CN102000341B - Polyethylene oxide and matrix type surfactant in suppository composition - Google Patents
Polyethylene oxide and matrix type surfactant in suppository composition Download PDFInfo
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- CN102000341B CN102000341B CN2010102277044A CN201010227704A CN102000341B CN 102000341 B CN102000341 B CN 102000341B CN 2010102277044 A CN2010102277044 A CN 2010102277044A CN 201010227704 A CN201010227704 A CN 201010227704A CN 102000341 B CN102000341 B CN 102000341B
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Abstract
The invention discloses a polyethylene oxide and application of a suppository matrix of which the molecular structure contains polyoxyethylene groups and C8-C24 alkyl in improving the stability of a suppository composition containing a fatty glyceride matrix. The invention also discloses a suppository composition of which the stability and the intracavity administration reservation functions are improved. The suppository composition comprises a fatty glyceride matrix, polyethylene oxide, a suppository matrix of which the molecular structure contains polyoxyethylene groups and C8-C24 alkyl anda suppository medicine, wherein the polyethylene oxide content is not lower than 1%, and the suppository matrix content is not lower than 10%.
Description
Technical field
The present invention relates to contain in polyethylene glycol oxide and the molecular structure polyoxyethylene groups ((CH
2CH
2O)
n -) and carbon number be the purposes of suppository base in suppository composition of the alkyl of C8～C24.It also relates to a kind of stability and reaches the suppository composition that " inner chamber administration stick effect " is enhanced or improves, more specifically, this suppository composition comprises fatty glyceride substrate, and content is not less than 1% polyethylene glycol oxide, and content is not less than in 10% the molecular structure and contains polyoxyethylene groups ((CH
2CH
2O)
n -) and carbon number be suppository base and a kind of suppository medicine of the alkyl of C8～C24.
Background technology
Technical background
Fatty glyceride is the substrate a kind of commonly used of suppository.Yet, be that the suppository of substrate has " wearing out " characteristic with the fatty glyceride, namely usually rise to some extent at Long-term Storage after date fusing point, melt degeneration and can change as not melting change under the body temperature, rate of releasing drug changes, so that influences clinical practice.Confirm that the matrix components fatty glyceride in this type of suppository in preparation and storage polymorphic transformation takes place easily.Make the initial stage, substrate is astable crystal formation (A type), after the storage, is transformed into stable crystal formation (Type B) gradually.Because the transformation of crystal formation, physical property changes, and increases 2～4 ℃ as fusing point, softening time lengthening, the change time lengthening of melting (surpassing 30min usually), and rate of releasing drug is slack-off.
In addition, be that the suppository of substrate is in storage with the fatty glyceride, when especially packing is not intact, under high humidity environment, compositions such as the additive that the hydrophilic in the suppository is better, lipophile is relatively poor and medicine may be separated out from suppository, form the same thing of one deck frost on the suppository surface, so-called " scum " phenomenon namely occurs, so that influence clinical practice.
Though the surfactant blending is in the suppository of substrate with the fatty glyceride, can send out the generation that delays said process to a certain extent, effect is usually unsatisfactory.
Therefore, need the more stable suppository composition that contains fatty glyceride substrate in the reality.
Goal of the invention
Main purpose of the present invention just provides and contains polyoxyethylene groups ((CH in a kind of polyethylene glycol oxide and the molecular structure
2CH
2O)
n -) and carbon number be the purposes of suppository base in the suppository composition that contains fatty glyceride substrate of the alkyl of C8～C24.
Another main purpose of the present invention just provides a kind of stable suppository composition that contains fatty glyceride substrate.
Other purposes are referring to following description.
Summary of the invention
The inventor is surprised to find that, is being the suppository composition of substrate with the fatty glyceride, adds in polyethylene glycol oxide and a kind of molecular structure and contains polyoxyethylene groups ((CH
2CH
2O)
n -) and carbon number be the suppository base of the alkyl of C8～C24, as matrix type surfactants such as polysorbate 61, polysorbate65, Polyethylene Glycol (30) stearate, Polyethylene Glycol (40) stearates, can improve the stability of this suppository composition, delay or stop its " wear out " phenomenon and " scum " phenomenon, particularly during their large usage quantities.In addition, the inventor also is surprised to find that, the mucosal adhesive performance of above-mentioned polyethylene glycol oxide is enhanced or improves, its " inner chamber administration stick effect " is enhanced or improves in other words, namely allow medicine to be retained in around the point of care of medicine-feeding part such as body cavity lower position, prevent or reduce drug wastage, so that drug effect is further brought into play.On this basis, the inventor has realized the present invention.
The present invention relates to contain polyoxyethylene groups ((CH in polyethylene glycol oxide and a kind of molecular structure
2CH
2O)
n -) and carbon number be the purposes that the suppository base of the alkyl of C8～C24 be used for to improve the stability of the suppository composition that contains fatty glyceride substrate.
The invention still further relates to the suppository composition that a kind of stability and " inner chamber administration stick effect " are enhanced or improve, this suppository composition comprises a kind of fatty glyceride substrate, content is not less than 1% polyethylene glycol oxide, and a kind of content is not less than in 10% the molecular structure and contains polyoxyethylene groups ((CH
2CH
2O)
n -) and carbon number be suppository base and a kind of suppository medicine of the alkyl of C8～C24, the content of mentioned component is that gross weight with suppository composition is basic calculation.
The invention still further relates to the suppository composition that a kind of stability and " inner chamber administration stick effect " are enhanced or improve; this suppository composition comprises a kind of fatty glyceride substrate; capric monoglyceride (monodecanoyl-glycerol); lauric monoglyceride (monolauroyl-glycerol); content is not less than 1% polyethylene glycol oxide, and a kind of content is not less than in 10% the molecular structure and contains polyoxyethylene groups ((CH
2CH
2O)
n -) and carbon number be suppository base and (F) a kind of suppository medicine of the alkyl of C8～C24, the content of mentioned component is that gross weight with suppository composition is basic calculation.
Term " active component ", " bioactive ingredients ", " medical active component ", " active matter ", " activating agent " that the present invention uses reaches " bioactive substance ", " medicine " etc. and refers to that any material has detectable biological effect and comprises any physiological, diagnosis, preventative or pharmacological effect when it bestows live body.This term is intended to include but not limited to material any pharmacy, therapeutic, preventative, the threpsology.
The term that the present invention uses " comprises " and reaches " containing " and refer to include but not limited to or can also comprise other one-tenth similar implication of grading except this thing.
The term " a kind of " that the present invention uses refers to comprise at least a kind of, can for a kind of, two kinds or more kinds of.
Detailed Description Of The Invention
Below above-mentioned suppository composition is done detailed explanation.
Be used for fatty glyceride substrate of the present invention, for example can be fatty acid glycerine one ester, fatty acid diglyceride, fatty acid triglycercide and their mixture, fatty acid described herein is generally the pure or fatty acid mixed that carbon number is C10～C18, more preferably carbon number is the pure or fatty acid mixed of C14～C18, for example vegetable fatty acid that obtains from Oleum Cocois, olive oil.The fusing point of these fatty glyceride is not less than 25 ℃ of temperature usually, preferably is not less than 37 ℃, but preferably is not higher than 45 ℃, more preferably is not higher than 42 ℃.The example such as the Suppocire(Gattefosse Co. that can be used for fatty glyceride of the present invention, Ltd makes), Witepsol(Dynamic Nobel Chemicals Co. Ltd makes), Pharmasol (Nippon Oils and Fats manufacturing), Cremao(Aarhus makes), Akosoft or Akosol (Karlshamns manufacturing) Novata (Cognis manufacturing), Wecobee (Stepan manufacturing).
More preferably; above-mentioned fatty glyceride substrate also contains capric monoglyceride (single caprin; 44～46 ℃ of fusing points; can in warm water, disperse) and lauric monoglyceride (glyceryl monolaurate; 62～63 ℃ of fusing points; can in warm water, disperse), this is because they have high melt point and have the fusing point that is lower than body temperature in vivo external, thereby will make suppository composition have better weather and release preferably.
Polyethylene glycol oxide be a kind of acidproof alkaline-resisting, relatively low water absorption again and appropriateness swellability (about 2～8 times of swelling), have mucosa and attach property and to mucosa nonirritant and hypersensitive biocompatibility macromolecule resin relatively preferably, be fit to do " the inner chamber administration keeps substrate ".
Suppository composition in the present invention, selecting molecular weight usually for use is 50,000～7,000,000 polyethylene glycol oxide, preferably is 100,000～5,000,000 polyethylene glycol oxide for molecular weight.When suppository composition was the suppository of usual manner (non-slow release mode contains the rapid release mode) release, preferred molecular weight was the polyethylene glycol oxide of 50,000～400,000 (not containing), and preferred molecular weight is 80,000～350,000 polyethylene glycol oxide; During for the suppository of slow release mode release, preferred molecular weight is 400,000～7,000,000 polyethylene glycol oxide, and more preferably molecular weight is 600,000～5,000,000 polyethylene glycol oxide.
Contain polyoxyethylene groups ((CH in the molecular structure
2CH
2O)
n -) and carbon number be the suppository base of the alkyl of C8～C24, be good avirulent to the non-irritating suppository base composition of mucosa as matrix type surfactants such as polysorbate 61, polysorbate65, Polyethylene Glycol (30) stearate and Polyethylene Glycol (40) stearates, not only with fatty glyceride excellent compatibility is arranged, can be scattered in the substrate fatty glyceride equably, and water soluble or be scattered in the warm water of 37 ℃ of about temperature again, suitable especially the present invention makes substrate.They have very suitable characteristic as physical characteristic, drug release feature, biocompatibility such as suitable molten point, dissolubilities, restricted or the application in high proportion hardly of ratio in suppository base of the present invention, can more effectively play the performance surfactant to the Stabilization of fatty glyceride substrate with respect to conventional surfactants, more effectively alleviate, alleviate the effect of polyethylene glycol oxide contingent " salt poisoning " effect and " gel blockage " effect, improve " inner chamber administration reservation " effect of the function of polyethylene glycol oxide.
In the present invention, contain polyoxyethylene groups ((CH in the molecular structure
2CH
2O)
n -) and carbon number be that the suppository base of the alkyl of C8～C24 is preferably selected for use and contained polyoxyethylene groups ((CH in the molecular structure
2CH
2O)
n -) and carbon number be the suppository base of C12～C18 alkyl, preferred embodiment such as polysorbate 61, polysorbate65, Polyethylene Glycol (30) stearate and Polyethylene Glycol (40) stearate or its mixture, more preferably polysorbate 61 is or/and Polyethylene Glycol (40) stearate, because of its better physicochemical property such as fusing point and biocompatibility.
It is believed that and contain polyoxyethylene groups ((CH in the molecular structure
2CH
2O)
n -) and carbon number be that the suppository base of the alkyl of C8～C24 contains identical group-OCH with polyethylene glycol oxide
2CH
2-, the two can form stronger associated complex, can produce synergism with each other, can improve effect separately, can reduce surfactant as this stronger associated complex, as " migration " property in fatty glyceride substrate such as polysorbate 61, polysorbate65, Polyethylene Glycol (30) stearate and Polyethylene Glycol (40) stearate, thereby improve them to the Stabilization of fatty glyceride substrate.For another example, can promote that by this associated complex polyethylene glycol oxide is uniformly dispersed at oleaginous base, overcome polyethylene glycol oxide and disperse defectives such as difficult even at oleaginous base, form even or basic substrate uniformly, improve or improve " inner chamber administration reservations " effect of polyethylene glycol oxide, effectively avoid or alleviate suppository composition batch with criticize between the inhomogeneity and other diversityes such as the retention diversity that show when reaching release between individuality and individuality.
It is believed that and contain polyoxyethylene groups ((CH in the molecular structure in the substrate
2CH
2O)
n -) and carbon number be that the associated complex that forms between the suppository base of alkyl of C8～C24 and polyethylene glycol oxide can be evenly or be distributed in the fatty glyceride substantially equably, change or destroy its original crystal or crystalline structure, energy stops or delays its crystal conversion, particularly reduces and contains polyoxyethylene groups ((CH in the molecular structure
2CH
2O)
n -) and carbon number be suppository base " migration " property in fatty glyceride substrate of the alkyl of C8～C24, strengthened the effect that stops or delay the fatty glyceride crystal conversion, thereby more be conducive to improve or improve the stability of melting the degeneration energy, avoid or alleviate suppository composition melting problems such as degeneration can change, rate of releasing drug is slack-off, when particularly their consumptions are relatively large.
It is believed that and contain polyoxyethylene groups ((CH in the molecular structure in the substrate
2CH
2O)
n -) and carbon number be that the associated complex that forms between the suppository base of alkyl of C8～C24 and polyethylene glycol oxide has hydrophilic and lipophile preferably, can with pharmaceutical carrier in hydrophilic composition etc. form the stronger associated complex of active force by Qing Key etc., increase the energy barrier that it " overflows " from oleaginous base significantly, thereby reduce the probability that it is separated out from oleaginous base, alleviate " scum " phenomenon, when particularly their consumptions are relatively large.
The inventor finds to adopt in the above-mentioned molecular structure of big consumption contains polyoxyethylene groups ((CH
2CH
2O)
n -) and carbon number be that the suppository base of alkyl and the polyethylene glycol oxide of C8～C24 is conducive to bring into play its effect, based on the gross weight of suppository composition, contain polyoxyethylene groups ((CH in the common molecular structure
2CH
2O)
n -) and carbon number be that the consumption of suppository base of the alkyl of C8～C24 is not less than 10%, preferably be not less than 20%, more preferably be not less than 30%, the consumption of polyethylene glycol oxide is not less than 1% usually, preferably is not less than 3%, more preferably is not less than 10%.
In order to allow polyethylene glycol oxide be contained polyoxyethylene groups ((CH in the above-mentioned molecular structure
2CH
2O)
n -) and carbon number be the suppository base micellization (association) more fully or more fully of the alkyl of C8～C24, bring into play above-mentioned effect better, contain polyoxyethylene groups ((CH in the molecular structure
2CH
2O)
n -) and carbon number be that the suppository base of the alkyl of C8～C24 is used suitable proportion and is not higher than 1 ︰ 1 usually in suppository composition, preferably 1 ︰, 100～1 ︰ 2, more preferably 1 ︰, 50～1 ︰ 3.
Any medicine or active component may be used to the present invention.Suitablely can be selected from for medicine of the present invention, but be not limited to this: the adrenocortical hormone of fitted chamber canal drug administration, local anesthetic, analgesic/analgesia/antibiotic medicine, antiinflammatory/antipruritic, Wound-healing agent, vitamin, sulfonamides, antibiotic, antifungal, antibacterial, antiviral agents, vasoconstrictor, antihistaminic, anesthetis, astringent, contraceptive, the termination of pregnancy medicine, defecation promoter, the hypnosis tranquilizer, antianxiety drugs, Anti-epileptics, excited inoitantia, antiparkinsonian drug, the central nervous system does medication, analgesics, skeletal muscle relaxant, autonomic drug, spasmolytic, antivertigo drug, antiemetic, cardiac tonic, anti-arrhythmic, diuretic, antihypertensive, the coronary vasodilator vasodilator, peripheral vasodilator, the hyperlipidemia medicine, breathe accelerator, the beta 2 receptor agonist, anti-Meniere's disease medicine, antitumor agent, antidiarrheal/intestinal function regulator, the ulcerative colitis therapeutic agent, the peptic ulcer therapeutic agent, resistance dysfunction medicine, Labor-inducing medicine, anthelmintic, bronchodilator, biological product or peptide class, anti-allergic drug, cathartic, enema, choleretic, at least a in multiple hormone except adrenocortical hormone and Chinese herbal medicine and the extract thereof or their mixture such as chemical recurrence due to taking drug square preparation, chemistry medicine/Chinese herbal compound preparation and Chinese herbal medicine (compound recipe) preparation.
About being compounded in the concrete medicine in the suppository composition of the present invention, its illustration can be to be selected from one or more following medicines, but is not limited to these:
Adrenocortical hormone, for example prednisone acetate dragon, prednisolone, acetic acid hydrocortisone, hydrocortisone, acetic acid cortisone, cortisone, acetic acid dexamethasone, dexamethasone, acetic acid triamcinolone;
Local anesthetic, lidocaine hydrochloride for example, lignocaine, dibucaine hydrochloride, dibucaine, procaine hydrochloride, procaine, tetracaine hydrochloride, tetracaine, chloroprocaine hydrochloride, chloroprocaine, bupivacaine hydrochloride, bupivacaine, the hydrochloric acid third handkerchief caine (propalacaine), the third handkerchief caine, meprylcaine hydrochloride ((mepurylcaine), meprylcaine, mepivacaine, benzocaine, orthocaine (orsocaine), Mucaine, Ethyl aminobenzoate., hydrochloric acid is to fourth aminobenzoyl diethylaminoethanol, oxidation polyethoxy decane or east flower labor belong to extract;
Analgesic/analgesia/antibiotic medicine, for example aspirin, acetaminophen, mefenamic acid, acetamido benzene, Phenacetin, diclofenac sodium, diclofenac potassium, the delicious suffering of Yin, buprenorphin hydrochloride, ibuprofen, mefenamic acid, aminophenazone, ketoprofen, piroxicam, ibuprofen, (S)-ibuprofen, naproxen, sulfasalazine, mesalazine, ketoprofen, meloxicam, benzydamine hydrochloride, ethenzamide and piroxicam;
Antiinflammatory/antipruritic, for example enoxolone, lisozima, diformazan isopropyl azulene, ichthyol, Camphora, crotamiton, lysozyme chloride, tribenoside, aluminium potassium sulfate, Radix Arnebiae (Radix Lithospermi) extract, rosskastanien extract, Hamamelis virginiana (witchhacel) extract, the cana Brava of processing, refined vitelline lecithin, elgen, d-Camphora, dl-Camphora, Oleum menthae, l-menthol, dl-menthol, Eucalyptus oil;
Vitamin, for example tocopherol acetate, tocopherol, vitamin D2, palmitic retinol, Vitamin A1 acetate, pyridoxine hydrochloride, hydrochloric acid pyridoxamine, phosphopyridoxamine, pyridoxal hydrochloride, pyridoxal 5-phosphate, riboflavin, Riboflavin butyrate, vitamin A oil, vitamin C, vitamin B6, vitamin e acetate, senior liver oil or liver oil;
Sulfonamides, for example sulfadiazine, sulfasomidine, sulfasomidine sodium, high sulfonamide, domian, domian sodium, homosulfamine;
Antibiotic or antifungal, for example cephalosporins such as ceftizoxime sodium, penicillins such as sodium ampicillin, quinolones such as norfloxacin, ofloxacin, ciprofloxacin, ciprofloxacin lactate, pefloxacin mesilate, levofloxacin lactate, Macrolide such as erythromycin, Tetracyclines such as tetracycline, quadracycline, tetramycin hydrochloride, antimycotic such as clotrimazole, miconazole, tinidazole, miconazole nitrate, econazole nitrate, terconazole (triaconazole), ketoconazole, Nitric acid butoconazole, sertaconazole, oxygen health azoles, Fazol (Schering), hachimycin, nysfungin, natamycin, ciclopirox olamine, nifuratel, econazole, econazole nitrate, miconazole, micatin, the chlorine trityl imidazole, bifonazole, terbinafine HCl and butenafine hydrochloride, other antibiotic such as streptomycin sulfate, gentamycin sulfate, lincomycin hydrochloride, clindamycin phosphate, polygynax, amphotericin B, kanamycin sulfate, metronidazole, ornidazole, secnidazole, chloromycetin, nitrofurantoin, fibrauretin, matrine, Sodium Houttuyfonate, pimaricin;
Antibacterial, for example ethacridine, chlorhexidine acetate, poly-aminoethyl glycine Arrcostab, isopropyl cresol, cetyl pyridine chlorine, dequalinium chloride, berberine chloride, benzalkonium chloride, Chlorhexidine hydrochloride, cetab, chlorination decahydronaphthalenes, phenol, resorcin, policresulen, povidone iodine;
Astringent, for example zinc oxide, tannic acid, albumin tannate and aluminum potassium sulfate;
Wound healing promoters, for example allantoin and chlorine hydroxyl aldioxa;
Vasoconstrictor, for example adrenalin hydrochloride, ephedrine hydrochloride, tetrahydrozoline hydrochloride, naphazoline hydrochloride, meta-synephrine hydrochloride, hydrochloric acid dl-methylephedrine and oxymetazoline hydrochloride;
Antihistaminic, for example diphenhydramine, diphhydramine hydrochloride, diphenhydramine tannate, diphenhydramine lauryl sulfate, chlorphenamine or diphenylpyraline hydrochloride;
Anesthetis, for example morphine hydrochloride, ethylmorphine hydrochloride, morphine sulfate, codeine phosphate, dihydrocodeine phosphate, cocaine hydrochloride or pethidine hydrochloride;
Contraceptive, for example mandelic acid, nonoxynolum;
Termination of pregnancy medicine, for example carboprost methylate, dinoprostone;
Defecation promoter, for example bisacodyl, glycerol;
Peptic ulcer therapeutic agent, for example cuscohygrylis;
Antiemetic, for example domperidone, Ondansetron Hydrochloride;
Progestogens medicine, for example Progesterone;
Resistance dysfunction medicine, for example Alprostadil, phentolamine mesylate;
Anthelmintic, for example Pyrantel Pamoate, levamisole hydrochloride bolt;
Antiviral agents, for example zidovudine;
Progestogens medicine, for example Progesterone;
Alora, for example estriol, estradiol, promestriene;
Labor-inducing medicine, for example PGE2;
Steroid hormone class, for example danazol;
Ulcerative colitis therapeutic agent, for example mesalazine;
Analgesics, for example morphine sulfate, tramadol hydrochloride;
Anti-Meniere's disease medicine, for example sodium bicarbonate;
Antitumor agent, for example 5-fluorouracil and ftorafur;
Beta 2 receptor agonist, for example clenbuterol hydrochloride;
Convulsion, epilepsy medicine, for example valpromide;
Bronchodilator, for example aminophylline;
Biological product class, for example recombinant human interferon alpha-2, recombinant human interferon alpha 2 b, peptide class such as insulin, recombined human granulocyte-macrophage stimulating factors, lactobacillus.
Can be used for the example of chemical recurrence due to taking drug square preparation of the present invention, chemical medicine/Chinese herbal compound preparation such as the following compound preparation of having sold in market, but be not limited thereto:
The metronidazole furanzolidon bolt, nifuratel-nysfungin vaginal suppository, the compound carraghenates bolt, compound recipe atropine ephedrine bolt, sappositorium bismuthi subgallatis compositum, sappositorium bismuthi subgallatis compositum II, compound recipe chlorhexidine acetate bolt, Compound Zedoary Turmeric Oil Suppositories, compound metronidazole suppository, the compound carraghenates bolt, compound recipe chlorhexidine metronidazole suppository, compound recipe chloromycetin bolt, compound recipe naproxen bolt, paracetamol compound suppository, compound hydrochloric acid clenbuterol bolt, indomethacin Radix Notoginseng Borneolum Syntheticum bolt, indomethacin albuterol bolt, compound recipe chloromycetin vaginal suppository, the Fenticonazole nitrate vaginal bolt, the indomethacin Roptazol suppository, the mixed estrin vaginal suppository, chlorquinaldol-promestriene vaginal suppository, U.S. hot oxazolone bolt (indomethacin/furazolidone), three-dimensional nysfungin bolt, the Sodamint bolt, the compound neomycin vaginal suppository, clindamycin and metronidazole pessary, the enema and suppositories bolt, the mandelic acid contraceptive suppository, metronidazole,clotrimazole and chlorhexidine acetate suppositories, the safe tampon of two azoles.
Can be used for the example of Chinese herbal and crude drugs preparations of the present invention such as the following compound preparation of having sold in market, but be not limited thereto:
Prostatitis peace bolt; the QIANLIETONG bolt; your logical bolt is closed in the prostatitis; putrefaction removing two fragrant bolts; hemorrhoid-eliminating suppository; the 'An Gong Niu Huang Wan ' bolt; the stemona root and hairy vein agrimony for treating gynecological inflammation bolt; BAOFUKANG SHUAN; ginseng stilbene warming YANG bolt; intestinal relaxes and leads to bolt; the FUKANG bolt; FUNINGSHUAN; Fuyankan suppository (gynopathy medicine); the FUYANLING bolt; FUYANPING SHUAN; GANGTAISHUAN; palace side's intestine moistening bolt; the cervix uteri cancer embolus; GONGJINGYANKANG SHUAN; the blood-activating analgetic bolt; HUAZHI SHUAN; the detoxifcation blood circulation promoting suppository; Jiuhua Zhichuang Shuan; health woman's antiinflammatory bolt; rehabilitation spirit bolt; Radix Sophorae Flavescentis Suppositoria; female clean bolt; LUOHUAZIZHU SHUAN; drip cock goes out; the clear bolt of Calculus Bovis hemorrhoid; the scorching clear bolt of basin; general Ji ZHICHUAN SHUAN; three flavor ZHICHUAN SHUAN; the Moschus ZHICHUAN SHUAN; the SHUANGHUANLIAN bolt; fever-reducing suppository for children; the children clearing heat bolt that reduces phlegm; anti-inflammatory suppository for children; the Fel Ursi bolt; the Fel Ursi ZHILING SHUAN; suppository of wild chrysanthemum flower; the bilingual bolt of YINQIAO; the leukorrhagia stopping XIAOMI SHUAN; control Mi Lingshuan; woman's vaginal suppository that must relax; the compound indigowoad leaf bolt; compound recipe Hibisci Mutabilis type of effervescent suppository; compound seabuckthorn fruit oil suppository; compound recipe rattan fruit ZHICHUAN SHUAN; the BAIAI bolt; cypress ginseng anti-inflammatory suppository for gynecopathy; the iced tea bolt; ice pure as jade bolt; rich property health bolt; hide the FUKANG bolt; the Radix Bupleuri bolt; intestinal is logical bolt easily; hemorrhoid-eliminating suppository with garden burnet; butterfly beniol bolt capsule; phoenix is spent clean cloudy bolt; the woman gets the health type of effervescent suppository; the peaceful type of effervescent suppository of woman; woman's lotus bolt that clears the snow; woman Shu Le bolt; the scorching clean bolt of woman; woman's inflammation is stopped bolt; the scorching embolism extinguishing of woman; the cloudy bolt that relaxes of woman; compound seabuckthorn fruit oil suppository; the compound recipe hemorrhoid-eliminating suppository; paracetamol compound suppository; the peaceful bolt of cervix uteri; the clean bolt of rubrum woman; Huangbaizhimi Suppository; the JIEERYIN bolt; the colitis bolt; the golden aster bolt; the Pedicellus Melo breather plug; the Sanguis Draxonis bolt; Calculus Bovis QIANLIEKANG bolt; the prostatitis blood circulation promoting suppository; prostatitis urinary system bolt; preceding Lenin's bolt; the bolt curing capsule of dispelling; match mould peace vaginal suppository; match mould peace ZHICHUAN SHUAN; the yellow bolt of Serpentis; medicine for treating chronic kidney failure; the Shu An tampon; woman's bolt relaxes; Shu Kangshuan; but pain bolt; Fimbriate orostachys herb suppository; XIAOMI SHUAN; the corydalis tuber analgesic bolt; analgesic suppository; ZHICHUAN SHUAN; LUOHUAZIZHU SHUAN.
One more preferably embodiment be, based on the gross weight of suppository composition: fatty glyceride content is generally 10～80%(w/w, below identical), preferred content is 20～70%, preferred content is 30～60%; The content of polyethylene glycol oxide is generally 1～30%, and preferred content is 3～20%, and preferred content is 5～20%; Contain polyoxyethylene groups ((CH in the molecular structure
2CH
2O)
n -) and carbon number be that the content of suppository base of the alkyl of C8～C24 is common 10～70%, preferred content is 20～60%, preferred content is 30～50%; With the suppository content of medicines be 0.1～30%.
Further, when fatty glyceride contains capric monoglyceride and lauric monoglyceride, gross weight based on suppository composition: fatty glyceride content is generally 10～70%(w/w, below identical), preferred content is 20～60%; The content of capric monoglyceride is generally 0.1～30%, and preferred content is 3～10%; The content of lauric monoglyceride is generally 5～70%, and preferred content is 10～50%; The content of polyethylene glycol oxide is generally 1～25%, and preferred content is 3～20%; Contain polyoxyethylene groups ((CH in the molecular structure
2CH
2O)
n -) and carbon number be that the content of suppository base of the alkyl of C8～C24 is common 10～50%, preferred content is 20～40%; With the suppository content of medicines be 0.1～20%.
The suppository composition that the present invention relates to can also add other additives in case of necessity except above-mentioned matrix components.Other additives comprise but are not limited to water solublity or water-insoluble filler, surfactant, antioxidant, antiseptic, coloring agent etc.These additive amount are generally 0.1～10%, based on the gross weight of pharmaceutical carrier, but not limited, decide on actual needs.
The rate of releasing drug of the suppository composition that the present invention relates to can be adjusted by the ratio of adjusting above-mentioned suppository composition matrix components, particularly contains polyoxyethylene groups ((CH in the kind of polyethylene glycol oxide and consumption and the molecular structure
2CH
2O)
n -) and carbon number be the consumption of suppository base of the alkyl of C8～C24.
The suppository composition that the present invention relates to is except being usual manner (non-slow release mode, contain the rapid release mode) suppository of release, suppository that also can the release of slow release mode, the example of its preparation application form comprises rectally suppository, vagina administration suppository, urethra administration suppository or auditory meatus administration suppository, preferably is vagina administration suppository.The profile that is used for suppository of the present invention has no particular limits, have only suitable clinical practice just, the example of suitable profile for suppository of the present invention such as sheet shape, ball shape, prismatic, pencil shape, sphere, bullet-shaped, top fuller shape, torpedo shape, ovum shape or duck chew shape etc.
The suppository composition that the present invention relates to has only suitable production reality just with conventional method production.Be at first, suppository bases such as fatty glyceride to be added in the polyethylene glycol oxide of fusion and mixing and the molecular structure contain polyoxyethylene groups ((CH as a method example
2CH
2O)
n -) and carbon number be in the mixing thing (70～80 ℃ of temperature maintenance) of suppository base of alkyl of C8～C24, constantly stir and make it mix homogeneously simultaneously, add medicine at last, stir and it be uniformly dispersed; The mixed melting thing is injected into suppository container and cooling curing shaping rapidly, etc.
Described the present invention thus in detail, obviously also various changes can have been arranged within the scope of the invention to those skilled in the art, the present invention is not subjected to the described restriction of description.
Description of drawings
Accompanying drawing 1: suppository soften time register (referring to,
Pharmaceutic adjuvant application technology (second edition), chief editors such as Hou Huimin, Chinese Medicine science and technology publishing house, in July, 2002 second edition, the 144th page).
Embodiment
In order to demonstrate the invention, provide following embodiment.Yet should be appreciated that the present invention is not limited only to these embodiment.
Embodiment 1 and reference examples 1～2
Embodiment 2～5 and reference examples 3～5
The polyethylene glycol oxide among the embodiment 1 (Polyox WSR N-12K), the consumption of Polyethylene Glycol (40) stearate and SuppocireB changes the 10mg/ grain respectively into, 100mg/ grain and 790mg/ grain (embodiment 2) or 30mg/ grain, 200mg/ grain and 670mg/ grain (embodiment 3) or 100mg/ grain, 400mg/ grain and 400mg/ grain (embodiment 4) or 200mg/ grain, 400mg/ grain and 300mg/ grain (embodiment 5) or 10mg/ grain, 20mg/ grain and 870mg/ grain (reference examples 3) or 30mg/ grain, 60mg/ grain and 810mg/ grain (reference examples 4) or 4mg/ grain, 100mg/ grain and 796mg/ grain (reference examples 5), other are constant, prepare the above embodiments or reference examples by following method.
Embodiment 1～5 and reference examples 1～5 preparation method:
In the polyethylene glycol oxide (Polyox WSR N-12K) that suppository base (Suppocire B) is added fusion and mixing and the mixing thing (temperature is kept 70～80 ℃ all the time) of Polyethylene Glycol (40) stearate, simultaneously constantly stir and make it mix homogeneously, add medicine at last, stir and it is uniformly dispersed.The mixed melting thing is injected into the suppository container and rapid cooling forming provides suppository.
Embodiment 6 and reference examples 6～7
Embodiment 7～10 and reference examples 8～10
The polyethylene glycol oxide among the embodiment 6 (Polyox N-80), the consumption of polysorbate 61 and Witepsol H15 changes the 15mg/ grain respectively into, 150mg/ grain and 879mg/ grain (embodiment 7) or 45mg/ grain, 300mg/ grain and 699mg/ grain (embodiment 8) or 150mg/ grain, 600mg/ grain and 294mg/ grain (embodiment 9) or 300mg/ grain, 600mg/ grain and 144mg/ grain (embodiment 10) or 5mg/ grain, 150mg/ grain and 889mg/ grain (reference examples 8) or 10mg/ grain, 150mg/ grain and 884mg/ grain (reference examples 9) or 45mg/ grain, 45mg/ grain and 939mg/ grain (reference examples 10), other are constant, prepare the above embodiments or reference examples by following method.
Embodiment 6～10 and reference examples 6～10 preparation methoies:
In the polyethylene glycol oxide (Polyox N-80) that suppository base (Witepsol H15, capric monoglyceride and lauric monoglyceride) is added fusion and mixing and the mixing thing (temperature is kept 70～80 ℃ all the time) of polysorbate 61; simultaneously constantly stir and make it mix homogeneously; add medicine at last, stir and it is uniformly dispersed.The mixed melting thing is injected into the suppository container and rapid cooling forming provides suppository.
Inspection example 1: suppository fusing point and the mensuration of softening time
Sample:
Embodiment 1 and 6 and the suppository product that has just prepared of reference examples 1～2 and 6～7 and 25～28 ℃ of lucifuge conditions under place 6 months complete airtight packages suppository product used as sample.
The suppository fusing point method of inspection:
Determined by following method: people's such as Muranishi method [" Zazai:Seizai kara Rinsho Oyo prepares suppository: take from a rash and use production) ", p.64,1985, Nanzan-do], be with a kind of suppository penetrometer (PM3 type, German ERWEKA makes).Test tube that suppository is housed is dipped in 30 ℃ the water-bath 10 minutes.Then temperature promotes with 0.2 ℃/minute speed.Temperature when the check pin runs through suppository is identified as fusing point (doing).Adding 5 milliliters in the test tube measures liquid (pH value is adjusted to 4.0 compound sodium chloride injection (ringer's solution) (Chinese Pharmacopoeia 2005 version two ones), measure the characteristic of body fluid such as the approximate vaginal secretion of liquid or urine, down together) fusing point of measuring is considered to be in the fusing point (wetting) of body cavity wet condition, does not add the fusing point that the fusing point of measuring liquid mensuration is considered to the dry storage condition.The condition of suppository is monitored at 37 ℃, and this temperature is equivalent to the temperature of body cavity.Measure 3 times, get its meansigma methods.The results are shown in Table 1 and table 2.
Suppository softens the time check method:
Apparatus is seen accompanying drawing 1.It is put in 37 ± 0.1 ℃ of waters bath with thermostatic control, after treating constant temperature, put into 1 in suppository sample, a Glass rod (heavy 15g) is put on suppository top, add 37 ± 0.1 ℃ mensuration liquid (pH value is adjusted to 4.0 compound sodium chloride injection (ringer's solution) (Chinese Pharmacopoeia 2005 version two ones)) in the apparatus and cover suppository 10cm at least, record glass rod lower end arrives the time of slit, is its softening time.Measure 3 times, get its meansigma methods.The results are shown in Table 1 and table 2.
Table 1 suppository fusing point, variation of melting point
※And the measurement result of softening time
Note: ※, variation of melting point be expression experience after June suppository with respect to the change of 0 month (producing the same day).
The result shows that embodiment melts the degeneration energy and stability is better than reference examples.
Table 2 suppository variation of melting point
※The measurement result of (doing) and softening time (wet, June)
Note: ※, variation of melting point be expression experience after June suppository with respect to the change of 0 month (producing the same day).
The result shows, contains polyoxyethylene groups ((CH in suppository base stability and polyethylene glycol oxide and the molecular structure
2CH
2O)
n -) and carbon number be that the consumption of suppository base of alkyl of C8～C24 is relevant, increase with their increase of consumption, it melts degeneration and also contains polyoxyethylene groups ((CH in polyethylene glycol oxide and the molecular structure
2CH
2O)
n -) and carbon number be that the consumption of suppository base of alkyl of C8～C24 is relevant.
Inspection example 2: the mensuration of drug release rate
Sample:
Embodiment 1,6 and reference examples 1,6 the suppository product that has just prepared and 25～28 ℃ of lucifuge conditions under place 6 months complete airtight packages suppository product used as sample.
The method of inspection:
The suppository sample is placed on a slice dialyser, and (U.S. Spectrum preparation) closed by a closer that has weight in the bottom of film.Then, its is immersed in 37 ℃ the detection liquid (adopting the double distilled water of pH7.0 and pH value to be adjusted to 4.0 compound sodium chloride injection (ringer's solution) (Chinese Pharmacopoeia 2005 version two ones) respectively) (1000 milliliters), and the medicine (embodiment 2 and reference examples 2 are measured the hydrocortisone acetass) that discharges into solution is used high effective liquid chromatography for measuring.The results are shown in Table 3.
The result that table 3 drug release rate is measured
The result shows, embodiment medicine-releasing performance particularly salt resistance ability and stability is better than reference examples.
Inspection example 3: edema inhibitory action check
Sample:
Embodiment 1,6 and reference examples 1～2,6～7 suppository product of under 25～28 ℃ of following lucifuge conditions of temperature, placing 6 months complete airtight packages used as sample.
The method of inspection:
After the fasting 24 hours, male Wistar mice (weighing 150～170 grams) is divided into 12 every group arbitrarily.(6% Oleum Tiglii is at ether: distilled water: pyridine: the brush in the ether=10:1:4:5) inserts 10 seconds of anus of every animal, in order to induce the inflammation effect the antiinflammatory inducing solution that immerses 0.16 milliliter.And then, sample or comparative sample (per 100 gram body weight, 3 mm dias, 10 mm lengths) are awarded mice.After the suppository administration, the anus of every animal is clamped to prevent that suppository from spilling.After 6 hours, rectum is removed and is collected from the tissue that anus cuts out 5～20 millimeters long.These are organized in, and wet condition is weighed and rectum-anus coefficient (RAC) is calculated as the edema index.The edema suppression ratio is calculated by the RAC of such mensuration.The results are shown in Table 4.
Table 4 edema inhibitory action assay
The result shows that the edema inhibitory action of embodiment is better than reference examples.
Inspection example 4: the stability under the high humidity environment (having or not " scum " phenomenon)
Sample: embodiment 1,6 and reference examples 1～2,6～7 and each 30 quilt of suppository product of under 25～28 ℃, lucifuge and relative humidity 95% condition, placing 3 months unlap use as sample.
The method of inspection: observe sample surfaces with order and have or not " scum " phenomenon.The results are shown in Table 5.
Table 5 observes the sample number result that " scum " phenomenon appears in sample surfaces
The result shows that the stability under the embodiment high humidity environment (" scum " phenomenon) is better than reference examples.
Inspection example 5: the mensuration of external retention
Sample:
Embodiment 1,6 and reference examples 1,6 the suppository product that has just prepared used as sample.
The method of inspection:
Adopt Sentikar-Fantelli method in-vitro evaluation suppository at the retention of damage location: a cellulose membrane (dialyser, size 36; Viskase Sale company) with after the deionized water wash, it is tied with line in the bottom, and be fixed on (20 centimetres of diameter 2 cm x) among the glass tubing.Sample and 5 milliliters
pH-number is adjusted to 4.0 compound sodium chloride injection (ringer's solution) (Chinese Pharmacopoeia 2005 version two ones) and injects glass tubing from the top of pipe.And then
pH-number is adjusted to 4.0 compound sodium chloride injection (ringer's solution) (Chinese Pharmacopoeia 2005 version two ones) (37 ℃) and circulates under strong 15 ± 2 centimeter water column conditions of hydraulic pressure.Measure the suppository position after 1 hour, 4 hours and 8 hours respectively.For judging the migration distance of suppository, when finishing test, circulation fluid is cooled off rapidly, in order to solidify suppository.Then, sample and cellulose membrane are removed and bone dry simultaneously.The suppository of lighting between 0～8 centimetre part from ligation is weighed subsequently.The results are shown in Table 6.
Table 6 retention rate (%) testing result (n=12)
The result shows that the retention property of embodiment is better than reference examples.Results suggest adds in the molecular structure and contains polyoxyethylene groups ((CH
2CH
2O)
n -) and carbon number be the suppository base of the alkyl of C8～C24, particularly add the inner chamber stick effect that volume PEO is conducive to improve PEO.
Claims (16)
1. molecular weight is 50,000～7,000,000 polyethylene glycol oxide and is selected from following suppository base material I for the purposes of the stability that improves the suppository composition that contains fatty glyceride substrate, wherein, above-mentioned suppository base material I is selected from polysorbate 61, polysorbate65, Polyethylene Glycol 30 stearates, Polyethylene Glycol 40 stearates or their mixture, above-mentioned fatty glyceride is selected from fatty acid glycerine one ester, fatty acid diglyceride, fatty acid triglycercide and their mixture, described fatty acid is that carbon number is the pure or fatty acid mixed of C10～C18, it is 29.6～79% above-mentioned fatty glyceride that above-mentioned suppository composition comprises content, content is 1～20% above-mentioned polyethylene glycol oxide, content is that 10～40% above-mentioned suppository base material I and content are 0.1～10.4% suppository medicine, and the content of mentioned component is that gross weight with this suppository composition is basic calculation.
2. according to the purposes of claim 1, wherein, described suppository base material I is selected from polysorbate 61 or/and Polyethylene Glycol 40 stearates.
3. according to the purposes of claim 1, wherein, described fatty glyceride substrate is selected from fatty acid glycerine one ester, fatty acid diglyceride, fatty acid triglycercide and their mixture, and described fatty acid is that carbon number is the pure or fatty acid mixed of C14～C18.
4. according to the purposes of claim 1, wherein, described polyethylene glycol oxide is that molecular weight is 100,000～5,000,000 polyethylene glycol oxide.
5. a stability reaches the suppository composition that " inner chamber administration stick effect " is enhanced, it is 29.6～79% fatty glyceride that this suppository composition comprises content, content is that 1～20% molecular weight is 50,000～7,000,000 polyethylene glycol oxide, content is that 10～40% suppository base material I and content are 0.1～10.4% suppository medicine, wherein, above-mentioned fatty glyceride is selected from fatty acid glycerine one ester, fatty acid diglyceride, fatty acid triglycercide and their mixture, described fatty acid is that carbon number is the pure or fatty acid mixed of C10～C18, above-mentioned suppository base material I is selected from polysorbate 61, polysorbate65, Polyethylene Glycol 30 stearates, Polyethylene Glycol 40 stearates or their mixture, the content of mentioned component are that gross weight with this suppository composition is basic calculation.
6. according to the suppository composition of claim 5, it is characterized in that described suppository base material I is selected from polysorbate 61 or/and Polyethylene Glycol 40 stearates.
7. according to the suppository composition of claim 5, it is characterized in that described fatty glyceride substrate is selected from fatty acid glycerine one ester, fatty acid diglyceride, fatty acid triglycercide and their mixture, described fatty acid is that carbon number is the pure or fatty acid mixed of C14～C18.
8. according to the suppository composition of claim 5, it is characterized in that described polyethylene glycol oxide is that molecular weight is 100,000～5,000,000 polyethylene glycol oxide.
9. according to the suppository composition of claim 5, it is characterized in that described suppository medicine is selected from the analgesic/analgesia/antibiotic medicine of fitted chamber canal drug administration, antipruritic, Wound-healing agent, vitamin, sulfonamides, antibiotic, antifungal, antibacterial, antiviral agents, vasoconstrictor, antihistaminic, anesthetis, astringent, contraceptive, the termination of pregnancy medicine, defecation promoter, the central nervous system does medication, skeletal muscle relaxant, autonomic drug, spasmolytic, antivertigo drug, antiemetic, cardiac tonic, anti-arrhythmic, diuretic, antihypertensive, the coronary vasodilator vasodilator, peripheral vasodilator, the hyperlipidemia medicine, breathe accelerator, the beta 2 receptor agonist, anti-Meniere's disease medicine, antitumor agent, antidiarrheal/intestinal function regulator, the ulcerative colitis therapeutic agent, the peptic ulcer therapeutic agent, resistance dysfunction medicine, Labor-inducing medicine, anthelmintic, bronchodilator, biological product, anti-allergic drug, cathartic, enema, choleretic, hormone and Chinese herbal medicine and their mixture.
10. according to the suppository composition of claim 5, it is characterized in that said composition also contains capric monoglyceride and lauric monoglyceride.
11. according to the suppository composition of claim 5, it is characterized in that said composition also comprises water solublity or water-insoluble filler, water soluble surfactant active, antioxidant, antiseptic or coloring agent or their mixture.
12. according to the suppository composition of claim 5, it is characterized in that said composition is the suppository of slow release mode release.
13. according to the suppository composition of claim 12, it is characterized in that it is 600,000～5,000,000 polyethylene glycol oxide that described polyethylene glycol oxide is selected from molecular weight.
14. according to the suppository composition of claim 5, it is characterized in that said composition is the suppository of non-slow release mode release.
15. according to the suppository composition of claim 14, it is characterized in that it is 80,000～350,000 polyethylene glycol oxide that described polyethylene glycol oxide is selected from molecular weight.
16. according to the suppository composition of claim 5, it is characterized in that said composition is vagina administration suppository.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2010102277044A CN102000341B (en) | 2010-07-16 | 2010-07-16 | Polyethylene oxide and matrix type surfactant in suppository composition |
| PCT/CN2011/077225 WO2012006967A1 (en) | 2010-07-16 | 2011-07-15 | Poly(ethylene oxide) and base surfactant in suppository composition |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2010102277044A CN102000341B (en) | 2010-07-16 | 2010-07-16 | Polyethylene oxide and matrix type surfactant in suppository composition |
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| CN102000341A CN102000341A (en) | 2011-04-06 |
| CN102000341B true CN102000341B (en) | 2013-09-11 |
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| WO2012006967A1 (en) * | 2010-07-16 | 2012-01-19 | Zhong Shuguang | Poly(ethylene oxide) and base surfactant in suppository composition |
| CN108178830A (en) * | 2018-01-03 | 2018-06-19 | 辽宁奥克医药辅料股份有限公司 | A kind of polyoxyethylene stearate（40）The preparation method of ester |
| CN112933067B (en) * | 2021-03-26 | 2023-01-06 | 河北医科大学 | Application of sodium houttuyfonate in preparation of medicine for preventing and treating nervous system diseases with Kv7/M channel as target |
| CN115529815A (en) * | 2021-04-27 | 2022-12-27 | 广州共禾医药科技有限公司 | Pharmaceutical composition of oseltamivir or pharmaceutically acceptable salt thereof for rectal administration, preparation method and application thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1280489A (en) * | 1997-10-08 | 2001-01-17 | 大正制药株式会社 | Suppository composition |
| US6270789B1 (en) * | 1999-01-29 | 2001-08-07 | Amato Pharmaceutical Products, Ltd. | Base for suppository |
-
2010
- 2010-07-16 CN CN2010102277044A patent/CN102000341B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1280489A (en) * | 1997-10-08 | 2001-01-17 | 大正制药株式会社 | Suppository composition |
| US6270789B1 (en) * | 1999-01-29 | 2001-08-07 | Amato Pharmaceutical Products, Ltd. | Base for suppository |
Non-Patent Citations (2)
| Title |
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| 王淑萍等.乳剂型栓剂基质的处方筛选.《武警医学院学报》.2008,第17卷(第4期),第272－274页. * |
| 陈惠红.栓剂基质研究进展.《中国药业》.2009,第18卷(第4期),第59-60页. * |
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