CN101863942B - Method for preparing isoprinosine and oral preparation thereof - Google Patents
Method for preparing isoprinosine and oral preparation thereof Download PDFInfo
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- CN101863942B CN101863942B CN 200910081872 CN200910081872A CN101863942B CN 101863942 B CN101863942 B CN 101863942B CN 200910081872 CN200910081872 CN 200910081872 CN 200910081872 A CN200910081872 A CN 200910081872A CN 101863942 B CN101863942 B CN 101863942B
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- isoprinosine
- dimethylin
- virahol
- acetaminobenzoic acid
- acid salt
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Abstract
The invention provides a method for preparing isoprinosine. The method comprises the following steps of: 1) performing a reaction on p-acetamino benzoic acid and dimethylamino isopropanol to obtain a dimethylamino isopropanol-p-acetamino-benzoate; and 2) performing the reaction on the dimethylamino isopropanol-p-acetamino-benzoate and inosine to obtain the isoprinosine. The preparation method is more suitable for industrial production and has higher yield. The invention also provides an isoprinosine oral preparation. The isoprinosine oral preparation comprises the following raw materials of isoprinosine, disintegration auxiliary agent, disintegrating agent and adhesive, wherein the weight ratio of the isoprinosine to the disintegration auxiliary agent to the disintegrating agent is 1:0.1-0.2:0.08-0.2 in turn. The oral preparation has the characteristics of faster disintegration and dissolution, and higher stability.
Description
Technical field
The present invention relates to a kind of preparation method of isoprinosine.
The invention still further relates to a kind of oral preparations of isoprinosine.
Background technology
Isoprinosine (Isoprinosine) is inosine and dimethylin Virahol-to the mixture of acetaminobenzoic acid salt (1: 3).
In more than 50 countries and regions such as European, Italian, Canadian, Japanese listing, clinical efficacy is remarkable for this product, and toxic side effect is little, is the antiviral and immune function controlling agents of a determined curative effect.Isoprinosine was an antiviral drug originally, and was all effective in cure to human herpes, influenza and rhinovirus infection.The patient who is used for herpes simplex infections is evident in efficacy.It is believed that the Anti-viral Treatment of this product, except due to its direct antivirus action, also relevant with its immuno-potentiation.Find that now isoprinosine has the effect of enhancing body immunologic function.Mainly to strengthen cellular immune function, again as a new immunomodulator.Clinical study shows, isoprinosine can increase the lymphopoiesis due to mitogenic factor, increases the generation of antibody and increases cytokine, as the generation of interleukin-22 (IL-2) etc.Clinical application is scorching, evident in efficacy in multiple bridou and focal sexual reproduction device.The characteristics such as it is high that this product has curative effect, and toxic side effect is little.Further studies have shown that, isoprinosine can promote the lymphocyte differentiation and regulate lymphocytic function to have the effect of AIDS virus resisting, can delay the course advancement of acquired immune deficiency syndrome (AIDS).Have in addition anti-ageing and the memory effect.External isoprinosine has been used for that various viral infections, immunity system are low, the treatment of CMV, EBV, influenza and upper and lower respiratory tract infection, herpes simplex, zoster, measles, parotitis, viral conjunctivitis; Also be used for simultaneously acute and chronic viral hepatitis type b, subacute sclerosing panencephalitis (SSPE), fatigue syndrome etc.(Scandinavian) is used for the treatment of acquired immune deficiency syndrome (AIDS) to isoprinosine in the Scandinavia.
Comprehensive domestic and foreign literature report, the synthetic of isoprinosine can be had by raw materials used difference many operational paths, but all there are the problems such as yield is low, solvent that use is inflammable and explosive and toxicity is large, aftertreatment is complicated in these operational paths.Synthetic adopt the monomethylaniline oxidation style according to the literature of isoprinosine more, concrete grammar is: take to monomethylaniline as raw material, react in aceticanhydride, generate acetamino-toluene.Through potassium permanganate oxidation, again with dimethylin Virahol salify and then compound with inosine, get isoprinosine.Its yield is about 60%.The method need with a large amount of potassium permanganate oxidations, be unfavorable for suitability for industrialized production.At present, adopt ether to carry out aftertreatment to salt-forming reaction in the monomethylaniline oxidation, also have bibliographical information to adopt the tetrahydrofuran (THF) aftertreatment, but yield is all undesirable.
At present, the listing formulation of isoprinosine is mainly Tablet and Capsula.But because isoprinosine has stronger water absorbability, thereby the relatively poor shortcoming of the equal existence and stability of Tablet and Capsula, and existing isoprinosine preparation all exists that disintegration is slow, dissolution rate and bioavailability low, thereby the problem that affects the treatment.
In sum, the inventor thinks and is necessary existing isoprinosine synthetic method is further optimized, and develops a kind of more stable, dissolution rate and the higher isoprinosine oral preparations of bioavailability, to satisfy domestic market demand.
Summary of the invention
The problems referred to above for prior art exists on the one hand, the invention provides a kind of synthetic method that is more suitable for the isoprinosine of suitability for industrialized production, further, the invention provides the synthetic method of the higher isoprinosine of a kind of yield.
On the other hand, the invention provides isoprinosine oral preparations and the preparation technology thereof that a kind of disintegration and stripping are faster, stability is higher.
According to an aspect of the present invention, the synthetic method of isoprinosine of the present invention comprises the steps:
1) to acetaminobenzoic acid and dimethylin isopropanol reaction, obtain dimethylin Virahol-to acetaminobenzoic acid salt;
2) dimethylin Virahol-to acetaminobenzoic acid salt and the inosine molar ratio reaction by 3: 1, obtain isoprinosine.
Preferably, in step 1) in, adopt ethyl acetate to the dimethylin Virahol of gained-acetaminobenzoic acid salt is carried out aftertreatment.
In synthetic route of the present invention, take inosine, dimethylin Virahol, to acetaminobenzoic acid as raw material.Acetaminobenzoic acid and dimethylin Virahol at dehydrated alcohol or methyl alcohol, are reacted in preferred dehydrated alcohol, make dimethylin Virahol-to acetaminobenzoic acid salt, and then make isoprinosine with inosine by the molar ratio reaction of 3: 1.
Concrete reaction is as follows:
Acetaminobenzoic acid and dimethylin Virahol are reacted in dehydrated alcohol, and its mol ratio is 1: 1.2, reacts 2～5 hours, for example 2 hours, add ethyl acetate, cooling, filtration, washing, drying, white crystalline powder, i.e. dimethylin Virahol-to acetaminobenzoic acid salt.Yield approximately 95%.
The second step complex reaction:
Get dimethylin Virahol-to acetaminobenzoic acid salt, inosine appropriate (inosine and dimethylin Virahol-be 1: 3 to acetaminobenzoic acid salt mol ratio), after water, dissolve with ethanol, stir evaporated under reduced pressure down respectively.Add the ethyl acetate azeotropic dehydration to anhydrous steaming, suspendible, separation, washing, drying get the white solid powder, i.e. isoprinosine.Yield approximately 98%.
Synthetic adopt the monomethylaniline oxidation style according to the literature of isoprinosine more, concrete grammar is: take to monomethylaniline as raw material, react in aceticanhydride, generate acetamino-toluene.Through potassium permanganate oxidation, again with dimethylin Virahol salify and then compound with inosine, get isoprinosine.Its yield is about 60%.
The method need be unfavorable for suitability for industrialized production with a large amount of potassium permanganate oxidations, and present domestic buying the acetaminobenzoic acid raw material, thus the inventor adopt the dimethylin Virahol with to the acetaminobenzoic acid salify, then prepare with the inosine complex reaction.This preparation method is simple and direct, and aftertreatment is simple, is conducive to suitability for industrialized production.
At present, adopt ether to carry out aftertreatment to salt-forming reaction in the monomethylaniline oxidation, also have bibliographical information to adopt the tetrahydrofuran (THF) aftertreatment, but yield is all undesirable.The ethyl acetate aftertreatment is adopted in the salt-forming reaction of technique of the present invention, makes dimethylin Virahol-to the easier crystallization of acetaminobenzoic acid salt.Ether, tetrahydrofuran (THF) than existing document are safer, more easily obtain target product.By salt-forming reaction comparative experiments (referring to embodiment 5), can find out, adopt ethyl acetate to carry out aftertreatment in salt-forming reaction, can significantly improve reaction yield.
According to a further aspect in the invention, the invention provides a kind of isoprinosine oral preparations, its raw materials used comprising: isoprinosine, help and collapse agent, disintegrating agent, tackiness agent, described isoprinosine, help the weight ratio that collapses agent and disintegrating agent to be followed successively by: 1: 0.1-0.2: 0.08-0.2.
Isoprinosine oral preparations of the present invention with isoprinosine as bulk drug, with cross-linked polyvinylpyrrolidone, croscarmellose sodium, micropowder silica gel etc. as auxiliary material, in the isoprinosine bulk drug of every 1 weight part, allocate disintegrating agent and suitable amount of adhesive that helping of 0.1-0.2 weight part collapsed agent, 0.08-0.2 weight part into.
Above-mentioned helping collapsed agent and is preferably micropowder silica gel, disintegrating agent is preferably cross-linked polyvinylpyrrolidone and/or croscarmellose sodium, and tackiness agent is preferably 3%～20% polyvidone ethanol (75%) solution or 1%～15% Vltra tears ethanol (75%) solution.Above-mentioned helping of enumerating collapsed agent, disintegrating agent and tackiness agent only for exemplary, and the present invention is not limited to this, and the helping of other this area routine collapsed agent, disintegrating agent and tackiness agent and all can be applied to selectively the present invention.
Simultaneously, for increasing the stability of product, add granule coating technique targetedly in preparation technology, to improve the stability of isoprinosine.
The preparation technology of isoprinosine oral preparations of the present invention is that isoprinosine and the above-mentioned auxiliary material of getting recipe quantity add appropriate tackiness agent, granulate, dry, whole grain, then select moistureproof coating powder to carry out dressing to it, drying is sieved, and the particle that obtains can be used for the preparation of the oral preparations such as capsule, sheet, granule.
Because isoprinosine has water absorbability, therefore moisture-sensitive in air adds the dressing operation, can play moisture-proof role.
By dressing consumption shaker test (referring to embodiment 6), can determine, during granule coating, control particle weightening finish 10%～12%, particle appearance is better, the color and luster homogeneous, content is more stable, and granule coating is complete, and moisture effect is remarkable.
The preparation method of isoprinosine oral preparations of the present invention comprises the steps:
1) with isoprinosine, help and collapse agent and disintegrating agent fully mixes;
2) add tackiness agent to make softwood, granulate, drying, whole grain;
3) with coating powder, particle is carried out dressing, get coated granule.
Oral preparations of the present invention is guaranteeing to collapse agent, disintegrating agent, tensio-active agent by adding appropriate helping under the suitable prerequisite of main ingredient dosage, and its disintegration and rate of dispersion are accelerated, and are conducive to improve bioavailability.And add the glue granule coating in technique after, medicine is hedged off from the outer world, can be moistureproof, anti-oxidation, greatly improved the stability of this product.Test-results (referring to embodiment 7) shows, oral preparations of the present invention has advantages of that quick disintegration, stripping, stability are high.
In order to understand better essence of the present invention, below by the description to better embodiment of the present invention, describe in detail but do not limit the present invention.
Description of drawings
Fig. 1: the infrared absorpting light spectra of the isoprinosine of the present invention's preparation;
Fig. 2～6: the nuclear magnetic resonance map of the isoprinosine of the present invention's preparation, wherein, Fig. 2 is the 1H-1HCOSY spectrum, and Fig. 3 is 1H NMR spectrum, and Fig. 4 is 13C NMR spectrum, and Fig. 5 is the DEPT-135 spectrum, Fig. 6 is HSQC 1H NMR spectrum;
Fig. 7 A: in the purity detecting of isoprinosine of the present invention, the high-efficient liquid phase chromatogram of isoprinosine reference substance solution;
Fig. 7 B: in the purity detecting of isoprinosine of the present invention, the high-efficient liquid phase chromatogram of isoprinosine need testing solution.
Embodiment
The present invention's test materials used if no special instructions, is commercially available purchase product.
The source of main raw material is as follows: inosine is purchased from Xinxiang, Henan China star pharmaceutical factory; To acetaminobenzoic acid, be purchased from Rongchang County Chemical Engineering Technology company limited; The dimethylin Virahol is purchased from Shanghai Westingarea Electrical Systems Co., Ltd..
Synthetic isoprinosine, concrete operations are as follows:
1, in the reactor of 100L, add acetaminobenzoic acid 25.65kg, add dehydrated alcohol 39.6L dissolving, drip dimethylin Virahol 16.35kg, exothermic heat of reaction.40 ℃～50 ℃ were reacted 2 hours.Cooling, separation, ethyl acetate washing, drying get white crystalline powder.Use the mixed solvent recrystallization.Get 37.5kg, yield 92.6%.Be dimethylin Virahol-to acetaminobenzoic acid salt, 146～148 ℃ of fusing points.
2. in the reactor of 100L, add the dimethylin Virahol that makes in step 1-to acetaminobenzoic acid salt 12.3kg, add ethanol 24.0L dissolving.Get inosine 3.9kg, add after water 7.8L dissolving.Stir lower evaporated under reduced pressure.Add the ethyl acetate azeotropic dehydration to anhydrous steaming, suspendible, separation, washing, drying get white solid powder 16.1kg, and reaction yield is 99.4%.This powder turns out to be isoprinosine through infrared absorption spectrum, magnetic resonance detection, is 23.7% through checking its Inosine Content, the dimethylin Virahol-and be 76.5% to the acetaminobenzoic acid salts contg.Above detection infrared absorption spectrum, nucleus magnetic resonance are completed by Henan Prov. Analytical Test Center, and purity detecting is that our company completes.Every check instrument and collection of illustrative plates are as follows:
1. infrared absorption spectrum
Instrument: Shimadzu 8700 type Fourier transform infrared spectroscopy, KBr pressed disc method.See Fig. 1.
2. nucleus magnetic resonance
Instrument: Bruker Avance 300 nuclear magnetic resonance spectrometers, solvent D2O. room temperature measuring HNMR, CNMR, DEPT-135, H-HCOSY HSQC and HMBC spectrum, the chemical shift of H and CNMR has the instrument auto-scaling.See Fig. 2～6.
3. purity detecting
Instrument: UltiMate 3000Pump
UltiMate 3000Variable Wavelength Detector
The chromatographic condition octadecylsilane chemically bonded silica be weighting agent (5um, φ 4.6 * 150mm); (get sodium acetate, anhydrous 4.1g, add water 1000ml and make dissolving, regulate PH to 5.0 with 1mol/L acetic acid)-methyl alcohol (92: 8) is moving phase with 0.05mol/L sodium acetate buffer solution; The detection wavelength is 248nm; Flow velocity 1.0ml/min; 25 ℃ of column temperatures.
Reference substance solution (1) precision takes approximately 17.5mg of inosine reference substance (self-control), puts in the 25ml measuring bottle, adds moving phase and dissolves and be diluted to scale, shake up, as the inosine stock solution, precision measures this solution 5ml and puts in the 50ml measuring bottle, add moving phase and be diluted to scale, shake up, and get final product.
Reference substance solution (2) precision take the dimethylin Virahol-to acetaminobenzoic acid salt reference substance (self-control) approximately 57.5mg put in the 25ml measuring bottle, adding moving phase dissolves and is diluted to scale, shake up, as dimethylin Virahol-to acetaminobenzoic acid salt stock solution, precision measures this solution 5ml and puts in the 50ml measuring bottle, add moving phase and be diluted to scale, shake up, and get final product.
Reference substance solution (3) precision respectively measures inosine stock solution and dimethylin Virahol-each 5ml of acetaminobenzoic acid salt stock solution is put in same 50ml measuring bottle, adds moving phase and is diluted to scale, shakes up, and get final product.
It is appropriate that need testing solution is got this product, accurately weighed, adds moving phase and dissolve and dilute and make the solution that every 1ml contains 0.3mg, as need testing solution.
Assay method precision respectively measures need testing solution and each 20ul of reference substance solution (3), the injection liquid chromatography records color atlas, measures peak area, calculate respectively inosine and dimethylin Virahol-to the content of acetaminobenzoic acid salt by external standard method, and get final product.Collection of illustrative plates is Fig. 7～8.
Embodiment 2
1. write out a prescription
Isoprinosine 500.0g
Cross-linked polyvinylpyrrolidone 40.0g
Micropowder silica gel 100.0g
2% hypromellose ethanol (75%) solution is appropriate
Make 1000 capsules
2. preparation technology
Former, auxiliary material were pulverized respectively 120 mesh sieves, got the recipe quantity supplementary material, fully mixed.Add tackiness agent to make softwood, granulate with 20 eye mesh screens, 60 ℃ of air seasonings, the 16 whole grains of eye mesh screen carry out dressing with the damp-proof coating powder to particle, and the pot temperature control is at 45-55 ℃, the rotating speed of pot is controlled at 40-50rpm, press particle weightening finish 11%, being made into concentration is 15% pure molten coating liquid, with suitable flow velocity hydrojet dressing, after dressing finishes, dry, the directly encapsulated or pack granulation agent of the particle of gained also can add moderate lubrication agent compressing tablet.
1. write out a prescription
Isoprinosine 250.0g
Microcrystalline Cellulose 50.0g
Croscarmellose sodium 25.0g
Magnesium Stearate 2.5g
15% polyvidone ethanol (75%) solution is appropriate
Make 1000
2. preparation technology is with embodiment 2.
Embodiment 4
1. write out a prescription
Isoprinosine 500.0g
Croscarmellose sodium 45.0g
5% hypromellose ethanol (75%) solution is appropriate
Make 1000 bags of particles
2. preparation technology is with embodiment 2.
Embodiment 5
1. write out a prescription
Isoprinosine 500.0g
Cross-linked polyvinylpyrrolidone 100.0g
Micropowder silica gel 100.0g
2% hypromellose ethanol (75%) solution is appropriate
Make 1000 capsules
2. preparation technology to granule coating, presses particle weightening finish 12%, the other the same as in Example 2.
1. write out a prescription
Isoprinosine 500.0g
Cross-linked polyvinylpyrrolidone 70.0g
Micropowder silica gel 100.0g
2% hypromellose ethanol (75%) solution is appropriate
Make 1000 capsules
2. preparation technology to granule coating, presses particle weightening finish 11%, the other the same as in Example 2.
Embodiment 7
1. write out a prescription
Isoprinosine 500.0g
Cross-linked polyvinylpyrrolidone 70.0g
Micropowder silica gel 50.0g
2% hypromellose ethanol (75%) solution is appropriate
Make 1000 capsules
2. preparation technology to granule coating, presses particle weightening finish 10%, the other the same as in Example 2.
Embodiment 8 salt-forming reaction comparative experimentss
For proving that ethyl acetate is more suitable for the post-treatment reagents as salt-forming reaction of the present invention, has done following experiment:
In the reaction flask of 100ml, add acetaminobenzoic acid 9g, add dehydrated alcohol 15ml dissolving, add dimethylin Virahol 6.2g in batches, reacted 2 hours.Add certain solvent and separate out, cooling, filtration, washing, drying get white crystalline powder.With ethanol/ethyl acetate mixed solvent recrystallization.Weigh, calculated yield.The results are shown in following table:
Table 1 salt-forming reaction test-results
By above result as can be known, adopt ethyl acetate to carry out aftertreatment in salt-forming reaction, can significantly improve reaction yield.
Embodiment 9 dressing consumption shaker tests
Select damp-proof coating powder preparation coating liquid, particle is increased weight by different ratios, when result showed particle weightening finish 10～12%, particle appearance was better, the color and luster homogeneous, and content is more stable.
Proterties and the content results of particle during table 2 particle weightening finish different ratios
| Weightening finish (%) | 6 | 7 | 9 | 10 | 12 | 15 |
| Particle appearance | Poor | Poor | Better | Good | Good | Better |
| Content | 98.1 | 98.5 | 99.1 | 99.5 | 99.8 | 99.0 |
Determine by following experiment whether dressing is complete when the particle weightening finish 10～12%:
Sample is placed in environment (the saturated KNO of relative humidity (RH) 90%
3Solution is placed in moisture eliminator bottom, and sample is put on the dividing plate of tool hole) place, placed 10 days under 25 ℃, in sampling in the 0th, 10 day, the inspection of increasing weight the results are shown in Table 1:
The capsule 's content water absorbability of table 3 different process relatively
| Coated granule | Coated granule not |
| The |
3％ | 3.2％ | 3.5％ | ---------- |
| The moisture absorption weightening finish | 2.0％ | 2.5％ | 2.2％ | 6.7％ |
Conclusion: can find out by table 3, during granule coating, control particle weightening finish 10%～12%, granule coating is complete, and moisture effect is remarkable.
The detection of embodiment 10 isoprinosine oral preparations
1. detect index and method:
1.1 disintegration
Detect according to two appendix XA test procedures disintegration of Chinese Pharmacopoeia version in 2005.
1.2 dissolution rate
Detect according to Chinese Pharmacopoeia version appendix XC the second method dissolution method in 2005.
Take water 1000ml as solvent, rotating speed is that per minute 100 turns, and operation, in the time of 5,10,20,30,45 minutes, get solution appropriate in accordance with the law, filters, and precision measures in subsequent filtrate 1ml to 50ml measuring bottle, is diluted with water to scale, shakes up, as test liquid.It is appropriate that another precision takes the isoprinosine reference substance, adds water and make to dissolve and dilute and make the solution product solution in contrast that approximately contains isoprinosine 10 μ g in every 1ml.Measure according to UV-Spectrophotometry (two appendix IV A of Chinese Pharmacopoeia version in 2005), measure optical density at the wavelength place of 259nm.Radiometer by both optical densitys is calculated stripping quantity.
1.3. exposure experiments to light
Get this product, be placed in lighting box, intensity of illumination is to place 10 days under the intensity of 4500 ± 500Lx, took a sample to check in the 0th, 5,10 day, and result and sample comparison in 0 day.
1.4. high temperature test
Get this product, be placed in interior the placement 10 days of thermostat container of 60 ℃, took a sample to check in the 0th, 5,10 day, result and 0 day sample are relatively.
1.5. high wet test
Get this product, be placed under the RH75% condition, placed 10 days in room temperature, took a sample to check in the 0th, 5,10 day, result and 0 day sample are relatively.
2 embodiment 2 sample detection results
2.1. disintegration time
| Example 1 sample | Commercially available isoprinosine capsule | |
| Disintegration time (minute) | 5.3 | 15.6 |
2.2. dissolution rate
| Time (minute) | 5 | 10 | 20 | 30 | 45 |
| Commercially available capsule | 42.5 | 50.8 | 66.1 | 84.3 | 95.8. |
| Example 1 sample | 80.4 | 93.7 | 97.8 | 98.9 | 99.1 |
2.3. exposure experiments to light:
| Time (my god) | Dissolution rate | Disintegration | Related substance (%) | Content (%) |
| 0 | 98.6％ | 5′10″ | 0.05 | 99.5 |
| 5 | 98.7％ | 5′05″ | 0.04 | 99.8 |
| 10 | 98.1％ | 6′52″ | 0.04 | 99.2 |
2.4. high temperature test:
| Time (my god) | Dissolution rate | Disintegration | Related substance (%) | Content (%) |
| 0 | 97.2％ | 5′11″ | 0.06 | 99.4 |
| 5 | 97.9％ | 5′25″ | 0.05 | 98.7 |
| 10 | 98.5％ | 5′42″ | 0.04 | 99.1 |
2.5. high wet test:
| Time (my god) | Dissolution rate | Disintegration | Related substance (%) | Content (%) |
| 0 | 98.5％ | 5′31″ | 0.06 | 99.6 |
| 5 | 99.0％ | 5′45″ | 0.03 | 98.9 |
| 10 | 98.1％ | 6′12″ | 0.05 | 98.1 |
3 embodiment 3 sample detection results
3.1. disintegration time
| Example 2 samples | Commercially available isoprinosine sheet | |
| Disintegration time (minute) | 6.4 | 18.9 |
3.2. dissolution rate
| Time (minute) | 5 | 10 | 20 | 30 | 45 |
| Commercially available | 45.9 | 58.7 | 69.1 | 88.7 | 98.6. |
| Example 2 samples | 82.7 | 92.9 | 98.4 | 99.1 | 99.9 |
3.3. exposure experiments to light:
| Time (my god) | Dissolution rate | Disintegration | Related substance (%) | Content (%) |
| 0 | 99.6％ | 6′10″ | 0.04 | 99.7 |
| 5 | 99.7％ | 7′05″ | 0.03 | 99.6 |
| 10 | 99.1％ | 7′52″ | 0.03 | 99.3 |
3.4. high temperature test:
| Time (my god) | Dissolution rate | Disintegration | Related substance (%) | Content (%) |
| 0 | 98.2％ | 6′11″ | 0.06 | 99.3 |
| 5 | 99.9％ | 5′25″ | 0.05 | 98.9 |
| 10 | 98.9％ | 5′42″ | 0.04 | 99.0 |
3.5. high wet test:
| Time (my god) | Dissolution rate | Disintegration | Related substance (%) | Content (%) |
| 0 | 98.4％ | 5′31″ | 0.06 | 99.1 |
| 5 | 99.5％ | 5′45″ | 0.03 | 98.6 |
| 10 | 99.1％ | 6′12″ | 0.05 | 98.1 |
Detected result to embodiment 4-7 sample is similar to the above results.
Conclusion: above detected result explanation, this product have advantages of quick disintegration, stripping, stable high.
Above description to better embodiment of the present invention does not limit the present invention, and those skilled in the art can make according to the present invention various changes or distortion, only otherwise break away from spirit of the present invention, all should belong to the scope of claims of the present invention.
Claims (2)
1. the preparation method of an isoprinosine, is characterized in that, comprises the steps:
1) to acetaminobenzoic acid and dimethylin isopropanol reaction, obtain dimethylin Virahol-to acetaminobenzoic acid salt, mol ratio is 1:1.2 acetaminobenzoic acid and dimethylin Virahol are reacted in dehydrated alcohol or methyl alcohol, react and add ethyl acetate after 2～5 hours in reaction solution, cooling, filtration, washing, drying, get white crystalline powder, i.e. dimethylin Virahol-paraacetaminobenzoic acid salt;
2) dimethylin Virahol-to the reaction of acetaminobenzoic acid salt and inosine, obtain isoprinosine.
2. preparation method claimed in claim 1, it is characterized in that, described step 2) be, get mol ratio and be the dimethylin Virahol of 1:3-to acetaminobenzoic acid salt, inosine, after water, dissolve with ethanol, stir lower evaporated under reduced pressure respectively, add the ethyl acetate azeotropic dehydration to anhydrous steaming, suspendible, separation, washing, drying get the white solid powder, i.e. isoprinosine.
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| CN101863942A (en) | 2010-10-20 |
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