CN107007838A - A kind of pharmaceutical composition containing enalapril maleate, folic acid and sour stabilizer - Google Patents
A kind of pharmaceutical composition containing enalapril maleate, folic acid and sour stabilizer Download PDFInfo
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- CN107007838A CN107007838A CN201610881568.8A CN201610881568A CN107007838A CN 107007838 A CN107007838 A CN 107007838A CN 201610881568 A CN201610881568 A CN 201610881568A CN 107007838 A CN107007838 A CN 107007838A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/401—Proline; Derivatives thereof, e.g. captopril
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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Abstract
The present invention provides a kind of new enalapril maleate folic acid compound preparation, by adding weight in the formulation than the sour stabilizer for 1%~5%, improves the stability under the conditions of preparation is placed in high temperature and for a long time.Do filler from the mixture of microcrystalline cellulose and single water and milk sugar simultaneously, improve dissolution of the folic acid in 0.1M hydrochloric acid mediums, final obtained tablet with it is commercially available basically identical.Said composition stability is good, it is ensured that the safe handling of medicine clinically, and technological operation is simple, suitable for industrialized production.
Description
Technical field
The invention belongs to field of medicine preparations, and in particular to one kind contains enalapril maleate, folic acid and sour stabilizer
Pharmaceutical composition.
Background technology
Chinese cardiocerebrovasculaevents events spectrum of disease and west crowd are significantly different.The annual morbidity of population of China cerebral apoplexy is
250/100000, the annual morbidity of cardiovascular event is 50/,100,000, and Cerebral Haemorrhage Invasion Rate is 5 times of occurrence of cardiovascular event rate.
In the clinical test that observation decompression influences on cardiocerebrovasculaevents events, China's Hypertensive Population cerebral apoplexy/myocardial infarction morbidity ratio
For 6~13: 1, and west Hypertensive Population is about 1: 1, and it is the topmost cardiovascular and cerebrovascular of China's Hypertensive Population to point out cerebral apoplexy
Event, and population of China there may be causes the risk factors of cerebral apoplexy outside blood pressure increases.
Hypertension, homocysteine (homocysteine, Hcy) mass formed by blood stasis, low folic acid are the important danger of cerebral apoplexy
Dangerous factor.Influenceed, raised (H types hypertension) with plasma Hcy level in Chinese hyperpietic by crowd's hereditary feature
It is probably to cause the major reason of China's cerebral apoplexy high incidence and sustainable development that ratio, which is up to 75%, H type hypertension occurred frequently,.Horse
It is, from population of China hereditary feature, to embody multiple risk factors (hypertension, high Hcy, low leaf to carry out sour enalapril Couteat of Folic Acid
Acid) integrated control compound medicine.Enalapril maleate reduces the blood pressure of hypertensive patient, and blood plasma homotype half can drop in folic acid
Cystine level, enalapril maleate folic acid obtains CFDA approval listings in March, 2008, for treating with blood plasma homotype
The elevated essential hypertension of cysteine levels, turns into for 2010《Chinese hypertension prevention and control guide》New highlight, enters for 2013
Enter National essential drugs list.
CN1269529C protects the pharmaceutical composition containing angiotensin converting enzyme inhibitors and B family vitamin, should
Composition can improve the curative effect of depressor, strengthen target organ protection function, reduce fundus hemorrhage, angina pectoris, renal failure
Etc. the incidence of complication.Examples 1 and 2 disclose the formulation and technology of enalapril maleate and folic acid compound preparation, repeat
It is operated, and it is poor that discovery obtains preparation stability, is placed 10 days under the conditions of 60 DEG C of high temperature, high humidity RH92.5%, impurity Yi Napu
Sharp diketone and enalaprilat are dramatically increased, and its structural formula is as follows：
Enalapril maleate, chemical name is N- [(S) -1- (carbethoxyl group) -3- phenylpropyls]-L- alanyl-L- dried meat
Propylhomoserin maleate.Enalapril maleate bulk drug is more stable, but enalapril maleate preparation is more unstable,
Compatible with multiple auxiliary materials bad, impurity substantially increases during storage, and degradation impurity is influenceed by solution ph, as solution ph ＜ 5
When, its main degradation products is enalapril diketone, and when solution ph >=5, main degradation products are enalaprilats.Existing rank
The method of Duan Zengjia enalapril maleate stability has following several：
(1) add alkaline matter sodium acid carbonate, can by the converting carboxylate groups of enalapril maleate into carboxylate anion,
Cyclization can be minimized, so as to suppress the generation of enalapril diketone.But the method is for the horse containing folic acid
Carry out sour enalapril compound medicine and do not apply to, sodium acid carbonate is added in prescription, 60 DEG C of high temperature is placed 10 days, enalapril diketone
Impurity still substantially increases, it is impossible to ensure medicine safe handling clinically and long-term storage.
(2) by enalapril with it is cyclodextrin encapsulated, then make preparation.By cyclodextrin encapsulated enalapril due to space
Limitation and intermolecular react to each other reduce the activity of its drug molecule, so as to limit under solid-state or in molecules in solution
The possibility of necleophilic reaction；But hydroxypropylβ-cyclodextrin is added in auxiliary material the bad anti-of renal toxicity and hemolytic to human body
Should, hydroxypropylβ-cyclodextrin is administered orally is giving mouse, rat, dog 5000mg/kg respectively, and administration time is up to 1 year, on
Experimental animal is stated except suffering from diarrhoea, administration time cancer of pancreas occurs up to partial rat at 2 years, the use of cyclodextrin exists dangerous
Risk.Hydrolysis of the dextrin in water is uneven, unstable, influences dissolution, and has certain suction-operated to medicine, may do
The assay of main ingredient is disturbed, therefore should avoid using dextrin in prescription.
(3) sour stabilizer is added, CN102357084 is reported adds malic acid or wine in enalapril maleate prescription
Stone acid, CN105125514 is reported to be added arginine to improve the stability of preparation in enalapril maleate prescription.With reference to
Its formula prepares enalapril maleate folic acid tablet, it is found that malic acid or arginine can not improve enalapril maleate leaf
The stability of sour compound preparation, is placed 10 days for 60 DEG C, enalapril maleate diketone still substantially increases, more than 2% in high temperature.
(4) suitable crystal formation is selected, enalapril maleate has polymorphism, point for having I types and II types, although have
Report that two kinds of crystal formation energy are similar, differ only 0.6kcal/mol, but II types are more unstable in slice, thin piece.
Folic acid, chemical name N- [4- [(2- amino -4- oxo-Isosorbide-5-Nitrae-dihydro -6- pteridine) methylamino] benzoyl]-L-
Glutamic acid, principal degradation impurity is dish acid, and its structural formula is as follows：
Pharmaceutical preparation stability refers to that pharmaceutical preparation, from the degree that keeps stable during use is prepared into, is often referred to medicine system
The vitro stability of agent.The most basic requirement of pharmaceutical preparation is safely, effectively, stably.Pharmaceutical preparation producing, store, make
During, it can be decomposed because of the influence of various factors rotten, so that cause curative effect of medication to reduce or side effect increase, some
Medicine even produces noxious material, it is also possible to cause larger economic loss.
After solid pharmaceutical preparation is administered orally, the absorption of medicine depends on medicine from the dissolution or release in preparation, medicine in life
Dissolving under the conditions of reason and the infiltration in intestines and stomach.Because the dissolution and dissolving of medicine have material impact to absorbing, therefore,
Dissolution in vitro experiment is possible to predict its internal behavior.According to CFDA regulation, the Dissolution Standards of imitation medicine should be with reference
Preparation is consistent.
Therefore enalapril maleate folic acid Formulation how is carried out, the stability of compound preparation is improved, preparation is improved
Quality, while preparation is consistent with commercially available dissolution, it is a problem of letter is to be solved.
The content of the invention
Present invention aims at a kind of new enalapril maleate folate composition is provided, said composition stability is good,
The safe handling of medicine clinically can be ensured, technological operation is simple, suitable for industrialized production.
Applicant adds different acidulants by attempting in prescription, such as citric acid, fumaric acid, maleic acid, malic acid,
Arginine, it is found that citric acid, malic acid and arginine can not improve the stabilizer of enalapril maleate preparation, and fumaric acid can be with
The stability of preparation is improved to a certain extent, and maleic acid can significantly improve preparation stability.Further screen maleic acid
Consumption, find when maleic content be 1~5% when, preparation stability is preferable.
But prepare enalapril maleate folic acid tablet with reference to CN1269529C, find dissolution with it is commercially available inconsistent.It is logical
Cross and different fillers is screened, discovery selects starch and microcrystalline cellulose to do filler, hydrochloric acid medium of the folic acid in 0.1M
Middle dissolution is significantly lower than commercially available.Analysis reason may influence the selection that the key factor of dissolution is filler.Due to starch and micro-
Crystalline cellulose is all insoluble in water, discharges relatively slow in hydrochloric acid solution, if doing filler, dissolution from water miscible lactose
It hurry up.According to CFDA regulation, the Dissolution Standards of imitation medicine should be consistent with reference preparation, it is more too fast than commercially available dissolution or excessively it is slow not
Meet the requirements.Therefore, applicant does filler from the mixture of microcrystalline cellulose and lactose, and its ratio is screened, and sends out
Now work as lactose：Microcrystalline cellulose weight ratio is 1.67~3:When 1, obtained tablet dissolution with it is commercially available similar.
The present invention provides a kind of pharmaceutical composition containing enalapril maleate, folic acid and sour stabilizer, and its feature exists
In described sour stabilizer is selected from maleic acid, fumaric acid or butanedioic acid more preferably maleic acid.
Preferred scheme of the present invention, count by weight percentage, sour stabiliser content are 1%~5%, preferably 2%~4%,
Further preferred 2%, 2.4%, 3%, 4%.
Preferred scheme of the present invention, it is characterised in that described sour stabilizer is maleic acid or fumaric acid, preferably maleic acid.
Preferred scheme of the present invention, it is characterised in that also including filler, adhesive, disintegrant and lubricant, described fills out
The mixture that agent is single water and milk sugar and microcrystalline cellulose is filled, described adhesive is selected from PVP K30 or hydroxypropyl methylcellulose E5,
Described disintegrant is Ac-Di-Sol, and described lubricant is magnesium stearate.
Preferred scheme of the present invention, it is characterised in that described microcrystalline cellulose is selected from MCC or microcrystalline cellulose
Element 102.
Preferred scheme of the present invention, it is characterised in that the weight ratio of single water and milk sugar and microcrystalline cellulose is 1.67~3:1, it is excellent
Select 1.67:1、2.2:1 or 3:1, i.e., 50:30、55:25 or 60:20.
The present invention also provides a kind of preparation method of enalapril maleate folate composition, comprises the following steps：
(1) weigh folic acid and single water and milk sugar is crossed 60 mesh sieve equal increments and mixed, sour stabilizer is added, with maleic acid Yi Napu
Profit mixed 60 mesh sieves；
(2) Ac-Di-Sol and adhesive are added, 60 mesh sieves is crossed and is well mixed by equal increments method, with crystallite
Cellulose mixed 60 mesh sieves；
(3) add magnesium stearate and mix tabletting.
The present invention also provides a kind of preparation method of enalapril maleate folate composition, comprises the following steps：
(1) enalapril maleate of recipe quantity, folic acid are weighed, single water and milk sugar, microcrystalline cellulose, sour stabilizer, is crosslinked
Sodium carboxymethylcellulose and adhesive, cross 100 mesh sieves well mixed by equal increments method；
(2) dry granulation, feeding 20~40rpm of rotating speed, pinch roller 2~4rpm of rotating speed, pinch roller spacing 0.3mm cross 20 mesh sieves
Obtain particle；
(3) particle for obtaining step (2) mixes tabletting with magnesium stearate.
Preferred scheme of the present invention, described sour stabilizer is maleic acid or fumaric acid of the weight than 1%~5%, preferably 1%
~5% maleic acid, further preferred 2%~4% maleic acid.
Preferred scheme of the present invention, described adhesive is selected from PVP K30 or hydroxypropyl methylcellulose E5, and described crystallite is fine
Dimension element is selected from MCC or microcrystalline cellulose 102.
The percentage by weight of sour stabilizer refers to calculate with whole tablet weight, the part by weight shared by sour stabilizer.Such as
Sour stabilizer weight ratio is 1%~5%, if whole tablet weight is 100mg, and sour stabilizer weight is 1mg~5mg.
Rotating speed：Rpm revs/min, pinch roller spacing：Mm millimeters.
Compared with prior art, the invention has the advantages that：
(a) in invention formulation prescription add 1%~5% maleic acid, significantly improve the stability of preparation, 60 DEG C of high temperature
Lower enalapril diketone impurity ＜ 1%, 40 DEG C, places 45 days enalapril diketone impurity ＜ 0.5%, is made under the conditions of RH75%
Enalapril maleate folic acid tablet than commercially available stabilization.
(b) by being screened to different fillers, discovery microcrystalline cellulose and milk-sugar mixture can improve folic acid in 0.1M
Dissolution in hydrochloric acid medium, reach with it is commercially available basically identical.
Brief description of the drawings
Fig. 1 is the commercially available, stripping curve that Rx13~Rx18 folic acid in tablets is in 0.1M hydrochloric acid mediums；
Fig. 2 is the commercially available, stripping curve that the folic acid in tablets of embodiment 4~7 is in 0.1M hydrochloric acid mediums.
Embodiment 1
By selecting different acid, citric acid, fumaric acid, malic acid, arginine and maleic acid screen suitable stabilization
Agent, without any acid is added in control, as a result as shown in table 1.
The sour stabilizer selection of table 1
Preparation technology：
(1) weigh folic acid and starch crosses the mixing of 60 mesh sieve equal increments, add sour stabilizer citric acid, fumaric acid, apple
Acid, arginine or maleic acid, 60 mesh sieves were mixed with enalapril maleate；
(2) weigh the disintegrant Ac-Di-Sol and adhesive PVP K30 of recipe quantity, cross 60 mesh sieves by etc.
Measure incremental method to be well mixed, 60 mesh sieves were mixed with microcrystalline cellulose 102；
(3) add magnesium stearate lubricant and mix tabletting, be made 1000.
Relevant substance detecting method：The detection of Waters high performance liquid chromatography e2695-2489 instruments, flow velocity 2.0mL/min,
Column temperature：50 DEG C, Detection wavelength 215nm, mobile phase A：0.01mol/L potassium dihydrogen phosphate buffer solutions adjust pH to be 2.2, Mobile phase B：
Acetonitrile, gradient elution mobile phase A/Mobile phase B volume ratio 90:10→70:30→90:10.
The preparation that control, prescription Rx1~Rx5 are obtained is in epidemic disaster RH 92.5% 60 DEG C high and 4500lx strong illuminations
Under the conditions of place 10 days carry out influence factor experiment, investigate its stability.As a result find, in humidity RH 92.5% and 4500lx
The sour impurity of enalapril diketone, enalaprilat, dish does not occur significant change in preparation under the conditions of strong illumination, but at 60 DEG C
Under hot conditions, enalapril diketone is dramatically increased in control, Rx1, Rx3, Rx4, is all higher than enalapril diketone in 2%, Rx2
For enalapril diketone increase minimum 1.25% in 1.85%, Rx5.It is possible thereby to illustrate, citric acid, malic acid, arginine
The stabilizer of enalapril maleate foliamin can not be improved, fumaric acid can improve the stabilization of preparation to a certain extent
Property, and maleic acid can significantly improve preparation stability, and next maleic acid consumption is further optimized.
Embodiment 2
The maleic acid consumption of table 2 is screened
Preparation method be the same as Example 1.
By investigating maleic acid consumption that percentage by weight is 0.1%~5% to the stability influence of preparation, by prescription
The preparation that Rx6~Rx12 is obtained places progress in 10 days under the conditions of epidemic disaster RH 92.5% 60 DEG C high and 4500lx strong illuminations
Influence factor is tested.As a result find, enalapril is double in preparation under the conditions of humidity RH 92.5% and 4500lx strong illuminations
The sour impurity of ketone, enalaprilat, dish does not occur significant change, but under 60 DEG C of hot conditions, enalapril diketone still increases
Plus.With the increase of maleic acid consumption in prescription, enalapril diketone impurity is gradually reduced, but when maleic acid consumption is increased to
Then impurity no longer reduces when 5%.Count by weight percentage, when maleic acid is 1%~5%, 60 DEG C of hot conditions are placed 10 days,
Enalapril diketone impurity is less than 1%.
But, above-mentioned prescription be slower than in 0.1M hydrochloric acid medium Folic Acid dissolution it is commercially available, and water, pH6.8, pH4.5 be situated between
In matter, folic acid 15min releases are complete, and enalapril maleate 15min in 0.1M hydrochloric acid, water, pH6.8 and pH4.5 media is released
Discharge complete.Therefore dissolution rate of the folic acid in 0.1M hydrochloric acid medium is improved, preparation is consistent with commercially available dissolution, is still one and treats
The problem of solution.
Preparation made from above-mentioned prescription, the reason for folic acid dissolution is slower, it may be possible to which filler selection is improper.According to CFDA's
Regulation, the Dissolution Standards of imitation medicine should be consistent with reference preparation, more too fast than commercially available dissolution or do not comply with requirement slowly excessively, connects down
That filler need to be screened.
Embodiment 3
The filler of table 3 is screened
| Composition | Rx13 | Rx14 | Rx15 | Rx16 | Rx17 | Rx18 |
| Enalapril maleate | 10.0g | 10.0g | 10.0g | 10.0g | 10.0g | 10.0g |
| Folic acid | 0.8g | 0.8g | 0.8g | 0.8g | 0.8g | 0.8g |
| Starch | 0 | 0 | 30.0g | 30.0g | 0 | 0 |
| Lactis Anhydrous | 80.0g | 0 | 50.0g | 0 | 0 | 0 |
| Single water and milk sugar | 0 | 80.0g | 0 | 50.0g | 50.0g | 50.0g |
| Microcrystalline cellulose 102 | 0 | 0 | 0 | 0 | 30.0g | 0 |
| MCC | 0 | 0 | 0 | 0 | 0 | 30.0g |
| Ac-Di-Sol | 5.0g | 5.0g | 5.0g | 5.0g | 5.0g | 5.0g |
| PVP K30 | 1.0g | 1.0g | 1.0g | 1.0g | 1.0g | 1.0g |
| Maleic acid | 2.0g | 2.0g | 2.0g | 2.0g | 2.0g | 2.0g |
| Magnesium stearate | 1.0g | 1.0g | 1.0g | 1.0g | 1.0g | 1.0g |
Method for preparing tablet thereof be the same as Example 1.
Determine, be situated between by dissolution of 0.1M hydrochloric acid solutions 500mL according to the second methods of C of two annex of Chinese Pharmacopoeia version in 2010 Ⅹ
Matter, rotating speed is 50rpm, in 5min, 10min, 15min, 30min, 45min and 60min to Rx11~Rx16 and commercially available maleic acid
Enalapril folic acid takes a measure, as a result as shown in table 4 and accompanying drawing 1.
Table 4 is commercially available, dissolution data of Rx13~Rx18 folic acid in tablets in 0.1M hydrochloric acid mediums
Similar factors f2 value scope is bigger in 0~100, f2, and the similitude of two curves is higher, U.S. FDA and European Union
EMA is provided：If the f2 values between tested and reference preparation stripping curve are not less than 50, then it is assumed that both are similar.
Rx13 and Rx14 does filler from Lactis Anhydrous or single water and milk sugar it can be seen from table 4 and accompanying drawing 1, and dissolution is bright
Aobvious faster than commercially available, f2 ＜ 50 are inconsistent with commercially available dissolution；Rx15 makes filler, Rx16 starch, list of starch, Lactis Anhydrous
Water and milk sugar is cooked filler, and dissolution is substantially slower than commercially available, and f2 ＜ 50 are inconsistent with commercially available dissolution；Rx17 MCCs and
Single water milk-sugar mixture does filler, and Rx18 does filler with microcrystalline cellulose 102 and single water milk-sugar mixture, and f2 ＞ 80 are molten
Go out with it is commercially available roughly the same.
Analyze reason, it may be possible to which Lactis Anhydrous, single water and milk syrup dissolubility are preferable, and starch, MCC and crystallite
Cellulose 102 is insoluble in be more suitable for selecting different filler mixtures to control dissolution in water, therefore preparation prescription.Experimental result
It is found surprisingly that, starch and Lactis Anhydrous, starch and single water milk-sugar mixture do filler, and dissolution is still slower than commercially available, still
Microcrystalline cellulose 102 and single water and milk sugar, MCC and single water milk-sugar mixture do filler, dissolution with it is commercially available similar.
Embodiment 4
Powder vertical compression
| Composition | Rx19 |
| Enalapril maleate | 10.0g |
| Folic acid | 0.8g |
| Single water and milk sugar | 60.0g |
| MCC | 20.0g |
| Ac-Di-Sol | 5.0g |
| PVP K30 | 1.0g |
| Maleic acid | 4.0g |
| Magnesium stearate | 1.0g |
Preparation technology：
(1) weigh folic acid and single water and milk sugar is crossed 60 mesh sieve equal increments and mixed, sour stabilizer maleic acid is added, with maleic acid
Enalapril mixed 60 mesh sieves；
(2) weigh the disintegrant Ac-Di-Sol and adhesive PVP K30 of recipe quantity, cross 60 mesh sieves by etc.
Measure incremental method to be well mixed, 60 mesh sieves were mixed with MCC；
(3) add magnesium stearate lubricant and mix tabletting, be made 1000.
Embodiment 5
Dry granulation
| Composition | Rx20 |
| Enalapril maleate | 10.0g |
| Folic acid | 0.8g |
| Single water and milk sugar | 55.0g |
| Microcrystalline cellulose 102 | 25.0g |
| Ac-Di-Sol | 5.0 |
| PVP K30 | 3.0 |
| Maleic acid | 2.5g |
| Magnesium stearate | 1.0g |
Preparation technology：
(1) enalapril maleate of recipe quantity, folic acid, single water and milk sugar, microcrystalline cellulose 102, maleic acid, crosslinking are weighed
Sodium carboxymethylcellulose and adhesive PVP K30, cross 100 mesh sieves well mixed by equal increments method；
(2) dry granulation, feeding rotating speed 30rpm, pinch roller rotating speed 4rpm, pinch roller spacing 0.3mm cross 20 mesh sieves and obtained
Grain；
(3) particle for obtaining step (2) mixes tabletting with magnesium stearate lubricant, is made 1000.
Embodiment 6
Powder vertical compression
| Composition | Rx21 |
| Enalapril maleate | 10.0g |
| Folic acid | 0.8g |
| Single water and milk sugar | 50.0g |
| Microcrystalline cellulose 102 | 30.0g |
| Ac-Di-Sol | 5.0 |
| Hydroxypropyl methylcellulose E5 | 5.0 |
| Maleic acid | 3.0g |
| Magnesium stearate | 1.0g |
Preparation technology：
(1) weigh folic acid and single water and milk sugar is crossed 60 mesh sieve equal increments and mixed, sour stabilizer maleic acid is added, with maleic acid
Enalapril mixed 60 mesh sieves；
(2) the disintegrant Ac-Di-Sol and adhesive hydroxypropyl methylcellulose E5 of recipe quantity are weighed, 60 mesh are crossed
Sieve is well mixed by equal increments method, and 60 mesh sieves were mixed with microcrystalline cellulose 102；
(3) add magnesium stearate lubricant and mix tabletting, be made 1000.
Embodiment 7
Dry granulation
| Composition | Rx22 |
| Enalapril maleate | 10.0g |
| Folic acid | 0.8g |
| Single water and milk sugar | 55.0g |
| MCC | 25.0g |
| Ac-Di-Sol | 5.0 |
| Hydroxypropyl methylcellulose E5 | 5.0 |
| Maleic acid | 2.0g |
| Magnesium stearate | 1.0g |
Preparation technology：
(1) enalapril maleate of recipe quantity, folic acid, single water and milk sugar, MCC, maleic acid, crosslinking are weighed
Sodium carboxymethylcellulose and adhesive hydroxypropyl methylcellulose E5, cross 100 mesh sieves well mixed by equal increments method；
(2) dry granulation, feeding rotating speed 25rpm, pinch roller rotating speed 3rpm, pinch roller spacing 0.3mm cross 20 mesh sieves and obtained
Grain；
(3) particle for obtaining step (2) mixes tabletting with magnesium stearate lubricant, is made 1000.
Comparative example 1
Prepared according to the method for CN1269529C embodiments 2
Comparative example 2
Add alkaline matter sodium acid carbonate
Preparation technology：
(1) weigh folic acid and single water and milk sugar is crossed 60 mesh sieve equal increments and mixed, alkali stabilizer sodium acid carbonate is added, with Malaysia
Sour enalapril mixed 60 mesh sieves；
(2) the disintegrant Ac-Di-Sol and adhesive hydroxypropyl methylcellulose E5 of recipe quantity are weighed, 60 mesh are crossed
Sieve is well mixed by equal increments method, and 60 mesh sieves were mixed with MCC；
(3) add magnesium stearate lubricant and mix tabletting, be made 1000.
The influence factor of embodiment 8 is tested
Respectively by commercially available enalapril maleate folic acid tablet (Chinese medicines quasi-word H20103723, product batch number 20160408),
The preparation that embodiment 4~7, comparative example 1 and comparative example 2 are obtained is in epidemic disaster RH 92.5% 60 DEG C high and 4500lx strong illuminations
Under the conditions of place 10 days carry out influence factor experiment, investigate its stability, as a result as shown in table 5.
Table 5 is commercially available, the experiment of the influence factor of embodiment 4~7 and the preparation of comparative example 1~2
As can be seen from Table 5, under the conditions of 60 DEG C of high temperature, enalapril diketone impurity in comparative example 1 and the preparation of comparative example 2
Substantially increase, higher than the increase of impurity in commercial preparation；Under the conditions of RH92.5%, in the preparation of comparative example 1 enalaprilat and
Increase of the enalapril diketone impurity also above impurity in commercial preparation.
Analyze reason, in the case of no sour stabilizer, supplementary product starch, microcrystalline cellulose, carboxylic in the preparation of comparative example 1
First sodium starch, magnesium stearate are poor with raw material enalapril maleate folic acid compatibility in 60 DEG C of high temperature, and the wet method system of comparative example 1
Grain also brings along the increase of enalapril diketone impurity.And the alkaline matter sodium acid carbonate added in comparative example 2 is not played
Stabilizer function, enalaprilat impurity still substantially increases.
Embodiment 4~7 adds weight than the maleic acid for 2%~4% in prescription, obtained enalapril maleate leaf
Sour compound preparation is relatively stablized under 60 DEG C of high temperature, RH92.5% and high light conditions, dish acid, enalaprilat and enalapril
Diketone impurity does not occur the increase for being less than commercially available enalapril diketone under the conditions of significant change, and 60 DEG C of high temperature, embodiment 4~7
Powder vertical compression or dry granulation are favorably improved the stability of preparation.
Conclusion：The preparation stability of comparative example 1 and comparative example 2 is bad, and the preparation stability of embodiment 4~7 is preferably, than
Commercially available stabilization.
The stability experiment of embodiment 9
Respectively by commercially available enalapril maleate folic acid tablet (Chinese medicines quasi-word H20103723, product batch number 20160408),
The preparation that embodiment 4~7 is obtained is placed under the conditions of 40 DEG C, humidity RH 75% and further investigates its stability in 45 days, as a result such as
Shown in table 6.
Table 6 is commercially available and the preparation stability of embodiment 4~7 is tested
As can be seen from Table 6,40 DEG C, place 45 days under the conditions of RH 75%, enalapril diketone in the preparation of embodiment 4~7
Impurity is more more stable than commercially available less than commercially available.
The dissolution data of embodiment 10
Determine, be situated between by dissolution of 0.1M hydrochloric acid solutions 500mL according to the second methods of C of two annex of Chinese Pharmacopoeia version in 2010 Ⅹ
Matter, rotating speed is 50rpm, in 5min, 10min, 15min, 30min, 45min and 60min to embodiment 4~7 and commercially available maleic acid
Enalapril folic acid takes a measure, as a result as shown in table 7 and accompanying drawing 2.
Table 7 is commercially available, dissolution data of the folic acid in tablets of embodiment 4~7 in 0.1M hydrochloric acid mediums
Similar factors f2 >=80 it can be seen from table 7 and accompanying drawing 2, tablet folic acid is in 0.1M salt made from embodiment 4~5
Dissolution in acid medium with it is commercially available basically identical.
It should be noted that the foregoing is merely illustrative of the preferred embodiments of the present invention, it is not intended to limit the invention
Scope, all any modification, equivalent replacement and improvement made within the principle of the present invention etc., it should be included in the present invention
Protection domain within.
Claims (10)
1. a kind of pharmaceutical composition containing enalapril maleate, folic acid and sour stabilizer, it is characterised in that described acid is steady
Determine agent and be selected from maleic acid, fumaric acid or butanedioic acid.
2. composition according to claim 1, it is characterised in that count by weight percentage, sour stabiliser content is 1%
~5%.
3. composition according to claim 1, it is characterised in that described sour stabilizer is maleic acid or fumaric acid.
4. composition according to claim 1, it is characterised in that also including filler, adhesive, disintegrant and lubrication
Agent, described filler is the mixture of single water and milk sugar and microcrystalline cellulose, and described adhesive is selected from PVP K30 or hydroxypropyl
Methylcellulose E5, described disintegrant is Ac-Di-Sol, and described lubricant is magnesium stearate.
5. composition according to claim 4, it is characterised in that described microcrystalline cellulose be selected from MCC or
Microcrystalline cellulose 102.
6. composition according to claim 4, it is characterised in that the weight ratio of single water and milk sugar and microcrystalline cellulose is 1.67
~3:1.
7. the preparation method of any one of claim 1~6 composition, comprises the following steps：
(1) weigh folic acid and single water and milk sugar is crossed 60 mesh sieve equal increments and mixed, add sour stabilizer, it is mixed with enalapril maleate
Closed 60 mesh sieves；
(2) Ac-Di-Sol and adhesive are added, 60 mesh sieves is crossed and is well mixed by equal increments method, with microcrystalline cellulose
Element mixed 60 mesh sieves；
(3) add magnesium stearate and mix tabletting.
8. the preparation method of any one of claim 1~6 composition, comprises the following steps：
(1) enalapril maleate of recipe quantity, folic acid are weighed, single water and milk sugar, microcrystalline cellulose, sour stabilizer, carboxylic first is crosslinked
Base sodium cellulosate and adhesive, cross 100 mesh sieves well mixed by equal increments method；
(2) dry granulation, feeding 20~40rpm of rotating speed, pinch roller 2~4rpm of rotating speed, pinch roller spacing 0.3mm cross 20 mesh sieves and obtained
Particle；
(3) particle for obtaining step (2) mixes tabletting with magnesium stearate.
9. the preparation method according to claim 7 or 8, it is characterised in that described sour stabilizer is weight than 1%~
5% maleic acid or fumaric acid.
10. the preparation method according to claim 7 or 8, it is characterised in that described adhesive be selected from PVP K30 or
Hydroxypropyl methylcellulose E5, described microcrystalline cellulose is selected from MCC or microcrystalline cellulose 102.
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| CN108896675A (en) * | 2018-07-06 | 2018-11-27 | 精晶药业股份有限公司 | A kind of efficient liquid phase detection method of L-citrulline-DL-malic acid |
| CN109350733A (en) * | 2018-06-08 | 2019-02-19 | 山东理工职业学院 | A kind of preparation method of enalapril maleate tablet |
| CN110320289A (en) * | 2018-03-30 | 2019-10-11 | 南京优科生物医药研究有限公司 | Composition containing ACEI, the detection method in relation to substance |
| CN110320288A (en) * | 2018-03-30 | 2019-10-11 | 南京优科生物医药研究有限公司 | Composition containing ACEI, the method for separating and detecting in relation to substance |
| CN110917151A (en) * | 2018-09-20 | 2020-03-27 | 杨敏 | Enalapril maleate tablet composition and preparation method thereof |
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| CN107007838B (en) | 2021-07-20 |
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