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WO2012006967A1 - Poly(oxyde d'éthylène) et matrice tensioactive dans une composition de suppositoires - Google Patents

Poly(oxyde d'éthylène) et matrice tensioactive dans une composition de suppositoires Download PDF

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Publication number
WO2012006967A1
WO2012006967A1 PCT/CN2011/077225 CN2011077225W WO2012006967A1 WO 2012006967 A1 WO2012006967 A1 WO 2012006967A1 CN 2011077225 W CN2011077225 W CN 2011077225W WO 2012006967 A1 WO2012006967 A1 WO 2012006967A1
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Prior art keywords
suppository
group
polyoxyethylene
fatty acid
suppository composition
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Chinese (zh)
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钟术光
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Priority claimed from CN2010102277044A external-priority patent/CN102000341B/zh
Priority claimed from CN2010102283505A external-priority patent/CN101919807B/zh
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Publication of WO2012006967A1 publication Critical patent/WO2012006967A1/fr
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    • 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
    • A61K9/02—Suppositories; Bougies; Bases therefor; Ovules
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers

Definitions

  • the present invention relates to polyoxyethylene and the use of a suppository base having a polyoxyethylene group (-(CH 2 CH 2 0) tenu -) and a fluorenyl group having a C8 to C24 molecular number in a suppository composition.
  • the 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) Stamm -) 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%.
  • Fatty acid glycerides are a common base for suppositories.
  • 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.
  • the matrix component fatty acid glyceride in such suppositories is prone to polymorphic transformation during preparation and storage.
  • 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.
  • 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.
  • 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.
  • 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) réelle -) 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.
  • 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.
  • 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) tenu -) 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) Stamm -) 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)êt -) 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.
  • active ingredient 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 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.
  • 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).
  • 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.
  • monodecanoyl glycerol glycerol monocaprate, melting point 44 to 46 ° C, which can be dispersed in warm water
  • monolauroyl glycerol glycerol monolaurate
  • melting point 62 ⁇ 63 ° C can be dispersed in warm water
  • 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".
  • 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.
  • 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.
  • a suppository base containing a polyoxyethylene group (_(CH 2 CH 2 0) Stamm -) 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.
  • the molecular structure contains a polyoxyethylene group (_(CH 2 CH 2 0) disturb -) and a thiol group having a carbon number of C8 to C24.
  • the agent matrix comprises a polyoxyethylene group (_(CH 2 CH 2 0) réelle -) and a suppository base having a carbon number of C12 ⁇ (: 18 ⁇ ), preferably an example such as polysorbate 61 , Polysorbate 65, polyethylene glycol (30) stearate and polyethylene glycol
  • a suppository base containing a polyoxyethylene group (_(CH 2 CH 2 0) Stamm -) 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
  • 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.
  • the molecular structure in the matrix contains an association between a suppository base of a polyoxyethylene group (_(CH 2 CH 2 0) tenu -) and a sulfhydryl group having a carbon number of C8 to C24 and a polyethylene oxide.
  • fatty acid glycerides 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) Stamm -) 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.
  • the molecular structure in the matrix contains an association between a suppository base of a polyoxyethylene group (_(CH 2 CH 2 0) consult -) 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) Stamm -) and a sulfhydryl group having a carbon number of C8 to C24 in the above molecular structure is advantageous.
  • a polyoxyethylene group (_(CH 2 CH 2 0) Stamm -) 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%.
  • (Association) a suppository base containing a polyoxyethylene group (_(CH 2 CH 2 0) Stamm -) 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.
  • 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
  • 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 ,
  • 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-Mézier's disease drugs such as sodium bicarbonate
  • Antineoplastic agents such as 5-fluorouracil and tegafur
  • a ⁇ 2 receptor agonist such as clenbuterol hydrochloride
  • Anticonvulsant such as valproic acid
  • a bronchodilator such as aminophylline
  • Bio 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:
  • 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, Kang
  • 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) tenu -) 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%.
  • the fatty acid glycerin contains monodecanoyl glycerol and monolauroyl glycerol
  • 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%.
  • 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) cough - 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) understand-) 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.
  • 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.
  • 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) Stamm -) 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.
  • 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 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).
  • Polyox WSR N-12K 100 100 ⁇
  • Example 2 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 3) or 30 mg / gran
  • Example 7 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.
  • 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
  • the measurement liquid is similar to vaginal fluid or urine and other body fluids
  • 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.
  • 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.
  • 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.
  • 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.
  • Test Example 3 Test for inhibition of edema
  • mice weight 150 to 170 g were arbitrarily divided into 12 groups.
  • 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.
  • Edema inhibition rate ( ) ( ⁇ -,, ⁇ , ⁇ . . ,. Iff ,, n ⁇ . ⁇ )
  • 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
  • Test Example 4 Stability under high humidity conditions (with or without "pan-frost” phenomenon)
  • Example 1 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.
  • Test Example 5 Determination of in vitro retention values
  • 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.
  • 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.

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Abstract

La présente invention concerne l'utilisation, dans une composition de suppositoires, de poly(oxyde d'éthylène) et d'une matrice pour suppositoires contenant du polyoxyéthylène et un alkyle en C8 à C24 alkyl dans la structure moléculaire, et une composition de suppositoires comprenant du poly(oxyde d'éthylène) et la matrice pour suppositoires, ladite composition de suppositoires comprenant une matrice de glycéride d'acide gras, du poly(oxyde d'éthylène) dont la teneur n'est pas inférieure à 1 %, la matrice pour suppositoires dont la teneur n'est pas inférieure à 10 % et un médicament.
PCT/CN2011/077225 2010-07-16 2011-07-15 Poly(oxyde d'éthylène) et matrice tensioactive dans une composition de suppositoires Ceased WO2012006967A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN201010228350.5 2010-07-16
CN2010102277044A CN102000341B (zh) 2010-07-16 2010-07-16 在栓剂组合物中的聚氧化乙烯及基质型表面活性剂
CN2010102283505A CN101919807B (zh) 2010-07-16 2010-07-16 栓剂组合物
CN201010227704.4 2010-07-16

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WO2012006967A1 true WO2012006967A1 (fr) 2012-01-19

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1097083B (de) * 1954-06-16 1961-01-12 Dr Martin Ruben Suppositorienmasse
KR940002654B1 (ko) * 1991-07-26 1994-03-28 태평양 제약 주식회사 직장용 좌제 조성물
RU2212882C1 (ru) * 2002-09-19 2003-09-27 Закрытое акционерное общество "Алтайвитамины" Суппозитории ректальные "олестезин"
CN101244237A (zh) * 2007-05-24 2008-08-20 海南碧凯药业有限公司 一种栓剂及其制备方法
CN101919807A (zh) * 2010-07-16 2010-12-22 钟术光 栓剂组合物
CN102000341A (zh) * 2010-07-16 2011-04-06 钟术光 在栓剂组合物中的聚氧化乙烯及基质型表面活性剂

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1097083B (de) * 1954-06-16 1961-01-12 Dr Martin Ruben Suppositorienmasse
KR940002654B1 (ko) * 1991-07-26 1994-03-28 태평양 제약 주식회사 직장용 좌제 조성물
RU2212882C1 (ru) * 2002-09-19 2003-09-27 Закрытое акционерное общество "Алтайвитамины" Суппозитории ректальные "олестезин"
CN101244237A (zh) * 2007-05-24 2008-08-20 海南碧凯药业有限公司 一种栓剂及其制备方法
CN101919807A (zh) * 2010-07-16 2010-12-22 钟术光 栓剂组合物
CN102000341A (zh) * 2010-07-16 2011-04-06 钟术光 在栓剂组合物中的聚氧化乙烯及基质型表面活性剂

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