WO2012006967A1 - Poly(ethylene oxide) and base surfactant in suppository composition - Google Patents

Abstract

A use of poly(ethylene oxide) and a suppository base containing polyoxyethylene and a C₈-C₂₄ alkyl in the molecular structure in a suppository composition, and a suppository composition comprising poly(ethylene oxide) and the suppository base, wherein the suppository composition comprises a fatty acid glyceride base, poly(ethylene oxide) with a content of no less than 1%, the suppository base with a content of no less than 10%, and a drug.

Description

 Polyoxyethylene and matrix surfactants in suppository compositions

 Technical field

The present invention relates to polyoxyethylene and the use of a suppository base having a polyoxyethylene group (-(CH ₂ CH ₂ 0) „ -) and a fluorenyl group having a C8 to C24 molecular number in a suppository composition. It also relates to a suppository composition which has improved or improved "internal administration retention", and more particularly, the suppository composition comprises a fatty acid glycerolipid matrix, a polyoxyethylene content of not less than 1%, and a content A suppository base containing a polyoxyethylene group (_(CH ₂ CH ₂ 0) „ -) and a sulfhydryl group having a carbon number of C8 to C24 and a suppository drug in a molecular structure of not less than 10%. technical background

 Fatty acid glycerides are a common base for suppositories. However, suppositories based on fatty acid glycerides have an "aging" characteristic, that is, the melting point often rises after a long-term storage period, and the melting properties change, such as the body temperature cannot be melted, and the rate of drug release changes, thereby affecting clinical application. It has been confirmed that the matrix component fatty acid glyceride in such suppositories is prone to polymorphic transformation during preparation and storage. At the beginning of the preparation, the matrix is an unstable crystal form (type A), and after storage, it gradually transforms into a stable crystal form (type B). Due to the transformation of the crystal form, the physical properties change, such as an increase in melting point of 2 to 4 ° C, a prolonged softening time, a prolonged melting time (usually more than 30 min), and a slower release rate.

 In addition, when the suppository is based on fatty acid glycerolipid, during storage, especially when the packaging is not perfect, in the high humidity environment, the hydrophilicity of the suppository is good, and the components and drugs such as drugs with poor lipophilicity may be Precipitates in the suppository, forming a layer of frost on the surface of the suppository, which is the phenomenon of so-called "pan-cream", which affects clinical application.

 Although the surfactant is incorporated into a suppository based on fatty acid glycerides, the above process can be delayed to a certain extent, but the effect is often unsatisfactory.

 Therefore, a more stable suppository composition containing a fatty acid glyceride matrix is required in practice. Purpose of the invention

The main object of the present invention is to provide a polyoxyethylene and a suppository base containing a polyoxyethylene group (_(CH ₂ CH ₂ 0) „ -) and a fluorenyl group having a carbon number of C8 to C24 in a molecular structure. Use in a suppository composition of a glycerolipid base.

 Another main object of the present invention is to provide a stable suppository composition comprising a fatty acid glyceride matrix.

 For other purposes, see the following instructions. Summary of the invention

The present inventors have unexpectedly discovered that in a suppository composition based on a fatty acid glyceride, polyoxyethylene is added and a molecular structure contains a polyoxyethylene group (_(CH ₂ CH ₂ 0) „ -) and a carbon number. a suppository base of C8 to C24, such as polysorbate 61, polysorbate 65, polyethylene glycol (30) stearate, polyethylene glycol (40) stearate, etc. The surfactant can improve the stability of the suppository composition, delay or prevent its "aging" phenomenon and "pan-cream" phenomenon, especially when the amount thereof is large. Moreover, the inventors have unexpectedly found that the above-mentioned poly-polymer The mucoadhesive property of ethylene oxide is improved or improved, or its "inner cavity drug retention" is improved or improved, that is, the drug is allowed to remain around the treatment site such as the lower part of the body cavity, preventing or reducing the drug. The present invention has been achieved by the present inventors.

The present invention relates to polyethylene oxide and a suppository base having a polyoxyethylene group (-(CH ₂ CH ₂ 0) „ -) and a sulfhydryl group having a carbon number of C8 to C24 in a molecular structure for improving fatty acid-containing glycerides Use of the stability of the suppository composition of the matrix.

The present invention also relates to a suppository composition which is improved or improved in "steep administration retention", the suppository composition comprising a fatty acid glycerolipid matrix having a content of not less than 1% of polyethylene oxide, a suppository base containing a polyoxyethylene group (_(CH ₂ CH ₂ 0) „ -) and a sulfhydryl group having a carbon number of C8 to C24 in a molecular structure of not less than 10%, and a suppository drug, The amount of the ingredients is calculated based on the total weight of the suppository composition.

The present invention also relates to a suppository composition which is improved or improved in "steep administration retention", the suppository The composition comprises a fatty acid glycerolipid matrix, monodecanoyl-glycerol, monoolauroyl-glycerol, polyoxyethylene having a content of not less than 1%, and a content of not less than a suppository base comprising a polyoxyethylene group (_(CH ₂ CH ₂ 0) „ -) and a sulfhydryl group having a carbon number of C8 to C24 in 10% of the molecular structure, and (F) a suppository drug, the above ingredients The content is based on the total weight of the suppository composition. The terms "active ingredient", "biologically active ingredient", "pharmaceutically active ingredient", "active substance", "active agent" and ""Biologically active substance", "drug" and the like means any substance having a detectable biological effect when it is administered to a living body, including any physiological, diagnostic, prophylactic or pharmacological effects. This term is intended to include, but is not limited to, any Pharmaceutical, therapeutic, preventive, nutritional substances.

 The terms "comprising" and "containing", as used in the present invention, are meant to include, but not limited to, or in addition to the meaning of other components and the like.

 The term "a" as used in the present invention means at least one, and may be one, two or more. Detailed description of the invention

 The above suppository compositions are described in detail below.

 The fatty acid glyceride base used in the present invention may be, for example, a fatty acid monoglyceride, a fatty acid diglyceride, a fatty acid triglyceride, and a mixture thereof, and the fatty acid herein is usually a C10~(:18 pure Or a mixed fatty acid, more preferably a C14~(:18 pure or mixed fatty acid, such as a vegetable fatty acid obtained from coconut oil or olive oil. The melting point of these fatty acid glycerides is usually not lower than 25 ° C, It is preferably not lower than 37 ° C, but preferably not higher than 45 ° C, more preferably not higher than 42 ° C. Examples of fatty acid glycerides which can be used in the present invention are Suppocire® (Gattefosse Co., Ltd) Manufactured, Witepsol® (manufactured by Dynamic Nobel Chemicals Co. Ltd.), Pharmasol (manufactured by Nippon Oi ls and Fats), Cremao® (manufactured by Aarhus), Akosoft @ or Akosol® (manufactured by Karlshamns) No vat a® (manufactured by Cognis), Wecobee® (made by St. An).

 More preferably, the above fatty acid glyceride base further contains monodecanoyl glycerol (glycerol monocaprate, melting point 44 to 46 ° C, which can be dispersed in warm water) and monolauroyl glycerol (glycerol monolaurate) , melting point 62~63 ° C, can be dispersed in warm water), because they have a higher melting point in vitro and a lower than body temperature melting point in the body, so that the suppository composition has better weather resistance and Good release.

 Polyethylene oxide is an acid and alkali resistant, relatively low water absorption and moderate swellability (swelling about 2 to 8 times). It has mucoadhesive properties and is not irritating and allergic to mucous membranes. A polymer resin with relatively good compatibility is more suitable as a "mainstay retention matrix".

 In the suppository composition of the present invention, polyethylene oxide having a molecular weight of 50,000 to 7,000,000 is preferably used, preferably polyethylene oxide having a molecular weight of 100,000 to 5,000,000. When the suppository composition is a suppository for the release of a conventional method (non-sustained release method, including immediate release method), a polyethylene oxide having a molecular weight of 50,000 to 400,000 (excluding) is preferred, and a molecular weight of 80,000 to 350,000 is preferred. Polyethylene oxide; in the case of a suppository for sustained release release, a polyethylene oxide having a molecular weight of 400,000 to 7,000,000 is preferred, and a polyethylene oxide having a molecular weight of 600,000 to 5,000,000 is more preferred.

a suppository base containing a polyoxyethylene group (_(CH ₂ CH ₂ 0) „ -) and a sulfhydryl group having a carbon number of C8 to C24, such as polysorbate 61, polysorbate 65, polyethyl Matrix-type surfactants such as diol (30) stearate and polyethylene glycol (40) stearate are excellent non-toxic suppository base ingredients which are not irritating to mucous membranes, not only with fatty acid glycerides Good compatibility, can be uniformly dispersed in the matrix fatty acid glycerolipid, and soluble in water or dispersed in warm water at a temperature of about 37 ° C, especially suitable for the present invention as a substrate. They have very suitable characteristics such as suitable Physical properties such as melting point, solubility, drug release characteristics, biocompatibility, and the ratio in the suppository base of the present invention can be applied almost unrestricted or in a high proportion, and can be used more effectively than ordinary surfactants. The stabilizing effect of the active agent on the fatty acid glyceride matrix, more effectively alleviating and alleviating the "salt poisoning" effect and "gel blocking" effect of polyethylene oxide, and enhancing the function of polyethylene oxide Guarantee "Effect.

In the present invention, the molecular structure contains a polyoxyethylene group (_(CH ₂ CH ₂ 0) „ -) and a thiol group having a carbon number of C8 to C24. Preferably, the agent matrix comprises a polyoxyethylene group (_(CH ₂ CH ₂ 0) „ -) and a suppository base having a carbon number of C12 〜 (: 18 垸), preferably an example such as polysorbate 61 , Polysorbate 65, polyethylene glycol (30) stearate and polyethylene glycol

(40) Stearate or a mixture thereof, more preferably polysorbate 61 or / and polyethylene glycol (40) stearate due to its better physical and chemical properties such as melting point and biocompatibility.

It is believed that a suppository base containing a polyoxyethylene group (_(CH ₂ CH ₂ 0) „ -) and a fluorenyl group having a carbon number of C8 to C24 in the molecular structure contains the same group as the polyoxyethylene - 0CH ₂ CH ₂ -, a strong association between the two, can produce synergy with each other, can enhance their respective roles, such as this strong association can reduce surfactants, such as polysorbate 61, Polysorbate 65, polyethylene glycol (30) stearate and polyethylene glycol (40) stearate in fatty acid glyceride matrix

"Swim", thereby increasing their stabilizing effect on the fatty acid glyceride matrix. For example, the association can promote the uniform dispersion of polyethylene oxide in the oily matrix, overcome the defects such as the difficulty in uniform dispersion of polyethylene oxide in the oily matrix, form a uniform or substantially uniform matrix, and improve or enhance the polyethylene oxide. The intraluminal administration retains the effect of effectively avoiding or alleviating the heterogeneity and other differences such as retention values of the suppository composition when it is released between the batch and the batch and between the individual and the individual.

It is believed that the molecular structure in the matrix contains an association between a suppository base of a polyoxyethylene group (_(CH ₂ CH ₂ 0) „ -) and a sulfhydryl group having a carbon number of C8 to C24 and a polyethylene oxide. It can be uniformly or substantially uniformly distributed in fatty acid glycerides, changing or destroying its original crystal or crystal structure, which can prevent or delay its crystal form transformation, especially reduce the molecular structure containing polyoxyethylene (_ (CH _{2 )} CH ₂ 0) „ -) and a thiol-based suppository base with a C8~C24 carbon group "walk away" in the fatty acid glyceride matrix, enhancing the role of preventing or delaying the crystallographic transformation of fatty acid glycerides, thereby It is beneficial to improve or improve the stability of the fusion performance, avoid or alleviate the problems of the change of the fusion performance of the suppository composition, the slow release rate, and the like, especially when they are used in a relatively large amount.

It is believed that the molecular structure in the matrix contains an association between a suppository base of a polyoxyethylene group (_(CH ₂ CH ₂ 0) „ -) and a sulfhydryl group having a carbon number of C8 to C24 and a polyethylene oxide. It has good hydrophilicity and lipophilicity, and can form a strong interaction with a hydrophilic component such as a hydrophilic component in a drug carrier, thereby greatly increasing its energy barrier from the oily matrix. , thereby reducing the possibility of precipitation from the oily matrix, alleviating the "pan-cream" phenomenon, especially when they are used in relatively large amounts.

The present inventors have found that the use of a relatively large amount of a suppository base and polyoxyethylene having a polyoxyethylene group (-(CH ₂ CH ₂ 0) „ -) and a sulfhydryl group having a carbon number of C8 to C24 in the above molecular structure is advantageous. To exert its effect, based on the total weight of the suppository composition, usually containing a polyoxyethylene group (_(CH ₂ CH ₂ 0) „ -) and a thiol group having a C8 to C24 carbon number in the molecular structure. The amount used is not less than 10%, preferably not less than 20%, more preferably not less than 30%, and the amount of polyethylene oxide is usually not less than 1%, preferably not less than 3%, more preferably not Less than 10%.

In order to allow the polyoxyethylene to be more or more completely micellized by a suppository base containing a polyoxyethylene group (_(CH ₂ CH ₂ 0) „ -) and a sulfhydryl group having a C8 to C24 carbon number in the above molecular structure. (Association), a suppository base containing a polyoxyethylene group (_(CH ₂ CH ₂ 0) „ -) and a sulfhydryl group having a carbon number of C8 to C24 in a molecular structure, in a suppository composition The suitable ratio for the medium application is usually not higher than 1:1, preferably 1:100 to 1:2, more preferably 1:50 to 1:3.

 Any drug or active ingredient can be used in the present invention. Drugs suitable for use in the present invention may be selected from, but not limited to, corticosteroids, local anesthetics, antipyretic/analgesic/anti-inflammatory drugs, anti-inflammatory/an anti-itching agents, wound healing agents, vitamins suitable for oral administration. , sulfonamides, antibiotics, antifungals, fungicides, antivirals, vasoconstrictors, antihistamines, anesthetics, astringents, contraceptives, termination of pregnancy drugs, defecation accelerators, hypnotic sedatives, anxiolytics, Anti-epileptic, stimulant, anti-shock palsy, central nervous system drug, analgesic, skeletal muscle relaxant, autonomic drug, antispasmodic, anti-vertigo, antiemetic, cardiotonic, antiarrhythmic , diuretics, antihypertensives, coronary vasodilators, peripheral vasodilators, anti-hyperlipidemic drugs, respiratory accelerators, beta 2 receptor agonists, anti-Minnel's disease drugs, anti-tumor agents, antidiarrheals / intestinal function regulator, ulcerative colitis therapeutic agent, therapeutic agent for digestive ulcer, resistance dysfunction drug, induction drug, anthelmintic drug, bronchial expansion a drug, a biological product or a peptide, an antiallergic drug, a laxative, an enema, a choleretic drug, a plurality of hormones other than adrenocortical hormone, and at least one of a Chinese herbal medicine and an extract thereof, or a mixture thereof such as a chemical Compound preparation, chemical/Chinese herbal compound preparation and Chinese herbal medicine (combination) preparation.

With regard to a specific drug compounded in the suppository composition of the present invention, an exemplified may be one or more drugs selected from the group consisting of But not limited to these:

 Adrenal cortex hormones, such as prednisolone acetate, prednisolone, hydrocortisone acetate, hydrocortisone, cortisone acetate, cortisone, dexamethasone acetate, dexamethasone, triamcinolone acetonide;

 Local anesthetics, such as lidocaine hydrochloride, lidocaine, dibucaine hydrochloride, dibucaine, procaine hydrochloride, procaine, tetracaine hydrochloride, tetracaine, chloroprocaine hydrochloride , chloroprocaine, bupivacaine hydrochloride, bupivacaine, propacaine hydrochloride, propacaine, mepivacaine hydrochloride (mepurylcaine), mepucaine, mepivaca , ethyl aminobenzoate, orsocaine, orocaine, ethylaminobenzoate, butylaminobenzoyldiethylaminoethanol, oxidized polyethoxylated oxime or Donghua labor Genus extract

 Antipyretic/analgesic/anti-inflammatory drugs such as aspirin, acetaminophen, mefenamic acid, acetamidobenzene, phenacetin, diclofenac sodium, diclofenac potassium, amygdalin, buprenorphine hydrochloride, isobutyl Phenylpropionic acid, mefenamic acid, aminopyrine, benzophenone, piroxicam, ibuprofen, dextroprofen, naproxen, sulfasalazine, mesalazine, ketoprofen, Meloxicam, benzalkonium hydrochloride, salicylamine and piroxicam;

 Anti-inflammatory/antipruritic drugs, such as glycyrrhetinic acid, lysozyme hydrochloride, dimethoprim, fish fat, camphor, crotamiton, chlorinated lysozyme, tribenzyl glycoside, potassium aluminum sulfate, comfrey extract, Rosskastanien extract, witch hacel extract, processed cana Brava, refined egg yolk lecithin, egg butter, d-camphor, dl-camphor, peppermint oil, 1-menthol, dl-menthol, eucalyptus Oil

 Vitamins such as tocopherol acetate, tocopherol, vitamin D2, retinyl palmitate, retinyl acetate, pyridoxine hydrochloride, pyridoxamine hydrochloride, pyridoxamine phosphate, pyridoxal hydrochloride, pyridoxal phosphate, nucleus Flavin, butyric acid riboflavin, vitamin A oil, vitamins (:, vitamin B6, vitamin E acetate, advanced liver oil or liver oil;

 Sulfonamides, such as sulfadiazine, sulfadiazine, sodium sulfathione, high sulfonamide, sulfisomethazine, sodium sulfisomethyrazine, ampicillin;

 Antibiotics or antifungal agents, such as cephalosporins such as ceftizoxime sodium, penicillins such as ampicillin sodium, quinolones such as norfloxacin, ofloxacin, ciprofloxacin hydrochloride, ciprofloxacin lactate, A Pefloxacin sulfonate, levofloxacin lactate, macrolides such as erythromycin, tetracyclines such as tetracycline, tetracycline hydrochloride, oxytetracycline hydrochloride, antifungal agents such as clotrimazole, miconazole, tinidazole, nitric acid Miconazole, econazole nitrate, terconazole, ketoconazole, butoconazole nitrate, sheraconazole nitrate, oxyconazole, isoconazole nitrate, trichostatin, mycin, natamycin , ciclopirox, nifuratel, chlorobenzazole, chlorobenzimidazole, dichlorobenzimidazole, dichlorobenzazole nitrate, chlorotrityl imidazole, bifonazole, chlorin Nafine and butenafine hydrochloride, other antibiotics such as streptomycin sulfate, gentamicin sulfate, lincomycin hydrochloride, clindamycin phosphate, neomycin sulfate, amphotericin B, kanamycin sulfate , metronidazole, ornidazole, secnidazole , chloramphenicol, nitrofurantoin, yellow vine, matrine, houttuyfonate, pimamycin;

 Fungicides, such as rivanol, chlorhexidine acetate, urethane ethyl glycinate, propyl cresyl, cetyl pyridyl chloride, cis-quinoline, berberine, benzalkonium chloride , chlorhexidine hydrochloride, cetyltrimethylammonium bromide, decalin chloride, phenol, resorcin, polycresol sulfonaldehyde, povidone iodine;

 Astringents such as zinc oxide, citric acid, albumin phthalate and potassium aluminum sulfate;

 Wound healing promoters such as allantoin and urinary allergic aluminum;

 Angiotensin, such as epinephrine hydrochloride, ephedrine hydrochloride, tetrahydrozoline hydrochloride, naphtholine hydrochloride, phenylephrine hydrochloride, dl-methylephedrine hydrochloride, and oxymetazoline hydrochloride;

 Antihistamines, such as diphenhydramine, diphenhydramine hydrochloride, diphenhydramine, diphenhydramine lauryl sulfate, chlorpheniramine maleate or diphenyl laure hydrochloride;

 Anesthetic, such as morphine hydrochloride, ethylmorphine hydrochloride, morphine sulfate, codeine phosphate, dihydrocodeine phosphate, cocaine hydrochloride or pethidine hydrochloride;

 Contraceptives, such as mandelic acid, nonoxynol;

 Termination of pregnancy drugs, such as carboprost methyl ester, dinoprostone;

 Defecation accelerators, such as bisacodyl, glycerin;

a therapeutic agent for digestive ulcers, such as red guar ester; Antiemetics, such as domperidone, ondansetron hydrochloride;

 Progestogen-like drugs, such as progesterone;

 Resistant dysfunction drugs, such as alprostadil, phentolamine mesylate;

 Anthelmintic drugs, such as pyrantel pamoate, levamisole hydrochloride;

 Antiviral drugs, such as zidovudine;

 Progestogen-like drugs, such as progesterone;

 Estrogens such as estriol, estradiol, and progesterone;

 Drugs of induction, such as prostaglandin E2;

 Steroid hormones, such as danazol;

 Ulcerative colitis therapeutic agent, such as mesalazine;

 Analgesics, such as morphine sulfate, tramadol hydrochloride;

 Anti-Ménière's disease drugs, such as sodium bicarbonate;

 Antineoplastic agents, such as 5-fluorouracil and tegafur;

 a β 2 receptor agonist, such as clenbuterol hydrochloride;

 Anticonvulsant, epileptic drug, such as valproic acid;

 a bronchodilator, such as aminophylline;

 Biological products such as recombinant human interferon a 2a, recombinant human interferon a 2b, peptides such as insulin, recombinant human granulocyte macrophage stimulating factor, lactic acid bacteria.

 Examples of the chemical compound preparation, the chemical/Chinese herbal compound preparation which can be used in the present invention are the following compound preparations which are commercially available, but are not limited thereto:

 Metronidazole furazolidone suppository, nifuratel-mycin vaginal suppository, compound carraghenate suppository, compound atropine ephedrine suppository, compound sub-gallate sputum suppository, compound sub-gallate sputum suppository II, compound chlorhexidine acetate Suppository, compound zedoary turmeric oil suppository, compound metronidazole suppository, compound carraghenate suppository, compound chlorhexidine metronidazole suppository, compound chloramphenicol suppository, compound naproxen suppository, compound pediatric antipyretic suppository, compound gram伦特罗栓, 吲哚美辛三七冰片栓, indomethacin sulphate suppository, compound chloramphenicol vaginal suppository, fenteconazole nitrate vaginal suppository, indomethacin suppurazone suppository, mixed estrogen vaginal suppository, chloroquine Nado-progestin vaginal suppository, mexazolone suppository (indomethacin/furazolidone), three-dimensional mycin-based suppository, compound sodium bicarbonate suppository, compound neomycin vaginal suppository, clindamycin metronidazole vagina Suppository, guide plug, mandelic acid contraceptive plug, diazepam suppository, diazepam cotton plug.

 Examples of the Chinese herbal medicine preparation which can be used in the present invention are the following commercially available compound preparations, but are not limited thereto: Qianlie Anshuan, Qianlietong suppository, forefront closure, suppository, phlegm, phlegm, Angong Niuhuangshuan, Baixianfuyanqingshuan, Baofukang suppository, Shenqi Wenyang suppository, Changshutong suppository, Fukang suppository, Funing suppository, Fuyankang suppository, Fuyanling suppository, Fuyanping suppository, anal Thai suppository , Gongfang Runsu suppository, cervical cancer suppository, cervicitis Kangshuan, Huayu analgesic suppository, Huayu suppository, detoxification live thrombus, Jiuhua hemorrhoid suppository, Kangfu Xiaoyan suppository, rehabilitation Lingshuan, Kushen suppository, Kunjing suppository , nude flower purple bead suppository, chlorpyrifos, bovine sputum sputum, pelvic sputum sputum, Puji hemorrhoids suppository, three-flavored hemorrhoids suppository, musk hemorrhoids suppository, Shuanghuanglian suppository, pediatric antipyretic plug, pediatric clearing phlegm, children Xiaoyan suppository, Xiongdan suppository, Xiongdanling suppository, wild chrysanthemum suppository, Yinqiao double-solution suppository, Zhidai Xiaoshuan suppository, Zhilingling suppository, Fubishu vaginal suppository, compound Daqingye suppository, compound Furong effervescent suppository, Compound seabuckthorn seed oil plug, compound rattan acne suppository, Baiai Suppository, Baishen Fuyan Suppository, Ice Tea Suppository, Bingyu Jieshuan, Bokangkang Suppository, Tibetan Women's Suppository, Chaihu Suppository, Intestinal Yitong Suppository, Diqi Xiaoshuan Suppository, Diemaitong Suppository Capsule, Fenghua Jieyin Suppository, Fudekang effervescent suppository, Funing effervescent suppository, Fuqing Xuelian suppository, Fushule suppository, Fuyanjie suppository, Fuyanshuan suppository, Fuyanxiaoshuan, Fuyin Shushuan, Compound seabuckthorn seed oil suppository, compound Xiaoshuan suppository, compound pediatric antipyretic suppository, cervical Ningshuan, red nucleus Jiejie suppository, Huangbaizhishuan suppository, Jieer Yin suppository, colitis sling, Jinju suppository, bitter clove ventilator, dragon blood sputum suppository, bezoar Qianliekang suppository , forefront thrombus, prostaglandin urinary embolus, prostaglandin suppository, sputum sedative capsule, sedative vaginal suppository, cytotoxic sputum suppository, snake shackle, kidney sling, sedative sedative, sedative suppository, Shukang suppository, pain Can be tied, Watson suppository, Xiaoshuan suppository, Yuanhu analgesic suppository, analgesic suppository, hemorrhoids suppository, naked flower purple bead suppository.

A more preferred embodiment is based on the total weight of the suppository composition: the fatty acid glyceride content is usually from 10 to 80% (weight/weight, the same below), and the preferred content is from 20 to 70%, more preferably It is 30 to 60%; the content of polyethylene oxide is usually from 1 to 30%, preferably from 3 to 20%, more preferably from 5 to 20%; The content of the suppository base of polyoxyethylene group (_(CH ₂ CH ₂ 0) „ -) and sulfhydryl group having C8 to C24 is usually 10 to 70%, preferably 20 to 60%, more preferably 1〜30%。 The content of the drug is 0. 1~30%.

Further, when the fatty acid glycerin contains monodecanoyl glycerol and monolauroyl glycerol, based on the total weight of the suppository composition: the fatty acid glyceride content is usually 10 to 70% (weight/weight, the same below) The content of monodecanoyl glycerol is usually from 0.1 to 30%, and the preferred content is from 3 to 10%; the content of monolauroyl glycerol is usually from 5 to 70%. Preferably, the content is 10 to 50%; the content of polyoxyethylene is usually 1 to 25%, and the preferred content is 3 to 20%; and the molecular structure contains polyoxyethylene (_ (CH ₂ CH ₂ 0) „ - 1〜20%。 The suppository drug content of 0. 1~20%. The content of the suppository drug is 0. 1~20%.

 The suppository composition according to the present invention may contain other additives as necessary in addition to the above-mentioned matrix components. Other additives include, but are not limited to, water soluble or water insoluble fillers, surfactants, antioxidants, preservatives, colorants, and the like. The amount of these additives is usually from 0.1 to 10%, based on the total weight of the pharmaceutical carrier, but is not limited thereto, depending on actual needs.

The release rate of the suppository composition of the present invention can be adjusted by adjusting the proportion of the matrix component of the suppository composition, in particular, the type and amount of polyethylene oxide and the molecular structure containing polyoxyethylene (_ (CH ₂ CH _{2 )} 0) „-) and the amount of the suppository base of the sulfhydryl group having a carbon number of C8 to C24.

 The suppository composition of the present invention is a suppository which can be released in a conventional manner (non-sustained release method, including immediate release method), and can also be released in a sustained release manner. Examples of the preparation form of the preparation include rectal suppository and vagina. A suppository, a urethral suppository or an ear canal suppository, preferably a vaginal suppository. The shape of the suppository used in the present invention is not particularly limited, and it is only suitable for clinical use, and examples of the shape suitable for the suppository of the present invention are, for example, a sheet shape, a pellet shape, a prism shape, a pencil shape, a spherical shape, a warhead shape, a round hammer shape, Torpedo, ovate or duck-shaped shape, etc.

The suppository compositions of the present invention are produced in a conventional manner and are only suitable for practical production. As an example of the method, first, a suppository base such as fatty acid glyceride is added to the melted and mixed polyethylene oxide and the molecular structure contains polyoxyethylene (_(CH ₂ CH ₂ 0) „ -) and the number of carbon atoms is C8~C24 sulfhydryl suppository matrix blend (temperature maintained at 70~80 °C), while stirring and mixing evenly, finally adding the drug, stirring and dispersing evenly; the mixed melt is injected into The suppository container is quickly cooled and solidified, and so on.

 The present invention has been described in detail, and it is obvious to those skilled in the art that various modifications may be made without departing from the scope of the invention. DRAWINGS

 Figure 1 : Suppository softening time measuring device (see, Pharmaceutical Excipient Application Technology (Second Edition), edited by Hou Huimin, China Medical Science and Technology Press, Second Edition, July 2002, p. 144). Example

 In order to illustrate the invention, the following examples are provided. However, it should be understood that the invention is not limited to the embodiments. Example 1 and Comparative Example 1~2

 Example 1 Comparative Example 1 Comparative Example 2

 Component mg/grain mg/grain mg/granule

 Diclofenac sodium 100 100 100

 Polyoxyethylene (Polyox WSR N-12K) 100 100 ―

 Polyethylene glycol ( 40 ) stearate 300 ― 300

 Suppocire B 500 800 600

Total 1000 1000 1000 Examples 2 to 5 and Comparative Examples 3 to 5 The amount of polyoxyethylene (Polyox WSR N-12K), polyethylene glycol (40) stearate and Suppocire B in Example 1 was changed to 10 mg / granule, 100 mg / granule and 790 mg / granule, respectively (Example 2) or 30 mg / granule, 200 mg / granule and 670 mg / granule (Example 3) or 100 mg / granule, 400 mg / granule and 400 mg / granule (Example 4) or 200 mg / granule, 400 mg / granule and 300 mg / granule (implementation Example 5) or 10 mg / granule, 20 mg / granule and 870 mg / granule (Comparative Example 3) or 30 mg / granule, 60 mg / granule and 810 mg / granule (Comparative Example 4) or 4 mg / granule, 100 mg / granule and 796 mg / granule ( Comparative Example 5), other unchanged, the above examples or comparative examples were prepared in the following manner.

 Examples 1 to 5 and Comparative Examples 1 to 5 Preparation methods:

 Add the suppository base (Suppocire B) to the melted and mixed polyoxyethylene (Polyox WSR N-12K) and polyethylene glycol (40) stearate (temperature is always maintained at 70~80 °C) While stirring constantly and mixing well, finally add the drug, stir and disperse it evenly. The mixed melt is injected into the suppository container and rapidly cooled to form a suppository. Example 6 and Comparative Example 6 to 7

 Example 6 Comparative Example 6 Comparative Example 7 Component mg/particle mg/particle mg/granule

 Naphazoline hydrochloride 1 1 1

 Lidocaine hydrochloride 70 70 70

 Diphenhydramine hydrochloride 10 10 10

 Hydrocortisone acetate 5 5 5

 Allantoin 20 20 20

 Vitamin E acetate 50 50 50

 Polyoxyethylene (Polyox N-80) 150 150

 Polysorbate 61 450 450

 Monodecanoyl glycerol 65 65 65

 Monolauroyl glycerol 235 235 235

 Wit sol H15 444 894 594

 Total 1500 1500 1500 Examples 7 to 10 and Comparative Examples 8 to 10

 The amounts of polyoxyethylene (Polyox N-80), polysorbate 61 and Witypsol sol H15 in Example 6 were changed to 15 mg/particle, 150 mg/particle and 879 mg/particle (Example 7) or 45 mg/, respectively. Granules, 300 mg/granule and 699 mg/granule (Example 8) or 150 mg/granule, 600 mg/granule and 294 mg/granule (Example 9) or 300 mg/granule, 600 mg/granule and 144 mg/granule (Example 10) or 5 mg / granules, 150 mg / granule and 889 mg / granule (Comparative Example 8) or 10 mg / granule, 150 mg / granule and 884 mg / granule (Comparative Example 9) or 45 mg / granule, 45 mg / granule and 939 mg / granule (Comparative Example 10), Otherwise, the above examples or comparative examples were prepared in the following manner.

 Examples 6 to 10 and Comparative Examples 6 to 10 Preparation methods:

 The suppository base (Witypsol sol H15, monodecanoyl glycerol and monolauroyl glycerol) is added to the melted and mixed polyoxyethylene (Polyox N-80) and polysorbate 61 ( The temperature is always maintained at 70~80 ° C), while stirring constantly and mixing well, finally add the drug, stir and disperse evenly. The mixed melt is injected into the suppository container and rapidly cooled to give a suppository. Test Example 1: Determination of melting point and softening time of suppositories

 Sample:

The freshly prepared suppository products of Examples 1 and 6 and Comparative Examples 1 to 2 and 6 to 7 and a suppository product which was completely sealed at 6 to 28 ° C for 6 months in the dark were used as samples. Test method for suppository melting point:

 It is determined as follows: Muranishi et al. ["Zazai: Seizai kara Rinsho Oyo preparation suppository U: taken from a rash application"), P. 64, 1985, Nanzan-do, with a suppository Throughput (PM3 type, manufactured by ERWEKA, Germany). A test tube containing a suppository was immersed in a water bath at 30 ° C for 10 minutes. The temperature was then increased at a rate of 0.2 ° C / minute. The temperature at which the test needle penetrates the suppository is identified as the melting point (dry). Add 5 ml of the test solution to the test tube (/?H compound sodium chloride injection (Linger's solution) adjusted to 4.0 (Chinese Pharmacopoeia 2005 edition 2), the measurement liquid is similar to vaginal fluid or urine and other body fluids The characteristics, the same as below) The melting point of the measurement is considered to be the melting point (wet) of the wet condition of the body cavity, and the melting point measured without the measuring liquid is considered to be the melting point of the dry storage condition. The condition of the suppository was monitored at 37 ° C, which is equivalent to the temperature of the human body cavity. The measurement was performed 3 times, and the average value was taken. The results are shown in Tables 1 and 2.

 Suppository softening time test method:

 The instrumentation is shown in Figure 1. Place it in a constant temperature water bath of 37 ± 0. 1 °C. After constant temperature, place one suppository sample, put a glass rod on the top of the suppository (weight 15g), and add 37 ± 0.1 °C to the instrument. Liquid (/3⁄4 value adjusted to 4.0 compound sodium chloride injection (Linger's solution) (Chinese Pharmacopoeia 2005 edition 2)) and over the suppository at least 10cm, record the time when the lower end of the glass rod reaches the slit, ie Soften it for it. The measurement was performed 3 times, and the average value was taken. The results are shown in Tables 1 and 2.

 Suppository melting point, melting point change ※ and softening time measurement results

 Melting point rc ) softening time (minutes)

 Test article dry dry melting point wet wet melting point wet

 0 months 6 months change month 6 month change 0 month 6 months

 Example 1 42. 7 43. 1 0. 4 36. 9 37. 0 0. 1 15. 7 17. 5 Comparative Example 1 39. 5 43. 4 3. 9 37. 0 40. 6 3. 6 23. 5 >60 Comparative Example 2 41. 4 43. 4 2. 0 36. 5 38. 0 1. 5 18. 5 49. 2 Example 6 44. 2 44. 5 0. 3 37. 0 37. 0 0 12 7 14. 6 Comparative Example 6 43. 4 47. 5 4. 1 37. 0 40. 9 3. 9 19. 8 >60 Comparative Example 7 40. 3 42. 6 2. 3 36. 8 38. 7 1 9 15. 5 38. 8 Note: ※, the change in melting point is a change in suppository relative to 0 month (on the day of production) after 6 months of experience.

 The results show that the melting performance and stability of the examples are superior to the comparative examples. Suppository melting point change ※ (dry) and softening time (wet, June)

 Melting point change softening time melting point change softening time test article test article

 (°C) (minutes) (°C) (minutes) Example 2 1. 6 25. 7 Example 7 1. 2 20. 7 Example 3 0. 9 20. 8 Example 8 0. 7 16. 5 Example 4 0. 5 17. 6 Example 9 0. 4 13. 2 Example 5 0. 3 18. 2 Example 10 0. 2 12. 4 Comparative Example 3 3. 4 >60 Comparative Example 8 2. 5 43. 6 Comparative Example 4 2. 8 50. 5 Comparative Example 9 2. 2 38. 7 Comparative Example 5 2. 5 45. 9 Comparative Example 10 2. 9 51. 3 Note: ※, the change in melting point means that it was experienced in June. The post suppository is changed relative to the month of 0 (the day of production).

The results showed that the stability of the suppository matrix was related to the amount of polyoxyethylene and the suppository base containing polyoxyethylene (-(CH ₂ CH ₂ 0) „-) and sulfhydryl groups having C8~C24. As their amount increases, their melting properties are also polyoxyethylene and a polyoxyethylene group (_(CH ₂ CH ₂ 0) „ -) and a fluorenyl group having a carbon number of C8 to C24. The amount of suppository base is related. Test Example 2: Determination of drug release rate

sample: The suppository products of Examples 1, 6 and Comparative Examples 1, 6 and the suppository products which were completely sealed at 6 to 28 ° C for 6 months were used as samples.

 Testing method:

 The suppository sample was placed on a piece of dialysis membrane and the bottom of the membrane was closed by a closure with a weight (manufactured by Spectrum, USA). Next, immerse it in a test solution at 37 ° C (distilled water of / 3⁄47.0 and compound sodium chloride injection (Linger's solution) adjusted to 4.0 (Chinese Pharmacopoeia 2005 edition 2)) (1000 The drug which was released into the solution in milliliters (the hydrocortisone acetate was measured in Example 2 and Comparative Example 2) was determined by high performance liquid chromatography. The results are shown in Table 3.

 Table 3 Results of drug release rate determination

 October June

 Test article

 Heavy distilled water Ringer's solution Heavy distilled water Ringer's solution Example 1 (2h) 76.6 75.8 73.7 70.5

 Comparative Example 1 (2h) 70.2 61.7 45.3 33.6

 Example 6 (lh) 98.5 95.5 95.7 92.3

 Comparative Example 6 (lh) 94.3 83.8 56.6 46.9

 The results showed that the drug release properties of the examples, particularly salt tolerance and stability, were superior to those of the comparative examples. Test Example 3: Test for inhibition of edema

 Sample:

 Examples 1, 6 and Comparative Examples 1 to 2, 6' 放置 A 6-month fully sealed packaged suppository product was used as a sample at a temperature of 25 to 28 ° C in the dark.

 Testing method:

 After 24 hours of fasting, male Wistar mice (weight 150 to 170 g) were arbitrarily divided into 12 groups. A brush immersed in 0.16 ml of an anti-inflammatory induction solution (6% of croton oil in diethyl ether: distilled water: pyridine: ether = 10:1:4:5) was inserted into the anus of each animal for 10 seconds to induce an inflammatory effect. Immediately thereafter, the sample or comparative sample (3 mm diameter per 100 g body weight, 10 mm length) was administered to the mice. After the suppository is administered, the anus of each animal is clamped to prevent the suppository from leaking out. After 6 hours, the rectum was removed and cut out from the anus. Tissues 5 to 20 mm long were collected. These tissues were weighed in a wet state and the rectal-anal coefficient (RAC) was calculated as an edema index. The edema inhibition rate was calculated from the RAC thus determined. The results are shown in Table 4.

 Straight/anal

 RAC = ^ X 1000

 Weight (g)

^,,^,.^ _f , , RAC of the unchecked group - AC of the unprocessed group,

Edema inhibition rate ( ) = (ι-,,^, _πή . . ,. _Iff ,, _n ^. ^ )

 Group AG - unprocessed group RAC

 Table 4 Test results of edema inhibition

 Test article RAC edema inhibition rate (%)

 Unprocessed group 0.74 ―

 Comparison group 2.12 ―

Example 1 1.04 78.3 Comparative Example 1 1.63 35.5 Comparative Example 2 1.78 24.6 Example 6 0.92 86.9 Comparative Example 6 1.57 39.8

 Comparative Example 7 L69 3LJ

 The results showed that the edema inhibition effect of the examples was superior to the control. Test Example 4: Stability under high humidity conditions (with or without "pan-frost" phenomenon)

 Samples: Example 1, 6 and Comparative Examples 1 to 2, 6 to 7 and 30 pieces of unpackaged suppository products placed at 25 to 28 ° C, protected from light and 95% relative humidity for 30 months were used. As a sample.

 Test method: Observe the surface of the sample for "pan-cream". The results are shown in Table 5.

 Table 5 Results of the number of samples with "pan-cream" on the surface of the sample

 Test article 1 week later (a) 4 weeks later (a) 8 weeks later (one) Example 1 0 1 3

 Comparative Example 1 3 11 22

 Comparative example 2 1 7 17

 Example 6 0 1 3

 Comparative example 6 5 13 24

 Comparative Example 7 3 10 19

 The results show that the stability of the example under high humidity environment ("pan-cream" phenomenon) is superior to the control. Test Example 5: Determination of in vitro retention values

 Sample:

 Examples 1, 6 and Comparative Examples The freshly prepared suppository products of Examples 1 and 6 were used as samples.

 Testing method:

 The Sentikar-Fantelli method was used to evaluate the retention of the suppository at the injury site in vitro: a cellulose membrane (dialysis membrane, size 36; ViskaseSale). After washing with deionized water, it was tied at the bottom and fixed in a glass tube. Medium (diameter 2 cm x 20 cm). A sample and a compound sodium chloride injection (Linger's solution) adjusted to a value of 5 ml / 7H to 4.0 (Chinese Pharmacopoeia 2005 edition 2) was injected into the glass tube from the upper side of the tube. The compound sodium chloride injection (Linger's solution) adjusted to 4.0 (Chinese Pharmacopoeia 2005 edition 2) (37 ° C) was circulated under a water pressure of 15 ± 2 cm water column. The suppository position was measured after 1 hour, 4 hours, and 8 hours, respectively. In order to judge the migration distance of the suppository, the circulating fluid is rapidly cooled at the same time as the end of the test to cure the suppository. Then, the sample was taken out at the same time as the cellulose film and completely dried. Subsequent to the portion between 0 and 8 cm from the ligation point was weighed. The results are shown in Table 6.

 Table 6 Retention rate (%) Test result (n=12)

 1 hour (%) 4 hours (%) 8 hours (%) Test article

 (AVE 士 RSD/%) (AVE 士 RSD/%) (AVE 士 RSD/%) Example 1 92.5±8· 46 70.5 ±7· 55 53.7±7· 03 Comparative Example 1 84.3 ±20· 2 34.6±17 · 3 16.2±12· 5 Example 3 88.4±8· 21 52.8±8·13 23.9±6· 35 Comparative Example 4 80.7±16.7 23.6±13·5 8.3±9·8 Example 6 89.7±8·71 55.7 ±8·32 26.8±8·22 Comparative Example 6 78.5±22·6 18.3±17·3 4.7±8·94 The results showed that the retention performance of the examples was superior to that of the comparative examples. The results suggest that the addition of molecular structure contains polyoxyethylene

(-(CH ₂ CH ₂ 0) „-) and a suppository base of a sulfhydryl group having a carbon number of C8 to C24, in particular, the addition of a large amount of PE0 is advantageous for enhancing the lumen retention of PE0.

Claims

WO 2012/006967 Claim PCT/CN2011/077225

1. Polyvinyl oxide and a suppository base containing a polyoxyethylene group (_(CH ₂ CH ₂ 0) „ -) and a sulfhydryl group having a carbon number of C8 to C24 in a molecular structure for improving a suppository containing a fatty acid glyceride matrix Use of the stability of the composition.

2. The use according to claim 1, wherein the amount of the polyethylene oxide is not less than 1%, and the molecular structure contains a polyoxyethylene group (-(CH ₂ CH ₂ 0) „-) and the number of carbon atoms is C8~ The suppository base of the thiol group of C24 is used in an amount of not less than 10%, and the content of the above ingredients is calculated based on the total weight of the suppository composition.

The use according to claim 1 or 2, characterized in that the molecular structure contains a suppository of polyoxyethylene (_(CH ₂ CH ₂ 0) „ -) and a fluorenyl group having a carbon number of C8 to C24. The matrix is selected from the group consisting of polyoxyethylene (_(CH ₂ CH ₂ 0) „ -) and a suppository base having a C12~(:18 fluorenyl group) in the molecular structure.

The use according to any one of the preceding claims, characterized in that the molecular structure contains a polyoxyethylene group (_(CH ₂ CH ₂ 0) „ -) and a fluorenyl group having a carbon number of C8 to C24. The suppository base is selected from the group consisting of polysorbate 61, polysorbate 65, polyethylene glycol (30) stearate, polyethylene glycol (40) stearate or mixtures thereof

The use according to any of the preceding claims, characterized in that the molecular structure contains a polyoxyethylene group (_(CH ₂ CH ₂ 0) „ -) and a fluorenyl group having a carbon number of C8 to C24. The suppository base is selected from the group consisting of polysorbate 61 or/and polyethylene glycol

(40) Stearate.

6. A suppository composition having improved stability and "internal administration retention", the suppository composition comprising a fatty acid glycerolipid matrix having a content of not less than 1% of polyethylene oxide, a content of which is not low a suppository base containing a polyoxyethylene group (_(CH ₂ CH ₂ 0) „ -) and a sulfhydryl group having a carbon number of C8 to C24 in 10% of the molecular structure, and a suppository drug, the content of the above component is Calculated based on the total weight of the suppository composition.

7. A suppository composition having improved stability and "internal administration retention", the suppository composition comprising a fatty acid glycerin in an amount of 10 to 80%, and a polyoxyethylene content of 1 to 30%, 1〜30%栓剂 The suppository comprising a polyoxyethylene group (_ (CH ₂ CH ₂ 0) „ -) and a thiol group having a C8~C24 The drug, the content of the above ingredients, is based on the total weight of the suppository composition.

8. A suppository composition having improved stability and "internal administration retention", the suppository composition comprising a fatty acid glyceride in an amount of 20 to 70%, and a polyoxyethylene content in an amount of 3 to 20%, 1〜30%栓剂。 The suppository comprising a polyoxyethylene (_ (CH ₂ CH ₂ 0) „ -) and a sulfhydryl group having a C8~C24, and a content of 0. 1~30% suppository The drug, the content of the above ingredients, is based on the total weight of the suppository composition.

The suppository composition according to any one of claims 6 to 8, characterized in that the molecular structure contains a polyoxyethylene group (-(CH ₂ CH ₂ 0) „-) and a carbon number of C8~ The thiol-based suppository base of C24 is selected from the group consisting of polyoxyethylene (_(CH ₂ CH ₂ 0) „ -) and a suppository base having a C12~(:18 fluorenyl group) in the molecular structure.

The suppository composition according to any one of claims 6 to 9, characterized in that the molecular structure contains a polyoxyethylene group (_(CH ₂ CH ₂ 0) „ -) and a carbon number of C8~ The thiol-based suppository base of C24 is selected from the group consisting of polysorbate 61, polysorbate 65, polyethylene glycol (30) stearate, polyethylene glycol (40) stearate or mixtures thereof

The suppository composition according to any one of claims 6 to 10, characterized in that the molecular structure contains a polyoxyethylene group (_(CH ₂ CH ₂ 0) „ -) and the number of carbon atoms is C8~ The thiol-based suppository base of C24 is selected from the group consisting of polysorbate 61 or/and polyethylene glycol (40) stearate.

 The suppository composition according to any one of claims 6 to 11, wherein the fatty acid glycerolipid substrate is selected from the group consisting of fatty acid monoglycerides, fatty acid diglycerides, fatty acid triglycerides, and mixtures thereof, the fatty acid It is a pure or mixed fatty acid having a carbon number of C14~(:18).

 The suppository composition according to any one of claims 6 to 12, wherein the polyethylene oxide is polyethylene oxide having a molecular weight of 50,000 to 7,000,000.

The suppository composition according to any one of claims 6 to 13, wherein the suppository drug is selected from the group consisting of corticosteroids suitable for intracavitary administration, local anesthetics, antipyretic/analgesic/anti-inflammatory drugs, anti-inflammatory/ Antipruritic, wound healing agents, vitamins, sulfonamides, antibiotics, antifungals, fungicides, antivirals, vasoconstrictors, antihistamines, anesthetics, WO 2012/006967 Claims PCT/CN2011/077225 Astringents, contraceptives, termination of pregnancy drugs, defecation accelerators, hypnotic sedatives, anxiolytics, anti-epileptics, excitatory refreshers, anti-shock palsy, central nervous system effects Medicine, analgesic, skeletal muscle relaxant, autonomic medicine, antispasmodic, anti-vertigo, antiemetic, cardiotonic, antiarrhythmic, diuretic, antihypertensive, coronary vasodilator, peripheral vasodilation Medicine, anti-hyperlipemia, respiratory accelerator, β 2 receptor agonist, anti-Minnel's disease drug, anti-tumor agent, diarrhea/intestinal function regulator, ulcerative colitis therapeutic agent, therapeutic agent for digestive ulcer , resistance dysfunction drugs, induction drugs, anthelmintic drugs, bronchodilators, biological products or peptides, antiallergic drugs, laxatives, enema, choleretic drugs, hormones other than adrenocortical hormones and Chinese herbal medicines and Its extracts and their mixtures.

 The suppository composition according to any one of claims 6 to 14 further comprising monodecanoyl-glycerol and monolauroyl-glycerol »

 The suppository composition according to any one of claims 6 to 15 further comprising a monodecanoyl-glycerol in an amount of from 0.1 to 30% and a monolauroylpropion in an amount of from 5 to 70%. Triol

(monolauroyl-glycerol), the content of the above ingredients is calculated based on the total weight of the suppository composition.

 17. The suppository composition according to any one of claims 6 to 16 further comprising a water-soluble or water-insoluble filler, a water-soluble surfactant, an antioxidant, a preservative or a coloring agent or a mixture thereof.

 18. A suppository composition according to any one of claims 6 to 17 which is a suppository for sustained release delivery.

 The suppository composition according to claim 18, wherein the polyethylene oxide is selected from polyethylene oxide having a molecular weight of from 600,000 to 5,000,000.

 20. A suppository composition according to any one of claims 6 to 17 which is a suppository which is a conventional (non-slow release) release.

 The suppository composition according to claim 20, wherein the polyethylene oxide is selected from polyethylene oxide having a molecular weight of 80,000 to 350,000.

 22. A suppository composition according to any one of claims 6 to 21 which is a vaginal suppository.