CN102872024B - Misoprostol medicine combination used in mouths - Google Patents
Misoprostol medicine combination used in mouths Download PDFInfo
- Publication number
- CN102872024B CN102872024B CN201210369464.0A CN201210369464A CN102872024B CN 102872024 B CN102872024 B CN 102872024B CN 201210369464 A CN201210369464 A CN 201210369464A CN 102872024 B CN102872024 B CN 102872024B
- Authority
- CN
- China
- Prior art keywords
- misoprostol
- mixture
- mannitol
- magnesium stearate
- preparation
- 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.)
- Expired - Fee Related
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- 210000002620 vena cava superior Anatomy 0.000 description 1
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 present invention relates to the pharmaceutical composition containing misoprostol used in oral cavity, can be used for promoting uterine contraction, prevention and therapy postpartum hemorrhage.The invention belongs to medical art.
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, uterine contractions fatigue is hemorrhage accounts for first place, and incidence rate is 50%-75%, accounts for 2/3 of postpartum hemorrhage.Reduce the basic health objectives that maternal mortality rate is many developing countries.The Section 5 MDGs emphasis of the United Nations is, by 2015, maternal death ratio is reduced 3/4.But, in the area of many scarcity of resources, recommend the intervening measure of these ratios of minimizing or cannot obtain, or too expensive pair is not risen.Many tradition be used for preventing treatment postpartum hemorrhage or post-abortion hemorrhage uterine contraction medicine, as oxytocin or other prostaglandins, only can store some months in room temperature or need cold preservation, and usually needing injection.
Misoprostol is a kind of prostatitis element E1 analog of synthesis, 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 it is then much stable than sterling with the mixture of hydroxypropyl emthylcellulose, can preserve at normal temperatures.The eighties in 20th century, early stage misoprostol was at first for peptic ulcer; ulcer healing can be impelled; or symptom is alleviated; its protection Gastroduodenal mucosal lesions is by suppressing basal gastric acid secretion; after irriate gastric acid secretion and night gastric acid secretion; and by reducing gastric secretion, suppress the activity of proteolytic enzyme in gastric juice, and realized by increase bicarbonate and mucus.After the eighties, misoprostol and mifepristone are used for antiearly pregnancy, and full connection can be made greatly to improve.Mifepristone can be combined by the progesterone receptor in health, and the vigor of progesterone in health is declined, once lack progesterone in health, will cause miscarriage.And misoprostol can make uterus that strong contraction occurs, conceived tissue is forced to excrete.
The researcher of various countries has done the effect that a large amount of clinical trials is applied to evaluate misoprostol at department of obstetrics and gynecology in recent years, and as cervix maturation, induced labor, postpartum hemorrhage etc., misoprostol is more and more widely used in department of obstetrics and gynecology field.The misoprostol preparation of China's listing is common oral tablet, and the representative preparation being used for the treatment of gastric ulcer is Cytotec (specification is every sheet 0.2mg); The misoprostol tablets by LC-MS (specification 0.2mg) that the representative preparation stopping early pregnancy is black bamboo Pharmaceutical is share with mifepristone.For the Vaginal Misoprostol sheet (specification is every sheet 25 μ g) of cervix maturation-stimulating, be now in clinical experimental stage, the preparation not for preventing or treat postpartum hemorrhage appropriate size.
At present, prevention or treatment postpartum hemorrhage promote that uterine contraction generally uses oxytocin clinically, but uterine smooth muscle has substantial connection to the sensitivity of contracting palace rope and body inner estrogen level, the sensitivity of gravid uterus to oxytocin also has individual variation, and oxytocin is larger to body of uterus excitation, less to cervix uteri excitation, clinical research finds, oxytocin uses more than 40U, continue to use and then promote uterine contraction DeGrain, and prostaglandin is the unsaturated fatty acid that a class is extensively present in body, action effect and hormone in vivo level have nothing to do, and misoprostol not only has uterine contraction effect consumingly, muscle fiber is shortened, and can frequency of uterine contraction be strengthened, therefore misoprostol can be selected 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 immediately after delivery of baby and prevent and cure the postpartum bleeding, average third stage of labor 5min, is mainly used in the puerpera of normal pregnancy vaginal delivery in more than 32 weeks.After using misoprostol, blood pressure is without significant change, illustrates that misoprostol does not affect blood pressure, does not increase the load of puerpera's cardiovascular system, the puerpera be particularly useful for suffering from the hypertensions such as preeclampsia, postpartum hemorrhage easily occurring.
The pharmaceutical composition that misoprostol is made with necessary pharmaceutic adjuvant by the present invention, its dosage form can be Sublingual tablet, chewable tablet, buccal tablets, oral cavity disintegration tablet, pelliculae pro cavo oris and drop pill, can in dissolved in oral cavity, disintegrate, dispersion without the need to drinking-water, or chew by oral cavity and make its disintegrate, dispersion, some drugs absorbs through lingual mucous membrane, cheek film, directly blood circulation is entered by jugular vein and superior vena cava, onset is rapid, the first pass effect of liver can be avoided, improve bioavailability, and alleviate gastrointestinal discomfort.This Pharmaceutical composition medication is simple, safe and effective, is 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 containing misoprostol used in oral cavity, have and can prepare promotion uterine contraction, the application in prevention and therapy postpartum hemorrhage medicine, for clinical practice provides a kind of easy, safe therapeutic choice.
The object of the present invention is achieved like this:
A kind of good mouthfeel, can in dissolved in oral cavity, disintegrate, dispersion without the need to drinking-water, or the pharmaceutical composition containing misoprostol making its disintegrate, dispersion is chewed by oral cavity, it is characterized in that in the pharmaceutical composition of per unit dosage containing misoprostol 0.2mg ~ 0.6mg, or the misoprostol of corresponding dosage-hypromellose mixture, and the pharmaceutic adjuvant of necessity 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 in the present invention is unstable at room temperature, but misoprostol-hypromellose mixture is then much stable than sterling, can preserve at normal temperatures.The present invention's preferred misoprostol-hypromellose mixture (including 1% misoprostol).
The pharmaceutic adjuvant added in described misoprostol Sublingual tablet, misoprostol chewable tablet and misoprostol buccal tablets comprises filler, binding agent and lubricant, also can comprise disintegrating agent and sweeting agent as required.The pharmaceutic adjuvant added in 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 Formulation object.
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 the mixture of one or more in cross-linking sodium carboxymethyl cellulose, crospolyvinylpyrrolidone, low-substituted hydroxypropyl level cellulose and 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 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 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 (i.e. misoprostol-hypromellose mixture 20 ~ 60g) in every 1000, containing filler 50 ~ 200g, containing disintegrating agent 5 ~ 10g, containing sweeting agent 0 ~ 20g, containing lubricant 0.5 ~ 5g, binding agent is appropriate.Preferably in the misoprostol Sublingual tablet of every 1000 containing misoprostol 0.2 ~ 0.6g (i.e. misoprostol-hypromellose mixture 20 ~ 60g), containing filler 80 ~ 120g, containing disintegrating agent 2 ~ 20g, containing sweeting agent 0.2 ~ 5g, containing lubricant 1 ~ 2g, binding agent is appropriate.
Described misoprostol chewable tablet, containing misoprostol 0.2 ~ 0.6g (i.e. misoprostol-hypromellose mixture 20 ~ 60g) in every 1000, containing filler 50 ~ 200g, containing sweeting agent 0.2 ~ 20g, containing lubricant 0.5 ~ 5g, binding agent is appropriate.Preferably in the misoprostol chewable tablet of every 1000 containing misoprostol 0.2 ~ 0.6g (i.e. misoprostol-hypromellose mixture 20 ~ 60g), containing filler 80 ~ 120g, containing sweeting agent 0.2 ~ 5g, containing lubricant 1 ~ 2g, binding agent is appropriate.
Described misoprostol oral cavity disintegration tablet, containing misoprostol 0.2 ~ 0.6g (i.e. misoprostol-hypromellose mixture 20 ~ 60g) in every 1000, containing filler 50 ~ 200g, containing disintegrating agent 5 ~ 15g, containing sweeting agent 0 ~ 20g, containing lubricant 0.5 ~ 5g, binding agent is appropriate.Preferably in the misoprostol oral cavity disintegration tablet of every 1000 containing misoprostol 0.2 ~ 0.6g (i.e. misoprostol-hypromellose mixture 20 ~ 60g), containing filler 80 ~ 120g, containing sweeting agent 0.2 ~ 5g, containing lubricant 1 ~ 2g, binding agent is appropriate.
Described misoprostol buccal tablets, containing misoprostol 0.2 ~ 0.6g (i.e. misoprostol-hypromellose mixture 20 ~ 60g) in every 1000, containing filler 50 ~ 200g, containing sweeting agent 0 ~ 20g, containing lubricant 0.5 ~ 5g, binding agent is appropriate.Preferably in the misoprostol buccal tablets of every 1000 containing misoprostol 0.2 ~ 0.6g (i.e. misoprostol-hypromellose mixture 20 ~ 60g), containing filler 80 ~ 120g, containing sweeting agent 0.2 ~ 5g, containing lubricant 1 ~ 2g, binding agent is appropriate.
The preparation method of described misoprostol Sublingual tablet, misoprostol chewable tablet, misoprostol oral cavity disintegration tablet and misoprostol buccal tablets comprises the method for preparing tablet thereof of direct powder compression, compressing dry granulation and other routine, preferred direct powder compression.
Tool of the present invention has the following advantages:
Misoprostol Sublingual tablet of the present invention, chewable tablet, buccal tablets and oral cavity disintegration tablet are placed in oral cavity when taking, without the need to drinking-water namely in dissolved in oral cavity, disintegrate, dispersion, or chew by oral cavity and make compositions disintegrate, dispersion, then, under medicine is absorbed rapidly or swallowed in oral cavity, curative effect can be played rapidly.
Misoprostol Sublingual tablet of the present invention, chewable tablet, buccal tablets and oral cavity disintegration tablet, all or part ofly absorb onset in oral cavity, can also be made up pelliculae pro cavo oris, the drop pill of rapid oral dissolution or disintegrate of 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, without the need to drinking-water, good mouthfeel, improves the compliance of patient.
Misoprostol Sublingual tablet of the present invention, chewable tablet, buccal tablets and oral cavity disintegration tablet, its preparation method is applicable to suitability for industrialized production.
Detailed description of the invention
Below in conjunction with embodiment, the present invention will be further described, but the present invention is not limited to these embodiments.
Embodiment 1
The preparation (1000 amounts) of misoprostol Sublingual tablet
Preparation method: by misoprostol-hypromellose mixture, mannitol, lactose, cross-linking sodium carboxymethyl cellulose, aspartame, the pretreatment of Magnesium Stearate 100 order; By above-mentioned pretreated stock and adjunct mix homogeneously; Detect the content of said mixture, calculate sheet weight, the shallow stamping of 8mm obtains finished product.
Measure according to inspection technique disintegration specified in 2010 editions Pharmacopoeias of the People's Republic of China, two annex XA, the results are shown in Table 1.
Dissolving the time limit (n=6) of table 1 misoprostol Sublingual tablet
Embodiment 2
The preparation (1000 amounts) of misoprostol chewable tablet
Preparation method: using part xylitol, pregelatinized Starch, crospolyvinylpyrrolidone, stevioside aqueous povidone solution as binding agent, soft material processed, 16 mesh sieves are granulated, after 60 DEG C of dryings, granulate, fully mix with part xylitol blend with misoprostol-hypromellose mixture, magnesium stearate, Pulvis Talci mix homogeneously; Detect the content of said mixture, calculate sheet weight, the shallow stamping of 10mm obtains finished product.
Embodiment 3
The preparation (1000 amounts) of misoprostol oral cavity disintegration tablet
Preparation method: 80 order pretreatment that mannitol, low-substituted hydroxypropyl cellulose, hydroxypropyl methylcellulose are sieved, mix soft material processed, 16 mesh sieves are granulated, after 60 DEG C of dryings, granulate, mixs homogeneously with misoprostol-hypromellose mixture, part mannitol mixture, magnesium stearate; Detect the content of said mixture, calculate sheet weight, the flat stamping of 6.5mm obtains finished product.
The disintegration time mensuration method of misoprostol oral cavity disintegration tablet is: get 6 10mL small beakers, add the water of 2mL constant temperature to 37 DEG C respectively, respectively put into this product 1, static placement 1 minute, 6 all should disintegrate in 1 minute, jolting is gently all 24 object screen clothes (can rinse with the water of no more than 5mL if desired) by aperture, remains without grit.Measurement result is in table 2.
The disintegration (n=6) of table 2 misoprostol oral cavity disintegration tablet
Embodiment 4
The preparation (1000 amounts) of misoprostol buccal tablets
Preparation method: mannitol, sorbitol, Icing Sugar, cyclamate are done blank granules, mixing with part mannitol mixture with misoprostol-hypromellose mixture, magnesium stearate mixs homogeneously; Detect the content of said mixture, calculate sheet weight, the flat stamping of 9mm obtains finished product.
Measure according to inspection technique disintegration specified in 2010 editions Pharmacopoeias of the People's Republic of China, two annex XA, the results are shown in Table 3.
Dissolving the time limit (n=6) of table 3 misoprostol buccal tablets
Claims (4)
1. a misoprostol Sublingual tablet, it is characterized in that every 1000 are made up of 0.6g misoprostol, 60g sorbitol, 20g mannitol, 20g lactose, 4g cross-linking sodium carboxymethyl cellulose, 3g aspartame and 1g magnesium stearate, its preparation method is: by misoprostol-hypromellose mixture, mannitol, lactose, cross-linking sodium carboxymethyl cellulose, aspartame, the pretreatment of Magnesium Stearate 100 order; By above-mentioned pretreated stock and adjunct mix homogeneously; Detect the content of said mixture, calculate sheet weight, the shallow stamping of 8mm obtains finished product.
2. a misoprostol chewable tablet, it is characterized in that every 1000 by 0.4g misoprostol, 220g xylitol, 70g pregelatinized Starch, 3g crospolyvinylpyrrolidone, 2g polyvinylpyrrolidone, 2g stevioside, 1g magnesium stearate and 2g Pulvis Talci composition, its preparation method is: by part xylitol, pregelatinized Starch, crospolyvinylpyrrolidone, stevioside aqueous povidone solution is as binding agent, soft material processed, 16 mesh sieves are granulated, after 60 DEG C of dryings, granulate, fully mix with part xylitol blend with misoprostol-hypromellose mixture, magnesium stearate, Pulvis Talci mix homogeneously, detect the content of said mixture, calculate sheet weight, the shallow stamping of 10mm obtains finished product.
3. a misoprostol oral cavity disintegration tablet, it is characterized in that every 1000 are made up of 0.2g misoprostol, 100g mannitol, 10g low-substituted hydroxypropyl cellulose, 2g hydroxypropyl methylcellulose and 1g magnesium stearate, its preparation method is: 80 order pretreatment of mannitol, low-substituted hydroxypropyl cellulose, hydroxypropyl methylcellulose being sieved, mix soft material processed, 16 mesh sieves are granulated, after 60 DEG C of dryings, granulate, mixs homogeneously with misoprostol-hypromellose mixture, part mannitol mixture, magnesium stearate; Detect the content of said mixture, calculate sheet weight, the flat stamping of 6.5mm obtains finished product.
4. a misoprostol buccal tablets, it is characterized in that every 1000 are made up of 0.4g misoprostol, 60g mannitol, 50g sorbitol, 30g Icing Sugar, the sweet match honey of 2g and 2g magnesium stearate, its preparation method is: mannitol, sorbitol, Icing Sugar, cyclamate are done blank granules, and mixing with part mannitol mixture with misoprostol-hypromellose mixture, magnesium stearate mixs homogeneously; Detect the content of said mixture, calculate sheet weight, the flat stamping of 9mm obtains finished product.
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| TN2017000003A1 (en) * | 2014-07-11 | 2018-07-04 | Azanta Danmark As | Misoprostol dispersible tablet. |
| US20160008310A1 (en) | 2014-07-11 | 2016-01-14 | Azanta A/S | Misoprostol dispersible tablet |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20010026808A1 (en) * | 1998-07-07 | 2001-10-04 | Woolfe Austen John | Anti-inflammatory pharmaceutical formulations |
| CN1939308A (en) * | 2005-09-28 | 2007-04-04 | 应圣俊 | Misoalprostacol suppository |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20010026808A1 (en) * | 1998-07-07 | 2001-10-04 | Woolfe Austen John | Anti-inflammatory pharmaceutical formulations |
| CN1939308A (en) * | 2005-09-28 | 2007-04-04 | 应圣俊 | Misoalprostacol suppository |
Non-Patent Citations (1)
| Title |
|---|
| 李泸湘,等.400μg米索前列醇口服和舌下含服预防产后出血的临床研究.《中国妇幼保健》.2007,第22卷(第18期),2548-2549. * |
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