg/瓶,以含阿司匹林赖氨酸计)
处方工艺:无菌阿司匹林赖氨酸3.00g,甘氨酸0.30g,按每瓶0.030g分装于10ml无菌的西林瓶中,加塞,压盖即得。
实施例1-M 阿司匹林赖氨酸注射剂的制备(处方规格60mg/瓶,以含阿司匹林赖氨酸计)
处方工艺:无菌阿司匹林赖氨酸6.00g,甘氨酸0.70g,按每瓶0.060g分装于10ml无菌的西林瓶中,加塞,压盖即得。
实施例1-M 阿司匹林赖氨酸注射剂的制备(处方规格90mg/瓶,以含阿司匹林赖氨酸计)
处方工艺:无菌阿司匹林赖氨酸9.00g,甘氨酸0.90g,按每瓶0.090g分装于15ml无菌的西林瓶中,加塞,压盖即得。
实施例1-N 阿司匹林L-精氨酸粉针剂的制备(处方规格120mg/瓶,以含阿司匹林L-精氨酸计)
处方工艺:取无菌阿司匹林L-精氨酸12.00g,甘氨酸0.90g,按每瓶120mg分装于15ml无菌的西林瓶中,加塞,压盖即得。
实施例1-O 水杨酸L-精氨酸小水针注射液的制备(处方:水杨酸23.37mg/3ml/支)
处方:药用水杨酸 23.37g,L-精氨酸29.8g,EDTA钙钠4水合物3.0g,1mol/L氢氧化钠溶液或1mol/L盐酸溶液 适量 加注射用水定容至3.0升
在洁净室中,称取处方量的药用水杨酸,L-精氨酸,EDTA钙钠4水合物,置于2升注射用水中,搅拌溶解,用适量的1mol/L氢氧化钠溶液和或1mol/L盐酸溶液调节溶液pH值至约7.4左右,加注射用水定容至3.0升,加入0.01%药用活性炭(重量体积比g/L),搅拌30分钟,过滤,0.22微孔滤膜过滤两次,按体积分别灌封于已灭菌的安培瓶中,115℃灭菌30分钟,取出冷却至室温,灯检后即得。
实施例1-P 水杨酸L-精氨酸小水针注射液的制备(处方:水杨酸23.37mg/6ml/支)
处方:药用水杨酸 23.37g,L-精氨酸29.8g,EDTA钙钠4水合物3.0g,1mol/L氢氧化钠溶液或1mol/L
硫酸溶液 适量 加注射用水定容至6.0升
在洁净室中,称取处方量的药用水杨酸,L-精氨酸,EDTA钙钠4水合物,置于2升注射用水中,搅拌溶解,用适量的1mol/L氢氧化钠溶液和或1mol/L硫酸溶液调节溶液pH值至约7.2左右,加注射用水定容至6.0升,加入0.04%药用活性炭(重量体积比g/L),搅拌30分钟,过滤,0.22微孔滤膜过滤两次,按体积分别灌封于已灭菌的安培瓶中,115℃灭菌30分钟,取出冷却至室温,灯检后即得。
实施例2
患者A 男性,年龄 46岁,患有季节性花粉症6年以上,每年因花粉发病数月;与花粉接触后,出现鼻痒,打喷嚏、流鼻滴、眼睛痒等症状,采用穴位疗法,于患者的大椎穴、扶突穴、天突穴、肺俞穴分别注射L-精氨酸阿司匹林(1%)的生理盐水溶液0.5ml/次,qd,连续4天,第二天鼻痒、打喷嚏、流鼻滴、眼睛痒等症状减轻,第三天,症状消失,身体康复,一个月内,虽再与花粉接触,未出现过敏性症状。
实施例3 鼻炎及过敏性疾病的治疗与预防
患者B 男性,年龄 15岁,患有鼻炎和季节性花粉症3年,每年因花粉发病数月,与花粉接触后,出现鼻痒,打喷嚏、流鼻滴、眼睛痒等,采用穴位疗法,于患者的迎香穴注射赖氨匹林(1%)的生理盐水溶液0.2ml/次,qd,连续3天,大椎穴、天突穴分别注射赖氨匹林1%的生理盐水溶液0.3ml/次,qd,连续4天,每个扶突穴、肺俞穴分别注射赖氨匹林1%的生理盐水溶液0.2ml/次,qd,连续4天;第二天鼻痒、打喷嚏、流鼻滴、眼睛痒等症状明显减轻,第三天,鼻痒、打喷嚏、流鼻滴等症状消失;然后,再于大椎穴、天突穴、肺俞穴注射上述溶液0.2ml/次/天,四天一次,连续给药5次,患者身体康复,一个月内,虽与花粉和尘螨过敏物有接触,未出现过敏性症状。
实施例4
患者C 男性,年龄 60岁,患有过敏性鼻炎10年,经常出现鼻痒,打喷嚏、流鼻滴等症状,采用穴位疗法,于患者的迎香穴注射实施例1-G法制备的水杨酸赖氨酸注射液0.2ml/次,qd,连续4天,于患者的每个迎香穴、大椎穴、扶突穴、天突穴、肺俞穴分别注射实施例1-G法制备的水杨酸赖氨酸注射剂0.4ml/次,qd,连续3天,之后再隔3天一次,连续给药3次,给药方法方式及剂量同第一次,第三天鼻痒、打喷嚏、流鼻滴等症状减轻,第四天,症状基本消失,患者身体康复;然后,再于大椎穴、天突穴、肺俞穴注射上述溶液0.2ml/次,一周一次,连续给药4次,之后的一个月内,虽与花粉接触,未出现过敏性鼻炎症状。
实施例5 鼻炎及过敏性疾病的防治
患者D 女性,年龄 33岁,患有鼻炎和花粉症5年,与花粉接触出现症状后,连续三天每天都感到鼻痒,多次打喷嚏、流鼻滴,并且咽喉起小泡,采用穴位疗法,于患者的迎香穴注射实施例1-H法制备的水杨酸L-精氨酸小水针注射液0.5ml/次,qd,连续4天,于患者的每个大椎穴、扶突穴、天突穴、肺俞穴分别注射上述注射液0.4ml/次,qd,连续4天,第二天鼻痒、打喷嚏、流鼻滴、咽喉不适等症状减轻,第四天,症状消失,患者身体康复;之后,再于大椎穴、天突穴、肺俞穴注射上述溶液0.2ml/次,一周一次,连续给药4次,在这四周的治疗期和之后的一个月内,虽再与花粉有接触,鼻炎也未发作或未出现过敏性症状。
实施例6 哮喘病及过敏性疾病的防治
患者E 男性,年龄 59岁,患有哮喘病15年,每周不定期发病,发病后需要喷雾激素或吸入β受体激动剂,患者还患有花粉症。采用穴位疗法,于患者的每个大椎穴、扶突穴、天突穴、肺俞穴、定喘穴分别注射精氨酸阿司匹林(1%)的生理盐水溶液0.5m/次,qd,连续4天,之后,再于大椎穴、天突穴、肺俞穴注射上述溶液0.4ml/次,四天一次,连续给药5次,在给药治疗期及随后的一个月内观察发现,虽多次与花粉接触,花粉症也未发作或未出现过敏性症状,哮喘病也未见发作。
实施例7 哮喘病及过敏性疾病的治疗与预防
患者F 女性,年龄 47岁,患有哮喘病4年,每周不定期发病,发病后需要喷雾吸入激素或吸入β受体激动剂,与花粉接触后,出现鼻痒,打喷嚏、流鼻滴,并突然发作的胸闷、气喘、呼吸困难、咳嗽症状,用丙酸倍氯米松吸入气雾剂控制症状后,采用穴位疗法,于患者的每个大椎穴、扶突穴、天突穴、肺俞穴、定喘穴分别注射精氨酸阿司匹林(1%)的0.9%生理盐水溶液0.5ml/次,qd,每个足三里穴、丰隆穴、魄户穴分别注射精氨酸阿司匹林(1%)的0.9%生理盐水溶液0.2ml/次,qd,连续4天,当天患者感到胸闷减轻、呼吸舒畅,第三天,鼻痒、打喷嚏、流鼻滴等症状未再出现,胸闷、气喘、呼吸困难、咳嗽症状亦未见出现,患者身体康复;然后,再于大椎穴、天突穴、肺俞穴注射上述溶液0.5ml/次,五天一次,连续给药5次,穴位注射治疗期间,停用其它药物,治疗期间和停药后的一个月内,虽再与花粉接触,未出现过敏性症状,停药后的一个月内,哮喘病也未见发作。
实施例8 慢阻肺的防治
患者G 女性,年龄 55岁,慢阻肺确诊2年,夜间发作,有胸闷、气喘、呼吸困难、咳嗽等症状,发病后需要喷雾激素或吸入β受体激动剂;采用穴位疗法,于患者的每个大椎穴、扶突穴、天突穴、肺俞穴、定喘穴、风门穴分别注射精氨酸阿司匹林(1%)的生理盐水溶液0.5ml/次,qd,每个孔最穴、足三里、合谷穴、尺泽穴、丰隆穴分别上述溶液0.2ml/次,qd,连续7天,当天病人感到呼吸舒畅、浑身温热,第七天,患者感到轻松舒服;七天后,再于大椎穴、天突穴、肺俞穴、定喘穴、足三里穴注射上述溶液0.3ml/次,四天一次,连续给药10次,停药后一个月内,患者身体康复,夜间未见胸闷、气喘、呼吸困难、咳嗽症状发作。
实施例9 支气管炎和哮喘病的防治
患者H,女性,年龄 53岁,患有支气管炎和哮喘病5年,运动后经常发作,咳喘得厉害,经常半夜突感呼吸困难,嗓子里像有异物感,胸闷,发病后需要吸入激素丙酸倍氯米松或吸入β受体激动剂,采用穴位疗法,于患者的每个大椎穴、扶突穴、天突穴、肺俞穴、定喘穴分别注射赖氨匹林(1%)的生理盐水溶液0.5ml/次,qd,连续6天,每个足三里穴、膻中穴、丰隆穴、尺泽穴、魄户穴分别上述溶液0.2ml/次,qd,连续6天;六天后,再于大椎穴、天突穴、肺俞穴、定喘穴、足三里穴注射上述溶液0.3ml/次,四天一次,连续给药6次,治疗期间及停药后一个月内,虽然有运动,但支气管炎和哮喘病未见发作。
实施例10 鼻炎的防治
患者I,男性,年龄 23岁,患有慢性鼻炎4年,经常感到鼻腔不舒服,鼻塞时轻时重,或双侧长期反复交替性鼻塞,冬季、夜间、受凉时鼻塞加重,头昏等;采用穴位疗法,于患者的每个迎香穴、鼻通穴、足三里、尺泽穴分别注射赖氨匹林(1%)的生理盐水溶液0.2ml/次,qd,每个大椎穴、扶突穴、天突穴、肺俞穴分别注射上述溶液0.5ml/次,qd,连续6天,第二天鼻塞、头昏等症状减轻,第六天,鼻塞、头昏症状消失,随后,改为每个迎香穴、大椎穴、扶突穴、天突穴、肺俞穴分别注射上述溶液0.3ml/次,qd,一周注射一次,连续五周,停药后一个月内,未发生鼻塞,鼻炎未见发作。
实施例11 哮喘病的防治
患者共八人, 男女各半,年龄 19-62岁,患有哮喘病2-15年,每周均有反复发作,喘息、气急、胸闷或咳嗽、咽痒,肺部可闻及哮鸣音,既往发病都曾有接受过其它方法治疗使症状得以缓解史,患者每周不定期发病,发病后需要喷雾激素或吸入β受体激动剂,并有哮喘病典型症状出现;患者发作后采用穴位疗法,于患者的每个大椎穴、扶突穴、天突穴、肺俞穴、定喘穴分别注射赖氨匹林(1%)的生理盐水溶液0.5ml/次,qd,每个足三里穴、膻中穴、尺泽穴、丰隆穴、魄户穴、孔最穴分别上述溶液0.2ml/次,qd,分别均连续给药6天;随后,再于大椎穴、天突穴、肺俞穴、定喘穴、足三里穴注射上述溶液0.4ml/次,均为四天一次,连续给药6次,之后,均改为一周注射一次,连续给药四周,第二天喘息、气急、胸闷或咳嗽、咽痒等症状减轻,第6-8天,患者的症状显著减轻或基本消失,治疗期结束,患者的症状消失,停药后一个月内,患者的哮喘病也均未见发作。
实施例12 慢阻肺的防治
患者共八人,男女各半,年龄 45-65岁,慢阻肺确诊病程2-4年,每周不定期发病,发病后需要喷雾激素或吸入β受体激动剂,患者发病后出现心慌、气短、咳嗽,有痰等症状,采用穴位疗法,于患者的每个大椎穴、扶突穴、天突穴、肺俞穴、定喘穴、风门穴分别注射精氨酸阿司匹林(1%)的生理盐水溶液0.5ml/次,qd,于患者的每个中府穴、孔最穴、足三里、合谷穴、尺泽穴、丰隆穴分别上述溶液0.2ml/次,qd,均连续7天,随后于患者的每个大椎穴、扶突穴、天突穴、肺俞穴、尺泽穴分别注射精氨酸阿司匹林(1%)的生理盐水溶液0.5ml/次,qd,连续3天,然后改为三天注射一次,连续给药三次,之后,改为五天注射一次,连续7次;第一天,加服说明书剂量的橘红丸,大蜜丸一次2丸,一天两次,连续给药三天,第二天,心慌、气短、咳嗽等症状减轻,第八天,症状基本消失;停药后一个月内,未见慢阻肺病明显症状发作。
工业实用性等及其说明等:
以上通过具体实施方式和实施例对本发明进行了详细说明,不过应理解,这些说明并不对本发明的范围构成任何限制,相关技术人员明显能在在不偏离本发明的精神和保护范围的情况下,可以对本发明的技术方案及其实施方式进行多种修饰、改进和替换与组合,来实现本发明技术,这些均因落入本发明的保护范围内。特别需要指出的是,可以理解,很多细节的变化是可能的,所有相类似的替换和改动对本领域技术人员来说是显而易见的,它们都被视为包括在本发明的精神、范围和内容中,本发明并不限于上述实施例。
Claims (7)
- 治疗和预防人或哺乳动物的过敏性疾病或哮喘或慢阻肺或支气管炎疾病的药物,其特征为:该药物为水杨酸或阿司匹林或其前药、药学上可接受的盐、复盐、溶剂化物或其药学上可接受的酯或醚或其药学上可接受的包合物,或含有它们中任何一种的药用组合物。
- 根据权利要求1所述的治疗和预防人或哺乳动物的过敏性疾病或哮喘或慢阻肺或支气管炎疾病的药物,其特征为:该药物为水杨酸或阿司匹林或其前药、药学上可接受的盐、复盐、溶剂化物或其药学上可接受的酯或醚或其药学上可接受的包合物,或含有它们中任何一种的药用组合物,和药学上可接受的载体。
- 根据权利要求1、2任一所述的治疗和预防人或哺乳动物的过敏性疾病或哮喘或慢阻肺或支气管炎疾病的药物,其特征为:该药物为水杨酸或阿司匹林或其前药、药学上可接受的盐、复盐、溶剂化物或其药学上可接受的酯或醚或其药学上可接受的包合物,或含有它们中任何一种的药用组合物,水杨酸或阿司匹林衍生物选自但不仅限于水杨胺、水杨酸、阿司匹林及其药学上可接受的盐,选自但不仅限于乙酰水杨酸或水杨酸钠、水杨酸L-精氨酸、水杨酸精氨酸、水杨酸L-组氨酸、水杨酸L-赖氨酸、水杨酸DL-赖氨酸、水杨酸葡甲胺盐、水杨酸乙二胺盐、乙酰水杨酸或水杨酸L-瓜氨酸、乙酰水杨酸或水杨酸双异丙胺、水杨酸胆碱镁、乙酰水杨酸或水杨酸镁、水杨酸镁4水合物、水杨酸葡乙胺、乙酰水杨胺、沙利芬saliphen、水杨酸萘酯、水杨丙磺酸、双水杨酯、最著酸、水杨吗啉、水杨胺、水杨各可酯、水杨酸甲酯、乙基水杨胺、阿司匹林L-精氨酸、D-精氨酸阿司匹林、精氨酸阿司匹林、赖氨酸阿司匹林、L-赖氨酸阿司匹林、D-赖氨酸阿司匹林、阿司匹林葡甲胺盐中的一种或多种。
- 根据权利要求1-3任一所述的治疗和预防人或哺乳动物的过敏性疾病或哮喘或慢阻肺或支气管炎疾病的药物,其特征为:该药物为水杨酸或阿司匹林或其前药、药学上可接受的盐、复盐、溶剂化物或其药学上可接受的酯或醚或其药学上可接受的包合物,或含有它们中任何一种的药用组合物,其给药途径为穴位给药,粉针制剂以生理盐水或无菌用水或葡萄糖水中的一种或几种稀释后穴位给药,给药剂量选自但不仅限于0.1-40mg/个穴位,单个穴位的给药剂量可以阿司匹林或乙酰水杨酸或乙酰水杨酸精氨酸或乙酰水杨酸赖氨酸或水杨酸或折算乙酰水杨酸或水杨酸为计给药重量;给药液体量选自但不仅限于0.01-2ml/个穴位。
- 根据权利要求1-4任一所述的治疗和预防人的过敏性疾病或哮喘或慢阻肺或支气管炎疾病的药物,其特征为:该药物可以是单独给药或与其它药物联合给药,联合给药,选自但不仅限于维生素C片或胶囊或颗粒剂或注射液、维生素C钠片或注射液、川贝枇杷膏、急支糖浆、橘红丸、甘草片、复方甘草片、玉屏风散、藿香正气丸或颗粒中国传统的中成药制剂或抗组胺药物、鼻用糖皮质激素和白三烯受体拮抗剂中的一种或多种,以上包括药学上可接受的药物剂型,联合抗生素或抗菌药给药可以用于合并细菌感染。
- 根据权利要求1-5任一所述的治疗和预防人或哺乳动物的过敏性疾病或哮喘或慢阻肺或支气管炎疾病的药物,其特征为:以经络系统的穴位给药,穴位选自但不仅限于中医的经络系统经脉或络脉或十二经脉、奇经八脉、十二经别、十二经筋、十二皮部、十五脉络、孙络浮络或足太阳经、足太阴脾经的穴位或阿是穴或奇穴,选自但不仅限于大椎穴、太阳穴、百会穴、迎香穴、肺俞穴、扶突穴、中府穴、天突穴、天容穴、颈百劳穴、天溪穴、膻中穴、气海穴、背俞穴、肾俞穴、脾俞穴、膈腧穴、血海穴、列缺穴、尺泽穴、太渊穴、合谷穴、丰隆穴、印堂穴、足三里、曲池穴、风池穴、天枢穴、内庭穴、孔最穴、鱼际穴、膏肓穴、夹脊穴、膻中穴、外关穴、风门穴、尺泽穴、定喘穴、大抒穴、丰隆穴、阴陵穴、胸1-7夹脊、天府穴、百劳穴、魄户穴、孔最穴、支正穴、太溪穴、身柱穴、气户穴、云门穴、中府穴、隐白穴、期门穴、阿是穴或奇穴中的一个或多个;在上述穴位或其临近可单点或左右两侧或多点注射给药;给药次数或间隔选自但不仅限于每日或隔日注射1-2次,亦可选自但不仅限于隔2-5日一次或一到两周一次或1次/3周或1次/月或1次/5周或1次/6周或1次/8周或1次/9周或1次/10周或更长。
- 根据权利要求1-6任一所述的治疗和预防人或哺乳动物的过敏性疾病或哮喘或慢阻肺或支气管炎疾病的药物,其特征为:该药物为水杨酸或阿司匹林或其前药、药学上可接受的盐、复盐、溶剂化物或其药学上可接受的酯或醚或其药学上可接受的包合物,或含有它们中任何一种的药用组合物的相应低剂量的注射剂;对于本发明药物的注射剂,譬如注射用精氨酸阿司匹林、阿司匹林L-精氨酸、阿司匹林赖氨酸注射剂、注射用赖氨匹林、水杨酸葡甲胺注射剂、或水杨酸L-精氨酸注射剂等衍生物注射剂中,以折算为含水杨酸或阿司匹林重量处方规格选自但不仅限于3-50mg/瓶或支计,较优选自但不仅限于3-30mg/瓶或支,更较优选自但不仅限于5-25mg/瓶或支。
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