CN106860404A - A kind of sildenafil citrate taste masking resin complexes and its application - Google Patents
A kind of sildenafil citrate taste masking resin complexes and its application Download PDFInfo
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- CN106860404A CN106860404A CN201710247596.9A CN201710247596A CN106860404A CN 106860404 A CN106860404 A CN 106860404A CN 201710247596 A CN201710247596 A CN 201710247596A CN 106860404 A CN106860404 A CN 106860404A
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- sildenafil citrate
- taste masking
- resin
- resin complexes
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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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
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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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- Life Sciences & Earth Sciences (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract
The invention discloses a kind of sildenafil citrate taste masking resin complexes and preparation method thereof, the technical problem to be solved is the bad odor of masking agentses active component sildenafil citrate, makes it have good mouthfeel.Taste masking resin complexes are prepared from acid type cationic ion-exchange resin for sildenafil citrate by static exchange method, and both weight ratios are 0.5: 13: 1.The sildenafil citrate taste masking resin complexes prepared using the present invention can further be made chewable tablets, oral disnitegration tablet, granule, supensoid agent.The present invention compared with prior art, using ion exchange technique, can effectively cover the bad odor of sildenafil citrate, improve patient's compliance, and preparation process is simple is suitable for industrialized production.
Description
Technical field
The present invention relates to field of pharmaceutical preparations, specifically, the present invention is that a kind of sildenafil citrate taste masking resin is answered
Compound and its application.
Background technology
Oral formulations are easy to use due to its, are the widest preparations of current clinical practice the features such as security is good, but
Most medicine has different degrees of bitter taste, causes mouthfeel bad, and patient is difficult to receive, poor compliance.Conventional taste masking
Method has the auxiliary materials such as addition flavouring, the transformation of bitter drug chemical constitution, prepares micro-capsule or microballoon taste masking, prepares solid dispersions
Deng.Addition auxiliary material is to mitigate bitter taste by disturbing taste bud, and method is most simple, low cost, but acts on limited, to the extremely bitter and Yishui River
The effect of drugs of solution is not good, and medicines structure modification is made into prodrug, is overcome again while bitter drug curative effect is kept bad
Taste, its technical difficulty is larger.
Ion exchange resin (Ion Exchange Resin, IER) is the poly- electrolysis that a class has ionizable functional group
Matter class functional high molecule material, with space network, as drug delivery system (Drug delivery system,
DDS effective carrier) has Drug loading capacity very high, can carry out ion exchange or absorption with other ionic species in solution.
Usually white or faint yellow solid, insoluble in general acid, aqueous slkali and organic solvent.Ion exchange resin is by 3 part groups
Into：Mesh skeleton with three dimensions stereochemical structure；Irremovable active group is connected with covalent bond with mesh skeleton carrier
Group, also known as functional group；Combined with ionic bond with active group, the electric charge active ion opposite with active group is also known as balanced
Ion.Due to the ion-exchange capacity and micro-porous adsorption ability of ion exchange resin, regulating drug release, part can be applied to
It is administered, covers adverse drug odor, improves physical and chemical properties of drugs and medicine etc..And ion exchange resin has chemistry lazy
Property, it is not absorbed by the body, thus without locally or systemically toxic action, with security higher.It is external existing multiple at present with
Ion exchange resin is pharmaceutical preparation list marketing prepared by carrier.
Sildenafil citrate, chemical entitled 1- [4- ethyoxyls -3- [5- (6,7- dihydro -1- methyl -7- oxos -3- third
Base -1H- pyrazolo [4,3d] pyrimidine)] benzene sulfonyl] -4- methylpiperazine citrates, structural formula is as follows：
Sildenafil citrate is to treat anginal by one kind of Pfizer (Pfizer) drugmaker development and production
Medicine.Find that its anginal effect for the treatment of is general in clinical test, and have special-effect to treatment impotence.U.S.'s food
Drug administration (FDA) is in the official approval of March 27 medicine in 1998 as the special-purpose medicaments for treating erectile dysfunction.But
Sildenafil citrate has strong bitter taste in itself, and hygroscopicity is strong, and easy moisture absorption is gone bad under normality.Its listing formulation is piece
Agent.For the patient, the patient of water intaking inconvenience that have aphetite disorder or difficulty, the clinical practice of this tablet is restricted.Pass through
The masking methods such as conventional auxiliary material dilution, flavouring, are difficult to realize complete, good taste masking.Patent CN104644574A is public
A kind of sildenafil citrate taste masking preparation and preparation method thereof is opened, has been that sildenafil citrate is mixed with hydroxypropyl cellulose
Conjunction is made melting dispersion, then cuts into particle, after the particle and Compritol 888 ATO co-ground, mixes with other auxiliary materials,
It is pressed into and is available for oral tablet.But there is following drawback using the method：1st, preparation technology is complicated, and high cost is, it is necessary to special
Equipment double screw extruder and impact grinder；High-temperature process is needed when the 2nd, preparing melting dispersion, is not suitable for temperature sensitive medicine
Thing；3rd, the melting dispersion existence and stability problem for preparing.
Ion exchange resin can form compound with ionic drug, medicine is covered into ion exchange resin skeleton
Its bad odor.Again because the dissociation of medicine is based on ion exchange mechanism, the saliva of oral cavity secretion measures less, ion concentration
Relatively low, the residence time is very short in the oral cavity for resin particle during oral administration, and medicine also has not enough time to desorption and just comes into stomach
In.Therefore, it can effectively cover adverse drug odor, improve patient's compliance.
Taste masking resin complexes of the present invention, its final application form includes but is not limited to chewable tablets, mouth
Cavity disintegrating tablet, supensoid agent.
The content of the invention
Sheltered wherein it is an object of the invention to provide a kind of method for preparing sildenafil citrate drug-resin complex
The bad odor of active constituents of medicine, improves medicine stability and patient's compliance.
To achieve the above object, the present invention uses following technical scheme：
A kind of sildenafil citrate taste masking resin complexes, it is characterised in that sildenafil citrate and ion exchange
The weight ratio of resin is 0.5: 1-3: 1, preferably 1: 1.
Described sildenafil citrate taste masking resin complexes, it is characterised in that：The ion exchange resin is
Purolite C115K MR、Amberlite IRP-88、Amberlite IRP-69、Amberlite IRP-64、Tulsion
One or more in T-339.
Described sildenafil citrate taste masking resin is prepared from by static exchange method, and design parameter is：Selection 100
The ion exchange resin of~200 mesh particle diameters, ion-exchange reactions starting liquor strength is 3~20mg/mL, and reaction temperature is 25 DEG C
~60 DEG C, the reaction time is 4hr~10hr.Wherein, the preferred 12mg/mL of sildenafil citrate concentration, the reaction temperature
Preferably 40 DEG C of degree, reaction time preferred 8hr.
A kind of preparation method of sildenafil citrate taste masking resin complexes, comprises the following steps：
Ion exchange resin is added in the drug solution of sildenafil citrate and water composition, is held under the conditions of 40 DEG C
Continuous stirring 8hr stands, suction filtration separation resin salt and liquid, cleans filter cake repeatedly to exchange equilibrium, dries, sieves, obtains citron
Sour silaenafil drug-resin complex.
Described sildenafil citrate and water composition drug solution, wherein solid-liquid ratio is 1: 20~200, preferably 1:
60。
Described drying mode uses heated-air drying, fluidized bed drying or vacuum drying.
The particle diameter of described sildenafil citrate taste masking resin complexes is 40~100 mesh, preferably 100 mesh.
Taste masking resin complexes of the present invention, its final application form includes but is not limited to chewable tablets, mouth
Cavity disintegrating tablet, supensoid agent.
It is an advantage of the invention that：The present invention compared with prior art, sildenafil citrate is entered with ion exchange resin
Row ion-exchange reactions, forms drug-resin complex, has effectively sheltered the bad odor of wherein active constituents of medicine, mouthfeel
Well, stability, patient's compliance of medicine are improve.
Brief description of the drawings
Fig. 1 is that chewable tablets prepared by the embodiment of the present invention four and embodiment five is molten with commercially available sildenafil citrate chewable tablets
Go out curve comparison schematic diagram.
Fig. 2 is sildenafil citrate bulk drug SEM (SEM) schematic diagram.
Fig. 3 is ion exchange resin SEM (SEM) schematic diagram.
Fig. 4 shows for sildenafil citrate bulk drug with the electron microscope (SEM) of ion exchange resin physical mixture
It is intended to.
Fig. 5 is sildenafil citrate resin complexes SEM (SEM) schematic diagram.
Specific embodiment
It is prepared by embodiment one, sildenafil citrate drug-resin complex
Prescription is constituted：
Sildenafil citrate 8.4g
Ion exchange resin 8.4g
Water 500mL
Preparation method：
By above prescription by sildenafil citrate and water composition drug solution, the ion exchange resin of 200 mesh sieves will be crossed
It is added thereto, persistently stirs 8hr to exchange equilibrium under the conditions of 40 DEG C, stands, suction filtration separation resin salt and liquid, cleans repeatedly
Filter cake, dries in vacuum drying chamber, sieves, obtaining sildenafil citrate drug-resin complex.
Determined after dissociated, the content of sildenafil citrate is in sildenafil citrate drug-resin complex
66.7%.
It is prepared by embodiment two, sildenafil citrate drug-resin complex
Prescription is constituted：
Sildenafil citrate 8.4g
Ion exchange resin 4.0g
Water 500mL
Preparation method：
By above prescription by sildenafil citrate and water composition drug solution, the ion exchange resin of 200 mesh sieves will be crossed
It is added thereto, persistently stirs 8hr to exchange equilibrium under the conditions of 40 DEG C, stands, suction filtration separation resin salt and liquid, cleans repeatedly
Filter cake, dries in vacuum drying chamber, sieves, obtaining sildenafil citrate drug-resin complex.
Determined after dissociated, the content of sildenafil citrate is in sildenafil citrate drug-resin complex
39.8%.
It is prepared by embodiment three, sildenafil citrate drug-resin complex
Prescription is constituted：
Sildenafil citrate 6g
Ion exchange resin 6g
Water 500mL
Preparation method：
By above prescription by sildenafil citrate and water composition drug solution, the ion exchange resin of 200 mesh sieves will be crossed
It is added thereto, persistently stirs 8hr to exchange equilibrium under the conditions of 40 DEG C, stands, suction filtration separation resin salt and liquid, cleans repeatedly
Filter cake, dries in vacuum drying chamber, sieves, obtaining sildenafil citrate drug-resin complex.
Determined after dissociated, the content of sildenafil citrate is in sildenafil citrate drug-resin complex
25.4%.
Example IV, sildenafil citrate medical resin chewable tablets (specification：50mg)
The gained sildenafil citrate drug-resin complex of Example one (crossing 40 mesh sieves) is tested as follows.
Prescription is constituted：
Preparation technology：
(1) flavouring of recipe quantity, adhesive, disintegrant is weighed to be well mixed, add recipe quantity citric acid west ground that
Non-drug resin complexes are well mixed；
(2) filler for weighing recipe quantity is well mixed with step (1) powder, adds glidant, the lubricant of recipe quantity,
Well mixed, tabletted, mouthfeel is sweet and smell is fragrant.
Embodiment five, sildenafil citrate medical resin chewable tablets (specification：50mg)
The gained sildenafil citrate drug-resin complex of Example one (crossing 100 mesh sieves) is tested as follows.
Prescription is constituted：
Preparation technology：
(1) flavouring of recipe quantity, adhesive, disintegrant is weighed to be well mixed, add recipe quantity citric acid west ground that
Non-drug resin complexes are well mixed；
(2) filler for weighing recipe quantity is well mixed with step (1) powder, adds glidant, the lubricant of recipe quantity,
Well mixed, tabletted, mouthfeel is sweet and smell is fragrant.
Embodiment six, sildenafil citrate medical resin oral disnitegration tablet (specification：50mg)
The gained sildenafil citrate drug-resin complex of Example one (crossing 100 mesh sieves) is tested as follows.
Prescription is constituted：
Preparation technology：
(1) after weighing pigment, flavouring, the disintegrant mixed in equal amounts of recipe quantity, 100 mesh sieves are crossed and is well mixed；
(2) weigh sildenafil citrate drug-resin complex and microcrystalline cellulose is well mixed；
(3) it is (1) and (2) is well mixed, add the lactose of recipe quantity to be well mixed, with 2% PVPP solution system
Standby softwood, 20 mesh sieves granulation is dried to pellet moisture under the conditions of 50 DEG C and is less than 3%, 24 mesh sieve whole grains；
(4) superfine silica gel powder and magnesium stearate of additional recipe quantity are always mixed, compressing tablet after being well mixed.
With reference to Chinese Pharmacopoeia four general rule 0921 disintegration time limited inspection techniques of version in 2015：Determine mouth prepared by above-described embodiment
The disintegration time of cavity disintegrating tablet, while determining oral disnitegration tablet disintegration in vivo by volunteer.
The external Mean disintegration time of the oral disnitegration tablet of above-described embodiment is 17 seconds.
The oral disnitegration tablet of above-described embodiment Mean disintegration time in the oral cavity is 20.3 seconds, meets oral disnitegration tablet
It is required that, and mouthfeel is sweet, smell delicate fragrance.
Embodiment seven, sildenafil citrate resin oral suspension (specification：10mL∶0.05g)
The gained sildenafil citrate drug-resin complex of Example one (crossing 100 mesh sieves) is tested as follows.
Prescription is constituted：
Preparation technology：
Sildenafil citrate drug-resin complex is dispersed in aqueous dispersion, suspending is weighed by recipe quantity
Agent, flavouring, preservative are added thereto, stirring, and purified water is added after each component is completely dissolved or is uniformly dispersed to aequum,
Stir and evenly mix.Good mouthfeel, without bitter taste.
Determined with reference to Chinese Pharmacopoeia four oral suspensions sedimentation volume ratio inspection techniques of version in 2015：Sedimentation volume ratio is
0.95。
Embodiment eight, investigates influence of the taste masking resin complexes particle diameter to dissolution.
According to the regulation of Chinese Pharmacopoeia four dissolution rates of general rule 0931 of version in 2015 and the method for drug release determination method second to this
Chewable tablets prepared by inventive embodiments four and embodiment five carries out dissolution test with commercially available sildenafil citrate chewable tablets.Determine
Condition is as described below.
Rotating speed：50rpm
Dissolution medium volume：900mL
Dissolution medium：PH4.5 acetate buffers
Assay method：Ultraviolet spectrophotometry, Detection wavelength 290nm
With reference to normal oral solid pharmaceutical preparation stripping curve determine and compare guideline, to two stripping curves whether phase
Seemingly, using the similarity estimate (f in non-model dependence method2) evaluated.By the dissolution rate and commercially available citric acid of a certain preparation
Silaenafil chewable tablets is contrasted, the f for calculating2When value is between 50~100, it is believed that two stripping curves are in the absence of notable
Sex differernce, f2Value is closer to 100, and similarity degree is higher；Conversely, it is then dissimilar, that is, there is significant difference.f2Computing formula is such as
Under：
Stripping curve measurement result is as shown in following table and accompanying drawing 1.
Stripping curve contrast (dissolution rate, %) of the table sildenafil citrate chewable tablets in pH4.5 acetate buffers
| Time (min) | Commercial preparation | Example IV | Embodiment five |
| 3 | 35.07 | 19.63 | 33.99 |
| 5 | 53.39 | 35.83 | 51.19 |
| 10 | 65.37 | 55.59 | 71.75 |
| 15 | 71.11 | 68.43 | 73.48 |
| 30 | 76.33 | 74.48 | 75.55 |
| 45 | 78.11 | 75.29 | 77.07 |
| 60 | 78.82 | 75.07 | 78.51 |
| 90 | 79.27 | 75.27 | 79.26 |
| 120 | 79.76 | 76.33 | 79.65 |
| f2 | 57.2 | 97.6 |
As shown above, the f of embodiment five2Value shows the similitude of the dissolution characteristic higher with commercial preparation, so
The particle diameter of sildenafil citrate taste masking resin complexes preferably 100 mesh.
Embodiment nine, the thing of sildenafil citrate drug-resin complex mutually differentiates-scanning electron microscopy (SEM)
Take sildenafil citrate bulk drug, ion exchange resin, bulk drug and ion exchange resin physical mixture,
The sildenafil citrate drug-resin complex of the gained of embodiment one is appropriate in sample panel, spreading out even, is placed in SU8010
Observe and be compared under Semi-In-Lens FE-SEM, as a result as shown in accompanying drawing 2, accompanying drawing 3, accompanying drawing 4 and accompanying drawing 5.
Accompanying drawing 2 shows that sildenafil citrate bulk drug is in the good rhabdolith of feature；Accompanying drawing 3 shows, ion exchange
Resin is block structure；Accompanying drawing 4 shows, physical mixture has sildenafil citrate bulk drug and ion exchange resin simultaneously
Two kinds of structural forms；Accompanying drawing 5 shows, in the absence of the bar-shaped crystalline substance of sildenafil citrate in sildenafil citrate resin complexes
Body, illustrates that drug-resin complex is not general physical mixed, but there occurs interaction.
Claims (8)
1. a kind of sildenafil citrate taste masking resin complexes, it is characterised in that sildenafil citrate and amberlite
The weight ratio of fat is 0.5: 1-3: 1.
2. sildenafil citrate taste masking resin complexes according to claim 1, it is characterised in that：The ion exchange
Resin be Purolite C115K MR, Amberlite IRP-88, Amberlite IRP-69, Amberlite IRP-64,
One or more in Tulsion T-339.
3. sildenafil citrate taste masking resin complexes according to claim 1, it is characterised in that：The citric acid west
That non-taste masking resin of ground is prepared from by static exchange method, and design parameter is：Select the ion exchange of 100~200 mesh particle diameters
Resin, ion-exchange reactions starting liquor strength is 3~20mg/mL, and reaction temperature is 25 DEG C~60 DEG C, and the reaction time is 4hr
~10hr.
4. a kind of preparation method of sildenafil citrate taste masking resin complexes, it is characterised in that comprise the following steps：Will be from
Sub-exchange resin is added in the drug solution of sildenafil citrate and water composition, is persistently stirred under the conditions of 25 DEG C~60 DEG C
4hr~10hr is stood, suction filtration separation resin salt and liquid, cleans filter cake repeatedly to exchange equilibrium, is dried, sieves, is obtained citron
Sour silaenafil drug-resin complex.
5. the preparation method of sildenafil citrate taste masking resin complexes according to claim 4, it is characterised in that：Will
Sildenafil citrate and water composition drug solution, wherein solid-liquid ratio is 1: 20~200.
6. the preparation method of sildenafil citrate taste masking resin complexes according to claim 4, it is characterised in that：Institute
The drying mode stated uses heated-air drying, fluidized bed drying or vacuum drying.
7. the preparation method of sildenafil citrate taste masking resin complexes according to claim 4, it is characterised in that：Institute
The particle diameter of the compound stated is 40~100 mesh.
8. sildenafil citrate taste masking resin complexes according to claim 1, it is characterised in that：Described medicine is covered
The final application form of taste resin complexes includes but is not limited to chewable tablets, oral disnitegration tablet, supensoid agent.
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| CN201710247596.9A CN106860404A (en) | 2017-04-13 | 2017-04-13 | A kind of sildenafil citrate taste masking resin complexes and its application |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710247596.9A CN106860404A (en) | 2017-04-13 | 2017-04-13 | A kind of sildenafil citrate taste masking resin complexes and its application |
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ID=59162287
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108392639A (en) * | 2018-04-13 | 2018-08-14 | 江苏亚邦爱普森药业有限公司 | A kind of pharmaceutical composition and preparation method thereof containing sildenafil citrate |
| CN108553437A (en) * | 2018-06-08 | 2018-09-21 | 姚静 | One kind passing through mercaptopurine chewable tablets and preparation method thereof made from ion exchange technique |
| CN112353802A (en) * | 2020-11-26 | 2021-02-12 | 山东诚创蓝海医药科技有限公司 | Vonola fumarate taste masking composition and application thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104168895A (en) * | 2012-02-28 | 2014-11-26 | 首尔制药株式会社 | High-content fast dissolving film with masking of bitter taste comprising sildenafil as active ingredient |
| WO2016001937A2 (en) * | 2014-06-30 | 2016-01-07 | Rubicon Research Private Limited | Modified release pharmaceutical preparations |
-
2017
- 2017-04-13 CN CN201710247596.9A patent/CN106860404A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104168895A (en) * | 2012-02-28 | 2014-11-26 | 首尔制药株式会社 | High-content fast dissolving film with masking of bitter taste comprising sildenafil as active ingredient |
| WO2016001937A2 (en) * | 2014-06-30 | 2016-01-07 | Rubicon Research Private Limited | Modified release pharmaceutical preparations |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108392639A (en) * | 2018-04-13 | 2018-08-14 | 江苏亚邦爱普森药业有限公司 | A kind of pharmaceutical composition and preparation method thereof containing sildenafil citrate |
| CN108553437A (en) * | 2018-06-08 | 2018-09-21 | 姚静 | One kind passing through mercaptopurine chewable tablets and preparation method thereof made from ion exchange technique |
| CN112353802A (en) * | 2020-11-26 | 2021-02-12 | 山东诚创蓝海医药科技有限公司 | Vonola fumarate taste masking composition and application thereof |
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