WO2011097788A1 - 己酮可可碱在预防或治疗便秘中的用途 - Google Patents

己酮可可碱在预防或治疗便秘中的用途 Download PDF

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Publication number
WO2011097788A1
WO2011097788A1 PCT/CN2010/001954 CN2010001954W WO2011097788A1 WO 2011097788 A1 WO2011097788 A1 WO 2011097788A1 CN 2010001954 W CN2010001954 W CN 2010001954W WO 2011097788 A1 WO2011097788 A1 WO 2011097788A1
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Prior art keywords
pentoxifylline
group
constipation
tablet
tablets
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PCT/CN2010/001954
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English (en)
French (fr)
Inventor
赵志全
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鲁南贝特制药有限公司
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Priority to JP2012552228A priority Critical patent/JP5575927B2/ja
Priority to AU2010345621A priority patent/AU2010345621B2/en
Priority to BR112012019619A priority patent/BR112012019619A2/pt
Publication of WO2011097788A1 publication Critical patent/WO2011097788A1/zh

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    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • 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
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/10—Laxatives

Definitions

  • the invention belongs to the field of medicine, and particularly relates to a new use of pentoxifylline, in particular to the use of pentoxifylline in the preparation of a medicament for preventing or treating constipation, and to a pentoxifylline for preventing or treating constipation.
  • Phosphodiesterase has the function of hydrolyzing intracellular second messenger cyclic adenosine monophosphate (cAMP) or cyclic guanosine monophosphate (cGMP), degrading intracellular cAMP or cGMP, thereby terminating the biochemical effects of these second messengers. . cAMP and cGMP play important regulatory roles in cellular activities. The adjustment of its concentration is mainly determined by the balance between the synthesis of nucleotide cyclase and the hydrolysis of phosphodiesterase (PDE). PDE is widely distributed in the human body, physiologically and in many research fields. In recent years, PDE as a new therapeutic target has attracted wide attention from many scholars and has become a new research hotspot.
  • the phosphodiesterase inhibitor is a large multigene family and is a drug that inhibits phosphodiesterase activity.
  • Phosphodiesterase inhibitors are compounds that inhibit the degradation of cAMP and cGMP in tissues.
  • PDE inhibitors include non-specific PDE inhibitors and specific PDE inhibitors. Specific PDE inhibitors can only inhibit one type of PDE. Types have little effect.
  • Non-specific phosphodiesterase (PDE) inhibitors include theophylline, aminophylline, pentoxifylline, pegvirin and caffeine.
  • Theophylline is a white amorphous crystalline alkaloid contained in tea. It is an isomer of theobromine, and its action and structure are similar to caffeine. It belongs to phosphodiesterase, which can increase the cAMP content of cells, and has the functions of relaxing smooth muscle, exciting heart muscle and diuresis.
  • Aminophylline is the most widely used double salt preparation of theophylline and ethylenediamine in China, and has been used clinically for many years. Aminophylline is more water soluble than theophylline and is easily dissolved and absorbed. However, aminophylline is more alkaline, local irritant, and oral gastrointestinal reactions such as nausea, vomiting, and loss of appetite. Pagivirin is a skeletal muscle relaxant.
  • Caffeine is an alkaloid extracted from tea and coffee fruit. Moderate use of fatigue and excitatory nerves is clinically used to treat neurasthenia and coma.
  • Pentoxifylline is an alkaloid obtained by extracting cocoa butter from cocoa beans and introducing a ketone group, and has a molecular formula of C 13 H 2 .
  • N 4 0 3 chemically known as 3,7-dimethylxanthine, is a methylxanthine derivative and a non-selective phosphodiesterase inhibitor.
  • PTX can increase the deformability of red blood cells, improve the hemorheological characteristics of white blood cells, inhibit the adhesion and activation of neutrophils; dilate microvessels; reduce blood viscosity; increase tissue oxygen partial pressure; have anti-inflammatory effect; base.
  • PTX was only used for the treatment of peripheral circulatory disorders; after being used as a vasodilator, it was used for treatment.
  • Vascular disease has a history of more than 10 years; also used for the treatment of peripheral vascular diseases such as arteriosclerosis, vascular embolism, diabetic angiopathy, frostbite, venous ulcer.
  • treatment for male infertility and stimulation of sperm motility in vitro was started.
  • it is effective against circulatory diseases of the inner ear, can resist liver fibrosis, and has protective effects on kidneys and lungs.
  • "Pentoxifylline promotes learning and memory function of aging rats and mice with induced memory impairment", Journal of Southern Medical University, Vol. 27, No.
  • Constipation especially chronic constipation, is a common symptom, and its etiology is complicated, causing many distress to patients, which seriously affects the quality of life of patients.
  • Chronic constipation can be divided into organic constipation and functional constipation from the etiology.
  • Organic constipation is mainly caused by constipation caused by organic causes.
  • the organic causes of chronic constipation are mainly gastrointestinal diseases (intestinal tumors, congenital megacolon, etc.), perianal diseases (rectal prolapse, rectal front) Severe), nervous system diseases (multiple sclerosis, Parkinson's disease, stroke, spinal cord injury and peripheral neuropathy), endocrine or metabolic diseases (diabetic bowel disease, hypothyroidism, parathyroid disease) and mental illness,
  • Constipation caused by drug-related factors opioid, anticholinergics, antidepressants, calcium channel antagonists, antacids, irons, antidiarrheals, diuretics, antihistamines, etc.
  • drug-related factors opioid, anticholinergics, antidepressants, calcium channel antagonists, antacids, irons, antidiarrheals, diuretics,
  • Functional constipation is the elimination of constipation caused by organic causes and other factors, and meets the following criteria: In the past 12 months, there are two or more symptoms that persist or accumulate for at least 12 weeks: (1) 1/ 4 time defecation laborious; (2) 1/4 time stool is a mass or hard; (3) more than 1/4 time defecation is not enough; (4) more than 1/4 time anal blockage or discharge difficulties; (5) Use more than 1/4 time for defecation to assist (support pelvic floor muscle obstruction); (6) less than 3 times per week.
  • STC slow transit constipation
  • 00C outlet obstructive constipation
  • IX mixed constipation
  • C-kit is a proto-oncogene located at the w-site of chromosome 5, which encodes a kit receptor, which is a tyrosine kinase membrane receptor.
  • kit receptor which is a tyrosine kinase membrane receptor.
  • Intestinal motility is closely related, so ICC can be identified using c-kit antibody markers.
  • 00C is coordinated with the function of the anal sphincter.
  • ⁇ The rectum is related to the abnormal threshold of the bowel reflex. The patient often complains about the difficulty of defecation, the feeling of falling anus, the feeling of defecation, the amount of defecation, the texture is hard or the soft stool is formed.
  • Mixed constipation is characterized by the above two characteristics. Because the pathogenesis of various types of constipation is different, we should pay attention to and analyze in detail the characteristics of patients' constipation, and conduct preliminary classification and take corresponding treatment measures.
  • constipation treatments are not satisfactory: or the treatment time is too long, or it is ineffective, or a small amount of loose stools is discharged, or the adverse reactions are so large that patients are difficult to accept.
  • non-drug treatment and drug treatment are used clinically, and in severe cases, surgical treatment is even needed.
  • Non-pharmacological treatments such as defecation instructions, dietary changes, and biofeedback treatments, all take a long time to resolve, and many patients are difficult to persist due to personal factors.
  • the main drugs for constipation are stimulant laxatives, lubricative laxatives, volumetric laxatives, and osmotic laxatives and agonist drugs.
  • Stimulating laxatives are strong and rapid, and are often used for fecal impaction and rapid laxative patients. They should not be used for a long time, because they stimulate the intestinal mucosa and intestinal wall plexus, improve mucosal permeability, and affect intestinal water, electrolytes and vitamins.
  • volumetric laxatives can increase the capacity of the stool, but can not effectively increase the colon tension, the use of intestinal motility retardation is limited; lubricative laxatives have poor mouthfeel , weak effect, long-term use can cause adverse reactions such as fat-soluble vitamin absorption disorder, perianal oil leakage; osmotic laxatives such as lactulose.
  • the invention provides a new use of pentoxifylline in the field of medicine, in particular to preparation of pentoxifylline
  • a medicament for preventing or treating constipation and a pharmaceutical composition comprising pentoxifylline for preventing or treating constipation, and a method for preventing or treating constipation by using pentoxifylline, especially for functional constipation .
  • Pentoxifylline is a non-selective phosphodiesterase inhibitor mainly used for thromboangiitis obliterans, cerebrovascular disorders, vascular headaches, peripheral vascular disease, cochlear disturbances, frostbite and hypoxia. Pain.
  • pentoxifylline causes constipation, dry mouth and other adverse reactions, the inventors have surprisingly found that pentoxifylline exhibits an unexpected effect in the treatment of constipation, especially functional constipation.
  • pentoxifylline has an unexpected effect in improving constipation, especially functional constipation, indicating that ketone cocoa Alkali can be used as a drug for the treatment of constipation.
  • the invention provides a pharmaceutical composition for preventing or treating constipation, especially functional constipation, which comprises pentoxifylline.
  • the pharmaceutical composition containing pentoxifylline can be prepared into a topical external preparation or an oral preparation according to a conventional formulation technique, wherein the topical external preparation is preferably a topical preparation suitable for anorectal administration, such as a spray, an aerosol, a suppository, or a gel.
  • Agents, creams, creams, ointments, solutions, emulsions and liposomal preparations; oral dosage forms are preferably ordinary tablets, enteric coated tablets, sustained release tablets, capsules, dropping pills, granules, powders and oral liquids .
  • the present invention also preferably exemplifies the weight percentage of pentoxifylline in the topical preparation. 01%_10% ⁇ Preferably, the weight percentage of pentoxifylline in the topical preparation is 0.1% _10%.
  • the excipient in the above topical preparation of the pharmaceutical composition is selected from the group consisting of semi-synthetic fatty acid glycerides, carbomer, triethanolamine, sodium sulfonate, liquid paraffin, monoglyceride, p-hydroxybenzoic acid, animal and vegetable oil, One or more of petrolatum, cellulose derivatives, polyethylene glycol, silicone, silicic acid, aluminum stearate, propylene glycol, lanolin, beeswax, talc, and zinc oxide _; One or more of lactose, talc, glycerol, sodium chloride and urea may also contain conventional propellants, such as chlorofluorocarbons and/or volatile unsubstituted hydrocarbons, volatile non-substituted hydrocarbons. Butane and propane. Topical tanning agents or drops can be formulated with aqueous or oily bases and can be prepared according to conventional methods of preparation.
  • the excipient of the above-mentioned pharmaceutical composition topical preparation may further comprise one or more preservatives, such as chlorhexidine acetate and benzalkonium bromide; the external preparation can make pentoxifylline and form under aseptic conditions
  • the agent is mixed, preferably, it also contains a propellant.
  • the above-mentioned pharmaceutical composition topical external preparation is preferably a transmucosal pharmaceutical dosage form which can be formulated with a mucoadhesive polymer to delay the release of the active ingredient in the anal mucosa.
  • the transmucosal pharmaceutical dosage form maintains contact with the mucosa while rapidly disintegrating and/or dissolving, thereby causing local or systemic absorption.
  • Transmucosal drug delivery allows the active substance to effectively enter the systemic circulation and reduce the immediate metabolism of the drug by the liver and small intestinal wall flora.
  • the above topical topical preparation is a suppository or an aerosol
  • the suppository contains polysorbate 80, glycerin and gelatin; and the aerosol contains Freon F 12 , glycerin, benzalkonium bromide and urea.
  • the pharmaceutical composition containing chlorhexholic acid is an oral preparation
  • the pharmaceutical composition preferably contains 10 mg to 100 mg of pentoxifylline. More preferably, the composition is a tablet, granule or capsule containing from 10 mg to 100 mg of pentoxifylline.
  • the pharmaceutical composition is a tablet containing 10 mg to 100 mg of pentoxifylline, it may be a plain tablet, an enteric tablet or a sustained release tablet.
  • the ordinary tablets are relative to other tablet dosage forms, which only need to be prepared by conventional preparations;
  • the enteric coated tablets are outer coatings and enteric coatings in conventional tablets to avoid The stimulating effect of the stomach, after the enteric-coated tablet enters the intestinal tract, the drug is released after the coating dissolves;
  • the sustained-release tablet is prepared by using a special drug material in order to reduce the number of administrations and reduce the release rate of the drug.
  • the above pharmaceutical composition is a common tablet, it is composed of pentoxifylline and an excipient, wherein the excipient includes a diluent, a binder and a disintegrating agent, and the diluent is selected from the group consisting of starch, dextrin, lactose and microcrystals.
  • the excipient includes a diluent, a binder and a disintegrating agent, and the diluent is selected from the group consisting of starch, dextrin, lactose and microcrystals.
  • the binder is selected from one or more of hydroxypropylmethylcellulose, ethylcellulose, sodium carboxymethylcellulose, and polyvinylpyrrolidone
  • the disintegrating agent is selected from the group consisting of one or more of hydroxypropylmethylcellulose, ethylcellulose, sodium carboxymethylcellulose, and polyvinylpyrrolidone.
  • the excipient of the above-mentioned conventional tablet further comprises a wetting agent and/or a lubricant, wherein the wetting agent is selected from the group consisting of water, ethanol or a mixture thereof, and the lubricant is selected from the group consisting of magnesium stearate, zinc stearate and One or more of micronized silica gel.
  • a wetting agent is selected from the group consisting of water, ethanol or a mixture thereof
  • the lubricant is selected from the group consisting of magnesium stearate, zinc stearate and One or more of micronized silica gel.
  • the content of pentoxifylline in the above conventional tablet is preferably 10 mg, 25 mg, 50 mg or 75 mg.
  • the preferred content of pentoxifylline in the ordinary tablets is mainly based on the fact that the ordinary tablets of the content specification have better therapeutic effects on functional constipation.
  • the above pharmaceutical composition is an enteric coated tablet, it consists of a pentoxifylline tablet, a barrier layer and an enteric layer.
  • the pentoxifylline tablet is any of the above-mentioned ordinary tablets of crotonic alkali, and the pentoxifylline enteric-coated tablet can be first coated with a film coating powder solution and then coated with an enteric coating powder solution.
  • the diluent in the pentoxifylline tablet is selected from the group consisting of lactose and microcrystalline cellulose; a wetting agent and a solution selected from the group consisting of ethanol; the binder is selected from the group consisting of hydroxypropylmethylcellulose, ethylcellulose, and carboxy One or more of sodium methylcellulose and polyvinylpyrrolidone; the disintegrant 'selected from sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, croscarmellose sodium, and cross-linked poly-dimensional One or more of the ketones; the lubricant is selected from magnesium stearate.
  • the content of pentoxifylline in the pentoxifylline enteric-coated tablet is preferably 25 mg or 50 mg.
  • the preferred content of pentoxifylline in enteric-coated tablets is mainly based on the fact that the enteric-coated tablets of this content have better therapeutic effects on functional constipation.
  • the above pharmaceutical composition is a sustained release tablet, it is a matrix tablet prepared by pressing or fusion technique from pentoxifylline, an excipient and one or more inert solid skeleton materials, and the commonly used skeleton material includes hydrophilic condensation. Rubber skeleton materials, bioerodible framework materials and insoluble framework materials.
  • the hydrophilic gel skeleton material is selected from one or more of hypromellose, carbomer, sodium alginate, methyl cellulose, sodium carboxymethyl cellulose, hydrophilic gel skeleton material. It swells after exposure to water or gastrointestinal fluids, forming a gel barrier that controls the release of the drug.
  • the bioerodible framework material is triglyceride, hydrogenated castor oil, Stearyl alcohol, stearic acid, carnauba wax, gastric or enteric acrylic resin, enteric cellulose, and the like.
  • the insoluble matrix material is a water-insoluble polymer material, including ethyl cellulose, an acrylic resin (such as a permeable acrylate, for example, a methacrylic acid-methyl acrylate copolymer) or a mixture thereof, and the gastrointestinal fluid is infiltrated. After the skeleton pores, the drug dissolves and passes through the passage of the extremely fine pores existing in the skeleton, and is slowly released to release.
  • a plurality of different dissolution or dissolution properties of the framework material can be used as the framework material in the pentoxifylline sustained release tablets.
  • the excipient in the above-mentioned pentoxifylline sustained-release tablet may be one or more selected from the group consisting of a diluent, a wetting agent, a binder, a disintegrant, and a lubricant.
  • the diluent is selected from one or more of the group consisting of starch, dextrin, lactose and microcrystalline cellulose;
  • the wetting agent is selected from the group consisting of water, ethanol or a mixture thereof, and the binder is selected from the group consisting of hydroxypropylmethylcellulose, B One or more of cellulose, sodium carboxymethylcellulose, and polyvinylpyrrolidone;
  • the disintegrant is selected from the group consisting of sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, croscarmellose sodium, and One or more of crospovidone;
  • the lubricant is selected from one or more of magnesium stearate, zinc stearate, and micronized silica gel.
  • the content of pentoxifylline in the sustained release tablet is preferably 75 ⁇ 3 ⁇ 4 or 80 mg.
  • the content of pentoxifylline in the sustained-release tablet is mainly based on the fact that the sustained-release tablet of the content specification is superior in the therapeutic effect on functional constipation.
  • the present invention provides the use of pentoxifylline for the preparation of a medicament for preventing or treating constipation, especially functional constipation.
  • the medicament is the above pharmaceutical composition of the invention.
  • the present invention provides a method of treating constipation, especially functional constipation, which comprises administering to a patient a therapeutically effective amount of a pharmaceutical composition comprising pentoxifylline.
  • a pharmaceutical composition comprising pentoxifylline.
  • the above-mentioned effective amount of the pharmaceutical composition may be administered orally to the patient, or an effective amount of the above pharmaceutical composition may be administered to the patient for topical administration, such as administration to the corresponding rectal anal area or diseased anal tissue, such as the external anus or Internal anal tissue or anal.
  • a topical external preparation of pentoxifylline including a suppository, an aerosol, an ointment and the like.
  • the topical preparation should be cleaned before the administration, which will facilitate the absorption of the drug in the rectal mucosa.
  • the subject of pentoxifylline in the treatment of functional constipation includes humans or animals.
  • the particular dosage of pentoxifylline will depend on a number of factors, all of which are well known to those skilled in the art.
  • the specific pharmaceutical dosage form, the subject being treated, the condition, the age, the weight, and the clinical condition of the recipient for example, the specific pharmaceutical dosage form, the subject being treated, the condition, the age, the weight, and the clinical condition of the recipient.
  • the range of the dose to be administered differs depending on the pentoxifylline to be used, the route of administration, and the like:
  • oral preparations include tablets, capsules, enteric coated tablets, drops, granules, powders, oral solutions, according to the amount of pentoxifylline, oral dose of 10mg-100mg / time, daily 1-3 times.
  • the topical preparations include sprays, suppositories, gels, creams, creams, ointments, solutions, emulsions, and liposome preparations, and the external dose is the same as the oral preparation, based on the amount of pentoxifylline.
  • the time of administration depends on the degree of relief of clinical symptoms and their symptoms.
  • oral preparations include tablets, capsules, enteric coated tablets, drops, granules, powders, oral solutions, according to the amount of pentoxifylline, oral dose of 10mg-100mg / time, daily 1 -3 times.
  • the topical preparations include sprays, suppositories, gels, creams, creams, ointments, solutions, emulsions, and liposome preparations, and the external dose is the same as the oral preparation, based on the amount of pentoxifylline.
  • the time of administration depends on the degree of relief of clinical symptoms and their symptoms.
  • the effective dose of the oral preparation or the topical preparation can be appropriately adjusted according to the amount of the child, which is to those skilled in the art. It is easy to do.
  • the present invention also provides an experimental study for treating a functional constipation by the above pharmaceutical composition containing pentoxifylline.
  • the invention establishes a mouse model of slow transit constipation by subcutaneous injection of morphine in the test case of the mouse, records the weight of the feces of the mouse, and compares the colonic transmission function between the experimental group and the control group by using the activated carbon gavage method; using immunohistochemistry Technical calculations of c-kit positive cell area The number of Cajal cells (ICC) in colon tissue of the two groups of mice was compared.
  • ICC Cajal cells
  • mice in the model control group had reduced feces, decreased intestinal propulsion (prolonged discharge of the first black stool), and decreased intestinal ICC (decreased c-kit positive cell area), which was significantly different from the normal group.
  • the pentoxifylline treatment group including the tablet group and the suppository group
  • the average daily bowel movement of mice increased, the intestinal propulsion of mice increased, and the number of intestinal ICC increased. Studies have shown that pentoxifylline has an unexpected effect in improving the symptoms of slow transit constipation.
  • non-selective phosphodiesterases inhibit therapeutic functions such as theophylline, aminophylline, caffeine, and pegaverine.
  • the effect of sexual constipation is far less than that of pentoxifylline.
  • the present inventors have surprisingly found that the daily average stool volume, the first black stool discharge time, and the c-kit positive cell area are significant in the pentoxifylline suppository group compared with the pentoxifylline tablet group. The difference (p ⁇ 0.05) indicates that the direct administration of pentoxifylline rectal mucosa is superior to the oral administration of pentoxifylline in the treatment of constipation in slow-transmission mice.
  • the present invention also passes the test example 3 pentoxifylline on the effect of loperamide-induced rectal mucosal mucus in constipation rats, indicating that loperamide-induced constipation rats have significantly reduced intestinal mucosal epithelial mucus compared with normal rats.
  • pentoxifylline After pentoxifylline, the intestinal mucosal mucus of rats increased significantly, and there was significant difference.
  • the intestinal mucosal epithelial mucus of rats in the pentoxifylline topical group increased significantly and was significant.
  • Sexual differences p ⁇ 0.05
  • the secretion of goblet cells in normal colonic mucosa is rich in mucin, and mucin combines with water to form mucus, which constitutes mucus protection. Mechanical protection of the mucosa.
  • a decrease in mucus secretion is a manifestation of a weakening of the colon, or a decrease in the ability to fix water, or a decrease in the secretion of cellular mucins.
  • the present invention surprisingly finds that pentoxifylline has an unexpected effect in improving colonic function and increasing intestinal mucus secretion by administration of pentoxifylline. It can be seen that pentoxifylline in the treatment of functional constipation not only improves the symptoms of functional constipation, but also significantly improves the function of the intestinal mucosa, thereby making it possible to achieve a significant improvement in functional constipation.
  • the external preparation of pentoxifylline is generally superior to the oral preparation of pentoxifylline, but since the oral preparation has the advantage of convenient administration, the oral preparation of pentoxifylline is developed for therapeutic function. Sexual constipation is feasible.
  • the present invention also provides a clinical trial of the above-mentioned pharmaceutical composition containing pentoxifylline in the treatment of functional constipation by Test Example 4.
  • the results of clinical treatment showed that the ordinary tablets lOmg group, the ordinary tablets 50mg group, the ordinary tablets 80mg group, the sustained release tablets 75mg group, the sustained release tablets lOOmg group, the enteric coated tablets lOmg group, the enteric coated tablets 50mg group functional constipation clinical volunteers Significantly improved symptoms, the treatment effective rate was 58.33% - 87. 50%, the average total effective rate was 78.38%, the incidence of adverse reactions was small, 0% 8.33%, the average incidence of adverse reactions 2.
  • the high-dose pentoxifylline tablet group containing the low dose of lOmg-lOOmg pentoxifylline is more effective in treating functional constipation, the incidence of adverse reactions is significantly lower, and has statistics. difference.
  • the low dose tablet of lOmg-lOOmg pentoxifylline provided by the present invention can be used as a drug for treating functional constipation.
  • the granules or capsules containing 10 mg of 100 mg of pentoxifylline may preferably have a dose of 10 mg to 100 mg of mannitol base tablet to achieve the same or similar effects in treating functional constipation, which is to those skilled in the art. It is foreseeable. This further demonstrates that the pharmaceutical composition of the present invention containing 10 mg - 100 mg of pentoxifylline can be used as a drug for treating functional constipation.
  • Preparation process Weigh the prescribed amount of gelatin, add appropriate amount of purified water to the vessel, place it for about 1 hour, make it swell and soften, then add the prescription amount of glycerin and then heat it on the water bath to dissolve the gelatin, continue heating and stirring; Pentoxifylline, polysorbate 80. After mixing, add the prepared glycerin gelatin solution, stir well, then pour it into the mold with the lubricant coated, cool, and cut off the overflow part of the die. , demoulding, quality inspection, packaging, a total of 3 ⁇ 4 100 tablets.
  • Preparation process take the semi-synthetic fatty acid glycerin in the vessel, heat and melt in a water bath, wait until the temperature drops to about 5CTC, add glycerin, polysorbate 80, stir evenly, add pentoxifylline, stir evenly, stir well and then inject it
  • the mold of the lubricant is slightly overflowed to the die, cooled, solidified, and then the overflow part is removed, demoulding, quality inspection, packaging, and a total of 100 capsules.
  • Preparation process take polyethylene glycol 4000 and polyethylene glycol 1000 in a dish, the water bath is heated and melted, until the temperature drops to about 50 °C, plus Add glycerin, stir evenly, add pentoxifylline, stir evenly, mix well and then inject into the mold with lubricant to slightly overflow the die, cool, solidify and then remove the overflow part, demoulding, quality inspection, Packing, a total of 1000 tablets.
  • Preparation Process Take glyceryl monostearate, stearic acid-white petrolatum, triethanolamine water bath to melt, and mix as a oil phase. In addition, an appropriate amount of purified water is taken to dissolve the pentoxifylline into the water.
  • Preparation process Under normal temperature and pressure, weigh 10g of pentoxifylline, dissolved in an appropriate amount of distilled water, and then added to the proportion of each component in the prescription, namely, glycerol 30g, urea 2g, benzalkonium bromide 0 Lg, sodium chloride 0. 9g, and finally add distilled water to 100ml, fully mix, canned, sealed, and finished the finished product.
  • the pentoxifylline 10g is weighed in an appropriate amount of distilled water, and then added to the proportion of each component in the prescription, namely, 10 g of glycerin, 2 g of urea, 2 g of ammonium bromide. , the right amount of propellant F 12 , and finally add distilled water to 100ml, fully mix, canned, sealed, test
  • Preparation Process Mixing pentoxifylline with auxiliary microcrystalline cellulose and sodium carboxymethyl starch, adding appropriate amount of starch slurry to soft material, and then granulating through 16 mesh sieve.
  • the wet granules were dried at 60 Torr, the dry granules were sieved through a 16-mesh sieve, the fine powder in the dry granules was sieved out, mixed with magnesium stearate, and then mixed with the dry granules, and compressed, and a total of 1000 tablets were prepared.
  • the tablet content specification is 10 mg/tablet.
  • Preparation process Mixing pentoxifylline after 80 mesh sieve with lactose and microcrystalline cellulose, using soft material made of 50% ethanol, granulating through 20 mesh, 6 (blast drying under TC conditions, 20 mesh) The granules were sieved, and then a prescribed amount of sodium carboxymethylcellulose and magnesium stearate were added and uniformly compressed to prepare a total of 1,000 tablets.
  • the tablet content was 25 mg/tablet.
  • the pentoxifylline and the auxiliary microcrystalline cellulose and sodium carboxymethyl starch are uniformly mixed, and an appropriate amount of starch slurry is added to prepare a soft material, which is then sieved through a 16 mesh sieve.
  • the wet granules were dried at 6 (TC dry, the dry granules were sieved through a 16 mesh sieve, the fine powder in the dry granules was sieved out, mixed with zinc stearate, and then mixed with the dry granules, and compressed, and a total of 1000 tablets were prepared. Tablets contain a specification of 80tng/tablet.
  • Preparation Process The pentoxifylline and the auxiliary materials mannitol, lactose, sodium carboxymethyl starch are uniformly mixed, and an appropriate amount of starch slurry is added to prepare a soft material, which is then sieved through a 16 mesh sieve.
  • the wet granules were dried at 60 ° C, the dry granules were sieved through a 16 mesh sieve, the fine particles in the dry granules were sieved out, mixed with magnesium stearate, and then mixed with the dry granules, and compressed into pieces to prepare 1,000 pieces.
  • the tablet content is 50 mg/tablet.
  • the pentoxifylline and the auxiliary microcrystalline cellulose and sodium carboxymethyl starch were uniformly mixed, and an appropriate amount of starch was added to prepare a soft material, which was sieved through a 16 mesh sieve.
  • the wet granules are dried at 60 ° C, the dry granules are sieved through a 16 mesh sieve, the fine powder in the dry granules is sieved out, mixed with magnesium stearate, and then mixed with the dry granules, compressed, and then film coated.
  • the intestine solution coating, the isolation layer gained 3% weight, the enteric coating weight gain 8%, a total of 1000 tablets.
  • the content of enteric tablets was 10 mg/tablet.
  • Preparation Process Mixing pentoxifylline after 80 mesh sieve with lactose and microcrystalline cellulose, using 50% ethanol to make soft material, sifting through 20 mesh, blast drying at 60 °C, 20 mesh The granules are sieved, and then the ⁇ -prepared amount of sodium carboxymethylcellulose and magnesium stearate are mixed and uniformly compressed, and then film coating and intestinal solution coating are carried out, the weight of the separator is 3%, and the weight of the enteric coating is 8 %, a total of 1000 pieces.
  • the enteric tablet content is 25 mg/tablet.
  • Preparation Process The pentoxifylline and the auxiliary microcrystalline cellulose and sodium carboxymethyl starch are uniformly mixed, and an appropriate amount of starch slurry is added to form a soft material, which is then sieved through a 16 mesh sieve.
  • the wet granules are dried at 60 Torr, the dry granules are sieved through a 16 mesh sieve, the fine powder in the dry granules is sieved out, mixed with zinc stearate, and then mixed with the dry granules, compressed, and then subjected to film coating and intestines.
  • the solution was coated, the weight of the separator was 3%, and the weight of the enteric coating was 8%, and a total of 1000 tablets were prepared.
  • the content of enteric tablets was 50 mg/tablet. ⁇
  • Preparation process Mix pentoxifylline and auxiliary mannitol, lactose, sodium carboxymethyl starch, and add appropriate amount of starch slurry to make soft materials.
  • the granules were sieved through a 16 mesh sieve.
  • the wet granules are dried at 60 ° C, the dry granules are sieved through a 16 mesh sieve, the fine powder in the dry granules is sieved out, mixed with magnesium stearate, and then mixed with the dry granules, compressed, and then film coated.
  • the intestine solution coating, the isolation layer gained 3% weight, the enteric coating weight gain 8%, a total of 1000 tablets.
  • the enteric tablet content is 50 mg/tablet.
  • HPMC 15M 60g Stearic Acid 110g Microcrystalline Cellulose 30g
  • the raw and auxiliary materials are mixed and hooked, passed through 80 mesh sieve, 8% PVPK3 Q 70% ethanol aqueous solution made of soft material, 30 mesh sieve wet granules, dried at 50 ° C, added magnesium stearate, mixed and compressed, and a total of 1000 Tablets, sustained release tablets content specification is lOOmg / tablet.
  • the raw materials are mixed evenly, passed through 80 mesh sieve, 8% PVPK3 Q 70% ethanol aqueous solution made of soft material, 30 mesh sieve wet granules, dried at 50 ° C, added magnesium stearate, mixed and compressed, and a total of 1000 tablets were prepared.
  • the sustained release tablet content is 80 mg/tablet.
  • Preparation Process The theophylline and the auxiliary microcrystalline cellulose and sodium carboxymethyl starch are uniformly mixed, and an appropriate amount of the starch slurry is added to make the soft material, and the granules are sieved through a 16 mesh sieve.
  • the wet granules are dried at 6 (TC dry, the dry granules are sieved through a 16 mesh sieve, the fine powder in the dry granules is sieved out, mixed with magnesium stearate, and then mixed with the dry granules, and tableted, that is, obtained.
  • Test Example 1 Effect of pentoxifylline on a mouse model of slow transit constipation
  • mice Eighty ICR rats were randomly divided into 6 experimental groups, 1 normal control group and 1 model control group, with 10 rats in each group.
  • the six experimental groups were: pentoxifylline tablet group; pentoxifylline suppository group; theophylline tablet group; aminophylline tablet group; caffeine tablet group; pagilin tablet group. All mice were placed in 80 mouse metabolic cages, SPF-level environmental words. After 3 days of adaptive feeding, mice in the experimental group and the model control group were injected subcutaneously with morphine hydrochloride 2. 5 mg / (kg * d), and the normal control group was injected with the same amount of physiological saline.
  • mice stool volume, dry stool weight and mouse body weight were recorded every 3 days, and the daily average defecation weight (g) of the mice was calculated.
  • the daily average defecation volume of the mice was reduced, and the daily average defecation volume was significantly different from that of the normal control group as a sign of successful establishment of the slow transit constipation mouse model, and the injection administration was stopped after the successful modeling.
  • mice given the successful modeling were administered according to the following administration scheme, and the pentoxifylline tablet group was administered with pentoxifylline by intragastric administration at a dose of pentoxifylline.
  • pentoxifylline suppository group rectal administration of pentoxifylline suppository, the dose is 1mg / (kg * d) according to pentoxifylline ;
  • the tablet group, the caffeine tablet group and the pagivirin tablet group were administered at a dose of 1 mg/(kg ⁇ !) and administered by intragastric administration.
  • mice stools were administered to the normal control group and the model control group.
  • the number of mice stools, the dry weight of the stool, and the body weight of the mice were recorded every other day, and the daily average defecation weight (g) of the mice was calculated.
  • the average daily bowel movement of mice decreased compared with the normal group, indicating an increase in the degree of slow transit constipation.
  • the first black stool discharge time was determined by the method of activated carbon gavage. All mice discontinued for 1 week were fasted for 24 hours, and 2 ml of lOOmg/tnl activated carbon suspension was orally administered. The time from the start of the filling of the activated carbon was recorded, and the time from the gavage to the discharge of the first black stool was recorded. The longer the first black discharge time, the greater the slow transit constipation.
  • the cervical vertebrae dislocation method was sacrificed.
  • the pylorus was removed by laparotomy to the entire intestine of the rectum. Two to three colon tissues of each mouse were taken, 4% formaldehyde solution was fixed, and paraffin-embedded serial sections (thickness: 4 ⁇ 5) ⁇ ⁇ ; After dewaxing and hydration, slice into EDTA buffer of ⁇ 8.0, boil for 15 min, keep warm for 10 min, cool at room temperature; rinse with PBS solution (pH 7.6) 3 times, each time for 5 min ; Add 50 ⁇ 13% hydrogen peroxide to block the activity of endogenous peroxidase, incubate for 10 min at room temperature; wash 3 times with PBS solution (pH 7.6) for 5 min each time; remove serum and add primary antibody (1:500) Incubate at 50 ⁇ l, 37 °C for 60 min, rinse with PBS for 3 times, 5 min each time; remove PBS solution, add biotin-labele
  • the five high-power field (X 200) is selected for each slice, and the Lecia RX250 image analysis system is applied.
  • the Qwin software marks and calculates the c-kit positive cell area. The smaller the c-kit positive cell area compared to the normal group, the greater the degree of slow transit constipation.
  • the experimental data was entered into the SPSS 10. 0 statistical software package. The statistical method was selected by t test, p ⁇ 0.05, the difference was significant. Result
  • pentoxifylline tablet group and pentoxifylline suppository group mice day The average defecation volume, the first black stool discharge time, and the c-kit positive cell area all had significant or extremely significant differences. This indicates that pentoxifylline is significantly better than slow-acting constipation in treating slow transit constipation. It is a non-selective phosphodiesterase inhibitor such as theophylline, aminophylline, caffeine, and pegvirin.
  • Caffeine film set 4.25 ⁇ 1.70 300 ⁇ 36 68.8 ⁇ 9.8
  • Pentoxifylline suppository group 9.80 ⁇ 2.62 170 ⁇ 64***' 4 ⁇ 98.0 ⁇ 11.2
  • M was compared with the normal control group, p ⁇ 0.01;*p ⁇ 0.05 compared with the pentoxifylline tablet group;
  • ⁇ was compared with the pegvirin group, ⁇ 0.05; ⁇ ⁇ compared with the pagivirin group, p ⁇ 0.01;
  • C-kit is a proto-oncogene located at the w-site of chromosome 5, which encodes a kit receptor, which is a tyrosine kinase membrane receptor.
  • kit receptor which is a tyrosine kinase membrane receptor.
  • the pentoxifylline administration group includes a tablet and a suppository group, and it is unexpected in improving the above symptoms of slow transit constipation, that is, increasing the daily average stool volume of the mouse, enhancing the intestinal propulsion of the mouse, and increasing the amount of intestinal ICC.
  • the efficacy of the drug is tested. Test Example 2 Effect of pentoxifylline on rat anal sphincters
  • Theophylline tablets, the preparation process is the same as the control example 1; the aminophylline tablet, the preparation process is the same as the control example 2; the caffeine tablet, the preparation process is the same as the control example 3; the pegaverine tablet, the preparation process is the same as the control example; 0. 9% NaCl solution; pentoxifylline tablets, the preparation process is the same as in Example 10; pentoxifylline aerosol, the preparation process is the same as in Example 9.
  • pentoxifylline gavage group pentoxifylline 0. 15mg / kg ⁇ d;
  • pentoxifylline topical group pentoxifylline 0. 15mg / kg ⁇ d ;
  • the saline solution was administered by intragastric administration. 0. 15 mg/kg * d;
  • Theophylline group theophylline is administered by intragastric administration 0. 15mg/kg * d;
  • aminophylline group the administration of aminophylline by intragastric administration 0. 15mg/kg ⁇ d;
  • Caffeine group caffeine for oral administration 0. 15mg/kg, d;
  • pegvirin was administered orally 0. 15 mg/kg ⁇ d.
  • the perianal sphincter electromyogram of the 7 groups of animals was measured at 1 h before administration and 72 h after administration, and anorectal manometry was performed at the same time.
  • Anal sphincter surface electromyography was performed using a Counterpoint MK II neuromyograph produced by DANTEC. Filter band 500-1000Hz, sensitivity 0. 2- lmV/cm, scanning speed 0. 5- lms, using surface electrode placed on the skin around the anus, recording the anal sphincter EMG of 4 groups of experimental animals, using the software The average amplitude of the potential and the average time limit.
  • a multi-channel rectal anal tube manometer was used, and a self-made micro-balloon (maximum 0.5 ml) pressure-measuring catheter was used to measure the anorectal manometry of the test animals.
  • the micro-multipolar probe penetrates into the rectum and rectum 0. 5cm, measuring the rectal rectal pressure, anorectal maximum voluntary systolic pressure and rectal anal inhibition. Because the anal canal of the rat is short and thin, and there is no obvious boundary with the rectum, only a single balloon is used for anorectal manometry. At the same time, the measured values were recorded by a multi-channel physiological recorder.
  • test animals were sacrificed.
  • the anal sphincter tissues of the four groups of experimental animals were excised, pathological sections were taken, and hematoxylin-eosin (HE) staining was performed.
  • HE hematoxylin-eosin
  • the electromyogram motor potential amplitude decreased in all treatment groups at 72 hours after treatment, and the mean time limit was improved, but theophylline, aminophylline, caffeine, pagivirin group and physiology There was no significant difference in the saline group.
  • the pentoxifylline gavage group and the topical group had significant differences compared with the saline group.
  • the pentoxifylline gavage group and the topical group had significant differences in reducing potential amplitude; compared with theophylline group and the pegaverine group In comparison, there was a significant difference in the extension time of the pentoxifylline gavage group and the topical group. See Table 2 for details.
  • Pentoxifylline is administered to 62 soil 26 : 4.8 soil 0.6** ⁇
  • the pentoxifylline gavage group and the topical group reduced the rectal rectal pressure, the anorectal maximum voluntary systolic blood pressure, and the rectal anal inhibition reflex value.
  • the airbag capacity has a significant difference;
  • the pentoxifylline topical group was more effective in reducing the anal rectal resting pressure, the anorectal maximum voluntary systolic pressure, and the rectal anal inhibition reflex value than the pentoxifylline gavage group. Good, but there was no statistical difference between the intragastric group and the external use group. See Table 4 for details. For obstructive constipation with more than 50% of functional constipation, continuous ankle and pressure increase of the internal and external anal sphincter is one of the major pathophysiological changes.
  • Test Example 3 Effect of pentoxifylline on rectal mucosal mucus in rats with constipation induced by loperamide
  • mice We then divided the rats into the pentoxifylline gavage group, the pentoxifylline topical group, one model control group, and one normal control group, with 5 rats in each group. Adaptive feeding for 3 days.
  • the intragastric group, the external use group, and the model control group were injected subcutaneously with loperamide 1. 5nig/kg, and the loperamide was dissolved in 0.9% NaCl solution and injected once a day at 09: 00 and 18: 00. .
  • Rats in the normal group were injected with 0.9% NaCl solution, and the experimental method was the same as the model group.
  • the rats in the group were intraperitoneally administered with pentoxifylline tablets at a dose of 1. 5 mg/kg per day .
  • the rats in the external group were administered with pentoxifylline suppository 1. 5 mg/kg.
  • the doses are all in terms of the amount of pentoxifylline.
  • the model control group and the normal control group were given distilled water, and the dosage and method were the same as above.
  • the intestinal mucosal epithelial mucus was abundant in the normal control group; the intestinal mucosal epithelial mucus in the model control group was significantly reduced, which was significantly different from the normal group (p ⁇ 0.01).
  • pentoxifylline has an unexpected effect in improving colonic function and increasing intestinal mucus secretion by administration of pentoxifylline. It can be seen that pentoxifylline in the treatment of functional constipation not only improves the symptoms of functional constipation, but also increases the secretion of intestinal mucus mucus, significantly improves the function of intestinal mucosa, and thus fundamentally achieves a significant improvement in functional constipation.
  • Table 4 Effect of pentoxifylline on rectal mucosal mucus in rats with constipation induced by loperamide
  • Enteric-coated tablets 50 mg group, oral enteric-coated tablets (50 mg/tablet, preparation process as in Example 16) - one tablet, 3 times a day.
  • constipation improved significantly, interval and stool were close to normal, or stool was slightly dry and the interval between bowel movements was within 72 h, and most of the symptoms disappeared;
  • Efficacy (Clinical Healing Number + Significant Number + Effective Number) / Total number of cases in the treatment group X 100%
  • Adverse Reaction Rate Number of Adverse Reactions / Total number of cases in the treatment group X 100%.
  • the results of clinical treatment showed that the ordinary tablets lOmg group, the ordinary tablets 50mg group, the ordinary tablets 80mg group, the sustained release tablets 75mg group, the sustained release tablets lOOmg group, the enteric coated tablets 10mg group, the enteric coated tablets 50mg group functional constipation clinical volunteers
  • the treatment effective rate was 58.33% - 87.50%
  • the average total effective rate was 78.38%
  • the incidence of adverse reactions was small, 0% 8.33%, the average incidence of adverse reactions 2. 08%
  • the effective rate of the sustained-release tablets 400mg group and the enteric-coated tablets 120mg group was 41.67%- 50. 00%
  • the average effective rate was 45.83%
  • the incidence of adverse reactions was 12.12. 50%-33.3%
  • the average incidence of adverse reactions was 22.92%, and there was also aggravation of functional constipation.
  • the high-dose pentoxifylline tablet group containing the low dose of lOmg-lOOmg pentoxifylline is more effective in treating functional constipation, the incidence of adverse reactions is significantly lower, and has statistics. difference.
  • the low dose tablet of 10 mg-100 mg of pentoxifylline provided by the present invention can be used as a medicine for treating functional constipation. The results are shown in Table 5. Table 5 Observation of the efficacy of pentoxifylline tablets in clinical constipation patients with functional constipation
  • composition granules or capsules containing 10 mg to 100 mg of pentoxifylline can replace the above pentoxifylline tablets to achieve the same or similar effects in the treatment of functional constipation, which is foreseen by those skilled in the art. .

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Description

己酮可可碱在预防或治疗便秘中的用途 技术领域
本发明属于医药领域， 具体涉及己酮可可碱的一种新用途， 特别涉及己酮可可碱在制备 预防或治疗便秘的药物中的用途， 还涉及用于预防或治疗便秘的包含己酮可可碱的药物组合 物， 以及用己酮可可碱预防或治疗便秘的方法， 所述便秘尤其为功能性便秘。 背景技术
磷酸二酯酶 （PDE ) 具有水解细胞内第二信使环磷酸腺苷 （cAMP ) 或环磷酸鸟苷 ( cGMP )的功能， 降解细胞内 cAMP或 cGMP,从而终结这些第二信使所传导的生化作用。 cAMP和 cGMP对于细胞活动起着重要的调节作用。而其浓度的调节主要由核苷酸环化酶 的合成和磷酸二酯酶（PDE)水解作用之间的平衡决定。 PDE 在人体内分布广泛， 生理作 用 及多个研究领域。 近年来， PDE作为新的治疗靶点， 引起了众多学者广泛的关注， 成为一个新的研究热点。
磷酸二酯酶抑制剂是一个多基因大家族， 是抑制磷酸二酯酶活性的药物。 磷酸二酯 酶抑制剂是可以抑制组织中 cAMP和 cGMP降解的化合物， PDE抑制剂包括非特异性 PDE抑制 剂和特异性 PDE抑制剂， 特异性 PDE抑制剂仅能够抑制一种类型的 PDE， 对其他类型则几乎 没有作用。 非特异性磷酸二酯酶 (PDE)抑制剂包括茶碱、氨茶碱、 己酮可可碱、 帕吉维林和 咖啡因等。
茶碱是茶中所含的白色不定形的结晶状生物碱，为可可碱的异构体，作用和结构都 类似咖啡碱。 属于磷酸二酯酶， 能使细胞 cAMP含量提高， 具有松弛平滑肌、 兴奋心脏肌 以及利尿的作用。氨茶碱是国内应用最广泛的茶碱与乙二胺的复盐制剂， 临床上已经使 用多年。氨茶碱比茶碱水溶性高，易于溶解和吸收。但氨茶碱碱性较高，局部刺激性大， 口服易致恶心、 呕吐、 食欲下降等胃肠道反应。 帕吉维林是一种骨骼肌松弛药。 咖啡因是 从茶叶、 咖啡果中提炼出来的一种生物碱， 适度地使用有祛除疲劳、 兴奋神经的作用， 临床上用于治疗神经衰弱和昏迷复苏。
己酮可可碱（PTX) 是从可可豆中提取的可可豆碱、 再引入已酮基而得到的一种生物碱， 分子式为 C13H2。N403， 化学名称为 3， 7-二甲基黄嘌呤， 是甲基黄嘌呤衍生物， 是一种非选择 性磷酸二酯酶抑制剂。 PTX可增加红细胞的变形性， 改善白细胞的血流变特征， 抑制嗜中性 粒细胞的黏附和激活； 扩张微血管； 降低血液粘滞度； 增加组织氧分压； 有抗炎作用； 可消 除自由基。 60年代， PTX仅用于末梢循环障碍的治疗； 后作为一种血管扩张药， 被用于治疗 血管性疾病， 已有 10余年的历史； 还用于动脉硬化、 血管栓塞、 糖尿病性血管病变、 冻疮、 静脉溃疡等外周血管疾病的治疗。 70年代， 开始用于男性不育， 体外刺激精子活力的治疗， 疗效显著。此外， 对内耳循环障碍性疾病有效， 可抗肝纤维化， 对肾、肺等有保护作用。《己 酮可可碱促进学习记忆作用的实验研究》 （Pentoxifylline promotes learning and memory function of aging rats and mice with induced memory impairment, 南方医禾斗大学学报 2007年第 27卷第 11期）详细公开了己酮可可碱具有改善学习记忆的作用。 《已酮可可碱对人肝癌细 胞的放射增敏作用及其作用机制的研究》公开了不同浓度的 PTX作用于人肝癌 HepG2和 Hep3b 细胞株 48h后， 其细胞毒性呈剂量依赖性， 最适浓度为 2mmol/L。 PTX在小肠内吸收良好， 其 在血浆中的半衰期为 30 min; 主要在肝脏中去甲基及氧化代谢， 主要以 3-甲基嘌呤及 7_甲 基嘌呤两种形式排出。
便秘， 尤其是慢性便秘， 是一种常见的症状， 其病因复杂， 给患者带来许多苦恼， 严重 影响患者的生活质量。 随着社会发展， 生存压力增加、 竞争激烈， 以及饮食结构等生活习惯 的改变， 便秘的发生率成上升趋势。
国际上有关功能性胃肠病，包括便秘，在诊断、病理生理学以及治疗方面于 1994年推出 了罗马 I标准， 2000年推出了罗马 II标准。 国际上对便秘的概念以罗马 II标准为通用标准。 即便秘是指粪便干结、 排便困难或排便不尽感和排便次数减少。
从病因学上慢性便秘可以分为器质性便秘和功能性便秘。 器质性便秘主要是由于器质性 病因引起的便秘， 慢性便秘的器质性病因主要有胃肠道疾病 （肠道肿瘤、 先天性巨结肠等）、 肛周疾病（直肠脱垂、直肠前突）、 神经系统疾病（多发性硬化、 帕金森病、脑卒中、脊髓损 伤及周围神经病变)、 内分泌或代谢性疾病 （糖尿病肠病、 甲状腺功能低下、 甲状旁腺疾病） 和精神病， 同时还应排除药物性因素（阿片类药物、 抗胆碱药、 抗抑郁药、 钙通道拮抗剂、 抗酸剂、 铁剂、 抗腹泻药、 利尿剂、 抗组胺药等） 引起的便秘。
功能性便秘是排除器质性病因及其他因素导致的便秘， 并符合以下标准： 在过去的 12个 月中， 持续或累积至少 12周有以下两个或两个以上症状： （1 ) 1/4时间排便费力； （2) 1/4时 间粪便是呈团块状或坚硬； （3 ) 大于 1/4时间排便不尽感； （4)大于 1/4时间肛门有阻塞感或 排出困难； （5 )大于 1/4时间排便时需用物协助 （支持盆底肌阻碍）； ( 6 )每周排使小于 3次。 根据排便困难发生部位和动力障碍， 功能性便秘一般分为三种类型： 慢传输型便秘（STC)、 出口梗阻型便秘（00C)和混合型便秘 ( IX) 0 STC是功能性便秘的常见的类型， 约占 40%， 而 00C则 多发生在儿童、 妇女和老年人。 STC与结肠运动障碍有关， 在曼谷胃肠动力疾病新分 类中， 明确肠神经病、 肠肌病、 帕金森病、 内分泌疾病或脊髓损伤等可导致结肠传输延迟， 成为 STC。 慢传输型便秘患者肠道 Cajal间质细胞（ICC)数量减少、 体积缩小， 故可认为 ICC 减少是慢传输型便秘肠道组织细胞学的主要特点。 c-kit为一种原癌基因， 位于 5号染色体 w 位点上， 它编码 kit受体， 后者属酪氨酸激酶膜受体。 在 ICC表达均表达 c-kit， 并且 ICC能过 kit受体接受各种信号， 如果阻断 kit受体， 不但 ICC发育受到影响， 而且其功能也将丧失， 故 ICC有无 c-kit表达与肠道动力密切相关， 因此可以利用 c-kit抗体标记识别 ICC。 00C则与肛门 括约肌功能协调^^直肠对排便反射感阈值异常有关， 患者常主诉排便费力、 肛门下坠感、 排 便不尽感、 排便量少、 质地较硬或成形软便。 混合型便秘是具备上述两个特点。 由于各种类 型便秘发病机制不同， 所以应重视和详细分析患者对便秘的自身感受特点， 初步进行分型， 采取相应治疗措施。
功能性便秘特殊的病变部位和发病机制使临床治疗非常困难， 目前常用的便秘治疗药物 疗效不理想： 或治疗时间过长， 或无效， 或排出少量稀便， 或不良反应大以致患者难以接受。 目前临床上采用非药物治疗和药物治疗， 严重者甚至需要进行外科手术治疗。
釆用非药物治疗， 如排便方式的指导、 饮食等生活习惯的改变和生物反馈治疗等， 大都 需要经过较长的时间才能够缓解， 很多患者因个人因素难以坚持下去。
治疗便秘的主要药物有剌激性泻药、 润滑性泻药、 容积性泻药以及渗透性缓泻剂和促动 力药物等。 刺激性泻药作用强而迅速， 多用于大便嵌塞和需迅速通便患者， 不宜长期应用， 因其刺激肠黏膜和肠壁神经丛， 提高黏膜通透性， 影响了肠内水、 电解质和维生素吸收以至 紊乱， 还可致大肠肌无力， 形成用药依赖性和大便失禁； 容积性泻药可以增加大便的容量， 但不能有效地增加结肠张力， 肠道运动迟缓者使用受限； 润滑性泻药口感差， 作用弱， 长时 间使用可以引起脂溶性维生素吸收障碍、 肛周油质渗漏等不良反应； 渗透性缓泻剂例如乳果. 糖， 不在小肠内吸收， 他们通过结肠细菌分解并释放有机酸而在结肠内产生作用， 存在腹胀 或腹痛以及长期应用疗效差和易引起肠道菌群改变等缺点； 而肠动力药物常常需要联合其他 药物使用， 副作用也较大。
对于占功能性便秘 50%以上的出口梗阻型便秘，肛门内外括约肌的持续痉挛和压力升高 是其主要的病理生理改变之一。 目前主要是采取手术、 生物反馈等治疗方法对其进行治疗， 通过降低肛门括约肌的压力， 从而缓解其肛直肠出口的梗阻症状。 治疗手段虽多， 但疗效却 不能令人满意。 手术治疗时间长、 创伤大， 且可能出现肛门失禁、 复发等并发症。 而生物反 馈治疗常需长期、 反复治疗， 疗效不确定。 近年来， 人们开始考虑使用各种药物降低肛门括 约肌的压力， 从而达到治疗出口梗阻型便秘的效果。 发明内容
本发明提供了己酮可可碱在医药领域的一种新的用途，具体涉及己酮可可碱在制备 预防或治疗便秘的药物中的应用， 还涉及用于预防或治疗便秘的包含己酮可可碱的药物组 合物， 以及用己酮可可碱预防或治疗便秘的方法， 所述便秘尤其为功能性便秘。 己酮可可碱 作为一种非选择性磷酸二酯酶抑制剂， 主要用于血栓闭塞性脉管炎、 脑血管障碍、 血管性头 痛、 末梢血管病、 耳蜗扰乱症、 冻疮及缺氧所产生的痛症。 虽然己酮可可碱在临床上使用会 引起便秘、 口干等不良反应， 但是经过试验研究， 发明人惊奇地发现己酮可可碱在治疗便秘 尤其是功能性便秘表现出预料不到的效果。
现有技术没有报道己酮可可碱在治疗功^性便秘上的研究， 本发明通过试验研究惊奇地 发现己酮可可碱在改善便秘尤其是功能性便秘具有预料不到的效果， 表明己酮可可碱可以作 为治疗便秘的药物使用。
根据本发明的一个方面， 本发明提供了一种预防或治疗便秘 （尤其是功能性便秘） 的药 物组合物， 它含有己酮可可碱。 含有己酮可可碱的药物组合物可以根据常规制剂技术制备成 局部外用制剂或口服制剂， 其中局部外用制剂优选适合肛门直肠给药的局部外用制剂， 比如 喷雾剂、 气雾剂、 栓剂、 凝胶剂、 乳膏剂、 霜剂、 软膏剂、 溶液剂、 乳胶剂和脂质体制剂； 口服剂型优选普通片剂、 肠溶衣片、 缓释片、 胶囊、 滴丸、 颗粒剂、 散剂和口服液。
本发明还对己酮可可碱在局部外用制剂中的重量百分含量进行了优选。 优选地， 己酮可 可碱在局部外用制剂中的重量百分含量为 0. 1%_10%。
上述药物组合物局部外用制剂中的赋形剂选自半合成脂肪酸甘油脂、卡波姆、三乙醇胺、 十二院基硫酸钠、 液体石蜡、 单硝酸甘油脂、 对羟基苯甲酸、 动植物油、 凡士林、 纤维素衍 生物、 聚乙二醇、 硅酮、 硅酸、 硬脂酸铝、 丙二醇、 羊毛脂、 蜂蜡、 滑石粉和氧化锌中的一 种或多种_; 喷雾剂赋形剂选自乳糖、 滑石粉、 丙三醇、 氯化钠和尿素中的一种或多种， 还可 以含有常用的推进剂， 例如氯氟烃和 /或挥发性非取代烃， 挥发性非取代烃优选丁烷和丙烷。 外用搽剂或滴剂可用水性或油性基质来配制， 可以按照常规制备方法进行制备。
上述药物组合物局部外用制剂的赋形剂中还可以包含一种或多种防腐剂， 例如醋酸洗必 泰和苯扎溴铵等； 外用制剂可在无菌条件下将己酮可可碱与赋形剂混合， 优选地， 它还含有 推进剂。
上述药物组合物局部外用制剂优选透黏膜药物剂型， 它可用黏膜粘附性聚合物来配制， 从而延缓有效成分在肛门黏膜内的释放。 透黏膜药物剂型可与黏膜保持接触， 同时迅速崩解 和 /或溶解，从而引起局部性或全身性的吸收。透黏膜药物传递可使活性物质有效进入全身循 环， 并减少肝和小肠壁菌群对药物的立即代谢。
优选地， 上述局部外用制剂为栓剂或气雾剂， 栓剂中含有聚山梨酯 80、 甘油和明胶； 气 雾剂中含有氟里昂 F12、 甘油、 苯扎溴铵和尿素。 当含有己雨可可碱的药物组合物为口服制剂时， 其中， 所述的药物组合物优选含有 lOmg-lOOmg的己酮可可碱。 更优选地， 所述组合物为含有 10mg- lOOmg己酮可可碱的片剂、 颗粒剂或胶囊。 - 当所述的药物组合物为含有 10mg- lOOmg的己酮可可碱片剂时，它可以是普通片、肠溶片 或缓释片。 对于本领域的技术人员来说， 普通片是相对于其他片剂剂型而言的， 它仅仅需要 常规制剂制备即可； 肠溶片是在常规片剂的外包隔离衣和肠溶衣以避免对胃的刺激作用， 肠 溶片进入到肠道后， 包衣溶解后释放药物； 缓释片是为了减少给药次数， 降低药物的释放速 度而使用特殊药物材料制备的。
当上述药物组合物为普通片时， 由己酮可可碱和赋形剂组成，其中的赋形剂包括稀释剂、 粘合剂和崩解剂， 稀释剂选自淀粉、 糊精、 乳糖和微晶纤维素中的一种或多种， 粘合剂选自 羟丙基甲纤维素、 乙基纤维素、 羧甲基纤维素钠和聚乙烯吡咯烷酮中的一种或多种， 崩解剂 选自羧甲基淀粉钠、 低取代羟丙基纤维素、 交联羧甲基纤维素钠和交联聚维酮中的一种或多 种。
优选地，上述普通片的赋形剂中还包括润湿剂和 /或润滑剂，其中润湿剂选自水、乙醇或 它们的混合物， 润滑剂选自硬脂酸镁、 硬脂酸锌和微粉硅胶中一种或多种。
优选地， 上述普通片中己酮可可碱的含量优选为 10mg、 25mg、 50mg或 75mg。 普通片中 己酮可可碱含量的优选， 主要是基于该含量规格的普通片对功能性便秘的治疗疗效更优的原 因。
当上述药物组合物为肠溶片时， 它由己酮可可碱片、 隔离层和肠溶层组成。 所述的己酮 可可碱片为上述任意一种己兩可可碱普通片，己酮可可碱肠溶片可以先以薄膜衣粉溶液包衣， 再以肠溶衣粉溶液包衣制得。优选地，所述的己酮可可碱片中稀释剂选自乳糖和微晶纤维素； 润湿剂和选自乙醇溶液； 粘合剂选自羟丙基甲纤维素、 乙基纤维素、 羧甲基纤维素钠和聚乙 烯吡咯烷酮中的一种或多种； 崩解剂'选自羧甲基淀粉钠、 低取代羟丙基纤维素、 交联羧甲基 纤维素钠和交联聚维酮中的一种或多种； 润滑剂选自硬脂酸镁。
优选地， 己酮可可碱肠溶片中己酮可可碱的含量优选为 25mg或 50mg。 肠溶片中己酮可 可碱含量的优选， 主要是基于该含量规格的肠溶片对功能性便秘的治疗疗效更优的原因。
当上述药物组合物为缓释片时， 它是由己酮可可碱、 赋形剂和一种或多种惰性固体骨架 材料通过压制或融合技术制成的骨架片， 常用的骨架材料包括亲水凝胶骨架材料、 生物溶蚀 性骨架材料和不溶性骨架材料。 所述的亲水凝胶骨架材料选自羟丙甲纤维素、 卡波姆、 海藻 酸钠、 甲基纤维素、 羧甲基纤维素钠中的一种或多种， 亲水凝胶骨架材料遇水或胃肠液后膨 胀，形成凝胶屏障而控制药物的释放。所述的生物溶蚀性骨架材料有甘油三酯、氢化蓖麻油、 硬脂醇、 硬脂酸、 巴西棕榈蜡、 胃溶或肠溶丙烯酸树脂、 肠溶性纤维素等。 所述的不溶性骨 架材料为水不溶性高分子材料， 包括乙基纤维素、 丙烯酸树脂（如渗透性丙烯酸酯， 再如， 甲基丙烯酸-丙烯酸甲酯共聚物）或其混合物等， 胃肠液渗入骨架孔隙后，药物溶解并通过骨 架中存在的极细孔经的通道， 缓缓向外扩散而释放。
优选地， 可以将多种不同溶解或溶蚀性质的骨架材料作为己酮可可碱缓释片中的骨架材 料。
上述己酮可可碱缓释片中的赋形剂可以选自稀释剂、 润湿剂、 粘合剂、 崩解剂和润滑剂 中的一种或多种。 其中稀释剂选自淀粉、 糊精、 乳糖和微晶纤维素中的一种或多种； 润湿剂 选自水、 乙醇或它们的混合物， 粘合剂选自羟丙基甲纤维素、 乙基纤维素、 羧甲基纤维素钠 和聚乙烯吡咯烷酮中的一种或多种； 崩解剂选自羧甲基淀粉钠、 低取代羟丙基纤维素、 交联 羧甲基纤维素钠和交联聚维酮中的一种或多种； 润滑剂选自硬脂酸镁、 硬脂酸锌和微粉硅胶 中一种或多种。
优选地， 缓释片中己酮可可碱的含量优选为 75π¾或 80mg。 缓释片中己酮可可碱含量的 优选， 主要是基于该含量规格的缓释片对功能性便秘的治疗疗效更优的原因。
根据本发明的另一个方面， 本发明提供了己酮可可碱在制备预防或治疗便秘， 尤其是功 能性便秘的药物中的用途。 优选地， 所述药物为本发明的上述药物组合物。
根据本发明的又一个方面， 本发明提供了一种治疗便秘 （尤其是功能性便秘） 的方法， 该方法包括向患者施用治疗有效量的含有己酮可可碱的药物组合物。 优选地， 可以给与患者 口服施用上述有效量的药物组合物， 或者将有效量的上述药物组合物向患者局部外用给药， 如施用于相应直肠肛门区或患病肛门组织， 例如外肛或内肛组织或肛道。 本发明优选向功能 性便秘患者的直肠肛门区直接给与有效量的上述药物组合物， 即优选己酮可可碱的局部外用 制剂， 包括栓剂、 气雾剂和软膏剂等。 局部外用制剂在给药之前， 应当将肛门区清洗干净， 这样将利于药物在直肠黏膜的吸收。
己酮可可碱治疗功能性便秘的对象包括人或动物。 己酮可可碱的具体剂量取决于许多因 素， 这些都是本领域技术人员所熟知的。 例如具体的药物剂型， 所治疗对象、 病情、 年龄、 体重和接受者的临床情况。 给药剂量的范围根据所用的己酮可可碱、 给药途径等存在下列不 同：
( 1 )成年人， 口服制剂包括片剂、 胶囊、 肠溶衣片、 滴剂、 颗粒剂、 散剂、 口服溶液， 按照己酮可可碱的量计， 口服剂量为 10mg- lOOmg/次， 每日 1-3次。 局部外用制剂包括喷雾 剂、 栓剂、 凝胶剂、 乳膏剂、 霜剂、 软膏剂、 溶液剂、 乳胶剂和脂质体制剂， 按照己酮可可 碱的量计， 外用剂量同口服制剂。 用药时间具体根据临床症状及其症状的缓解程度而定。 (2)儿童， 口服制剂包括片剂、胶囊、肠溶衣片、 滴剂、 颗粒剂、 散剂、 口服溶液， 按 照己酮可可碱的量计， 口服剂量为 10mg-100mg/次， 每日 1-3次。局部外用制剂包括喷雾剂、 栓剂、 凝胶剂、 乳膏剂、 霜剂、 软膏剂、 溶液剂、 乳胶剂和脂质体制剂， 按照己酮可可碱的 量计， 外用剂量同口服制剂。 用药时间具体根据临床症状及其症状的缓解程度而定。
(3) 3岁以下的幼儿， 动物包括猪、 狗、 羊、 牛、 虎等， 口服制剂或局部外用制剂的有 效剂量可以按照儿童用药量进行适当的调整， 这对于本领域的技术人员来说是容易做到的。
本发明还提供了将上述含有己酮可可碱的药物组合物治疗功能性便秘的试验研究。 本发 明通过试验例 1小鼠皮下注射吗啡诱导建立了慢传输型便秘小鼠模型，记录小鼠粪便重量，利 用活性炭灌胃法试验比较实验组与对照组小鼠结肠传输功能； 利用免疫组化技术计算 c-kit 阳性细胞面积比较两组小鼠结肠组织中 Cajal细胞（ICC) 数量。 给药后， 模型对照组小鼠粪 便减少， 肠道推进力减弱（首粒黑便排出时间延长） ， 肠道 ICC数量减少（c-kit阳性细胞面 积减小）， 与正常组差异显著。给药非选择性磯酸二酯酶抑制剂己酮可可碱、 茶碱、 氨茶碱、 咖啡因、 帕吉维林后， 结果发现己酮可可碱治疗组 （包括片剂组和栓剂组） 小鼠日均排便量 增加， 小鼠肠道推进力增强， 肠道 ICC数量增加。 研究表明， 己酮可可碱在改善慢传输型便 秘的症状方面具有预料不到的效果， 其它非选择性磷酸二酯酶抑制如茶碱、氨茶碱、咖啡因、 帕吉维林在治疗功能性便秘效果远远不如己酮可可碱。 另外， 本发明还惊奇地发现， 与己酮 可可碱片剂组相比， 己酮可可碱栓剂组小鼠日均排便量、首粒黑便排出时间以及 c-kit阳性细 胞面积均具有显著性差异 （p<0. 05) ， 这表明己酮可可碱直肠黏膜直接给药治疗慢传输型小 鼠便秘的效果还优于己酮可可碱口服给药。
对于占功能性便秘 50%以上的出口梗阻型便秘，肛门内外括约肌的持续痉挛和压力升高 是其主要的病理生理改变之一。 本发明通过试验例 2研究表明， 己酮可可碱治疗组的肛直肠 静息压、 最大自主收缩压和直肠肛门抑制反射值明显下降， 说明其有效地降低了肛门括约肌 的肌张力， 达到了松弛肛门括约肌的效果。 病理组织学切片观察发现， 己酮可可碱治疗组的 肛门括约肌纤维有一定程度的萎缩。 己酮可可碱能有效降低肛门括约肌的压力， 为临床治疗 慢性出口梗阻型便秘提供了新的方法和思路， 值得进一步研究。
本发明还通过试验例 3己酮可可碱对洛哌丁胺诱导的便秘大鼠直肠黏膜黏液的影响， 表 明洛哌丁胺诱导的便秘大鼠肠黏膜上皮黏液较正常大鼠明显减少， 给药己酮可可碱后大鼠肠 黏膜上皮黏液明显增多， 且具有显著性差异； 并且与己酮可可碱灌胃组相比， 己酮可可碱外 用组大鼠肠黏膜上皮黏液明显增多，且具有显著性差异（p<0. 05)，这表明直肠给药对于增强 肠黏膜功能效果更加明显。
正常结肠黏膜杯状细胞的分泌液富含黏蛋白，黏蛋白与水结合形成黏液，构成黏液保障， 对黏膜起到机械性保护作用。 黏液分泌的减少是结肠功能衰弱的表现， 或固水能力减少， 或 细胞黏蛋白分泌减少。本发明通过给药己酮可可碱，惊奇地发现己酮可可碱在改善结肠功能， 增加肠黏膜黏液正常分泌方面具有意想不到的效果。 可见， 己酮可可碱治疗功能性便秘， 不 仅仅在改善功能性便秘症状上， 并且能显著改善肠黏膜的功能， 从而有可能实现功能性便秘 的显著改善。
作为治疗功能性便秘的药物使用， 己酮可可碱外用制剂一般会优于己酮可可碱的口服制 剂， 但是由于口服制剂具有服药方便的优势， 因此开发己酮可可碱的口服制剂用于治疗功能 性便秘是可行的。
本发明还通过试验例 4将上述含有己酮可可碱的药物组合物片剂治疗功能性便秘的临床 试验。 临床治疗结果显示， 普通片 lOmg组、 普通片 50mg组、 普通片 80mg组、 缓释片 75mg 组、 缓释片 lOOmg组、 肠溶片 lOmg组、 肠溶片 50mg组功能性便秘临床志愿者的症状明显改 善， 治疗有效率为 58. 33%- 87. 50%， 平均总有效率为 77. 38%， 不良反应发生率较小， 为 0%-8. 33%， 平均不良反应发生率为 2. 08%； 然而缓释片 400mg组、 肠溶衣片 120mg组有效率 为 41. 67%-50. 00%， 平均有效率为 45. 83%， 不良反应发生率较大， 为 12. 50%_33. 3%， 平均不 良反应发生率为 22. 92%， 而且还出现了功能性便秘症状加重的现象。
由此可见，含有 lOmg-lOOmg己酮可可碱低剂量的片剂组较高剂量己酮可可碱片剂组在治 疗功能性便秘方面有效率较高， 不良反应发生率显著降低， 并具有统计学差异。 本发明提供 的 lOmg- lOOmg己酮可可碱低剂量片剂能够作为治疗功能性便秘的药物使用。
含有 10mg 100mg己酮可可碱的组合物颗粒剂或胶囊替换含量优选为 lOmg-lOOmg的己爾 可可碱片剂在治疗功能性便秘方面能够取得相同或相近的效果， 这对于本领域的技术人员来 说是可以预见的。这进一步说明本发明的含有 lOmg- lOOmg己酮可可碱的药物组合物能够作为 治疗功能性便秘的药物使用。
具体实施方式
以下通过实施例或试验例进一步描述本发明，但本发明不仅仅限于以下实施例或试验例。 (一） 己爾可可碱的药物制剂部分
实施例 1 己酮可可碱栓剂
己酮可可碱 45g
聚山梨酯 80 5g
甘油 3000g
明胶 900g 纯化水 加至 4500g
制备工艺- 称取处方量的明胶， 置器皿中加入适量的纯化水， 放置 lh左右， 使其溶胀变软， 然后加 入处方量甘油后置水浴上加热， 使明胶溶解， 继续加热并搅拌； 取已酮可可碱、聚山梨酯 80. 混匀后加入已制好的甘油明胶溶液中，搅拌均匀后，趁热灌入已涂好润滑剂的栓模中，冷却， 削去模口上溢出的部分， 脱模， 质检、 包装， 共¾ 100粒。
实施例 2 己酮可可碱栓剂
己酮可可碱 50
半合成脂肪酸甘油脂 4500g
甘油 400g
聚山梨酯 80 50g
制备工艺- 取半合成脂肪酸甘油脂置器皿中， 水浴加热融化， 待温度降至 5CTC左右， 加入甘油、 聚 山梨酯 80， 搅拌均匀， 加入己酮可可碱， 搅拌均匀， 搅匀后注入涂有润滑剂的栓模中至稍溢 出模口为度， 冷却， 凝固后削去溢出部分， 脱模， 质检， 包装， 共制 100粒。
实施例 3 己酮可可碱栓剂
己酮可可碱 50g
聚乙二醇 4000 2450g
聚乙二醇 1000 2450g
甘油 50g
制备工艺：
取聚乙二醇 4000和聚乙二醇 1000置器皿中， 水浴加热融化， 待温度降至 50°C左右， 加 入甘油， 搅拌均匀， 加入己酮可可碱， 搅拌均匀， 搅匀后注入涂有润滑剂的栓模中至稍溢出 模口为度， 冷却， 凝固后削去溢出部分， 脱模， 质检， 包装， 共制 100粒。
实施例 4 己酮可可碱栓剂
己酮可可碱 500g
聚乙二醇 4000 2250g
聚乙二醇 1000 2200g
甘油 50g
制备工艺- 取聚乙二醇 4000和聚乙二醇 1000置器皿中， 水浴加热融化， 待温度降至 50°C左右， 加 入甘油， 搅拌均匀， 加入己酮可可碱， 搅拌均匀， 搅匀后注入涂有润滑剂的栓模中至稍溢出 模口为度， 冷却， 凝固后削去溢出部分， 脱模， 质检， 包装， 共制 1000粒。
实施例 5 己酮可可碱凝胶剂
己酮可可碱 10g
卡波姆 10g
丙二醇 60ml
甘油 50ml
三乙醇胺
纯化水' 加至 lOOOg
制备工艺：
将卡波姆缓慢加入到处方 j 50%左右的水中， 边加边搅拌直至形成透明的凝胶基质， 将 己酮可可碱溶于适量水中， 再加入基质中， 搅拌均匀， 加入丙二醇、 甘油、 纯化水至全』 三乙醇胺调节 PH值至中性， 即得。
实施例 6 己酮可可碱乳膏剂
己酮可可碱 20g
单硬脂酸甘油酯 48g
硬脂酸 120g
白凡士林 100g
三乙醇胺 15g
尼泊金乙脂 3g
十二垸基硫酸钠 12g
甘油 18g
纯化水 加至 lOOOg
制备工艺- 按处方量取单硬脂酸甘油酯、 硬脂酸- 白凡士林、 三乙醇胺水浴加热至熔化， 混勾， 作 为油相。 另外取适量的纯化水， 将己酮可可碱溶解到水中。
取甘油、 十二垸基硫酸钠、 纯化水、 尼泊金乙脂混合加热至 80°C左右， 作为水相。 待油 相温度为 80°C左右时，搅拌下将己酮可可碱溶液加入其中，并使温度保持在 8(TC左右。将搅 拌均勾后的油相， 在慢速搅拌下， 缓缓加入水相中， 后加速搅拌 30min， 停止搅拌， 即得乳 实施例 7 己酮可可碱软膏剂 己酮可可碱 10g
单硬脂酸甘油酯 100g
石蜡 100g
白凡士林 46g
液体石蜡 '53g
丙二醇 50g
司盘 80 5g
对羟基苯甲酸乙酯 lg
纯化水 加至 lOOOg
制备工艺- 取石蜡、单硬脂酸甘油酯、 白凡士林、液状石蜡、丙二醇、司盘 80和对羟基苯甲酸乙酯 于水浴上加热熔化并保持 80'C，搅拌下缓慢加入 80'C的水，边加边搅拌至冷凝，即软膏基质。 取己酮可可碱溶于适量的纯化水中， 加入到基质中， 最后加水至 1000g， 搅拌均匀， 即得。 实施例 8 己酮可可碱喷雾剂
己酮可可碱 10g
蒸馏水 适量
甘油 30g
尿素 2g
苯扎溴铵 0. lg
氯化钠 0. 9g
蒸馏水 加至 100ml
制备工艺- 在常温常压下， 称量己酮可可碱 10g， 溶于适量的蒸馏水中， 再按照处方中各组分的配 比分别加入其中，即甘油 30g，尿素 2g，苯扎溴铵 0. lg,氯化钠 0. 9g，最后加蒸馏水至 100ml， 充分混匀， 罐装， 封口， 检验得成品。
实施例 -9 己酮可可碱气雾剂
己酮可可碱 10g
蒸馏水 适量
甘油 5g
尿素 2g 苯扎溴铵 0. lg
氟里昂 F12 适量
蒸馏水 加至 100ml
制备工艺：
在常温常压下， 称量己酮可可碱 10g， 溶于适量的蒸馏水中， 再按照处方中各组分的配 比分别加入其中， 即甘油 10g， 尿素 2g， ： ^扎溴铵 0. lg, 适量抛射剂 F12， 最后加蒸馏水至 100ml, 充分混匀， 罐装， 封口， 检验得成
己酮可可碱普通片
己酮可可碱 10g
微晶纤维素 200g
羧甲基淀粉钠 8g
1. 5g
8%淀粉浆
制备工艺- 将己酮可可碱和辅料微晶纤维素、 羧甲基淀粉钠混合均勾， 加入适量的淀粉浆制软材， 然过 16目筛制粒。 湿颗粒在 60Ό干燥， 干颗粒过 16目筛整粒， 筛出干粒中的细粉， 与硬脂 酸镁混匀， 然后再与干颗粒混匀， 压片， 共制 1000片。 片剂含量规格为 10mg/片。
实施例 11 己酮可可碱普通片
己酮可可碱 25g
乳糖 55g
微晶纤维素 15g
羧甲基纤维素钠 10g
1. 5g
50%乙醇
制备工艺- 将过 80目筛后的己酮可可碱和乳糖、 微晶纤维素混合均匀， 用 50%乙醇制软材， 过 20 目筛制粒， 6(TC条件下鼓风干燥， 20目筛整粒， 然后加入处方量的羧甲基纤维素钠和硬脂酸 镁混合均匀压片， 共制 1000片。 片剂含量规格为 25mg/片。
实施例 12 己酮可可碱普通片
己酮可可碱 80g 微晶纤维素 200g
羧甲基淀粉钠 8g
硬脂酸锌 1. 5g
8%淀粉浆 适量
制备工艺：
. 将己酮可可碱和辅料微晶纤维素、 羧甲基淀粉钠混合均匀， 加入适量的淀粉浆制软材， 然过 16目筛制粒。 湿颗粒在 6(TC干燥， 干颗粒过 16目筛整粒， 筛出干粒中的细粉， 与硬脂 酸锌混匀， 然后再与干颗粒混匀， 压片， 共制 1000片。 片剂含 j 规格为 80tng/片。
实施例 13 己酮可可碱普通片
己酮可可碱 50g
甘露醇 100g
. 乳糖 80g
羧甲基淀粉钠 8g
硬脂酸镁 1. 5g
8%淀粉浆 适量
制备工艺- 将己酮可可碱和辅料甘露醇、乳糖、羧甲基淀粉钠混合均匀，加入适量的淀粉浆制软材， 然过 16目筛制粒。湿颗粒在 60°C干燥， 干颗粒过 16目筛整粒， 筛出干粒中的细 ， 与硬脂 酸镁混匀， 然后再与干颗粒混匀， 压片， 共制 1000片。 片剂含量规格为 50mg/片。
实施例 14 己酮可可碱肠溶片
己酮可可碱 10g
微晶纤维素 200g
羧甲基淀粉钠 8g - 1. 5g
8%淀粉浆 适量
制备工艺：
将己酮可可碱和辅料微晶纤维素、 羧甲基淀粉钠混合均匀， 加入适量的淀粉装制软材， 然过 16目筛制粒。 湿颗粒在 60'C干燥， 干颗粒过 16目筛整粒， 筛出干粒中的细粉， 与硬脂 酸镁混匀， 然后再与干颗粒混匀， 压片， 然后进行薄膜包衣和肠溶液包衣， 隔离层增重 3%， 肠溶衣增重 8%,共制 1000片。 肠溶片剂含量规格为 lOmg/片。
实施例 15 己酮可可碱肠溶片 己酮可可碱 25g
孚 L糖 55g
微晶纤维素 15g
羧甲基纤维素钠 10g
1. 5g
50%乙醇
制备工艺- 将过 80目筛后的己酮可可碱和乳糖、 微晶纤维素混合均匀， 用 50%乙醇制软材， 过 20 目筛制粒， 60°C条件下鼓风干燥， 20目筛整粒， 然后加 λ处方量的羧甲基纤维素钠和硬脂酸 镁混合均匀压片，然后进行薄膜包衣和肠溶液包衣，隔离层增重 3%，肠溶衣增重 8%，共制 1000 片。 肠溶片剂含量规格为 25mg/片。
实施例 16 己酮可可碱肠溶片
己酮可可碱 50g
微晶纤维素 200g
羧甲基淀粉钠 8g
、 硬脂酸锌 1. 5g
8%淀粉浆
制备工艺- 将己酮可可碱和辅料微晶纤维素、 羧甲基淀粉钠混合均匀， 加入适量的淀粉桨制软材， 然过 16目筛制粒。 湿颗粒在 60Ό干燥， 干颗粒过 16目筛整粒， 筛出干粒中的细粉， 与硬脂 酸锌混匀， 然后再与干颗粒混匀， 压片， 然后进行薄膜包衣和肠溶液包衣， 隔离层增重 3%, 肠溶衣增重 8%,共制 1000片。 肠溶片剂含量规格为 50mg/片。 ―
实施例 17 己酮可可碱肠溶片
己酮可可碱 25g
甘露醇 100g
乳糖 80g
羧甲基淀粉钠 8g
硬脂酸镁 1. 5g
8%淀粉浆
制备工艺- 将己酮可可碱和辅料甘露醇、乳糖、羧甲基淀粉钠混合均匀，加入适量的淀粉浆制软材， 然过 16目筛制粒。 湿颗粒在 60'C干燥， 干颗粒过 16目筛整粒， 筛出干粒中的细粉， 与硬脂 酸镁混匀， 然后再与干颗粒混匀， 压片， 然后进行薄膜包衣和肠溶液包衣， 隔离层增重 3%， 肠溶衣增重 8%，共制 1000片。 肠溶片剂含量规格为 50mg/片。
实施例 18 己酮可可碱缓释片
己酮可可碱 100g
HPMC ( 15M) 60g 硬脂酸 110g 微晶纤维素 30g
8%PVPK3O70%乙醇水溶液（以 PVPK30量计） 16g 硬脂酸镁 3g
制备工艺：
原辅料混合均勾，过 80目筛， 8% PVPK3Q70%乙醇水溶液制软材， 30目筛制湿颗粒， 50°C 烘干， 加入硬脂酸镁， 混合压片， 共制得 1000片， 缓释片含量规格为 lOOmg/片。
实施例 19 己酮可可碱缓释片
己酮可可碱 80g
HPMC (K4M) 60g
硬脂醇 120g 乳糖 40g
8%PVPK3O70%乙醇水溶液（以 PVPK3O量计） 16mg 硬脂酸镁 3g
制备工艺：
原辅料混合均匀，过 80目筛， 8% PVPK3Q70%乙醇水溶液制软材， 30目筛制湿颗粒， 50°C 烘干， 加入硬脂酸镁， 混合压片， 共制得 1000片， 缓释片含量规格为 80mg/片。
实施例 20 己酮可可碱缓释片
己酮可可碱 75g 羧甲基纤维素钠 60g 硬脂酸 100g 微晶纤维素 30g
8%PVPK3O70%乙醇水溶液（以 PVPK30量计） 16g 硬脂酸镁 2g 制备工艺： 原辅料混合均勾，过 80目筛， 8% PVPK3O70%乙醇水溶液制软材， 30目筛制湿颗粒， 50°C 烘干， 加入硬脂酸镁， 混合压片， 共制得 1000片， 缓释片含量规格为 75mg/片。
实施例 21 己酮可可碱颗粒剂
己酮可可碱 10g 羧甲基纤维素钠 60g
8%PVPK3Q70%乙醇水溶液 （以 PVPK3O量计） 16g 糖粉 914g 制备工艺- 按照常规制备工艺制备。
实施例 22 己酮可可碱颗粒剂
己酮可可碱 100g 羧甲基纤维素钠 160g
8%PVPK3O70%乙醇水溶液 （以 PVPK3C量计） 16g 糖粉 724g 制备工艺：
按照常规制备工艺制备。
实施例 23 己酮可可减胶囊
己酮可可碱 10g 羧甲基纤维素钠 60g
8%PVPf3o70%乙醇水溶液 （以 PVPK30量计） 16g 糖粉 914g 制备工艺：
按照常规制备工艺制备后装入空胶囊中。
实施例 24 己酮可可碱胶囊
己酮可可碱 100g 羧甲基纤维素钠 160g
8%PVPK3O70%乙醇水溶液（以 PVPJOO量计） 16g 糖粉 724g 制备工艺：
按照常规制备工艺制备后装入空胶囊中。
对照例 1茶碱片剂 茶碱 10g
微晶纤维素 200g
羧甲基淀粉钠 8g
硬脂酸镁 1. 5g
8%淀粉浆 适量
制备工艺- 将茶碱和辅料微晶纤维素、羧甲基淀粉钠混合均匀， 加入适量的淀粉浆制软材， 然过 16 目筛制粒。 湿颗粒在 6(TC干燥， 干颗粒过 16目筛整粒， 筛出干粒中的细粉， 与硬脂酸镁混 匀， 然后再与干颗粒混匀， 压片， 即得。
对照例 2氨茶碱片剂
10g
200g
羧甲基淀粉钠 8g
1. 5g
8%淀粉浆
制备工艺： 同对照例 1。
对照例 3咖啡因片剂
咖啡因 10g
微晶纤维素 200g
羧甲基淀粉钠 8g
1. 5g
8%淀粉浆
制备工艺： 同对照例 1。
对照例 4帕吉维林片剂
帕吉维林 10g
微晶纤维素 200g
羧甲基淀粉钠 8g
1. 5g
8%淀粉浆
制备工艺： 同对照例 1。 (二） 己酮可可碱的药效学研究
试验例 1 己酮可可碱对慢传输型便秘小鼠模型的影响
1.试验目的
实验组小鼠皮下注射吗啡诱导建立慢传输型便秘小鼠模型， 记录小鼠粪便重量， 利用活 性炭灌胃法试验比较实验组与对照组小鼠结肠传输功能； 利用免疫组化技术比较两组小鼠结 肠组织中 Cajal细胞数量。
2.材料
无特殊病原体 SPF级 ICR鼠 80只， 山东新时代药业动物中心， 雌雄各半， 体重 20〜25 克； 小鼠代谢笼 (苏州冯氏实验动物公司）；注射用盐酸吗啡 (沈阳第一制药厂，规格 10 mg/支）； 生 理盐水； 一抗（ sc-168, Santa Cruz Biotechnology, Inc， 200 mg/ L)； 二抗（羊抗兔抗体， 中山生物科技公司）； 己酮可可碱片剂， 制备工艺同实施例 10; 己酮可可碱栓剂， 制备工艺同 实施例 3; 茶碱片剂， 制备工艺同对照例 1 ; 氨茶碱片剂， 制备工艺同对照例 2; 咖啡因片剂， 制备工艺同对照例 3; 帕吉维林片剂， 制备工艺同对照例 4。
3试验方法和步骤
3. 1 慢传输型便秘小鼠模型的建立
ICR鼠 80只， 随机分为 6个实验组， 1个正常对照组和 1个模型对照组， 每组 10只。 6个实验 组分别为： 己酮可可碱片剂组； 己酮可可碱栓剂组； 茶碱片剂组； 氨茶碱片剂组； 咖啡因片 剂组； 帕吉维林片剂组。 所有小鼠置入 80个小鼠代谢笼中， SPF级环境词养。 适应性喂养 3天 后， 实验组和模型对照组小鼠皮下注射盐酸吗啡 2. 5mg/ (kg * d)， 正常对照组注射等量生理盐 水。 每 3天记录一次小鼠大便粒数、 大便干重及小鼠体重， 计算小鼠日均排便重量（g) 。 以 小鼠日均排便量减少， 且日均排便量与正常对照组相比具有显著性差异作为慢传输型便秘小 鼠模型的建立成功的标志， 造模成功后停止注射给药。
3. 2 小鼠日均排便重量的测定
给与造模成功后 （饲养第 46天起） 的小鼠按照如下给药方案给药， 己酮可可碱片剂组小 鼠灌胃给药己酮可可碱， 给药剂量按照己酮可可碱计 lmg/ (kg * d) ; 己酮可可碱栓剂组直肠给 药己酮可可碱栓剂， 给药剂量按照己酮可可碱计 lmg/ (kg * d) ; 茶碱片剂组、 氨茶碱片剂组、 咖啡因片剂组和帕吉维林片剂组给药剂量均为 lmg/ (kg · ο!) , 灌胃给药。正常对照组和模型对 照组给与蒸馏水。每隔 1天记录一次小鼠大便粒数、大便干重及小鼠体重， 计算小鼠日均排便 重量（g) 。 小鼠日均排便量与正常组相比减少， 表明慢传输型便秘程度增大。
3. 3肠道传输功能测定 用活性炭灌胃法测定首粒黑便排出时间。 停药 1周的所有小鼠禁食 24小时， 经口灌入 lOOmg/tnl活性炭悬液 2ml。从活性炭灌胃完毕开始时计时，记录从灌胃到首粒黑便排出的时间。 首粒黑便排出时间越长表明慢传输型便秘程度越大。
3. 4免疫组化标记小鼠结肠组织 ICC及小鼠结肠组织 ICC数量的比较
实验结束后颈椎脱臼法处死， 剖腹取出幽门到直肠末端全部肠道， 分别取每只小鼠远端 结肠组织 2〜3处， 4%甲醛溶液固定， 石蜡包埋连续切片 (厚度 :4〜5 μ π ； 脱蜡和水化后， 切 片放入 ρΗ8. 0的 EDTA缓冲液， 煮沸 15 min， 保温 10min， 室温冷却； PBS液 (pH7. 6)冲洗 3次， 每 次 5min; 每张切片滴加 50 μ 13%双氧水以阻断内源性过氧化物酶的活性， 室温下孵育 lOmin; PBS液（pH7. 6) 冲洗 3次，每次 5min;去除血清，分别加入一抗（1 : 500) 50 μ 1， 37°C孵育 60min， PBS液冲洗 3次， 每次 5min; 去除 PBS液， 分别加入生物素标记的二抗（1： 50) 50 μ 1， 室温孵育 lOmin; PBS液冲洗 3次， 每次 3min; 去除 PBS液， 加 50 μ 1链霉菌抗生物素一过氧化物酶溶液， 室温孵育 lOmin; PBS液冲洗 3次， 每次 3min; 去除 PBS液， 加 2滴新鲜配制的 DAB， 显微镜下观 察 3〜 lOmin; 自来水冲洗； 苏木精复染， 0. 1%HC1乙醇分化， 流水冲洗返蓝； 梯度乙醇脱水干 燥 (二甲苯透明），中性树胶封固，细胞质呈棕色为阳性反应。每张切片选择五个高倍镜视野（ X 200)， 应用 Lecia RX250型图像分析系统及 Qwin软件标记并计算 c-kit阳性细胞面积。 c- kit 阳性细胞面积与正常组小鼠相比越小， 表明慢传输型便秘程度越大。
3. 5试验数据的统计学处理
实验数据录入 SPSS10. 0统计软件包，统计方法选用 t检验， p<0. 05为差异有显著性意义。 结果
实验结果表明-
( 1 )与正常组相比， 模型组小鼠日均排便量、 首粒黑便排出时间以及 c-kit 阳性细胞面 积均具有极其显著性差异 （p<0. 01 ) ， 表明慢传输型便秘小鼠模型建造成功；
(2)与模型组小鼠相比， 己酮可可碱片剂组、 己酮可可碱栓剂组小鼠日均排便量、首粒 黑便排出时间以及 C- kit 阳性细胞面积均具有显著性差异 （p<0. 05) ， 然而茶碱片剂组、 氨 茶碱片剂组、咖啡因片剂组、帕吉维林片剂组小鼠日均排便量、首粒黑便排出时间以及 c-kit 阳性细胞面积均无统计学意义 (p>0. 05) ， 这表明己酮可可碱能够明显改善小鼠排便量， 增 强小鼠肠道推进力并增加肠道 ICC数量， 缓解慢传输型小鼠便秘的症状， 然而茶碱、氨茶碱、 咖啡因、 帕吉维林无此功能。
(3)与茶碱片剂组、氨茶碱片剂组、 咖啡因片剂组、 帕吉维林片剂组相比， 己酮可可碱 片剂组、 己酮可可碱栓剂组小鼠日均排便量、首粒黑便排出时间以及 c-kit阳性细胞面积均具 有显著或极显著性差异性差异。 这表明己酮可可碱在治疗慢传输型便秘方面效果显著优于其 它非选择性磷酸二酯酶抑制如茶碱、 氨茶碱、 咖啡因、 帕吉维林。
(4)与己酮可可碱片剂组相比， 己酮可可碱栓剂组小鼠日均排便量、首粒黑便排出时间 以及 c- kit阳性细胞面积均更好， 虽无显著性差异（p>0.05)， 但表明己酮可可碱直肠给药治 疗慢传输型小鼠便秘的效果优于己酮可可碱口服给药。
表 1 己酮可可碱对慢传输型便秘小鼠的影响
项 目 粪便重量（g/d) 黑便排出时间 （min) c-kit 阳性的 ICC细胞面积
(104um2)
正常对照组 11.02±3.24 157±58 112.6±9.8
模型对照组 3.84±1.96 380 ±80·· 56·4±8.2"
茶碱片组 3.25±1.05 360±25 58.2±4·6
氨茶碱片组 2.98±1.28 332 ±56 60.4±5.8
咖啡因片组 4.25±1.70 300 ±36 68.8±9.8
帕吉维林片组 4.50±1.88 320±72 74.2±7.2
己酮可可碱片组 7.62 ±2.48一 195±7(Γ*½Δ 92.2±10.5****5Wi"
己酮可可碱栓剂组 9.80 ±2.62 170±64***'4Δ 98.0±11.2
'与模型对照组相比， P<0.05; **与模型对照组相比， p〈0.01;
M与正常对照组比较， p<0.01; *与己酮可可碱片剂组相比， p<0.05;
#与茶碱片组相比， p<0.05; ##与茶碱片组相比， p<0.01;
$$与氨茶碱片组相比， p<0.05; $$与茶碱片组相比， p<0.01;
&与咖啡因片组相比， p<0.05; &&与咖啡因片组相比， p<0.01;
Δ与帕吉维林片组相比， ρ〈0.05; Δ Δ与帕吉维林片组相比， p〈0.01;
5讨论
慢传输型便秘患者肠道 Cajal间质细胞（ICC)数量减少、体积缩小， 故可认为 ICC减少是 慢传输型便秘肠道组织细胞学的主要特点。 c-kit为一种原癌基因， 位于 5号染色体 w位点上， 它编码 kit受体， 后者属酪氨酸激酶膜受体。 ICC有无 c- kit表达与肠道动力密切相关， 因此可 以利用 c- kit抗体标记识别 ICC。本研究利用 c-kit抗体标记 ICC后对比两组小鼠阳性细胞数量， 给药后，模型对照组小鼠粪便减少，肠道推进力减弱，肠道 ICC数量减少，与正常组差异显著， 故本研究所造模型与慢传输型便秘生理、 病理组织细胞学特点一致。 己酮可可碱给药组包括 片剂和栓剂组， 在改善慢传输型便秘的上述症状即增加小鼠日均排便量， 增强小鼠肠道推进 力并增加肠道 ICC数量方面具有预料不到的药效。 试验例 2 己酮可可碱对大鼠肛门括约肌的影响
1材料与方法
1. 1材料：
6个雄性 Wister大鼠 70只， 体重 240± 10g， 来源： 山东新时代药业动物中心， 随即放进不 锈钢钢筋笼内饲养， 温度 24±0. 5Ό， 相对湿度为 55± 10%， 每天 07 : 00-19 : 00光照 12小时， 大 鼠自由进食和饮水， 统一标准餐进食。 茶碱片剂， 制备工艺同对照例 1 ; 氨茶碱片剂， 制备工 艺同对照例 2;咖啡因片剂，制备工艺同对照例 3;帕吉维林片剂，制备工艺同对照例； 0. 9%NaCl 溶液； 己酮可可碱片剂， 制备工艺同实施例 10; 己酮可可碱气雾剂， 制备工艺同实施例 9。
1. 2方法：
所有大鼠随机分为 7组， 每组 10只。 具体分组与给药如下：
己酮可可碱灌胃组， 给药己酮可可碱 0. 15mg/kg · d;
己酮可可碱外用组， 给药己酮可可碱 0. 15mg/kg · d;
生理盐水组， 灌胃给药生理盐水 0. 15mg/kg * d;
茶碱组， 灌胃给药茶碱 0. 15mg/kg * d;
氨茶碱组， 灌胃给药氨茶碱 0. 15mg/kg · d;
咖啡因组， 灌胃给药咖啡因 0. 15mg/kg， d;
帕吉维林组， 灌胃给药帕吉维林 0. 15mg/kg · d。
在给药前 lh、 给药后 72h， 分别检测 7组动物的肛周括约肌肌电图， 同时进行肛直肠测 压。 用 DANTEC公司生产的 Counterpoint MK II型神经肌电图仪进行肛门括约肌表面肌电图检 测。 滤波频带 500- 1000Hz, 灵敏度 0. 2- lmV/cm， 扫描速度 0. 5- lms， 采用表面电极置于肛门 周围皮肤， 记录 4组实验动物的肛门括约肌肌电图情况， 利用自带软件计算出电位平均振幅 及平均时限。
采用 RT-2070型多通道直肠肛管测压仪， 加以自制的微型气囊（最大 0. 5ml )测压导管， 行试验动物的肛直肠测压。 微型多极探头深入肛直肠内 0. 5cm， 测量肛直肠静息压、 肛直肠 最大自主收缩压和直肠肛门抑制反射值。 由于大鼠肛管短、 细， 与直肠无明显交界， 故仅用 单气囊行肛直肠测压。 同时， 通过多导生理记录仪记录测量值。
检测完毕后处死试验动物，切取 4组实验动物的肛门括约肌组织，行病理切片，苏木素- 伊红（HE)染色， 在 400倍光学显微镜下观察试验动物的肛门括约肌肌维组织形态学特点。
1. 3统计学处理：
所有统 学数据均采用平均值土方差。 采用 SPSS10. 0统计分析软件进行方差分析， 以 P〈0. 05为差异有统计学意义。 2结果
2.1 肛门括约肌肌电图的变化情况
实验结果显示 7组实验动物在治疗前后的肛周括约肌肌电图均为有规律的持续性电活动 7 组动物治疗前肌电图表现差异无统计学意义 (P〈0.05)， 电位振幅 (96.8 ±35.7) μν， 时限 (3.8±0.9)ms。
与生理盐水组相比， 治疗后 72h， 所有治疗组的肌电图运动电位振幅都有所降低， 平均 时限有所提高， 但茶碱、 氨茶碱、 咖啡因、 帕吉维林组与生理盐水组相比无显著性差异， 己 酮可可碱灌胃组和外用组与生理盐水组相比具有显著性差异；
与茶碱、 氨茶碱、 咖啡因、 帕吉维林组相比， 己酮可可碱灌胃组和外用组在降低电位振 幅方面具有显著性差异； 与茶碱组和帕吉维林组相比， 己酮可可碱灌胃组和外用组延长时限 方面具有显著性差异。 具体见表 2。
表 2 己酮可可碱肛门括约肌肌电图电位振幅及平均时限
电位振幅 （μν) 平均时限 （ms)
生理盐水组 98 ±32 3.8±0.9
茶碱组 85 ±28 3.7±0.8
氨茶碱组 82 ±26 4.0±1.1
咖啡因组 80±30 4.2±0.6
帕吉维林组 86 ±32 3.9±0.4
己酮可可碱灌胃 62土 26 : 4.8土0.6**Δ
己酮可可碱外用组 5.0±1.( Δ
注： '与生理盐水组相比， ρ〈0.05;
#与茶碱片组相比， ρ〈0.05;
1与氨茶碱片组相比， Ρ〈0.05;
&与咖啡因片组相比， ρ<0.05;
4与帕吉维林片组相比， ρ〈0.05。
2.2'肛直肠测压情况- 与生理盐水组相比， 治疗后 72h， 所有治疗组的肛直肠静息压、肛直肠最大自主收缩压、 直肠肛门抑制反射值的气囊容量均低于生理盐水组。 但茶碱、 氨茶碱、 咖啡因、-帕吉维林组 与生理盐水组相比无显著性差异， 己酮可可碱灌胃组和外用组与生理盐水组相比具有显著性 差异； . 与茶碱、 氨茶碱、 咖啡因、 帕吉维林组相比， 己酮可可碱灌胃组和外用组在降低肛直肠 静息压、 肛直肠最大自主收缩压、 直肠肛门抑制反射值的气囊容量具有显著性差异；
与己酮可可碱灌胃组相比， 己酮可可碱外用组在降低肛直肠静息压、 肛直肠最大自主收 縮压、 直肠肛门抑制反射值的气囊容量效果比己酮可可碱灌胃组更好， 但灌胃组和外用组无 统计学差异。 具体见表 4 - 对于占功能性便秘 50%以上的出口梗阻型便秘，肛门内外括约肌的持续痉挛和压力升高 是其主要的病理生理改变之一。 己酮可可碱治疗组的肛直肠静息压、 最大自主收缩压和直肠 肛门抑制反射值明显下降， 说明其有效地降低了肛门括约肌的肌张力， 达到了松弛肛门括约 肮的效果。 病理组织学切片观察发现， 己酮可可碱治疗组的肛门括约肌纤维有一定程度的萎 缩。 研究表明， 己酮可可碱能有效降低肛门括约肌的压力， 为临床治疗慢性出口梗阻型便秘 提供了新的方法和 路， 值得进一步研究。
表 3 己酮可可碱对肛直肠压力的影响
组别 静息压 /mmHg 最大 自 主收缩压 抑制反射值 /ml
/mmHg
生理盐水组 7.4±1· 7 22.9±4.7 0.39 ±0.08 茶碱片组 6.5±1· 5 18.2±5.4 0.32±0.10 氨茶碱片组 6.3±1.2 16.4±6.0 0.34 ±0.07 咖啡因片组 6.2±1.7 18.0±3.5 0.28 ±0.04 帕吉维林片组 7.0±1.8 20.0±7.2 0.36 ±0.03 己酮可可碱灌胃组 3.5±0.8 12.6±2.4 0.16±0.04 己酮可可碱外用组 3.2±1.0 11.2±2.4 0.12±0.02 注：
'与生理盐水组相比， p<0.05;
s与茶碱片组相比， p〈0.05;
'与氨茶碱片组相比， P〈0.05;
4与咖啡因片组相比， p〈0.05;
4与帕吉维林片组相比， p<0.05
试验例 3 己酮可可碱对洛哌丁胺诱导的便秘大鼠直肠黏膜黏液的影响
1.实验材料
8周龄的 SD大鼠， 体重 240±10g， 来源： 山东新时代药业动物中心， 随即放进不锈钢钢 筋笼内饲养， 温度 24±0. 5'C， 相对湿度为 55± 10%， 每天 07 : 00-19 : 00光照 12小时， 大鼠 自由进食和饮水， 统一标准餐进食。 洛哌丁胺 (Loperamide) , 0. 9%NaCl溶液， 己酮可可碱片 剂， 制备工艺同实施例 10; 己酮可可碱栓剂， 制备工艺同实施例 1。
2.实验方法与步骤
我们隨即将大鼠分为己酮可可碱灌胃组、 己酮可可碱外用组、 1个模型对照组、 1个正常 对照组，每组 5只。适应性饲养 3天。灌胃组、外用组、模型对照组皮下注射洛哌丁胺 1. 5nig/kg， 注射前洛哌丁胺溶解于 0. 9%NaCl溶液中，每天于 09 : 00和 18 : 00分别注射一次。正常组大鼠 注射 0. 9%NaCl溶液， 实验方法同模型组。
灌胃组大鼠每天于 10 : 00灌胃给药己酮可可碱片剂， 给药剂量 1. 5mg/kg; 外用组大鼠直 肠给药己酮可可碱栓剂 1. 5mg/kg， 给药剂量均按照己酮可可碱的量计。模型对照组和正常对 照组大鼠给与蒸镏水， 剂量和方法同上。
以上各组大鼠均笼养， 自由饮食， 用药 14天后， 将各组大鼠用氯氨酮麻醉， 剖腹， 割取 远端结肠 8cm， 纵向剖开， 冲净内容物， 10%中性福尔马林固定， 备用。 全部固定后的标本用 石蜡包埋，常规切片， AB-PAS染色。含黏液的细胞灰度值较低，不含黏液的细胞灰度值较高。 采用 IMS全真彩色图像分析系统（上海申腾信息技术公司产品）分析黏液阳性面积。 技术指 标为图像分辨率 512 X 512， 灰度等级为 256。 显微镜为 01ympus-BH2。 每个标本随机检测 6 个 10X 10低倍视野。 实验结果以均值士标准差表示， 采用 SPSS10. 0软件包进行方差分析。
3.结果
实验结果表明： "
( 1 ) 正常对照组大鼠肠黏膜上皮黏液丰富； 模型对照组大鼠肠黏膜上皮黏液明显减少， 与正常组相比具有极其显著性差异 （p〈0. 01 )。
(2)与模型组相比， 己酮可可碱灌胃组、外用组大鼠肠黏膜上皮黏液明显增多， 且具有 显著性差异。
(3)与己酮可可碱灌胃组相比， 己酮可可碱外用组大鼠肠黏膜上皮黏液明显增多，且具 有显著性差异 （p<0. 05)， 这表明直肠黏膜直接给药对于增强肠黏膜功能效果更加明显。
本发明通过给药己酮可可碱， 惊奇地发现己酮可可碱在改善结肠功能， 增加肠黏膜黏液 正常分泌方面具有意想不到的效果。 可见， 己酮可可碱治疗功能性便秘， 不仅仅在改善功能 性便秘症状上， 并且能增加肠黏膜黏液的分泌、 显著改善肠黏膜的功能， 进而从根本上实现 功能性便秘的显著改善。 表 4 己酮可可碱对洛哌丁胺诱导的便秘大鼠直肠黏膜黏液的影响
组别 数量 黏液面积 （μ πι2)
正常对照组 10 6200. 2 ±939. 2
模型对照组 10 1752. 8± 170. 0"
灌胃组 10 3979. 6 ± 199. 4**
外用组 10 4580. 4 ±246. 2***
与模型对照组相比， Ρ〈0. 01 ;
*与灌胃组相比， ρ<0. 05;
""与正常对照组比较， ρ<0. 01。
试验例 4 己酮可可碱对功能性便秘临床志愿者的疗效观察
1 临床资料
1. 1 诊断标准
参照 1999年罗马世界胃肠病会议制订的慢性功能性便秘的诊断标准 (罗马 II诊断标准）： 在过去的 12个月中，持续或累积至少 12周有以下两个或两个以上症状：（1 ) 1/4时间排便费力； (2 ) 1/4时间粪便是呈团块状或坚硬； （3)大于 1/4时间排便不尽感； （4)大于 1/4时间肛门 有阻塞感或排出困难； （5) 大于 1/4时间排便时需用物协助 （支持盆底肌阻碍）； (6)每周排 便小于 3次。不存在稀便， 也不符合肠易激综合征的诊断标准； 同时需除外肠道或全身器质性 病因以及药物因素所致的便秘。 根据排便困难发生部位和动力障碍， 功能性便秘一般分为三 种类型： 慢传输型便秘 （STC)、 出口梗阻型便秘 （00C)和混合型便秘 （MIX)。
1. 2一般资料
240例临床志愿者， 年龄 18〜65岁， 男 96例， 女 144例， 病程 1〜6年， 签署知情书。 临床诊断为功能性便秘， 其中慢传输型便秘患者 105例 （占 43. 75%)、 出口梗阻型便秘患者 50例 （占 20. 83%)、 混合型便秘患者 85例 （占 35. 42%)。
2 治疗方法
2. 1 治疗分组
按照给药片剂的含量规格共分为 10个治疗组， 每组 24名志愿者， 治疗时间为 7天。
普通片 10mg组， 口服普通片 （lOmg/片， 制备工艺同实施例 10)—次一片， 1日 3次。
普通片 50mg组， 口服普通片 （50mg/片， 制备工艺同实施例 13)—次一片， 1日 3次。
普通片 80mg组， 口服普通片 （80mg/片， 制备工艺同实施例 12)—次一片， 1日 3次。
缓释片 75mg组， 口服缓释片 （75mg/片， 制备工艺同实施例 20)—次一片， 1日 1次。 缓释片 lOOmg组， 口服缓释片 （lOOmg/片， 制备工艺同实施例 18)—次一片， 1日 1次。 肠溶片 25rag组， 口服肠溶片 （25mg/片， 制备工艺同实施例 15) —次一片， 1日 3次。
肠溶片 50mg组， 口服肠溶片 （50mg/片， 制备工艺同实施例 16) —次一片， 1日 3次。
缓释片 400mg组， 口服缓释片 （400mg/片， 制备工艺同实施例 18)—次一片， 1日 1次。 肠溶衣片 120mg组， 口服肠溶片 （lOOmg/片， 制备工艺同实施例 16)—次一片， 1日 3次。 普通片 lOOmg组， 口服普通片 （lOOmg/片， 制备工艺同实施例 10) —次一片， 1日 3次。
2. 2观测指标
(1)排便间隔时间、便质、排便费力情况。 （2)大便常规。 （3)钡灌肠检査。 （4)纤维肠镜检查。 (5)观察服药后不良反应发生情况， 记录恶心、 消化不良、胀气、头晕或头痛情况。记录不 良反应发生的总人数。 （1) (2)必做， （3) (4)选择性做。
3疗效标准与结果 '
3. 1疾病疗效标准
痊愈： 大便正常， 或恢复至病前水平， 其它症状全部消失；
显效： 便秘明显改善， 间隔时间及便质接近正常， 或大便稍干而排便间隔时间在 72 h以内， 其它症状大部分消失；
有效： 排便间隔时间缩短 1 d， 或便质干结改善， 其它症状均有好转；
无效： 便秘及其它症状均无改善。
3. 2数据处理
按照如下方式处理数据:有效率 =(临床痊愈数 +显效数 +有效数 )/治疗组病例总数 X 100%， 不良反应率=不良反应人数 /治疗组病例总数 X 100%。
3. 3治疗结果
临床治疗结果显示， 普通片 lOmg组、普通片 50mg组、普通片 80mg组、缓释片 75mg组、 缓释片 lOOmg组、 肠溶片 10mg组、 肠溶片 50mg组功能性便秘临床志愿者的症状明显改善， 治疗有效率为 58. 33%- 87. 50%,平均总有效率为 77. 38%,不良反应发生率较小，为 0%-8. 33%， 平均不良反应发生率为 2. 08% ; 然而缓释片 400mg 组、 肠溶衣片 120mg 组有效率为 41. 67%- 50. 00%， 平均有效率为 45. 83%， 不良反应发生率较大， 为 12. 50%- 33. 3%， 平均不良 反应发生率为 22. 92%, 而且还出现了功能性便秘症状加重的现象。
由此可见，含有 lOmg-lOOmg己酮可可碱低剂量的片剂组较高剂量己酮可可碱片剂组在治 疗功能性便秘方面有效率较高， 不良反应发生率显著降低， 并具有统计学差异。 本发明提供 的 lOmg- lOOmg己酮可可碱低剂量片剂能够作为治疗功能性便秘的药物使用。 结果见表 5。 表 5 己酮可可碱片剂对功能性便秘临床志愿者疗效观察
治疗组 病例数 有效率 /% 不良反应发生率 /% 备注 普通片 10mg组 24 58. 33 0AA"
普通片 50mg组 24 83. 33A* 0AA"
普通片 80mg组 24 75. 00A* 4. 17A*
缓释片 75mg组 24 87. 50A* 0AAW
缓释片 80mg组 24 83. 33A* 4. nAt
肠溶片 10mg组 24 66. 67A*
肠溶片 50mg组 24 87. 50A* 。"" 普通片 lOOmg组 24 62. 50A* 8. 33
肠溶片 120mg组 24 41. 67 12. 50 便秘加重 1例 缓释片 400mg组 24 50. 00 33. 33 便秘加重 2例
^与肠溶片 120rag组相比， p<0. 05 ;
'与缓释片 400mg组相比， p〈0. 05 ;
"与肠溶片 120mg组相比， p<0. 01；
"与缓释片 400mg组相比， p<0. 01.
含有 10mg-100mg 己酮可可碱的组合物颗粒剂或胶囊替换上述己酮可可碱片剂在治疗功 能性便秘方面能够取得相同或相近的效果， 这对于本领域的技术人员来说是可以预见的。 这 进一步说明本发明的含有 10mg-100mg 己酮可可碱的药物组合物能够作为治疗功能性便秘的 药物使用。
以上通过具体优选实施方式描述了本发明， 任何等同替换对于本领域的技术人员来说都 是显而易见的且包括在本发明之中， 在本发明范围之内的优选， 应当视作本发明给予的技术 启示的结果， 并包括在本发明之中。 所述的等同替换包括但不限于如下情形-
1、 选用本发明提供的任一口服制剂或局部外用制剂按照本发明的试验例 1-4进行实验; 或者对文献报道的有关功能性便秘的动物模型给予本发明提供的任一药物组合物制剂， 包括 口服制剂和局部外用制剂。
2、根据本发明公开的治疗功能性便秘的己酮可可碱剂量，按照体表面积或重量换算进行 实验， 视作本发明的给予的技术启示。

Claims

权利要求
1. 己酮可可碱在制备预防或治疗便秘的药物中的用途。
2. 如权利要求 1所述的用途， 其特征在于所述的便秘为功能性便秘。.
3. 如权利要求 1或 2所述的用途，其特征在于所述的药物是含有己酮可可碱的药物组合物。
4. 如权利要求 3所述的用途， 其特征在于所述的药物组合物为局部外用制剂。
5. 如权利要求 4所述的用途， 其特征在于己酮可可碱在所述的局部外用制剂中的重量百分 含量为 0. 1%-10%。
6. 如权利要求 4或 5所述的用途， 其特征在于所述的局部外用制剂为喷雾剂、 气雾剂、 栓 剂、 凝胶剂、 乳膏剂、 霜剂、 软膏剂、 溶液剂、 乳胶剂或脂质体制剂。
7. 如权利要求 3所述的用途， 其特征在于所述的药物组合物是口服制剂。
8. 如权利要求 7所述的用途， 其特征在于所述的药物组合物是片剂、 胶嚢、 滴丸、 颗粒剂、 散剂或口服液。
9. 如权利要求 7或 8所述的用途，其特征在于所述的药物组合物含有 10mg- lOOmg的己酮可 可碱。
10.如权利要求 7或 8所述的用途， 其特征在于所述的片剂为普通片、 肠溶片或缓释片。
11. 如权利要求 10所述的用途，其特征在于所述的普通片中己酮可可碱的含量为 10nig、25mg、
50mg或 75mg; 所述的肠溶片中己酮可可碱的含量为 25mg或 50mg;所述的缓释片中己酮 可可碱的含量为 75mg或 80mg。
12.一种药物组合物， 其含有己酮可可碱， 其用于预防或治疗便秘。
13.如权利要求 12所述的药物组合物， 其中所述的便秘为功能性便秘。
14.如权利要求 12或 13所述的药物组合物，其中所述药物组合物为权利要求 3-11中所述的 药物组合物。 ―
15.一种治疗便秘的方法， 其包括向患者施用治疗有效量的含有己酮可可碱的药物组合物。
16.如权利要求 14所述的方法， 其中所述的便秘为功能性 ¾秘。
17.如权利要求 15或 16所述的方法，其中所述药物组合物为权利要求 3-11中所述的药物组 合物。
PCT/CN2010/001954 2010-02-09 2010-12-03 己酮可可碱在预防或治疗便秘中的用途 WO2011097788A1 (zh)

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CN1330539A (zh) * 1998-12-14 2002-01-09 赛勒吉药物股份有限公司 用于治疗肛门直肠病的组合物和方法
CN101239050A (zh) * 2008-03-14 2008-08-13 沈阳双鼎制药有限公司 一种己酮可可碱缓释片及其制备方法

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CN1330539A (zh) * 1998-12-14 2002-01-09 赛勒吉药物股份有限公司 用于治疗肛门直肠病的组合物和方法
CN101239050A (zh) * 2008-03-14 2008-08-13 沈阳双鼎制药有限公司 一种己酮可可碱缓释片及其制备方法

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