CN106236728A - A kind of oseltamivir phosphate decentralized capsule and preparation method thereof - Google Patents
A kind of oseltamivir phosphate decentralized capsule and preparation method thereof Download PDFInfo
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- CN106236728A CN106236728A CN201610363770.1A CN201610363770A CN106236728A CN 106236728 A CN106236728 A CN 106236728A CN 201610363770 A CN201610363770 A CN 201610363770A CN 106236728 A CN106236728 A CN 106236728A
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- oseltamivir phosphate
- agent
- decentralized
- capsule
- sweeting agent
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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
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
- A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
-
- 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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
-
- 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
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
Abstract
The present invention provides a kind of oseltamivir phosphate decentralized capsule and preparation method thereof, described oseltamivir phosphate decentralized capsule comprises the oseltamivir phosphate of 5.0～45.0%, the sweeting agent of 0.1%～5.0% and other pharmaceutically acceptable adjuvants, wherein said sweeting agent is sucralose, aspartame or its mixture.The oseltamivir phosphate decentralized capsule that the present invention provides can join under together taking in slop and be suitable for child or children, and the most described capsule mouthfeel is excellent, good stability, it is simple to carries and preserves.On the other hand the present invention also provides for the method preparing described oseltamivir phosphate decentralized capsule, the method safety, it is simple to operation, is suitable for industrialized production.
Description
Technical field
The present invention relates to field of medicine preparations, more specifically, relate to a kind of oseltamivir phosphate decentralized capsule and system thereof
Preparation Method.
Background technology
Oseltamivir phosphate, chemistry entitled (-)-(3R, 4R, 5S)-4-acetamide-5-amino-3-(1-ethylpropoxy)
Cyclohexene-1-carboxylic acid, ethyl ester phosphate.Chemical structural formula is as follows:
Being released by the research and development of Roche Holding Ag of Switzerland, oseltamivir phosphate has the activity of the strongest suppression neuraminidase, right
A, Type B influenza virus are all effective, and its information such as character and preparation method is disclosed in WO 1998007685 A1 and WO
In 1996026933 A1.
The dosage form that oseltamivir phosphate lists at present has granule, capsule and dry suspension etc..Granule or be dry mixed outstanding
Agent is suitable for prepared before use and becomes liquid preparation, it is simple to old man, child and be not suitable for the crowd of swallowing and take.But department of phosphoric acid Austria
His Wei is a kind of king-sized medicine of bitterness, and therefore its pharmaceutical composition is difficult to swallow.
Chinese patent CN 101389323 B discloses a kind of pharmaceutical composition, and it contains excipient and phosphoric acid Ao Sita
Wei, wherein this excipient selected from 25 DEG C, 70% time equilibrium moisture content of relative humidity be sugar and the sugar alcohol of below 1 weight %
More than one, and the content of glucose contained in this sugar and sugar alcohol and mannose is respectively below 0.01 weight %.In order to press down
Make the bitterness of this pharmaceutical composition, described invention is also added into substantial amounts of sweeting agent (such as sucrose or Stevia rebaudiana (Bertoni) Hemsl extract) to cover
Lid bitterness.
Chinese patent CN 1820774 B discloses a kind of oseltamivir phosphate granula and preparation method thereof, described granule
Agent comprises the oseltamivir phosphate of 1.97～19.8 weight %, the diluent of 75.0～97.5 weight %, 0.1～5.0 weight %
Binding agent, and edible essence, sweeting agent and/or the food coloring of 1.0～5.0 weight %.
Summary of the invention
Summary of the invention
In prior art described above, disclosed embodiment employs sucrose, Stevia rebaudiana (Bertoni) Hemsl extract and saccharin sodium etc.
Sweeting agent, but after sweeting agent disclosed in these and oseltamivir phosphate are applied in combination, although it can cover phosphoric acid Ao Sita
The bitterness of Wei, but it can affect the stability of oseltamivir phosphate in prescription, causes impurity in oseltamivir phosphate compositions
Rapid development, is unfavorable for that the long-term of medicine preserves and safe handling.
The present invention provides a kind of oseltamivir phosphate decentralized capsule, and described capsule is different from common oral capsule, institute
State oseltamivir phosphate decentralized capsule, capsule 's content can be joined in slop (fruit juice, milk, fruit jam etc.) together
Under clothes, can well solve the difficult problem that child is administered.But oseltamivir phosphate has the biggest bitterness, direct and slop
Mixing is taken and is difficult to accept for child.It is thus desirable to add suitable odor mask, to ensure described phosphoric acid Ao Sita simultaneously
The stability of Wei decentralized capsule.Therefore, seek a kind of good mouthfeel, be easy to carry and the oseltamivir phosphate of excellent in stability
The prescription being convenient to child's use is Worth Expecting.
The present inventor, after sufficiently studying oseltamivir phosphate crystal formation, gropes through many experiments, finds one
Plant good mouthfeel, be easy to carry and the oseltamivir phosphate decentralized capsule of excellent in stability.Due to decentralized capsule mainly
By the medicine in capsule is mixed to child's use with slop, therefore described decentralized capsule being carried out taste masking is very
Necessary.The most unexpectedly, present invention discover that when using sucralose or aspartame as sweeting agent, can effectively rectify
The taste of orthophosphoric acid Oseltamivir decentralized capsule, has excellent stability simultaneously.
Here, one aspect of the present invention provides a kind of oseltamivir phosphate decentralized capsule；
On the other hand a kind of preparation method preparing described oseltamivir phosphate decentralized capsule is provided.
Term defines
In the present invention " % ", unless otherwise indicated refer both to mass percent.
In the present invention " RRT ", go out to be otherwise noted the outer relative retention time referred in chromatography detection.
In the present invention " v/v ", outside going out to be otherwise noted, refer to volume ratio.
Concrete numerical value involved in the present invention refers to this numerical value ± 5%.
Detailed Description Of The Invention
The present invention provides a kind of oseltamivir phosphate decentralized capsule, and described capsule comprises oseltamivir phosphate, sweeting agent
With other pharmaceutically acceptable adjuvants, wherein said sweeting agent is sucralose or aspartame.
The present invention also provides for a kind of oseltamivir phosphate decentralized capsule, and described capsule comprises oseltamivir phosphate, sweet taste
Agent and other pharmaceutically acceptable adjuvants, wherein said sweeting agent is sucralose, aspartame or its mixture.
The content of wherein said oseltamivir phosphate is 5.0%～45.0%, and the content of described sweeting agent is 0.1%
～5.0%.
Wherein said oseltamivir phosphate content is 30mg, 45mg or 75mg, based on Oseltamivir.
Wherein said pharmaceutically acceptable adjuvant can be filler, binding agent, disintegrating agent, fluidizer, lubricant, pH
One or more in regulator and edible essence.
Wherein said filler can be but not limited to lactose, microcrystalline Cellulose, mannitol, sorbitol, maltose alcohol,
One or more in xylitol, corn starch, dextrin, maltodextrin, pregelatinized Starch, sucrose and gelatin.The most preferred
One or more in sorbitol, maltose alcohol or mannitol.
Wherein said binding agent can be but not limited to methylcellulose, hydroxypropyl cellulose, hydroxypropyl methyl fiber
One or more in element, polyvidone, microcrystalline Cellulose and low-substituted hydroxypropyl cellulose.Wherein preferred hydroxypropyl methyl fiber
Element or polyvidone.
Wherein said disintegrating agent can be but not limited to cross-linking sodium carboxymethyl cellulose, polyvinylpolypyrrolidone, carboxymethyl shallow lake
One or more in powder sodium, corn starch and low-substituted hydroxypropyl cellulose.Wherein preferably cross-linking sodium carboxymethyl cellulose or
Polyvinylpolypyrrolidone.
Wherein said fluidizer can be but not limited to silica sol or Pulvis Talci or its mixture.
Wherein said lubricant can be but not limited to sodium stearyl fumarate, magnesium stearate, calcium stearate, stearic acid
One in zinc, sucrose stearate, hydrogenated vegetable oil, stearic acid, silica sol, Pulvis Talci and polyethylene glycol 6000 or
Several.Wherein preferred sodium stearyl fumarate.
Wherein said pH adjusting agent can be but not limited to citric acid and hydrate salt pharmaceutically acceptable with it thereof
Mixture, dihydrogen citrate alkali metal salt, sodium lactate or sodium succinate, preferably monohydrate potassium and sodium citrate combinations.
Wherein said edible essence can be but not limited to peach flavor, orange flavor, strawberry essence, creamy
One or more in essence, apple essence, flavoring pineapple essence and flavoring banana essence.Wherein preferred peach flavor or orange flavor.
In certain embodiments, oseltamivir phosphate decentralized capsule of the present invention, comprise 10.0%～40.0%
Oseltamivir phosphate, the sweeting agent of 0.5%～5.0% and other pharmaceutically acceptable adjuvants, wherein said sweeting agent is
Sucralose or aspartame.
In certain embodiments, oseltamivir phosphate decentralized capsule of the present invention, comprise 10.0%～40.0%
Oseltamivir phosphate, the sweeting agent of 0.5%～5.0% and other pharmaceutically acceptable adjuvants, wherein said sweeting agent is
Sucralose, aspartame or its mixture.
In certain embodiments, oseltamivir phosphate decentralized capsule of the present invention, comprise 10.0%～40.0%
Oseltamivir phosphate, the filler of 45.0%～85.0%, the disintegrating agent of 0%～5.0%, the bonding of 1.0%～4.0%
Agent, the sweeting agent of 0.5%～5.0%, the pH adjusting agent of 0.5%～5.0%, the lubricant of 0.5%～2.0%, 0.2%～
The fluidizer of 2.0%, it is also possible to comprise the edible essence of 0.1%～1.0% further, wherein said sweeting agent is trichlorine sugarcane
Sugar or aspartame.
In certain embodiments, oseltamivir phosphate decentralized capsule of the present invention, comprise 10.0%～40.0%
Oseltamivir phosphate, the filler of 45.0%～85.0%, the disintegrating agent of 0%～5.0%, the bonding of 1.0%～4.0%
Agent, the sweeting agent of 0.5%～5.0%, the pH adjusting agent of 0.5%～5.0%, the lubricant of 0.5%～2.0%, 0.2%～
The fluidizer of 2.0%, it is also possible to comprise the edible essence of 0.1%～1.0% further, wherein said sweeting agent is trichlorine sugarcane
Sugar, aspartame or its mixture.
In certain embodiments, oseltamivir phosphate decentralized capsule of the present invention, comprise 10.0%～40.0%
Oseltamivir phosphate, the filler of 45.0%～85.0%, the disintegrating agent of 0%～5.0%, the bonding of 1.0%～4.0%
Agent, the sweeting agent of 0.5%～5.0%, the pH adjusting agent of 0.5%～5.0%, the lubricant of 0.5%～2.0%, 0.2%～
The fluidizer of 2.0%, it is also possible to comprise the edible essence of 0.1%～1.0% further；Wherein said filler is manna
One or more in alcohol, sorbitol and maltose alcohol, disintegrating agent is cross-linking sodium carboxymethyl cellulose or polyvinylpolypyrrolidone, bonding
Agent is polyvidone or hydroxypropyl methylcellulose, and sweeting agent is sucralose or aspartame, pH adjusting agent be citric acid monohydrate and
The mixture of sodium citrate, lubricant is sodium stearyl fumarate, and fluidizer is Pulvis Talci or silica sol, edible essence
It is peach flavor or orange flavor.
In certain embodiments, oseltamivir phosphate decentralized capsule of the present invention, comprise 10.0%～40.0%
Oseltamivir phosphate, the filler of 45.0%～85.0%, the disintegrating agent of 0%～5.0%, the bonding of 1.0%～4.0%
Agent, the sweeting agent of 0.5%～5.0%, the pH adjusting agent of 0.5%～5.0%, the lubricant of 0.5%～2.0%, 0.2%～
The fluidizer of 2.0%, it is also possible to comprise the edible essence of 0.1%～1.0% further；Wherein said filler is manna
One or more in alcohol, sorbitol and maltose alcohol, disintegrating agent is cross-linking sodium carboxymethyl cellulose or polyvinylpolypyrrolidone, bonding
Agent is polyvidone or hydroxypropyl methylcellulose, and sweeting agent is sucralose, aspartame or its mixture, and pH adjusting agent is a water
Citric acid and the mixture of sodium citrate, lubricant is sodium stearyl fumarate, and fluidizer is Pulvis Talci or silica sol,
Edible essence is peach flavor or orange flavor.
In certain embodiments, oseltamivir phosphate decentralized capsule of the present invention, comprise 10.0%～40.0%
Oseltamivir phosphate, the filler of 45.0%～85.0%, the cross-linking sodium carboxymethyl cellulose of 0%～5.0%, 1.0%～
4.0% polyvidone, the sucralose of 0.5%～3.0%, the citric acid monohydrate of 0.5%～5.0% and sodium citrate mixture,
The sodium stearyl fumarate of 0.5%～2.0%, the Pulvis Talci of 0.2%～2.0% and 0.1%～the peach flavor of 1.0%；
Wherein said filler is one or more in sorbitol, mannitol and maltose alcohol.
In certain embodiments, oseltamivir phosphate decentralized capsule of the present invention, comprise 10.0%～40.0%
Oseltamivir phosphate, the sorbitol of 45.0%～85.0% and maltose alcohol, the polyvinylpolypyrrolidone of 0%～5.0%, 1.0%
～4.0% hydroxypropyl methylcellulose, the aspartame of 1.0%～3.0%, the citric acid monohydrate of 0.5%～5.0% and citric acid
Sodium mixture, the sodium stearyl fumarate of 0.5%～2.0%, the silica sol of 0.2%～2.0% and 0.1%～
The peach flavor of 1.0%.
On the other hand, present invention also offers a kind of preparation side preparing described oseltamivir phosphate decentralized capsule
Method, said method comprising the steps of:
A) respectively oseltamivir phosphate, filler, disintegrating agent, binding agent and pH adjusting agent are joined in granulation pot and premix
Uniformly, premix is prepared；
B) sweeting agent is dissolved in purified water preparation granulation liquid, described purified water account for premix 17.0%～
23.0%；
C) granulation liquid is joined in premix and carry out wet granulation, and carry out dried and screened granulate, it is thus achieved that be dried
Granule；
D) in dry granule, then add lubricant and fluidizer, mix homogeneously, be prepared as capsule.
Wherein, the d of described preparation method) step, it is also possible in dry granule, add edible essence or add sweet taste
Agent and essence, mix homogeneously, it is prepared as capsule.
Detailed description of the invention
In order to make those skilled in the art be more fully understood that technical scheme, disclose some further below non-
The present invention is described in further detail to limit embodiment.
Reagent used in the present invention all can be buied from the market or can be by method system described in the invention
Standby and obtain.
Embodiment 1
Preparation prescription:
Preparation method
Preparation batch is 1.5kg, is calculated as 6000 by 75mg specification.It is separately added into oseltamivir phosphate, mountain by recipe quantity
Pears alcohol, maltose alcohol, cross-linking sodium carboxymethyl cellulose, polyvidone, monohydrate potassium, sodium citrate add premix in granulation pot
Uniformly.The sucralose of prescription ratio is dissolved in the water accounting for pre-composition 17%-23%, obtains granulation liquid, use peristaltic pump to add
Granulation liquid is pelletized；Use fluid bed drying, then cross screen cloth granulate.In dry granule, add Pulvis Talci, stearic acid richness
Horse acid sodium and peach flavor, mix homogeneously.To always mix particles filled in capsule shells, 75mg specification fills 250mg always mixed
Grain, 45mg specification filling 150mg always mixes granule, and 30mg specification is filled 100mg and always mixed granule, i.e. obtains decentralized capsule.
Embodiment 2
Preparation prescription:
| Composition | Content |
| Oseltamivir phosphate | 39.40% |
| Sorbitol | 24.40% |
| Maltose alcohol | 24.40% |
| Polyvinylpolypyrrolidone | 2.00% |
| Sodium citrate | 3.00% |
| Monohydrate potassium | 1.00% |
| Hydroxypropyl methylcellulose | 2.00% |
| Aspartame | 2.00% |
| Pulvis Talci | 0.50% |
| Sodium stearyl fumarate | 1.00% |
| Peach flavor | 0.30% |
The preparation method of reference example 1 is prepared
Embodiment 3
Preparation prescription:
The preparation method of reference example 1 is prepared
Embodiment 4
Preparation prescription:
| Composition | Content |
| Oseltamivir phosphate | 39.40% |
| Mannitol | 45.30% |
| Cross-linking sodium carboxymethyl cellulose | 2.00% |
| Sodium citrate | 4.00% |
| Monohydrate potassium | 0.80% |
| Sucralose | 5.00% |
| Polyvidone | 2.00% |
| Pulvis Talci | 0.50% |
| Sodium stearyl fumarate | 1.00% |
The preparation method of reference example 1 is prepared
Embodiment 5
Preparation prescription:
The preparation method of reference example 1 is prepared
Embodiment 6
Preparation prescription:
| Composition | Content |
| Oseltamivir phosphate | 14.78% |
| Sorbitol | 34.71% |
| Maltose alcohol | 34.71% |
| Polyvinylpolypyrrolidone | 5.00% |
| Sodium citrate | 1.00% |
| Monohydrate potassium | 0.30% |
| Sucralose | 0.50% |
| Polyvidone | 4.00% |
| Pulvis Talci | 2.00% |
| Sodium stearyl fumarate | 2.00% |
| Peach flavor | 1.00% |
The preparation method of reference example 1 is prepared
Embodiment 7
Preparation prescription:
The preparation method of reference example 1 is prepared
Embodiment 8
Preparation prescription:
| Composition | Content |
| Oseltamivir phosphate | 9.85% |
| Sorbitol | 80.55% |
| Polyvinylpolypyrrolidone | 3.00% |
| Sodium citrate | 0.60% |
| Monohydrate potassium | 0.20% |
| Polyvidone | 3.00% |
| Aspartame | 1.00% |
| Pulvis Talci | 0.50% |
| Sodium stearyl fumarate | 1.00% |
| Orange flavor | 0.30% |
The preparation method of reference example 1 is prepared
Embodiment 9
Preparation prescription:
| Composition | Content |
| Oseltamivir phosphate | 39.40% |
| Mannitol | 45.30% |
| Cross-linking sodium carboxymethyl cellulose | 2.00% |
| Sodium citrate | 4.00% |
| Monohydrate potassium | 1.00% |
| Sucralose | 4.00% |
| Polyvidone | 2.00% |
| Pulvis Talci | 0.50% |
| Sodium stearyl fumarate | 1.30% |
| Peach flavor | 0.50% |
The preparation method of reference example 1 is prepared
Embodiment 10
Preparation prescription:
| Composition | Content |
| Oseltamivir phosphate | 39.40% |
| Mannitol | 45.80% |
| Cross-linking sodium carboxymethyl cellulose | 2.00% |
| Sodium citrate | 4.00% |
| Monohydrate potassium | 1.00% |
| Sucralose | 2.00% |
| Aspartame | 2.00% |
| Polyvidone | 2.00% |
| Pulvis Talci | 0.50% |
| Sodium stearyl fumarate | 1.00% |
| Peach flavor | 0.30% |
The preparation method of reference example 1 is prepared
Comparative example 1
Preparation prescription:
| Composition | Content |
| Oseltamivir phosphate | 39.40% |
| Sorbitol | 23.40% |
| Maltose alcohol | 23.40% |
| Cross-linking sodium carboxymethyl cellulose | 3.00% |
| Sodium citrate | 3.00% |
| Monohydrate potassium | 1.00% |
| Saccharin sodium | 3.00% |
| Polyvidone | 2.00% |
| Silica sol | 0.50% |
| Sodium stearyl fumarate | 1.00% |
| Peach flavor | 0.30% |
The preparation method of reference example 1 is prepared
Comparative example 2
Preparation prescription:
The preparation method of reference example 1 is prepared
Comparative example 3
Preparation prescription:
| Composition | Content |
| Oseltamivir phosphate | 39.40% |
| Sorbitol | 23.40% |
| Maltose alcohol | 23.40% |
| Cross-linking sodium carboxymethyl cellulose | 3.00% |
| Sodium citrate | 3.00% |
| Monohydrate potassium | 1.00% |
| Steviosin | 3.00% |
| Polyvidone | 2.00% |
| Silica sol | 0.50% |
| Sodium stearyl fumarate | 1.00% |
| Peach flavor | 0.30% |
The preparation method of reference example 1 is prepared
Experimental example 1
By above-described embodiment 1～10 and comparative example 1～3 gained oseltamivir phosphate decentralized capsule carry out according to middle traditional Chinese medicines
2010 editions annex XIX crude drug of allusion quotation and pharmaceutical preparation stability guideline carry out stability experiment examination, and experiment condition is as follows:
Sample is packaged in PVC/PVDC-AL aluminium-plastic bubble plate packing；At temperature 40 DEG C, relative humidity 75%；In 0 day, the 3rd
Inspect by random samples after individual month and 6th month, investigate the impurity situation of sample.
Analysis testing conditions:
Chromatographic column: Waters Xbridge C8,5 μm, 4.6mm × 250mm
Detection wavelength: 207nm
Column temperature: 50 DEG C
Flow velocity: 1.2mL/min
Sample size: 20 μ L
The operation time: about 35min
Rear operation: 3min.
Gradient:
| Time (min) | Mobile phase A, v/v | Mobile phase B, v/v | Flowing phase C, v/v |
| 0 | 75 | 15 | 10 |
| 5.0 | 75 | 15 | 10 |
| 5.1 | 60 | 30 | 10 |
| 35 | 60 | 30 | 10 |
Mobile phase A: weigh potassium dihydrogen phosphate 6.80g, is dissolved in 1L ultra-pure water, mixing, with potassium hydroxide regulation pH extremely
6.0, with 0.45 μm water system membrane filtration, ultrasonic and get final product.
Mobile phase B: methanol
Flowing phase C: acetonitrile
Under accelerated stability, data summarization is as follows:
Embodiment 1, embodiment 3～7 and embodiment 9, changed the kind of filler, ratio, have adjusted the place of crude drug
Side's ratio；Have adjusted the ratio of pH adjusting agent；Have adjusted the prescription ratio of sweeting agent；And investigated the essence shadow to prescription
Ring.Result shows, after acceleration environment 6 months, using sucralose is the prescription of sweeting agent, oseltamivir phosphate decentralized glue
The impurity of capsule has good stability, and sucralose and the crude drug compatibility are good, bring the beyond thought result of other sweeting agents.
Embodiment 2 and embodiment 8, employing aspartame is sweeting agent, and two prescriptions have adjusted the prescription of crude drug, sweeting agent
Ratio, result shows, the prescription with aspartame as sweeting agent, and the impurity stability of oseltamivir phosphate decentralized capsule is the most very
Good.
Embodiment 10, uses feed postition associated with aspartame and two kinds of sweeting agents of sucralose, and result shows two kinds
Sweeting agent is combined, and oseltamivir phosphate decentralized capsule stability is the most fine.
Comparative example 1, employing saccharin sodium is sweeting agent, accelerates 6 months less stable, the impurity of RRT=1.43, is accelerating
Reaching 0.28% during June, compared to the oseltamivir phosphate decentralized capsule of embodiment 1～10, impurity increases too fast, and impurity is stable
Property is poor.
Comparative example 2, employing acesulfame potassium is sweeting agent, accelerates 6 months poor stabilities, RRT=0.19 and RRT under acceleration environment
Quickly, wherein accelerate the impurity of RRT=1.43 during June is 1.48% to the impurity growth rate of=1.43.It is sweet for using acesulfame potassium
Taste agent, compared to the oseltamivir phosphate decentralized capsule of embodiment 1～10, impurity increases too fast, and stability risk is the highest.
Comparative example 3, employing steviosin is sweeting agent, accelerates 6 months poor stabilities, RRT=0.19 and RRT under acceleration environment
The impurity growth rate of=1.43 is very fast, and wherein accelerating the impurity of RRT=1.43 during June is 0.69%.It is sweet for using steviosin
Taste agent, compared to the oseltamivir phosphate decentralized capsule of embodiment 1～10, impurity increases too fast, and stability risk is high.
Experimental example 2
By the way of assessment mouthfeel, assessment embodiment 3～5,7～8 and embodiment 10 prepared acquisition phosphoric acid Ao Sita
The taste masking effect of Wei decentralized capsule, concrete grammar is as follows:
By embodiment 3～5,7～8 and embodiment 10 is prepared obtains oseltamivir phosphate decentralized capsule, join
In 200mL milk, testing milk-like taste, recruit 25 volunteers, every volunteer divides the milk taking different prescriptions 6 days, often
Position volunteer takes the order random alignment of milk.As follows to experimenter's survey result:
Investigating through mouthfeel and understand, the oseltamivir phosphate decentralized capsule that embodiment 1～10 provides can be very effective
Correct the bitterness of oseltamivir phosphate, easily accepted by experimenter.
To sum up described in embodiment,
The present invention provide oseltamivir phosphate decentralized capsule there is good mouthfeel, compared to use sucralose or
The reference preparation that beyond aspartame, the comparative example of sweeting agent obtains has during preserving, and impurity is more stable waits progress
Property, the preservation of medicine and the peace of medication are acted on all with good.
The method of the present invention is described by preferred embodiment, related personnel substantially can present invention,
In spirit and scope, method described herein and application it is modified or suitably changes and combine, realize and apply the present invention
Technology.Those skilled in the art can use for reference present disclosure, is suitably modified technological parameter and realizes.Special needs to be pointed out is, institute
Having similar replacement and change apparent to those skilled in the art, they are considered as being included in the present invention
In.
Claims (20)
1. an oseltamivir phosphate decentralized capsule, comprises oseltamivir phosphate, sweeting agent and other is pharmaceutically acceptable auxiliary
Material, wherein said sweeting agent is sucralose or aspartame.
2. an oseltamivir phosphate decentralized capsule, comprises oseltamivir phosphate, sweeting agent and other is pharmaceutically acceptable auxiliary
Material, wherein said sweeting agent is sucralose, aspartame or its mixture.
Oseltamivir phosphate decentralized capsule the most according to claim 1, the content of wherein said oseltamivir phosphate
It is 5.0%～45.0%；The content of described sweeting agent is 0.1%～5.0% or 0.5%～5.0%.
Oseltamivir phosphate decentralized capsule the most according to claim 3, wherein said oseltamivir phosphate content is
30mg, 45mg or 75mg, based on Oseltamivir.
Oseltamivir phosphate decentralized capsule the most according to claim 3, wherein said pharmaceutically acceptable adjuvant is
One or more in filler, binding agent, disintegrating agent, fluidizer, lubricant, pH adjusting agent and edible essence.
Oseltamivir phosphate decentralized capsule the most according to claim 5, comprises the department of phosphoric acid Austria of 10.0%～40.0%
His Wei, the filler of 45.0%～85.0%, the disintegrating agent of 0%～5.0%, the binding agent of 1.0%～4.0%, 0.5%～
The sweeting agent of 5.0%, the pH adjusting agent of 0.5%～5.0%, the lubricant of 0.5%～2.0%, the fluidizer of 0.2%～2.0%
Agent, wherein said sweeting agent is sucralose or aspartame.
Oseltamivir phosphate decentralized capsule the most according to claim 6, further comprises the food of 0.1%～1.0%
Use essence.
8., according to the arbitrary oseltamivir phosphate decentralized capsule described in claim 5～7, wherein said filler is breast
Sugar, microcrystalline Cellulose, mannitol, sorbitol, maltose alcohol, xylitol, corn starch, dextrin, maltodextrin, pregelatinated form sediment
One or more in powder, sucrose and gelatin.
9., according to the arbitrary oseltamivir phosphate decentralized capsule described in claim 5～7, wherein said binding agent is methyl
In cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvidone, microcrystalline Cellulose and low-substituted hydroxypropyl cellulose
One or more.
10., according to the arbitrary oseltamivir phosphate decentralized capsule described in claim 5～7, wherein said disintegrating agent is to hand over
One in connection sodium carboxymethyl cellulose, polyvinylpolypyrrolidone, carboxymethyl starch sodium, corn starch and low-substituted hydroxypropyl cellulose
Or it is several.
11. according to the arbitrary oseltamivir phosphate decentralized capsule described in claim 5～7, and wherein said fluidizer is glue
Body silicon dioxide or Pulvis Talci or its mixture.
12. according to the arbitrary oseltamivir phosphate decentralized capsule described in claim 5～7, and wherein said lubricant is hard
Fat acid fumaric acid sodium, magnesium stearate, calcium stearate, zinc stearate, sucrose stearate, hydrogenated vegetable oil, stearic acid, colloid two
One or more in silicon oxide, Pulvis Talci and polyethylene glycol 6000.
13. according to the arbitrary oseltamivir phosphate decentralized capsule described in claim 5～7, and wherein said pH adjusting agent is
Citric acid and the mixture of hydrate salt pharmaceutically acceptable with it, dihydrogen citrate alkali metal salt, sodium lactate or succinic acid
Sodium.
14. according to the oseltamivir phosphate decentralized capsule described in claim 5 or 7, and wherein said edible essence is water honey
One or more in Fructus Persicae essence, orange flavor, strawberry essence, cream flavour, apple essence, flavoring pineapple essence and flavoring banana essence.
15. 1 kinds of oseltamivir phosphate decentralized capsules, comprise the oseltamivir phosphate of 10.0%～40.0%, 45.0%～
The filler of 85.0%, the disintegrating agent of 0%～5.0%, the binding agent of 1.0%～4.0%, the sweeting agent of 0.5%～5.0%,
The pH adjusting agent of 0.5%～5.0%, the lubricant of 0.5%～2.0%, the fluidizer of 0.2%～2.0% and 0.1%～
The edible essence of 1.0%；Wherein said filler is one or more in mannitol, sorbitol and maltose alcohol, disintegrate
Agent is cross-linking sodium carboxymethyl cellulose or polyvinylpolypyrrolidone, and binding agent is polyvidone or hydroxypropyl methylcellulose, and sweeting agent is three
Chlorine sucrose or aspartame, pH adjusting agent is the mixture of citric acid monohydrate and sodium citrate, and lubricant is stearic acid fumaric acid
Sodium, fluidizer is Pulvis Talci or silica sol, and edible essence is peach flavor or orange flavor.
16. 1 kinds of oseltamivir phosphate decentralized capsules, comprise the oseltamivir phosphate of 10.0%～40.0%, 45.0%～
The filler of 85.0%, the cross-linking sodium carboxymethyl cellulose of 0%～5.0%, 1.0%～4.0% polyvidone, 0.5%～3.0%
Sucralose, the citric acid monohydrate of 0.5%～5.0% and sodium citrate mixture, the stearic acid richness horse of 0.5%～2.0%
Acid sodium, the Pulvis Talci of 0.2%～2.0% and 0.1%～the peach flavor of 1.0%；Wherein said filler be sorbitol,
One or more in mannitol and maltose alcohol.
17. 1 kinds of oseltamivir phosphate decentralized capsules, comprise the oseltamivir phosphate of 10.0%～40.0%, 45.0%～
The sorbitol of 85.0% and maltose alcohol, the polyvinylpolypyrrolidone of 0%～5.0%, 1.0%～4.0% hydroxypropyl methylcellulose,
The aspartame of 1.0%～3.0%, the citric acid monohydrate of 0.5%～5.0% and sodium citrate mixture, 0.5%～2.0%
Sodium stearyl fumarate, the silica sol of 0.2%～2.0% and 0.1%～the peach flavor of 1.0%.
The method of the oseltamivir phosphate decentralized capsule that 18. 1 kinds are prepared described in claim 6, comprises the following steps:
A) oseltamivir phosphate, filler, disintegrating agent, binding agent and pH adjusting agent are joined in granulation pot be mixed in advance respectively
Even, prepare premix；
B) sweeting agent is dissolved in purified water preparation granulation liquid, and described purified water accounts for the 17.0%～23.0% of premix；
C) granulation liquid is joined in premix and carry out wet granulation, and carry out dried and screened granulate, it is thus achieved that be dried granule；
D) in dry granule, then add lubricant and fluidizer, mix homogeneously, be prepared as capsule；
Wherein said sweeting agent is sucralose or aspartame.
The method of 19. 1 kinds of arbitrary oseltamivir phosphate decentralized capsules prepared described in claim 15～17, including following
Step:
A) oseltamivir phosphate, filler, disintegrating agent, binding agent and pH adjusting agent are joined in granulation pot be mixed in advance respectively
Even, prepare premix；
B) sweeting agent is dissolved in purified water preparation granulation liquid, and described purified water accounts for the 17.0%～23.0% of premix；
C) granulation liquid is joined in premix and carry out wet granulation, and carry out dried and screened granulate, it is thus achieved that be dried granule；
D) in dry granule, then add edible essence, lubricant and fluidizer, mix homogeneously, be prepared as capsule；
Wherein said sweeting agent is sucralose or aspartame.
20. methods according to claim 19, wherein said d) step is then to add edible perfume in dry granule
Essence, lubricant, sweeting agent and fluidizer, mix homogeneously, it is prepared as capsule.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201510296587X | 2015-06-03 | ||
| CN201510296587 | 2015-06-03 |
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| CN106236728A true CN106236728A (en) | 2016-12-21 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN111297823A (en) * | 2020-03-04 | 2020-06-19 | 石药集团中奇制药技术（石家庄）有限公司 | Preparation method of oseltamivir phosphate capsule |
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| CN1820744A (en) * | 2006-04-04 | 2006-08-23 | 中国人民解放军军事医学科学院毒物药物研究所 | Oseltamivir phosphate granula and its preparing method |
| WO2010143207A1 (en) * | 2009-06-11 | 2010-12-16 | Rubicon Research Private Limited | Taste-masked oral formulations of influenza antivirals |
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| WO2010143207A1 (en) * | 2009-06-11 | 2010-12-16 | Rubicon Research Private Limited | Taste-masked oral formulations of influenza antivirals |
| CN104367558A (en) * | 2013-08-15 | 2015-02-25 | 北京星昊医药股份有限公司 | Oseltamivir lyophilized orally-disintegrating tablets and preparation method thereof |
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| CN111297823B (en) * | 2020-03-04 | 2021-06-18 | 石药集团中奇制药技术（石家庄）有限公司 | Preparation method of oseltamivir phosphate capsule |
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