CN102872024A - Misoprostol medicine combination used in mouths - Google Patents
Misoprostol medicine combination used in mouths Download PDFInfo
- Publication number
- CN102872024A CN102872024A CN2012103694640A CN201210369464A CN102872024A CN 102872024 A CN102872024 A CN 102872024A CN 2012103694640 A CN2012103694640 A CN 2012103694640A CN 201210369464 A CN201210369464 A CN 201210369464A CN 102872024 A CN102872024 A CN 102872024A
- Authority
- CN
- China
- Prior art keywords
- misoprostol
- oral cavity
- tablet
- mouths
- mouth
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
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Landscapes
- Medicinal Preparation (AREA)
Abstract
The invention discloses a misoprostol medicine combination used in mouths. The misoprostol medicine combination can be used in mouths and is good in taste, can be dissolved, disintegrated and dispersed in the mouths without water drinking or can be disintegrated and dispersed by aid of mouth chewing and then be absorbed or swallowed in the mouths. The misoprostol medicine combination can be sublingual tablets, chewable tablets, mouth lozenges, mouth disintegrating tablets, mouth film agents and dropping pills, and preferably be the sublingual tablets, the chewable tablets, the mouth disintegrating tablets and the mouth lozenges. The medicine combination can be used for promoting uterine contraction and preventing and treating postpartum hemorrhage. The medicine combination is simple in dosing method, safe, efficient, capable of being accepted by people easily, simple in preparation process and suitable for industrial production.
Description
Technical field
The pharmaceutical composition that contains misoprostol that the present invention relates to use in the oral cavity can be used for promoting uterine contraction, prevention and treatment postpartum hemorrhage.The invention belongs to medical technical field.
Background technology
Postpartum hemorrhage is one of common severe complication of clinical obstetrics, is the first cause of current China maternal death.In four large reasons of postpartum hemorrhage, the hemorrhage first place that accounts for of the weak property of uterine contraction, incidence rate is 50%-75%, accounts for 2/3 of postpartum hemorrhage.Reducing maternal mortality rate is a basic health objectives of many developing countries.The 5th the MDGs emphasis of the United Nations is by 2015 the maternal death ratio to be reduced 3/4.Yet, in the area of many scarcity of resources, recommend to reduce the intervening measure of these ratios or can't obtain, or too expensive pair is not risen.Many tradition be used for preventing or treating postpartum hemorrhage or post-abortion hemorrhage uterine contraction medicine, such as oxytocin or other prostaglandins, only can store some months or need cold preservation in room temperature, and usually need the injection.
Misoprostol is a kind of synthetic prostatitis element E1 analog, and chemical name is (±) (11 α, 13E)-11,16-dihydroxy-16-methyl prostatitis alkane-9-ketone-13-alkene-1-acid methyl ester.Misoprostol is unstable at room temperature, but its mixture with hydroxypropyl emthylcellulose is then much stable than sterling, can preserve at normal temperatures.The eighties in 20th century, early stage misoprostol was used for peptic ulcer at first; can impel ulcer healing; or make sx↓; its protection Gastroduodenal mucosal lesions is by suppressing basal gastric acid secretion; behind the irriate gastric acid secretion and night gastric acid secretion; and by reducing gastric secretion, suppress the activity of proteolytic enzyme in the gastric juice, and realize by increase bicarbonate and mucus.Misoprostol and mifepristone are used for antiearly pregnancy after the eighties, and the artificial abortion rate is improved greatly.In a single day mifepristone can be combined by the progesterone receptor in health, and the vigor of progesterone in the health is descended, and lacks progesterone in the health, will cause miscarriage.And misoprostol can make the uterus that strong the contraction occurs, and forces conceived tissue to excrete.
The researcher of various countries has been done a large amount of clinical trials and has been estimated the effect that misoprostol is used at department of obstetrics and gynecology in recent years, and such as cervix maturation, induced labor, postpartum hemorrhage etc., misoprostol more and more is widely used in the department of obstetrics and gynecology field.The misoprostol preparation of China's listing is common oral tablet, and the representative preparation that is used for the treatment of gastric ulcer is Cytotec (specification is every 0.2mg); Share the representative preparation that stops early pregnancy with mifepristone is the misoprostol tablets by LC-MS (specification 0.2mg) of black bamboo Pharmaceutical.Be used for the Vaginal Misoprostol sheet (specification is every 25 μ g) of cervix maturation-stimulating, now be in clinical experimental stage, be not used for the preparation of prevention or treatment postpartum hemorrhage appropriate size.
At present, prevention or treatment postpartum hemorrhage promote uterine contraction generally to use oxytocin clinically, but uterine smooth muscle has substantial connection to sensitivity and the body inner estrogen level of contracting palace rope, gravid uterus also has individual variation to the sensitivity of oxytocin, and oxytocin is larger to the body of uterus excitation, less to the cervix uteri excitation, clinical research is found, oxytocin is used and is surpassed 40U, continue to use and then promote the uterine contraction DeGrain, and the unsaturated fatty acid in prostaglandin to be a class extensively the be present in body, action effect and hormone in vivo level are irrelevant, and misoprostol not only has consumingly uterine contraction effect, and muscle fiber is shortened, and can strengthen frequency of uterine contraction, so can select misoprostol to play the effect of control postpartum hemorrhage to the insensitive puerpera of oxytocin.El-Refacey H (1997) Given oral Misoprostol 600 μ g take Prevent and cure the postpartum bleeding immediately behind delivery of baby, average third stage of labor 5min is mainly used in the puerpera of normal pregnancy 32 above vaginal deliveries of week.Blood pressure illustrates that without significant change misoprostol does not affect blood pressure after using misoprostol, does not increase the load of puerpera's cardiovascular system, is particularly useful for suffering from the hypertension such as preeclampsia, easily the puerpera of postpartum hemorrhage occurs.
The pharmaceutical composition that the present invention makes misoprostol and necessary pharmaceutic adjuvant, its dosage form can be Sublingual tablet, chewable tablet, buccal tablets, oral cavity disintegration tablet, pelliculae pro cavo oris and drop pill, need not drinking-water can be in dissolved in oral cavity, disintegrate, dispersion, perhaps chew by the oral cavity and make its disintegrate, dispersion, some drugs absorbs through lingual mucous membrane, cheek film, directly enter blood circulation by jugular vein and superior vena cava, onset is rapid, can avoid the first pass effect of liver, improve bioavailability, and alleviate the gastrointestinal discomfort.This Pharmaceutical composition medication is simple, safe and effective, be easy to be accepted, and its preparation technology is simple, is suitable for suitability for industrialized production.
Summary of the invention
The object of the present invention is to provide the pharmaceutical composition that contains misoprostol that in the oral cavity, uses, can be used for promoting uterine contraction, prevention and treatment postpartum hemorrhage, select for clinical practice provides a kind of easy, safe treatment.
The object of the present invention is achieved like this:
A kind of good mouthfeel, need not drinking-water can be in dissolved in oral cavity, disintegrate, dispersion, perhaps chew the pharmaceutical composition that contains misoprostol that makes its disintegrate, dispersion by the oral cavity, it is characterized in that containing misoprostol 0.2mg～0.6mg in the pharmaceutical composition of per unit dosage, or the misoprostol of corresponding dosage-hypromellose mixture, and necessary pharmaceutic adjuvant is prepared into Sublingual tablet, chewable tablet, buccal tablets, oral cavity disintegration tablet, pelliculae pro cavo oris and drop pill.Preferably Sublingual tablet, chewable tablet, oral cavity disintegration tablet and buccal tablets.
Misoprostol crude drug among the present invention is unstable at room temperature, but misoprostol-hypromellose mixture is then much stable than sterling, can preserve at normal temperatures.The preferred misoprostol of the present invention-hypromellose mixture (including 1% misoprostol).
The pharmaceutic adjuvant that adds in described misoprostol Sublingual tablet, misoprostol chewable tablet and the misoprostol buccal tablets comprises filler, binding agent and lubricant, also can comprise disintegrating agent and sweeting agent as required.The pharmaceutic adjuvant that adds in the described misoprostol oral cavity disintegration tablet comprises filler, binding agent, disintegrating agent, sweeting agent and lubricant.Concrete pharmaceutic adjuvant composition and content are selected according to the Formulation purpose.
Described filler can be selected from any one or a few mixture of mannitol, microcrystalline Cellulose, glycine, lactose, starch, pregelatinized Starch, glucose, xylitol, sorbitol, Icing Sugar and dextrin.
Described disintegrating agent is selected from one or more the mixture in cross-linking sodium carboxymethyl cellulose, crospolyvinylpyrrolidone, low-substituted hydroxypropyl level cellulose and the carboxymethyl starch sodium;
Described binding agent is selected from any one or a few the mixture in water, ethanol, hypromellose, sodium carboxymethyl cellulose, polyvinylpyrrolidone, carbomer, gelatine size, mucialga of arabic gummy, sodium alginate and the syrup;
Described lubricant is selected from one or more mixture in stearic acid, magnesium stearate, calcium stearate, Pulvis Talci, micropowder silica gel, Macrogol 4000, polyethylene glycol 6000, hydrogenated vegetable oil, sodium lauryl sulphate, Stepanol MG and the fumaric acid sodium stearate;
Described sweeting agent is selected from any one or a few mixture of aspartame, stevioside, Icing Sugar, glycyrrhizin, sucralose, cyclamate, Talin and glucide;
Described misoprostol Sublingual tablet, containing misoprostol 0.2～0.6g in per 1000 (is misoprostol-hypromellose mixture 20～60g), contain filler 50～200g, contain disintegrating agent 5～10g, contain sweeting agent 0～20g, contain lubricant 0.5～5g, binding agent is an amount of.Containing misoprostol 0.2～0.6g in preferred per 1000 misoprostol Sublingual tablet (is misoprostol-hypromellose mixture 20～60g), contain filler 80～120g, contain disintegrating agent 2～20g, contain sweeting agent 0.2～5g, contain lubricant 1～2g, binding agent is an amount of.
Described misoprostol chewable tablet, containing misoprostol 0.2～0.6g in per 1000 (is misoprostol-hypromellose mixture 20～60g), contains filler 50～200g, contain sweeting agent 0.2～20g, contain lubricant 0.5～5g, binding agent is an amount of.Containing misoprostol 0.2～0.6g in preferred per 1000 misoprostol chewable tablet (is misoprostol-hypromellose mixture 20～60g), contain filler 80～120g, contain sweeting agent 0.2～5g, contain lubricant 1～2g, binding agent is an amount of.
Described misoprostol oral cavity disintegration tablet, containing misoprostol 0.2～0.6g in per 1000 (is misoprostol-hypromellose mixture 20～60g), contain filler 50～200g, contain disintegrating agent 5～15g, contain sweeting agent 0～20g, contain lubricant 0.5～5g, binding agent is an amount of.Containing misoprostol 0.2～0.6g in preferred per 1000 misoprostol oral cavity disintegration tablet (is misoprostol-hypromellose mixture 20～60g), contain filler 80～120g, contain sweeting agent 0.2～5g, contain lubricant 1～2g, binding agent is an amount of.
Described misoprostol buccal tablets, containing misoprostol 0.2～0.6g in per 1000 (is misoprostol-hypromellose mixture 20～60g), contains filler 50～200g, contain sweeting agent 0～20g, contain lubricant 0.5～5g, binding agent is an amount of.Containing misoprostol 0.2～0.6g in preferred per 1000 misoprostol buccal tablets (is misoprostol-hypromellose mixture 20～60g), contain filler 80～120g, contain sweeting agent 0.2～5g, contain lubricant 1～2g, binding agent is an amount of.
The preparation method of described misoprostol Sublingual tablet, misoprostol chewable tablet, misoprostol oral cavity disintegration tablet and misoprostol buccal tablets comprises direct powder compression, compressing dry granulation and other conventional method for preparing tablet thereof, preferred direct powder compression.
The present invention has following advantage:
Misoprostol Sublingual tablet of the present invention, chewable tablet, buccal tablets and oral cavity disintegration tablet place in the oral cavity when taking, need not drinking-water namely in dissolved in oral cavity, disintegrate, dispersion, perhaps chew by the oral cavity and make compositions disintegrate, dispersion, then under medicine is absorbed rapidly or is swallowed, can bring into play rapidly curative effect in the oral cavity.
Misoprostol Sublingual tablet of the present invention, chewable tablet, buccal tablets and oral cavity disintegration tablet all or part ofly absorb onset in the oral cavity, can also be made in the oral cavity pelliculae pro cavo oris, the drop pill of fast dissolving or disintegrate by above-mentioned raw materials and pharmaceutic adjuvant.
Misoprostol Sublingual tablet of the present invention, chewable tablet, buccal tablets and oral cavity disintegration tablet, taking convenience need not drinking-water, and good mouthfeel has improved patient's compliance.
Misoprostol Sublingual tablet of the present invention, chewable tablet, buccal tablets and oral cavity disintegration tablet, its preparation method is fit to suitability for industrialized production.
The specific embodiment
The present invention will be further described below in conjunction with embodiment, but the present invention is not limited to these embodiment.
Embodiment 1
The preparation of misoprostol Sublingual tablet (1000 amounts)
Preparation method: with the 100 order pretreatment of sieving of misoprostol-hypromellose mixture, mannitol, lactose, cross-linking sodium carboxymethyl cellulose, aspartame, magnesium stearate; With above-mentioned pretreated stock and adjunct mix homogeneously; Detect the content of said mixture, it is heavy to calculate sheet, and the shallow stamping of 8mm gets finished product.
Measure according to inspection technique disintegration of stipulating among two appendix XA of 2010 editions Pharmacopoeias of the People's Republic of China, the results are shown in Table 1.
The dissolving the time limit of table 1 misoprostol Sublingual tablet (n=6)
Embodiment 2
The preparation of misoprostol chewable tablet (1000 amounts)
Preparation method: use the polyvinylpyrrolidone aqueous solution as binding agent part xylitol, pregelatinized Starch, crospolyvinylpyrrolidone, stevioside, soft material processed, 16 mesh sieves are granulated, after 60 ℃ of dryings, granulate, fully mix magnesium stearate, Pulvis Talci mix homogeneously with the part xylitol blend with misoprostol-hypromellose mixture; Detect the content of said mixture, it is heavy to calculate sheet, and the shallow stamping of 10mm gets finished product.
Embodiment 3
The preparation of misoprostol oral cavity disintegration tablet (1000 amounts)
Preparation method: with the 80 order pretreatment of sieving of mannitol, low-substituted hydroxypropyl cellulose, hydroxypropyl methylcellulose, mix soft material processed, 16 mesh sieves are granulated, after 60 ℃ of dryings, granulate is with misoprostol-hypromellose mixture, part mannitol mixture, magnesium stearate mix homogeneously; Detect the content of said mixture, it is heavy to calculate sheet, and the flat stamping of 6.5mm gets finished product.
The disintegration time mensuration method of misoprostol oral cavity disintegration tablet is: get 6 10mL small beakers, the water that adds respectively 2mL constant temperature to 37 ℃, respectively put into 1 of this product, the static placement 1 minute, 6 all should disintegrate in 1 minute, gently jolting all is 24 purpose screen clothes (the in case of necessity water of available no more than 5mL flushings) by the aperture, and is residual without grit.Measurement result sees Table 2.
The disintegration (n=6) of table 2 misoprostol oral cavity disintegration tablet
Embodiment 4
The preparation of misoprostol buccal tablets (1000 amounts)
Preparation method: mannitol, sorbitol, Icing Sugar, cyclamate are done blank granule, mix with part mannitol mixture with misoprostol-hypromellose mixture, the magnesium stearate mix homogeneously; Detect the content of said mixture, it is heavy to calculate sheet, and the flat stamping of 9mm gets finished product.
Measure according to inspection technique disintegration of stipulating among two appendix XA of 2010 editions Pharmacopoeias of the People's Republic of China, the results are shown in Table 3.
The dissolving the time limit of table 3 misoprostol buccal tablets (n=6)
Claims (3)
- A good mouthfeel, need not drinking-water can be in dissolved in oral cavity, disintegrate, dispersion, perhaps chew the pharmaceutical composition that contains misoprostol that makes its disintegrate, dispersion by the oral cavity, it is characterized in that containing misoprostol 0.2mg～0.6mg in the pharmaceutical composition of per unit dosage, and necessary pharmaceutic adjuvant.
- 2. the pharmaceutical composition that contains misoprostol as claimed in claim 1 is characterized in that its dosage form is Sublingual tablet, chewable tablet, buccal tablets, oral cavity disintegration tablet, pelliculae pro cavo oris and drop pill.Preferably Sublingual tablet, chewable tablet, oral cavity disintegration tablet and buccal tablets.
- 3. the pharmaceutical composition that contains misoprostol as claimed in claim 1 is characterized in that can be used for promoting uterine contraction, prevention and treatment postpartum hemorrhage.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2965750A1 (en) * | 2014-07-11 | 2016-01-13 | Azanta A/S | Misoprostol dispersible tablet |
| WO2016004960A3 (en) * | 2014-07-11 | 2016-03-17 | Azanta A/S | Misoprostol dispersible tablet |
| US10688072B2 (en) | 2014-07-11 | 2020-06-23 | Azanta Danmark A/S | Misoprostol dispersible tablet |
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| US20010026808A1 (en) * | 1998-07-07 | 2001-10-04 | Woolfe Austen John | Anti-inflammatory pharmaceutical formulations |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2965750A1 (en) * | 2014-07-11 | 2016-01-13 | Azanta A/S | Misoprostol dispersible tablet |
| WO2016004960A3 (en) * | 2014-07-11 | 2016-03-17 | Azanta A/S | Misoprostol dispersible tablet |
| EP3238715A1 (en) * | 2014-07-11 | 2017-11-01 | Azanta Danmark A/S | Misoprostol dispersible tablet |
| AU2015287186B2 (en) * | 2014-07-11 | 2018-05-31 | Azanta Danmark A/S | Misoprostol dispersible tablet |
| US10688072B2 (en) | 2014-07-11 | 2020-06-23 | Azanta Danmark A/S | Misoprostol dispersible tablet |
| EA039069B1 (en) * | 2014-07-11 | 2021-11-30 | Асанта Данмарк А/С | Method for obtaining cervical ripening or the induction of labor comprising administration of a pharmaceutical composition of misoprostol, and use of misoprostol in the manufacture of such composition |
| US12005041B2 (en) | 2014-07-11 | 2024-06-11 | Azanta Danmark A/S | Misoprostol dispersible tablet |
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