CN102516143B - Tiopronin sterile powder and preparation and preparation method thereof - Google Patents
Tiopronin sterile powder and preparation and preparation method thereof Download PDFInfo
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- CN102516143B CN102516143B CN201210003568XA CN201210003568A CN102516143B CN 102516143 B CN102516143 B CN 102516143B CN 201210003568X A CN201210003568X A CN 201210003568XA CN 201210003568 A CN201210003568 A CN 201210003568A CN 102516143 B CN102516143 B CN 102516143B
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- 108010058907 Tiopronin Proteins 0.000 title claims abstract description 83
- 229960004402 tiopronin Drugs 0.000 title claims abstract description 83
- YTGJWQPHMWSCST-UHFFFAOYSA-N Tiopronin Chemical compound CC(S)C(=O)NCC(O)=O YTGJWQPHMWSCST-UHFFFAOYSA-N 0.000 title claims abstract description 81
- 239000000843 powder Substances 0.000 title claims abstract description 49
- 238000002360 preparation method Methods 0.000 title claims abstract description 40
- 238000002347 injection Methods 0.000 claims abstract description 43
- 239000007924 injection Substances 0.000 claims abstract description 43
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims abstract description 26
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims abstract description 15
- 238000001035 drying Methods 0.000 claims abstract description 9
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 21
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 claims description 21
- 238000001914 filtration Methods 0.000 claims description 19
- 239000000706 filtrate Substances 0.000 claims description 14
- 239000013078 crystal Substances 0.000 claims description 10
- 238000010992 reflux Methods 0.000 claims description 10
- 238000010521 absorption reaction Methods 0.000 claims description 9
- 239000003610 charcoal Substances 0.000 claims description 4
- 239000012467 final product Substances 0.000 claims description 4
- 239000012982 microporous membrane Substances 0.000 claims description 3
- 238000010298 pulverizing process Methods 0.000 claims description 3
- 239000002994 raw material Substances 0.000 abstract description 8
- 238000004519 manufacturing process Methods 0.000 abstract description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 abstract description 3
- 229910052799 carbon Inorganic materials 0.000 abstract 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 abstract 1
- 239000002510 pyrogen Substances 0.000 abstract 1
- 239000012535 impurity Substances 0.000 description 10
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- 230000014759 maintenance of location Effects 0.000 description 8
- 238000002425 crystallisation Methods 0.000 description 7
- 230000008025 crystallization Effects 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 229940079593 drug Drugs 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- 238000001291 vacuum drying Methods 0.000 description 4
- 238000009835 boiling Methods 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 230000008859 change Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 208000006454 hepatitis Diseases 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 230000003908 liver function Effects 0.000 description 2
- 210000003470 mitochondria Anatomy 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 238000004806 packaging method and process Methods 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 150000003254 radicals Chemical class 0.000 description 2
- 125000003396 thiol group Chemical group [H]S* 0.000 description 2
- -1 tiopronin compound Chemical class 0.000 description 2
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 1
- 206010008909 Chronic Hepatitis Diseases 0.000 description 1
- VVNCNSJFMMFHPL-VKHMYHEASA-N D-penicillamine Chemical compound CC(C)(S)[C@@H](N)C(O)=O VVNCNSJFMMFHPL-VKHMYHEASA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 208000004930 Fatty Liver Diseases 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 206010019708 Hepatic steatosis Diseases 0.000 description 1
- 206010019728 Hepatitis alcoholic Diseases 0.000 description 1
- GGLZPLKKBSSKCX-YFKPBYRVSA-N L-ethionine Chemical compound CCSCC[C@H](N)C(O)=O GGLZPLKKBSSKCX-YFKPBYRVSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 208000002353 alcoholic hepatitis Diseases 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 231100000012 chronic liver injury Toxicity 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 208000010706 fatty liver disease Diseases 0.000 description 1
- 150000002332 glycine derivatives Chemical class 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- 230000002440 hepatic effect Effects 0.000 description 1
- 231100000753 hepatic injury Toxicity 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 210000005229 liver cell Anatomy 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 229960005489 paracetamol Drugs 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 230000000452 restraining effect Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 238000010532 solid phase synthesis reaction Methods 0.000 description 1
- 231100000240 steatosis hepatitis Toxicity 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention relates to the field of pharmaceutical engineering, in particular to a tiopronin sterile powder and a preparation and a preparation method thereof. The preparation method disclosed by the invention comprises the following steps of: adding an ethyl formate-dissolvable tiopronin raw material into an active carbon heat removing source for injection; adding ether or methyl tert-butyl ether for recrystallizing; and drying at a low temperature to obtain tiopronin sterile powder which is free from pyrogen and has high purity. The preparation method disclosed by the invention is easy and convenient to operate, and has high yield; and the obtained tiopronin sterile powder has high purity and safe and reliability quality, is suitable for preparing a tiopronin sterile powder injection, and can be widely applied to mass production of tiopronin sterile powder injections.
Description
Technical field
The present invention relates to the pharmaceutics field, relate to specifically a kind of tiopronin aseptic powder and preparation and preparation method.
Background technology
Tiopronin, English name Tiopronin, chemistry N-(2-mercapto radical propionyl group) by name-glycine, be a kind of novel glycine derivative that contains free sulfhydryl groups, molecular formula is C
5H
9NO
3S, molecular weight is 163.20, structural formula is as follows:
Tiopronin is a kind of similar to Trolovol character sulfydryl medicine that contains, and has the effect of protection liver organization and cell.Experimentation on animals shows; tiopronin can be by providing sulfydryl; prevent the hepatic injury that tetracol phenixin, ethionine, paracetamol etc. cause; and the triglyceride level of chronic hepatic injury is accumulated restraining effect is arranged; can also make the activity decreased of ATP enzyme in liver cell mitochondria; thereby protection hepatic mitochondria structure, improve liver function.Be mainly used in clinically improving the liver function of all kinds of acute and chronic hepatitis patients and the detoxifcation that treatment fatty liver, alcoholic hepatitis, liver lesion induced by drugs injure heavy metal, in addition, tiopronin can also, by the Reversible binding of sulfydryl and free radical, be removed free radical.Tiopronin, also for reducing the toxic side effect of chemicotherapy, prevents the peripheral leukocytes minimizing of caused by radiotherapy and chemotherapy and the generation of secondary tumour.
The at present domestic production listing that water needle injection and lyophilized injectable powder and the aseptic powder injection preparation of tiopronin have been arranged.But because tiopronin itself contains free sulfhydryl groups, it is poor at water stability, and oxidizing reaction easily occurs, so very easily produces impurity in the tiopronin water needle injection, exists the storage time short, the drawback that validity period is short, and can therefore produce the drug safety problem.Powder injection can address the above problem, but because the production technique of tiopronin freeze-dried powder injection is stricter to equipment requirements, working condition is harsher, energy consumption is larger, be unfavorable for industrialized production, and in its production process, need with water, to contact for a long time, in the process of producing, also can produce a large amount of impurity, therefore likely cause quality product not meet the requirement of state-promulgated pharmacopoeia standard.
The aseptic powder injection preparation refers to and does not need medicine is made to the aqueous solution but directly bulk drug is refined into to sterilized powder, then under aseptic condition, carries out aseptic subpackaged and get final product.Tiopronin aseptic powder injection preparation has avoided tiopronin to contact with water, has reduced the generation of impurity.Yet in the production of the tiopronin aseptic powder injection preparation of having reported, the tiopronin aseptic powder is mainly to carry out purifying by re-crystallizing in ethyl acetate, but the boiling point of ethyl acetate is higher, it is 77 ℃, and the fusing point of tiopronin lower (96～99 ℃), less stable, at high temperature easily produce impurity, therefore in recrystallization and drying process, easily cause tiopronin to decompose, cause impurity in the process of production to increase.
Summary of the invention
In view of this, the present invention seeks to for deficiency of the prior art, a kind of yield is high, purity is high tiopronin aseptic powder and preparation and preparation method are provided.
For realizing purpose of the present invention, the present invention adopts following technical scheme:
A kind of preparation method of tiopronin aseptic powder comprises:
Step 1: tiopronin is dissolved with ethyl formate, be heated to reflux, add the injection charcoal absorption, filter;
Step 2: get step 1 gained filtrate, add ether or methyl tertiary butyl ether, heated and stirred is dissolved, positive press filtration;
Step 3: get step 2 gained filtrate and be refrigerated to-5～5 ℃ of crystallizatioies, collect the gained crystal, after filtration, at 15～30 ℃ of lower drying under reduced pressure, after pulverizing and get final product.
Wherein, tiopronin of the present invention refer to adopt that liquid phase is synthetic or solid phase synthesis is that obtain, tiopronin compound that tiopronin compound that not yet pass through refinement treatment or purity can not fulfilling medicinals.
Preparation method of the present invention adopts ethyl formate to dissolve the tiopronin raw material.Wherein, as preferably, the consumption of described ethyl formate is counted 4～10 times of tiopronin, more preferably 6～8 times by g/mL.Be that every 1g tiopronin preferably adds the ethyl formate of 4～10mL to dissolve, more preferably add 6～8mL ethyl formate to dissolve.
Preparation method of the present invention adds injection then to filter with charcoal absorption in the tiopronin that ethyl formate dissolves, to remove thermal source wherein.As preferably, described injection uses add-on by gac by g/mL, is 0.1%～0.5% of ethyl formate, and more preferably 0.2%～0.3%.Be that every 100mL milliliter ethyl formate preferably adds 0.1～0.5g injection to use by gac, more preferably add 0.2～0.3g injection to use by gac.
Described absorption is preferably and adds injection to reflux 30 minutes with heating activated carbon.
After the gained filtrate that preparation method's step 2 of the present invention is got step 1 filtering thermal source adds ether or methyl tertiary butyl ether heating for dissolving, the positive press filtration degerming.Wherein, the consumption of described ether or methyl tertiary butyl ether is preferably the 5v/v%～30v/v% of ethyl formate, more preferably 10v/v%～20v/v%.Be that every 100mL milliliter ethyl formate preferably adds 5～30mL ether or methyl tertiary butyl ether, described 10～20mL ether or the methyl tertiary butyl ether of more preferably adding.Described positive press filtration is preferably below 0.1Mpa, with 0.22 μ m filtering with microporous membrane.
Preparation method's step 3 of the present invention is got step 2 filtration sterilization gained filtrate low temperature crystallization, and gained crystal drying and crushing namely obtains the tiopronin aseptic powder.
Preparation method of the present invention adopts ethyl formate dissolving tiopronin raw material to add the injection gac except thermal source, then adds ether or methyl tertiary butyl ether to carry out recrystallization, dry at low temperatures pyrogen-free and the high tiopronin aseptic powder of purity of obtaining.Compared with prior art, preparation method of the present invention has avoided tiopronin to contact with water, has solved the problem of the easy oxidation generation of tiopronin impurity in tiopronin liquid drugs injection injection liquid and freeze-dried powder.And because the ethyl formate boiling point is lower, be only 53.4～54.4 ℃, and the boiling point of ethers reagent is also quite low, ether is 34 ℃, methyl tertiary butyl ether is 55.2 ℃, therefore recrystallization and vacuum-drying temperature are all relatively low, therefore utilize ethyl formate dissolving tiopronin ether or methyl tertiary butyl ether recrystallization can not cause the decomposition of tiopronin.In addition, adopt preparation method of the present invention to prepare the yield of tiopronin aseptic powder higher, reach 85～92%, and purity is also very high, reaches 99.3～99.8%.
The present invention also provides the tiopronin that is made by above-mentioned preparation method aseptic powder.
The present invention also provides a kind of tiopronin preparation, and it contains the tiopronin aseptic powder that preparation method of the present invention makes.
As preferably, described tiopronin preparation is the aseptic powder injection injection.
In an embodiment, aseptic powder injection injection of the present invention is obtained by the tiopronin aseptic powder direct packaging that preparation method of the present invention makes.
In other embodiments, aseptic powder injection injection of the present invention is obtained by tiopronin aseptic powder and the rear packing of sterile sodium bicarbonate mixing that preparation method of the present invention makes.Preferably, the weight ratio of described tiopronin aseptic powder and sodium bicarbonate is 1: 0.8～1.2, more preferably 1: 0.8～1.
The accompanying drawing explanation
Fig. 1 shows the HPLC color atlas of the tiopronin raw material in the embodiment of the present invention 1～3, and wherein relative retention time is that the peak of 7.248min is the absorption peak of tiopronin, and the peak of all the other relative retention times is impurity peaks;
Fig. 2 shows the HPLC color atlas of the tiopronin aseptic powder that the embodiment of the present invention 1 makes, and wherein relative retention time is that the peak of 7.301min is the absorption peak of tiopronin, and the peak of all the other relative retention times is impurity peaks;
Fig. 3 shows the HPLC color atlas of the tiopronin aseptic powder that the embodiment of the present invention 2 makes, and wherein relative retention time is that the peak of 7.257min is the absorption peak of tiopronin, and the peak of all the other relative retention times is impurity peaks;
Fig. 4 shows the HPLC color atlas of the tiopronin aseptic powder that the embodiment of the present invention 3 makes, and wherein relative retention time is that the peak of 7.260min is the absorption peak of tiopronin, and the peak of all the other relative retention times is impurity peaks.
Embodiment
The embodiment of the invention discloses a kind of tiopronin aseptic powder and preparation and preparation method.Those skilled in the art can use for reference this paper content, suitably improve processing parameter and realize.Special needs to be pointed out is, all similarly replace and change apparent to those skilled in the art, and they all are deemed to be included in the present invention.Product of the present invention and method are described by preferred embodiment, the related personnel obviously can be within not breaking away from content of the present invention, spirit and scope to product as herein described with method is changed or suitably change and combination, realize and apply the technology of the present invention.
For realizing purpose of the present invention, the present invention adopts following technical scheme:
A kind of preparation method of tiopronin aseptic powder comprises:
Step 1: get the tiopronin raw material, by g/mL, add the ethyl formate of 4～10 times to dissolve, be heated to reflux, by g/mL, the mode of by weight/volume percent adds 0.1%～0.5% injection charcoal absorption, filters;
Step 2: get step 1 gained filtrate, add ether or the methyl tertiary butyl ether of ethyl formate 5v/v%～30v/v%, heated and stirred is dissolved, below 0.1Mpa, with 0.22 μ m filtering with microporous membrane;
Step 3: get step 2 gained filtrate and be refrigerated to-5～5 ℃ of crystallizatioies, collect the gained crystal, after filtration, at 15～30 ℃ of lower drying under reduced pressure, after pulverizing and get final product.
In order further to understand the present invention, the present invention is described in detail below in conjunction with embodiment.Embodiment 1: the preparation of Thiopronine aseptic powder injection agent
(1) take 500g tiopronin raw material, purity is 95.3%, adds in reactor, adds 6 times of amounts, i.e. the ethyl formate of 3L, reflux;
(2) after tiopronin dissolves, add 9g injection gac, reflux was filtered after 30 minutes;
(3) after having filtered, in filtrate, add the 300mL methyl tertiary butyl ether, heated and stirred is dissolved;
(4) after dissolving, below 0.1Mpa, with the millipore filtration of 0.22 μ m, positive press filtration;
(5) after having filtered, filtrate is refrigerated to 0 ℃, and low temperature crystallization 2 hours;
(6), after crystallization completes, filter, and by the gained crystal 15 ℃ of vacuum-dryings 4 hours;
(7) after drying, crystal is pulverized, obtained white tiopronin aseptic powder 445.5g, yield is 89.1%, and purity is 99.8%;
(8), by tiopronin aseptic powder direct packaging, obtain tiopronin for injection aseptic powder injection injection.
Embodiment 2: the preparation of Thiopronine aseptic powder injection agent
(1) take 500g tiopronin raw material, purity is 95.3%, adds in reactor, adds 10 times of amounts, i.e. the ethyl formate of 5L, reflux;
(2) after tiopronin dissolves, add 25g injection gac, reflux was filtered after 30 minutes;
(3) after having filtered, in filtrate, add the 1000mL methyl tertiary butyl ether, heated and stirred is dissolved;
(4) after dissolving, below 0.1Mpa, with the millipore filtration of 0.22 μ m, positive press filtration;
(5) after having filtered, filtrate is refrigerated to 5 ℃, and low temperature crystallization 2 hours;
(6), after crystallization completes, filter, and by the gained crystal 30 ℃ of vacuum-dryings 3 hours;
(7) after drying, crystal is pulverized, obtained white tiopronin aseptic powder 456.5g, yield 91.3%.Purity is 99.5%;
(8) tiopronin aseptic powder and sterile sodium bicarbonate are mixed according to the weight ratio ratio of 1: 1, aseptic subpackaged, obtain tiopronin for injection aseptic powder injection injection.
Embodiment 3: the preparation of Thiopronine aseptic powder injection agent
(1) take 500g tiopronin raw material, purity is 95.3%, adds in reactor, adds 4 times of amounts, i.e. the ethyl formate of 2L, reflux;
(2) after tiopronin dissolves, add 4g injection gac, reflux was filtered after 30 minutes;
(3) after having filtered, in filtrate, add the 200mL ether, heated and stirred is dissolved;
(4) after dissolving, below 0.1Mpa, with the millipore filtration of 0.22 μ m, positive press filtration;
(5), after having filtered, filtrate is refrigerated to-5 ℃, and low temperature crystallization 2 hours;
(6), after crystallization completes, filter, and by the gained crystal 25 ℃ of vacuum-dryings 3 hours;
(7) after drying, crystal is pulverized, obtained white tiopronin aseptic powder 433.5g, yield 86.7%.Purity is 99.3%;
(8) tiopronin aseptic powder and sodium bicarbonate are mixed according to 1: 0.8 ratio of weight ratio, aseptic subpackaged, obtain tiopronin for injection aseptic powder injection injection.
The explanation of above embodiment is just be used to helping to understand product of the present invention and method and core concept thereof.It should be pointed out that for those skilled in the art, under the premise without departing from the principles of the invention, can also carry out some improvement and modification to the present invention, these improvement and modification also fall in the protection domain of the claims in the present invention.
Claims (4)
1. the preparation method of a tiopronin aseptic powder, is characterized in that, comprising:
Step 1: tiopronin is dissolved with ethyl formate, be heated to reflux, add the injection charcoal absorption, filter;
Step 2: get step 1 gained filtrate, add ether or methyl tertiary butyl ether, heated and stirred is dissolved, positive press filtration;
Step 3: get step 2 gained filtrate and be refrigerated to-5～5 ℃ of crystallizatioies, collect the gained crystal, after filtration, at 15～30 ℃ of lower drying under reduced pressure, after pulverizing and get final product.
2. preparation method according to claim 1, is characterized in that, the consumption of described ethyl formate is counted 4～10 times of tiopronin by g/mL.
3. preparation method according to claim 1, is characterized in that, the consumption of described ether or methyl tertiary butyl ether is the 5v/v%～30v/v% of ethyl formate.
4. preparation method according to claim 1, is characterized in that, described positive press filtration is below 0.1Mpa, with 0.22 μ m filtering with microporous membrane.
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| US20170172960A1 (en) * | 2015-12-22 | 2017-06-22 | Imprimis Pharmaceuticals, Inc. | Pharmaceutical formulations for treating kidney stones and methods for fabricating and using thereof |
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| CN104644569B (en) * | 2013-11-25 | 2018-01-02 | 马鞍山丰原制药有限公司 | A kind of tiopronin freeze-dried powder injection and preparation method thereof |
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| US8586636B2 (en) * | 2007-11-20 | 2013-11-19 | Lankenau Institute For Medical Research | Disulfide chemotherapeutic agents and methods of use thereof |
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| US20170172960A1 (en) * | 2015-12-22 | 2017-06-22 | Imprimis Pharmaceuticals, Inc. | Pharmaceutical formulations for treating kidney stones and methods for fabricating and using thereof |
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