CN102258492A - Neostigmine bromide slow release preparation and its preparation method - Google Patents
Neostigmine bromide slow release preparation and its preparation method Download PDFInfo
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- CN102258492A CN102258492A CN 201010179891 CN201010179891A CN102258492A CN 102258492 A CN102258492 A CN 102258492A CN 201010179891 CN201010179891 CN 201010179891 CN 201010179891 A CN201010179891 A CN 201010179891A CN 102258492 A CN102258492 A CN 102258492A
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Abstract
The present invention belongs to the technical field of medicinal preparation. The invention discloses a formula of a neostigmine bromide slow release preparation which can be taken once every day for treating myasthemia gravis, functional flatulence after being performed an operation and urinary retention, as well as its preparation method. The preparation is disclosed as a slow release tablet form composed of a skeleton core containing neostigmine bromide and the slow release preparation and a coating. The neostigmine bromide slow release preparation of the present invention is capable of overcoming the disadvantage of present medicament common tablets in the market, slowly releasing to keep stable blood and medicine concentration, acting for a longer period, possessing low toxicity and side effect and conveniently taking the preparation, and the slow release preparation keeps effective blood and medicine concentration for a long time, reduces the medicine taking frequency, raises the compliance of the patients and reduces the side-effect due to over peak concentration. The invention has the advantages of simple preparation technology, low cost, easy control and easy industrial production.
Description
Technical field
The invention belongs to field of medicaments, relate to neostigmine bromide slow releasing tablet and preparation method thereof.
Background technology
Neostigmine bromide is a kind of cholinesterase inhibitor, neuromuscular junction position acetylcholine concentration is increased, the molecule that replaces non-depolarizing muscular relaxant effectively from its caudacoria, make the excited conduction of acetylcholine performance mediator, thereby muscular tension is recovered, be usually used in treating myasthenia gravis, the operation functional intestinal tympanites in back and urine retention clinically.Oral peak time is 1～3 hour, and the average blood plasma half-life is 0.87 hour, and domestic market listing preparation is the conventional tablet of neostigmine bromide, specification is every 15mg, and is oral, and usual amounts is a 15mg (1), 3 times on the one, patient's consumption of myasthenia gravis is decided on the state of an illness.This medicine need be taken when clinical treatment for a long time, and long-time frequent drug administration is made troubles to the patient, and blood concentration fluctuation is bigger in the body, easily causes toxic and side effects.In order to reduce administration number of times, improve patient's compliance, reduce the side effect that causes owing to peak concentration is too high, keep the effective blood drug concentration of long period, be necessary to develop the slow releasing tablet that slow release effect can reach 24 hours.Through inquiry patent and document, still there is not any research report of neostigmine bromide slow releasing tablet at present.
Summary of the invention
Technical problem to be solved by this invention provides a kind of slow release effect can reach neostigmine bromide slow releasing tablet of 24 hours and preparation method thereof.Can be administered once every day, have low take frequency, the advantage of few side effects.The neostigmine bromide slow releasing tablet that the present invention prepares can be used for treating myasthenia gravis, the operation functional intestinal tympanites in back and urine retention.The neostigmine bromide slow releasing tablet can overcome the shortcoming of present listing product neostigmine bromide conventional tablet, slowly discharges comparatively stable blood concentration and longer action time, and it is little to have toxic and side effects, takes convenient advantage.The neostigmine bromide slow releasing tablet can keep the effective blood drug concentration of long period, can reduce administration number of times, improves patient's compliance, reduces the too high side effect that causes of peak concentration.Neostigmine bromide slow releasing tablet preparation technology provided by the invention is simple, and cost is lower, is easy to control, is easy to suitability for industrialized production.
The technical problem that at first will solve of the present invention has provided a kind of prescription of neostigmine bromide slow releasing tablet.
Label is a matrix tablet, comprises following each component, and its weight consists of:
Neostigmine bromide 600-800 part
Hypromellose 1500-2500 part
Lactose 800-1200 part
Magnesium stearate 3000-3500 part
Pulvis Talci 100-180 part
95% alcoholic solution 100-150 part
Hypromellose (HPMC) can be HPMC K4M in the above core component, HPMC K15M or HPMCK100M.
Comprise the coatings I of the coating solution I composition of following each component, its weight consists of:
Sustained release film coat material 200-300 part
Polyethylene Glycol PEG 10-20 part
Neostigmine bromide 5-10 part
Comprise the coatings II of the coating solution II composition of following each component, its weight consists of:
Sustained release film coat material 10-15 part
Polyethylene Glycol PEG 1-2 part
Sustained release film coat material in the coatings can be an ethyl cellulose, cellulose acetate or both combinations, and the PEG in the coatings can be PEG6000, PEG4000, perhaps both combinations.
1. another technical problem to be solved of the present invention has provided a kind of preparation method of neostigmine bromide slow releasing tablet.This method comprises the following steps: (1) label preparation: take by weighing neostigmine bromide, HPMC, lactose and sieve by the label recipe quantity, mix homogeneously, with 95% alcoholic solution is wetting agent agent system soft material, the granulation of sieving, behind wet grain drying, granulate adds magnesium stearate, Pulvis Talci mixing, said mixture is put into the tablet machine compacting in flakes, obtain label.(2) coating: aqueous dispersion or acetone soln with coating solution I, carry out coating, to increasing weight to the 5%-8% of plate core weight.Aqueous dispersion or the acetone soln of reuse coating solution II carry out coating, to increasing weight to the 0.3%-1% of plate core weight.Drying, promptly.
The active component of preparation of the present invention is a neostigmine bromide, adopts matrix type to realize the slow release of medicine in conjunction with film controlling type.
The label that the present invention relates to is a matrix tablet, and adopting polymer substance hydroxypropyl methylcellulose HPMC is framework material.Hydroxypropyl methylcellulose HPMC is a hydrophilic gel material, has to expand and adhesion property, can prolong drug in the gastrointestinal time of staying.The rate of release of water soluble drug neostigmine bromide depends primarily on the diffusion velocity of medicine by gel layer, but only depend on hydrophilic gel material can not obtain ideal controlled-release effect, even adopt different framework materials, and the weight of framework material reach sheet heavy about 50%, drug release is still too fast in preceding two hours, sees Table 1.
Prescription 1: neostigmine bromide 4.5g, HPMC K4M 12.0g, lactose 6.0g, magnesium stearate 0.45g, Pulvis Talci 0.95g.
Prescription 2: neostigmine bromide 4.5g, HPMC K100M 12.5g, lactose 5.5g, magnesium stearate 0.45g, Pulvis Talci 0.95g prescription 3: neostigmine bromide 4.5g, HPMC K100M 7.0g, HPMC K15M 5.5g, lactose 5.5g, magnesium stearate 0.45g, Pulvis Talci 0.95g
Table 1 be 6 respectively according to prescription 1, prescription 2 and write out a prescription 3, by label preparation method of the present invention, the neostigmine bromide slow releasing tablet for preparing, according to Chinese Pharmacopoeia 2005 editions, the average cumulative release (%) that adopts agar diffusion method to measure.
Table 1
So on the basis of framework controlled release of the present invention, consider the binding film controlled release, dual controlled release mechanism obtains the more satisfactory sustained release of medicine, making one only needs oral administration once, can reach curative effect.
The coating membrane that the present invention relates to, with insoluble macromolecular material cellulose acetate is coating material, PEG6000 is rate of release regulator (porogen), the small amount of drug that adds in the coatings (coatings that coating solution I forms) than nexine both can discharge rapidly from preparation and play certain rapid release effect, the effect that also can produce rate of release regulator (porogen) simultaneously makes the drug slow in the label discharge the performance curative effect.Outside the clothing layer that coating solution I forms, wrap the coating rete that coating solution II forms again, water soluble drug is isolated from the outside comes, avoid because the hygroscopicity of medicine causes the medicament sustained-release tablets instability.
Adopting cellulose acetate is the film coating material, is the rate of release regulator with PEG 6000 only, and the slow releasing tablet releasing effect that obtains is not ideal enough.See Table 2.
The label prescription is: neostigmine bromide 4.5g, HPMC K4M 12.0g, lactose 6.0g, magnesium stearate 0.87g, Pulvis Talci 0.75g.By label preparation method preparation of the present invention.
Coating prescription 1: coating solution 1 is cellulose acetate 0.75g, PEG60000.045g, acetone 25ml.Coating weightening finish reach sheet heavy 5%.
Coating prescription 2: coating solution 1 is cellulose acetate 0.75g, PEG60000.045g, acetone 25ml.Coating weightening finish reach sheet heavy 8%.
Coating prescription 3: coating solution 2: cellulose acetate 0.75g, PEG60000.06g, acetone 25ml.Coating weightening finish reach sheet heavy 8%.
Coating prescription 4: coating solution 3: cellulose acetate 0.75g, PEG60000.09g, acetone 25ml.Coating weightening finish reach sheet heavy 8%.
Table 2 be 6 respectively on above-mentioned label with the coating 1-4 that writes out a prescription, be coating solution 1, coating solution 1, coating solution 2 and coating solution 3 coatings (coating weightening finish reach successively sheet heavy 5%, 8%, 8%, 8%) the neostigmine bromide slow releasing tablet for preparing after, according to Chinese Pharmacopoeia 2005 editions, the average cumulative release (%) that adopts agar diffusion method to measure.
Table 2
As can be seen from Table 2, coating solution 1 (coating weightening finish reach sheet heavy 5%), the neostigmine bromide slow releasing tablet that makes behind the coating discharges better in earlier stage, but the later stage discharges very fast, so consider to increase coatings thickness, coating solution 1 (the coating weightening finish reach sheet heavy 8%), coating solution 2 (the coating weightening finish reach sheet heavy 8%) and coating solution 3 (the coating weightening finish reach sheet heavy 8%) neostigmine bromide slow releasing tablet later stage of making behind the coating discharges better, but discharge slowly early stage, and coating solution 3 clothing film hardnesses descend to some extent.So consider to use coating solution 2 coatings, and reduce its clothing film gain in weight to increase release in early stage, (the neostigmine bromide water solublity is strong to consider to add in coating membrane neostigmine bromide increase release in early stage simultaneously, both can from preparation, discharge rapidly and play certain rapid release effect, the effect that also can produce the rate of release regulator simultaneously, make the drug slow in the label discharge the performance curative effect), see Table 3.
The label prescription is: neostigmine bromide 4.5g, HPMC K4M 12.0g, lactose 6.0g, magnesium stearate 0.87g, Pulvis Talci 0.75g.
Coating prescription 5: coating solution 2 is cellulose acetate 0.75g, PEG60000.06g, acetone 25ml.Coating weightening finish reach sheet heavy 6.3%.
Coating prescription 6: coating solution 4 is cellulose acetate 0.75g, PEG60000.045g, neostigmine bromide 0.0225g, acetone 25ml, dehydrated alcohol 5ml.Coating weightening finish reach sheet heavy 6.3%.
Table 3 be 6 respectively on above-mentioned label with coating solution 1, coating solution 1, coating solution 2 and coating solution 3 coatings (coating weightening finish reach successively sheet heavy 5%, 8%, 8%, 8%) the neostigmine bromide slow releasing tablet for preparing after, according to Chinese Pharmacopoeia 2005 editions, the average cumulative release that adopts agar diffusion method to measure.
Table 3
Cause the medicament sustained-release tablets instability for fear of hygroscopicity owing to medicine, increase the stability of neostigmine bromide slow releasing tablet, wrap coating solution 2 again outside the clothing layer that coating prescription 6 forms, the coating rete that coating solution 2 is formed allows water soluble drug be isolated from the outside and comes.
So on the basis of framework controlled release of the present invention, combine the film controlled release, dual controlled release mechanism obtains the more satisfactory sustained release of medicine, only needed oral administration once, can reach curative effect in 1st.
Simple employing skeleton or film controlled release that this patent is different from common research report design slow releasing tablet, the present invention utilizes framework controlled release and film controlled release dual controlled release mechanism to prepare lasting 24 hours neostigmine bromide slow releasing tablet of slow release effect first, the used coating solution of this law is different from conventional coating solution, the present invention has added a spot of medicine in the film coating solution (this small amount of drug both can discharge rapidly from preparation and play certain rapid release effect, the effect that also can produce rate of release regulator (porogen) simultaneously makes the drug slow in the label discharge the performance curative effect).Simultaneously, outside the clothing layer that coating solution I forms, wrap the coating rete that coating solution II forms again, water soluble drug is isolated from the outside comes, avoid because the hygroscopicity of medicine causes medicament sustained-release tablets instability (experimental results show that the neostigmine bromide slow releasing tablet stability that this law makes is fine).The neostigmine bromide slow releasing tablet for preparing can keep the effective blood drug concentration of long period, can reduce administration number of times, improves patient's compliance, reduces the too high side effect that causes of peak concentration.Can realize only need being administered once in 1st, be used for the treatment of myasthenia gravis, the operation functional intestinal tympanites in back and urine retention.
Description of drawings:
The release in vitro curve of the neostigmine bromide slow releasing tablet that Fig. 1 makes for embodiment 1
Experimental condition:, adopt the average release of 6 neostigmine bromide slow releasing tablet of agar diffusion method mensuration according to Chinese Pharmacopoeia 2005 editions.Experimental result shows that the neostigmine bromide slow releasing tablet can slowly discharge medicine, has slow releasing function.
The body giving drugs into nose of the neostigmine bromide slow releasing tablet that Fig. 2 makes for embodiment 1 is for kinetics
Adopt random packet, own control cross-over experiment method experimentizes.Average blood drug level-time graph in the body behind 9 experimental rabbit single oral dose slow releasing tablet and the ordinary tablet.High-efficient liquid phase technique is measured drug level.Experimental result shows that the neostigmine bromide slow releasing tablet can slowly discharge medicine, has slow releasing function.
In order to further specify the present invention and advantage thereof, provided following certain embodiments, should understand these embodiment only has in specifying rather than as the restriction of the scope of the invention.
Embodiment 1:
Label is a matrix tablet, comprises following each component, and its weight consists of:
750 parts of neostigmine bromides
2000 parts of HPMC K4M
1000 parts of lactose
3333 parts of magnesium stearate
145 parts of Pulvis Talci
125 parts of 95% alcoholic solution
The prescription of coating solution I, coating solution I comprise following each component, and its weight consists of:
250 parts of cellulose acetate
15 parts of PEG6000
8 parts of neostigmine bromides
6667 parts in acetone
1667 parts of dehydrated alcohol
The prescription of coating solution II, coating solution II comprise following each component, and its weight consists of:
13 parts of cellulose acetate
1 part of PEG6000
417 parts in acetone
Preparation method comprises the following steps: the preparation of (1) label: take by weighing neostigmine bromide, HPMC K4M, lactose and cross 100 sieves by the label recipe quantity, mix homogeneously, with 95% alcoholic solution is wetting agent agent system soft material, crossing 24 mesh sieves granulates, after wet granular placed 50 ℃ of dryings,, add magnesium stearate, Pulvis Talci mixing with 20 mesh sieve granulate, said mixture is put into the tablet machine compacting in flakes, obtain label.(2) coating: the neostigmine bromide with recipe quantity among the coating solution I is dissolved in the dehydrated alcohol of recipe quantity earlier, get the cellulose acetate and the PEG6000 (grinding and cross 80 mesh sieves earlier) of recipe quantity again, add acetone and dehydrated alcohol (being dissolved with neostigmine bromide), prepare coating solution I, carry out coating, to increasing weight to 6.3% of plate core weight.Get the cellulose acetate and the PEG6000 (grinding and cross 80 mesh sieves earlier) of recipe quantity among the coating solution II, be dissolved in acetone, prepare coating solution II, carry out coating, to increasing weight to 0.3% of plate core weight.Drying promptly gets the neostigmine bromide slow releasing tablet.
Every contains neostigmine bromide 45mg.
Embodiment 2:
Label is a matrix tablet, comprises following each component, and its weight consists of:
700 parts of neostigmine bromides
2000 parts of HPMC K15M
1000 parts of lactose
3000 parts of magnesium stearate
130 parts of Pulvis Talci
125 parts of 95% alcoholic solution
The prescription of coating solution I, coating solution I comprise following each component, and its weight consists of:
250 parts of ethyl celluloses
15 parts of PEG4000
8 parts of neostigmine bromides
The prescription of coating solution II, coating solution II comprise following each component, and its weight consists of:
13 parts of ethyl celluloses
1 part of PEG6000
The same substantially example I of preparation method.Difference is with the aqueous dispersion coating of coating solution.
Embodiment 3:
Label is a matrix tablet, comprises following each component, and its weight consists of:
650 parts of neostigmine bromides
2000 parts of HPMC K100M
1000 parts of lactose
3000 parts of magnesium stearate
120 parts of Pulvis Talci
110 parts of 95% alcoholic solution
The prescription of coating solution I, coating solution I comprise following each component, and its weight consists of:
210 parts of cellulose acetate
15 parts of PEG6000
5 parts of neostigmine bromides
6000 parts in acetone
1500 parts of dehydrated alcohol
The prescription of coating solution II, coating solution II comprise following each component, and its weight consists of:
13 parts of cellulose acetate
1 part of PEG6000
400 parts in acetone
The same substantially example I of preparation method.
Embodiment 4:
Label is a matrix tablet, comprises following each component, and its weight consists of:
800 parts of neostigmine bromides
2500 parts of HPMC K4M
1200 parts of lactose
3500 parts of magnesium stearate
180 parts of Pulvis Talci
150 parts of 95% alcoholic solution
The prescription of coating solution I, coating solution I comprise following each component, and its weight consists of:
300 parts of ethyl celluloses
20 parts of PEG6000
10 parts of neostigmine bromides
7000 parts in acetone
2000 parts of dehydrated alcohol
The prescription of coating solution II, coating solution II comprise following each component, and its weight consists of:
15 parts of ethyl celluloses
2 parts of PEG6000
450 parts in acetone
The same substantially example I of preparation method.
Embodiment 5:
Label is a matrix tablet, comprises following each component, and its weight consists of:
650 parts of neostigmine bromides
2300 parts of HPMC K100M
1000 parts of lactose
3000 parts of magnesium stearate
120 parts of Pulvis Talci
110 parts of 95% alcoholic solution
The prescription of coating solution I, coating solution I comprise following each component, and its weight consists of:
210 parts of cellulose acetate
12 parts of PEG6000
5 parts of neostigmine bromides
6000 parts in acetone
1500 parts of dehydrated alcohol
The same substantially example I of preparation method.
Embodiment 6:
Label is a matrix tablet, comprises following each component, and its weight consists of:
800 parts of neostigmine bromides
2500 parts of HPMC K4M
1200 parts of lactose
3500 parts of magnesium stearate
180 parts of Pulvis Talci
150 parts of 95% alcoholic solution
The prescription of coating solution I, coating solution I comprise following each component, and its weight consists of:
300 parts of ethyl celluloses
18 parts of PEG6000
10 parts of neostigmine bromides
The prescription of coating solution II, coating solution II comprise following each component, and its weight consists of:
15 parts of ethyl celluloses
1 part of PEG6000
Preparation method is substantially with embodiment 2.
Claims (7)
1. take every day the neostigmine bromide slow releasing tablet that can be used for treating myasthenia gravis, the operation functional intestinal tympanites in back and urine retention once, it is characterized in that this tablet is made up of label and coatings:
Contain the label that neostigmine bromide and following adjuvant are formed, its weight consists of:
Neostigmine bromide 600-800 part
Hypromellose 1500-2500 part
Lactose 800-1200 part
Magnesium stearate 3000-3500 part
Pulvis Talci 100-180 part
95% alcoholic solution 100-150 part
Comprise the coatings I of the coating solution I composition of following each component, its weight consists of:
Sustained release film coat material 200-300 part
Polyethylene Glycol PEG 10-20 part
Neostigmine bromide 5-10 part
Comprise the coatings II of the coating solution II composition of following each component, its weight consists of:
Sustained release film coat material 10-15 part
Polyethylene Glycol PEG 1-2 part
2. neostigmine bromide slow releasing tablet according to claim 1 is characterized in that its coatings can be made up of coatings I and coatings II, or its coatings contains coatings I, does not contain coatings II.
3. neostigmine bromide slow releasing tablet according to claim 1, hypromellose in the sheet core component (HPMC) can be HPMC K4M, HPMC K15M, HPMC K100M or any two or three combination.
4. neostigmine bromide slow releasing tablet according to claim 1, the sustained release film coat material in the coatings can be an ethyl cellulose, cellulose acetate or both combinations.
5. neostigmine bromide slow releasing tablet according to claim 1, the PEG in the coatings can be PEG6000, PEG4000, perhaps both combinations.
6. neostigmine bromide slow releasing tablet according to claim 1, coating solution can be aqueous dispersion or acetone soln.
7. a preparation method of taking neostigmine bromide slow releasing tablet once every day is characterized in that this method comprises the following steps:
(1) label preparation: take by weighing neostigmine bromide, HPMC, lactose and sieve by the label recipe quantity, mix homogeneously, with 95% alcoholic solution is wetting agent agent system soft material, the granulation of sieving, behind wet grain drying, granulate adds magnesium stearate, Pulvis Talci mixing, said mixture is put into the tablet machine compacting in flakes, obtain label.(2) coating: aqueous dispersion or acetone soln with each component of coating solution I, carry out coating, to increasing weight to the 5%-8% of plate core weight.The aqueous dispersion or the acetone soln of each component of reuse coating solution II carry out coating, to increasing weight to the 0.3%-1% of plate core weight.Drying, promptly.
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103054823A (en) * | 2012-12-30 | 2013-04-24 | 北京阜康仁生物制药科技有限公司 | Solid preparation taking distigmine bromide as active ingredient |
| CN103191059A (en) * | 2013-03-31 | 2013-07-10 | 重庆医科大学 | Neostigmine bromide muhivescular liposome and preparation method thereof |
| CN104523567A (en) * | 2014-12-25 | 2015-04-22 | 海南卫康制药(潜山)有限公司 | Neostigmine bromide composition freeze-dried tablet and preparation method thereof |
| CN105434403A (en) * | 2015-12-30 | 2016-03-30 | 成都医学院 | Pyridostigmine bromide coated sustained-release pellets and preparation method thereof |
| CN105943537A (en) * | 2016-06-28 | 2016-09-21 | 顾万清 | Compound anisodamine and neostigmine sustained-release tablet and preparation method thereof |
| WO2020014072A1 (en) * | 2018-07-09 | 2020-01-16 | Gt Biopharma, Inc. | Neostigmine pharmaceutical combination for treating myasthenia gravis |
| US11389420B2 (en) * | 2017-07-25 | 2022-07-19 | Das-Mg, Inc. | Pharmaceutical compositions and methods utilizing neostigmine and an NK-1 antagonist for treating myasthenia gravis |
| US11896582B2 (en) | 2017-01-09 | 2024-02-13 | Das-Mg, Inc. | Use and composition for treating myasthenia gravis and other myasthenic syndromes |
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| US20020110593A1 (en) * | 1999-06-04 | 2002-08-15 | Adel Penhasi | Delayed total release two pulse gastrointestinal drug delivery system |
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Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103054823A (en) * | 2012-12-30 | 2013-04-24 | 北京阜康仁生物制药科技有限公司 | Solid preparation taking distigmine bromide as active ingredient |
| CN103191059A (en) * | 2013-03-31 | 2013-07-10 | 重庆医科大学 | Neostigmine bromide muhivescular liposome and preparation method thereof |
| CN103191059B (en) * | 2013-03-31 | 2014-12-10 | 重庆医科大学 | Neostigmine bromide muhivescular liposome and preparation method thereof |
| CN104523567A (en) * | 2014-12-25 | 2015-04-22 | 海南卫康制药(潜山)有限公司 | Neostigmine bromide composition freeze-dried tablet and preparation method thereof |
| CN105434403A (en) * | 2015-12-30 | 2016-03-30 | 成都医学院 | Pyridostigmine bromide coated sustained-release pellets and preparation method thereof |
| CN105943537A (en) * | 2016-06-28 | 2016-09-21 | 顾万清 | Compound anisodamine and neostigmine sustained-release tablet and preparation method thereof |
| US11896582B2 (en) | 2017-01-09 | 2024-02-13 | Das-Mg, Inc. | Use and composition for treating myasthenia gravis and other myasthenic syndromes |
| US11389420B2 (en) * | 2017-07-25 | 2022-07-19 | Das-Mg, Inc. | Pharmaceutical compositions and methods utilizing neostigmine and an NK-1 antagonist for treating myasthenia gravis |
| US12023315B2 (en) | 2017-07-25 | 2024-07-02 | Somerset Therapeutics, Llc | Pharmaceutical compositions and methods utilizing neostigmine and an NK-1 antagonist for treating myasthenia gravis |
| WO2020014072A1 (en) * | 2018-07-09 | 2020-01-16 | Gt Biopharma, Inc. | Neostigmine pharmaceutical combination for treating myasthenia gravis |
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|---|---|
| CN102258492B (en) | 2012-12-26 |
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