CN107567332A - Oral solid formulation containing Oseltamivir and preparation method thereof - Google Patents
Oral solid formulation containing Oseltamivir and preparation method thereof Download PDFInfo
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Abstract
The present invention provides a kind of comprising Oseltamivir or oral solid formulation of its pharmaceutically acceptable salt and organic acid and preparation method thereof.
Description
Technical field
Oseltamivir or the solid pharmaceutical preparation of its pharmaceutically acceptable salt are included the present invention relates to a kind of, more specifically,
Be related to it is a kind of and existing Oseltamivir preparation it is high compared to initial dissolution rate and also can ensure that work while dissolution deviation is low
Oral solid formulation containing Oseltamivir of stability of property composition and preparation method thereof.
Background technology
The therapeutic agent for being typically used as being referred to as the A types influenza (H1N1) of new type influenza or novel influenza
Containing the Oseltamivir phosphate (oseltamivir phosphate) as principal component, and suspending agent or glue are turned to by preparation
Wafer.
But when Oseltamivir phosphate turns to capsule by preparation, active component that every capsule planted agent is contained contains
Measure more (30mg, 45mg or 75mg).Furthermore it is known that Oseltamivir phosphate its storage stability compared with Oseltamivir free alkali
Height, even if granularity is adjusted in order to increase dissolution rate smaller, can not also be readily available required initial dissolution rate, and
And it is difficult to quality management because the deviation of dissolution rate is higher.
In contrast to this, due to Oseltamivir free alkali have the deviation of significantly excellent initial dissolution rate and dissolution rate compared with
It is low, therefore Oseltamivir free alkali is favourable in terms of galenic pharmacy.Further, since Oseltamivir free alkali and Oseltamivir phosphate phase
It is lower than its molecular weight and need to be filled into that the content of the active component in capsule is relatively few, it thus be accordingly used in the productivity ratio for preparing capsule
It is higher than Oseltamivir phosphate.
The content of the invention
Technical problem
It is an object of the invention to provide a kind of oral solid formulation containing Oseltamivir free alkali, its by make containing
The stability increase of the active component of the preparation of Oseltamivir free alkali is with the preparation identical containing Oseltamivir phosphate etc.
It is more than level, so as to and preparation on the market it is same compared to its initial dissolution rate is higher, dissolution deviation is lower and productivity ratio is high
When, additionally it is possible to ensure the stability of active component.
Another object of the present invention is to provide a kind of preparation side of the oral solid formulation containing Oseltamivir free alkali
Method.
Technical scheme
An aspect of of the present present invention provides a kind of oral solid formulation, comprising：
Oseltamivir or its pharmaceutically acceptable salt；And
Organic acid.
Another aspect of the present invention provides a kind of method for preparing the oral solid formulation involved by the invention described above, the party
Method includes：
Prepare the system of the particle comprising Oseltamivir or its pharmaceutically acceptable salt, diluent, disintegrant and adhesive
Grain step；
The whole grain step of whole grain is carried out to above-mentioned particle；
By the particle after above-mentioned whole grain and disintegrant and the rear blend step of mix lubricant；And
Formulation step optionally is carried out to the above-mentioned mixture being obtained by mixing after,
Wherein, organic acid is added in above-mentioned granulation step or rear blend step.
Beneficial effect
Solid pharmaceutical preparation containing Oseltamivir free alkali involved in the present invention includes the organic acid as stabilizer, therefore
There is stability more than same levels compared with the preparation containing Oseltamivir phosphate.Therefore, according to the present invention, it is possible to provide one
Kind of the solid pharmaceutical preparation containing Oseltamivir, itself and existing Tamiflu capsule be excellent compared to initial dissolution rate and dissolution deviation is small and
While effective, also there is the advantages of productivity ratio is high when preparing capsule, and also ensure the stability of active component.
Embodiment
Below, the present invention is described in more detail.
Implication phase of all technical terms used in the present invention to be commonly understood by with one of ordinary skill in the art
With implication use, unless otherwise defined.In addition, this specification describes preferable method or sample, but it is similar or
Equivalent method or sample is also contained in the scope of the present invention.All publications recorded in this manual with bibliography
Content be incorporated herein by reference in their entirety.
An aspect of of the present present invention provides a kind of oral solid formulation, comprising：
Oseltamivir or its pharmaceutically acceptable salt；And
Organic acid.
In this manual, " organic acid " refers to the general name of the acid organic compound of display, specifically, " organic acid "
For carboxylic acid, sulfonic acid, sulfinic acid, sulfenic acids, phenol, enol, mercaptan, phosphonic acids, phosphoric acid, boric acid, imidic acid, hydrazonic acid, hydroximic acid, different
Hydroximic acid etc., there is the compound of the acid functional group of display (following, to be " acidic functionality " by its appropriate abbreviation).
Above-mentioned organic acid can play the effect of the stabilizer as the increase active component i.e. stability of Oseltamivir.It is above-mentioned
Organic acid can use a kind of organic acid, and can also be used by combining a variety of organic acids.
In a specific example of the present invention, above-mentioned organic acid is the organic acid with 1 to 5 carbon atom, and includes tool
There is the organic acid of carboxylic acid.
The above-mentioned organic acid with carboxylic acid can be organic with 1 to 5 carbon atom and with two carboxylic acid functionals
Acid, such as with malonic acid, succinic acid, tartaric acid, fumaric acid, glutaric acid, its any combination etc., but it is not limited to this.It is excellent
It is tartaric acid, fumaric acid or combinations thereof to choose and state organic acid.
It can determine to be adapted to stabilized amount according to the specific composition of above-mentioned organic acid, for example, relative to above-mentioned solid system
About 0.3~6 weight % organic acid may be present in agent total content, more specifically, can be deposited relative to above-mentioned solid pharmaceutical preparation total content
In about 0.5~5 weight % organic acid.
Above-mentioned Oseltamivir or its pharmaceutically acceptable salt can include Oseltamivir free alkali (free base) or phosphoric acid
Oseltamivir (phosphate), in addition to this it is possible to include other any pharmaceutically acceptable salts.
In a specific example of the present invention, the active component of above-mentioned solid pharmaceutical preparation can be Oseltamivir free alkali, department of Austria
His Wei free alkali can have the particle mean size size (d of the particle of particle the middle and low grade 90%(0.9)) big for less than 200 μm of particle
It is small, more specifically, there can be 10 μm~200 μm of particle size.
In this manual, " particle mean size size (the d of the particle of inferior grade 90%(0.9)) " refer to utilizing granulometry
During measurement device granularity, from the particle of minimum to the particle mean size size of the particle equivalent to total population 90%.
Known Oseltamivir free alkali its stability compared with Oseltamivir phosphate is relatively low, but Oseltamivir free alkali has
Following advantage：The initial dissolution rate higher than Oseltamivir phosphate is obtained by adjusting granularity, and the deviation of dissolution rate is smaller
(PCT/KR2015/006128).In addition, Oseltamivir free alkali has the advantages of in following pharmacy：With Oseltamivir phosphate
It is relatively low compared to its molecular weight, when being prepared into capsule, it is necessary to which the mixing object amount containing active component being filled into capsule is less,
So as to prepare Oseltamivir free alkali with higher productivity ratio.
Oral solid formulation involved by the invention described above using above-mentioned organic acid because that can make Oseltamivir free alkali
Stable components (with reference to test example 3).Therefore, above-mentioned oral solid formulation can have lives with being used as comprising Oseltamivir free alkali
The stability of the similar active component of situation comprising Oseltamivir phosphate while property composition, therefore above-mentioned solid pharmaceutical preparation has
Following advantage：Can also there will be pharmacy in terms of above-mentioned initial dissolution rate and capsule manufacture rate compared with Oseltamivir phosphate
The Oseltamivir free alkali of upper superiority uses as active component.
Above-mentioned oral solid formulation can be any solid pharmaceutical preparation well-known in the art.In a specific example of the present invention
In, above-mentioned oral solid formulation is the oral solid formulation containing particle, and above-mentioned particle includes Oseltamivir or it pharmaceutically may be used
The salt of receiving and pharmaceutically acceptable additive.
Above-mentioned organic acid can be contained in the preparation process of above-mentioned particle.It can contain in the preparation process of above-mentioned particle upper
Organic acid is stated to refer to that above-mentioned organic acid can be added in the arbitrary steps in the preparation technology of particle and prepared, it is specific and
Speech, including following situation：Added in the mixture comprising active component, diluent and disintegrant and contain above-mentioned organic acid,
Either in the slurry containing adhesive add and containing above-mentioned organic acid or granulation after with disintegrant and mix lubricant
Shi Tianjia simultaneously contains above-mentioned organic acid, or can be the combination of these situations.In addition, those skilled in the art can be according to particle
Specific preparation method carry out the appropriate addition step for selecting organic acid.
On above-mentioned organic acid, can determine to be adapted to stabilized amount according to the specific composition of organic acid, for example, containing
About 0.3~6 weight % above-mentioned organic acid may be present in the oral solid formulation of above-mentioned particle, more specifically, above-mentioned solid
About 0.5~5 weight % above-mentioned organic acid may be present in body preparation.In a specific example of the present invention, above-mentioned organic acid is wine
Stone acid, content of the tartaric acid in solid pharmaceutical preparation is about 0.3~6 weight %.It is above-mentioned organic in another concrete example of the present invention
Acid is fumaric acid, and content of the fumaric acid in solid pharmaceutical preparation is about 0.3~6 weight % (test example 4).
In a specific example of the present invention, the moisture of above-mentioned particle is below about 3.5 weight %.If moisture
Increase, then the stability of active component is likely to decrease (with reference to test example 5).
Above-mentioned pharmaceutically acceptable additive may be selected from by diluent, disintegrant, adhesive, lubricant and its any group
The group being combined into, diluent, disintegrant, adhesive and lubricant are included in a concrete example.
Above-mentioned diluent, which can be used while can be used in particle preparation, to be influenceed on the zone of action of active component
Any diluent, such as can be used selected from pregelatinized starch, mannitol, lactose, microcrystalline cellulose and its any combination composition
Diluent in group, but it is not limited to this.
Above-mentioned disintegrant, which can be used while can be used in particle preparation, to be influenceed on the zone of action of active component
Any disintegrant, such as can be used selected from being received, PVPP, sodium starch glycollate, low taken by cross-linked carboxymethyl cellulose
For the disintegrant in the group of hydroxypropyl cellulose and its any combination composition, but it is not limited to this.
Above-mentioned adhesive, which can be used while can be used in particle preparation, to be influenceed on the zone of action of active component
Any adhesive.In a concrete example, above-mentioned adhesive can be hydrophilic adhesive.When using hydrophilic adhesive, energy
The stability of enough further increase active components.Above-mentioned hydrophilic adhesive can be selected from by PVP, hydroxypropyl cellulose,
What hydroxypropyl methyl cellulose, light anhydrous silicic acid, alumina silicate, calcium silicates, calcium monohydrogen phosphate, calcium carbonate and combinations thereof formed
Group, but it is not limited to this.In a specific example of the present invention, above-mentioned hydrophilic adhesive is PVP, hydroxypropyl cellulose
Or combinations thereof.
The above-mentioned oral solid formulation containing particle can be granule, tablet, capsule or dry syrup.
In a specific example of the present invention, above-mentioned oral solid formulation is capsule, includes the department of Austria as active component
His Wei free alkali.Because above-mentioned solid pharmaceutical preparation includes Oseltamivir free alkali, therefore its molecular weight compared with Oseltamivir phosphate
It is relatively low and to need to be filled into the mixing object amount in capsulae vacuus relatively few.Therefore, can not only by above-mentioned solid pharmaceutical preparation activity into
The stability divided ensures existing preparation degree on the market, additionally it is possible to above-mentioned solid pharmaceutical preparation is prepared with high production rate,
And can have high initial dissolution rate and low dissolution deviation, therefore preferably.
In a specific example of the present invention, above-mentioned oral solid formulation is capsule, includes the department of Austria as active component
His Wei free alkali, Oseltamivir free alkali can have the particle mean size size (d of the particle of particle the middle and low grade 90%(0.9)) it is about
Less than 200 μm of particle size, more specifically, there can be about 10 μm to 200 μm of particle size.
The capsule of above-mentioned capsule can be used any capsule well-known in the art, for example, with gelatine capsule, gelatin-
PEG capsules or HPMC (hydroxypropyl methyl cellulose) capsule etc..
In a concrete example, the capsule is the capsule that moisture is about 3-7 weight %, and this capsule is specially HPMC
Capsule, but it is not limited to this.
Another aspect of the present invention provides a kind of method for preparing the oral solid formulation involved by the invention described above, the party
Method includes：
Prepare the system of the particle comprising Oseltamivir or its pharmaceutically acceptable salt, diluent, disintegrant and adhesive
Grain step；
The whole grain step of whole grain is carried out to above-mentioned particle；
By the particle after above-mentioned whole grain and disintegrant and the rear blend step of mix lubricant；And
Formulation step optionally is carried out to the above-mentioned mixture being obtained by mixing after,
Wherein, organic acid is added in above-mentioned granulation step or rear blend step.
On the detailed description of above-mentioned solid pharmaceutical preparation preparation method, directly can apply to involved by the one side of the invention described above
And oral solid formulation explanation.
Above-mentioned particle-making step can prepare particle according to any preparation method of granules well known in the art, can be by wet
Formula particle method or dry type particle method prepare particle.
Above-mentioned wet granulate method by comprising Oseltamivir or its pharmaceutically acceptable salt, diluent and disintegrant it is mixed
Compound is combined with slurry come executable drying process afterwards of pelletizing.In said mixture, slurry or mixture and slurry
In can add and mix above-mentioned organic acid.
Solvent for preparing above-mentioned slurry can be water, ethanol, isopropanol, acetone or combinations thereof.It can pass through
Except adhesive in addition in above-mentioned solvent further addition pharmaceutical field in can generally use additive such as surfactant,
Buffer or combinations thereof prepare above-mentioned slurry., can be by dissolving hydrophilic binder in ethanol according to a concrete example
Agent prepares above-mentioned slurry.
Due to considering the stability of active component, thus temperature at no more than about 60 DEG C, preferably at no more than about 50 DEG C
Temperature, more preferably in the temperature no more than 40 DEG C, most preferably at a temperature of no more than about 20 DEG C to 40 DEG C, air can be passed through
Dry, fluidized bed is dry, oven drying or microwave drying perform above-mentioned drying process.
Above-mentioned dry type particle method can be to including Oseltamivir or its pharmaceutically acceptable salt, diluent, disintegrant and viscous
The mixture of mixture uses rolled-on method (roller compacting) or pressed disc method (slugging).One in the present invention is specific
Rolled-on method can be used in example.Specifically, roll and refer to by being pressed while making powder by between two rollers with defined
The method of power pressing prepares the method for particle.Above-mentioned rolled-on method can be performed using roller.Afterwards, it is appropriate big in order to obtain
Small particle, the mixture after rolling can be as needed further across use grinder (fitz-mill) or oscillator
Etc. (oscillator) carry out crushing and the process of whole grain.
In above-mentioned dry type particle method, comprising Oseltamivir or its pharmaceutically acceptable salt, diluent, disintegrant and
Added in the mixture of adhesive and contain above-mentioned organic acid.
With in the rear blend step of disintegrant and mix lubricant, above-mentioned disintegrant may be used at preparation containing particle
Any disintegrant used in capsule, for example, can be used selected from received by cross-linked carboxymethyl cellulose, PVPP, hydroxyacetic acid
The group of sodium starch, low-substituted hydroxypropyl cellulose and its any combination composition.In a concrete example, above-mentioned disintegrant is crosslinking carboxylic
Methylcellulose is received.Above-mentioned lubricant is selected from being made up of magnesium stearate, talcum, sodium stearyl fumarate and its any combination
Group, in a concrete example, above-mentioned lubricant is the combination of talcum and sodium stearyl fumarate.In this post in blend step
It can also add and mix above-mentioned organic acid.
Above-mentioned formulation step can according to using particle and preparation turns to the well-known in the art any of solid pharmaceutical preparation
Method is performed, such as any known method of tablet, capsule or dry syrup can be turned to according to preparation to perform above-mentioned system
Agent step.
Below, according to following embodiments, the present invention is described in detail.But following embodiments are only used for illustrating
The present invention, the scope of the present invention are not limited to this.
Test example 1：The Mandatory Decomposition experiment of Oseltamivir free alkali
The accurate burning for weighing Oseltamivir (INIST ST companies, South Korea) free alkali 100mg and being put into that volume is 100mL
In bottle, make its dissolving after addition distilled water 10mL in the flask.Then, according to utilizing the strong acid of following records, weak acid, strong
The Mandatory Decomposition experiment method that base and weak base base are carried out is by Oseltamivir Mandatory Decomposition.
1) compare：Placed two hours in 60 DEG C of baking oven after addition distilled water 10mL and reacted it, then
It is cooled to normal temperature and distilled water 10mL is added dropwise afterwards.
2) strong acid：Placed two hours in 60 DEG C of baking oven after addition 0.1N hydrogen chloride (HCl) 10mL and make its progress
Reaction, it is subsequently cooled to that 0.1N sodium hydroxides (NaOH) 10mL (neutralization) is added dropwise after normal temperature.
3) weak acid：Placed two hours in 60 DEG C of baking oven after addition 0.001N hydrogen chloride 10mL and it is carried out instead
Should, it is subsequently cooled to that 0.001N sodium hydroxides 10mL (neutralization) is added dropwise after normal temperature.
4) strong-base group：Placed two hours in 60 DEG C of baking oven after addition 0.1N sodium hydroxides 10mL and it is carried out instead
Should, it is subsequently cooled to that 0.1N hydrogen chloride 10mL (neutralization) is added dropwise after normal temperature.
5) weak base base：Placed two hours in 60 DEG C of baking oven after addition 0.001N sodium hydroxides 10mL and make its progress
Reaction, it is subsequently cooled to that 0.001N hydrogen chloride 10mL (neutralization) is added dropwise after normal temperature.
Then, extract solution is added in each sample obtained by above-mentioned decomposition experiment (by methanol 245mL, acetonitrile
The mixed liquid of 135mL and 0.01N phosphoric acid 620mL), and 100mL medicine is accurately measured to be used as inspection liquid.According to being embodied in
The pharmaceuticals of American Pharmacopeia (USP) are respectively discussed in " Oseltamivir phosphate capsule (Oseltamivir phosphate Capsule) "
Impurity analysis method measure the impurity of the inspection liquid got, and calculate the content of total impurities.The knot is shown in table 1 below
Fruit.
[table 1]
| Total impurities (%) | |
| Control | 64.8 |
| Strong acid | 8.9 |
| Weak acid | 2.6 |
| Strong-base group | 98.1 |
| Weak base base | 80.9 |
It was found from above-mentioned table 1, Oseltamivir is more stable in acid condition, unstable under the conditions of neutrality to the pH of alkalescence
Determine and decompose.That is, it can confirm that Oseltamivir is most stable under the conditions of weakly acidic pH.
Test example 2：The Moisture stability experiment of Oseltamivir free alkali
Weigh Oseltamivir (the INIST ST companies) principal component of appropriate amount and be put into HDPE (high density polyethylene (HDPE)) bottle
In culture dish (Petri dish), the Oseltamivir principal component is set to expose under conditions of 25 DEG C, 90% relative humidity one
And taken out after three days, 100mg is accurately weighed respectively and is added in the flask that volume is 100mL, is added and is carried in the flask
Liquid (by methanol 245mL, the mixed liquid of acetonitrile 135mL and 0.01N phosphoric acid 620mL) is taken, and accurately measures 100mL liquid
To be used as inspection liquid.Pharmaceuticals according to American Pharmacopeia (USP) is embodied in respectively discuss " Oseltamivir phosphate capsule (Oseltamivir
Phosphate Capsule) " in impurity analysis method measure the impurity of the inspection liquid got, and calculate the content of total impurities.
The result is shown in table 2 below.
[table 2]
| Total impurities (%) | |
| Initial inspection liquid | 0.21 |
| Inspection liquid after being exposed one in HDPE bottles under 25 DEG C, 90% relative humidity | 0.21 |
| Inspection liquid after being exposed three in HDPE bottles under 25 DEG C, 90% relative humidity | 0.22 |
| Inspection liquid after being exposed one in culture dish under 25 DEG C, 90% relative humidity | 3.59 |
| Inspection liquid after being exposed three in culture dish under 25 DEG C, 90% relative humidity | 18.31 |
It is unstable if Oseltamivir is exposed in moisture it was found from above-mentioned table 2.
Embodiment 1：The preparation (1) of Oseltamivir granule
To be formed with Table 3 below identical by Oseltamivir (INIST ST companies, South Korea), pregelatinized starch, crosslinking carboxylic
Methylcellulose is received mixed with tartaric acid after, glued using the slurry that PVP is dissolved into 70% ethanol and formed
Close, and taken after being dried in a manner of moisture is about 2 weight % with 20 mesh sieves sieve and prepare wet granulate.
Cross-linked carboxymethyl cellulose is added in the particle prepared to receive, after talcum and sodium stearyl fumarate and progress
Mixing, to prepare granule.
Embodiment 2：The preparation (2) of Oseltamivir granule
In addition to fumaric acid is used as stabilizer instead of above-mentioned tartaric acid, composition same as Example 1 and side are utilized
Method prepares granule.
Embodiment 3：The preparation (3) of Oseltamivir granule
To be formed with Table 3 below identical by Oseltamivir (INIST ST companies, South Korea), pregelatinized starch and crosslinking carboxylic
Methylcellulose is received after mixing, is glued using the slurry that PVP and tartaric acid are dissolved into 70% ethanol and formed
Close, and taken after being dried in a manner of moisture is about 2 weight % with 20 mesh sieves sieve and prepare wet granulate.
Added in the particle prepared and mix cross-linked carboxymethyl cellulose receive, talcum and sodium stearyl fumarate and
Prepare Oseltamivir granule.
Embodiment 4：The preparation (4) of Oseltamivir granule
In addition to fumaric acid is used as stabilizer instead of tartaric acid, composition same as Example 3 and method system are utilized
Standby granule.
Embodiment 5：The preparation (5) of Oseltamivir granule
To be formed with Table 3 below identical by Oseltamivir (INIST ST companies, South Korea), pregelatinized starch and crosslinking carboxylic
Methylcellulose is received after mixing, is bonded using the slurry that PVP is dissolved into 70% ethanol and formed, and
Taken after being dried in a manner of moisture is about 2 weight % with 20 mesh sieves sieve and prepare wet granulate.
Added in the particle prepared and mix tartaric acid, cross-linked carboxymethyl cellulose is received, talcum and stearoyl alcohol are rich
Horse acid sodium and prepare Oseltamivir granule.
Embodiment 6：The preparation (6) of Oseltamivir granule
In addition to fumaric acid is used as stabilizer instead of tartaric acid, composition same as Example 5 and method system are utilized
Standby granule.
Comparative example 1：The preparation (7) of Oseltamivir granule
Sell from the marketFiller is isolated in capsule 75mg and obtains Oseltamivir granule.
Comparative example 2：The preparation (8) of Oseltamivir granule
To be formed with table 4 below identical by Oseltamivir (INIST ST companies, South Korea), pregelatinized starch and crosslinking carboxylic
Methylcellulose is received after mixing, is bonded using the slurry that PVP is dissolved into 70% ethanol and formed, and
Taken after being dried in a manner of moisture is about 2 weight % with 20 mesh sieves sieve and prepare wet granulate.
Added in the particle prepared and mix cross-linked carboxymethyl cellulose receive, talcum and sodium stearyl fumarate and
Prepare Oseltamivir granule.
Composition, content and the technique of embodiment and comparative example are shown into table 4 in Table 3 below.
[table 3]
[table 4]
Test example 3：By the stability of kinds of organic acids evaluation granule
Weigh the Oseltamivir granule obtained by above-described embodiment 1 to 6 and comparative example 1 and 2 of appropriate amount and be put into
In HDPE bottles, after being placed six months under 40 DEG C, the acceleration environment of 75% relative humidity, according to being embodied in American Pharmacopeia
(USP) pharmaceuticals respectively discuss the impurity point in " Oseltamivir phosphate capsule (Oseltamivir phosphate Capsule) "
Analysis method measures impurity, and calculates the content of impurity C and total impurities.The result is shown in table 5 below.
[table 5]
| Impurity C (%) | Total impurities (%) | |
| Embodiment 1 | 0.18 | 0.34 |
| Embodiment 2 | 0.12 | 0.23 |
| Embodiment 3 | 0.21 | 0.43 |
| Embodiment 4 | 0.14 | 0.30 |
| Embodiment 5 | 0.08 | 0.19 |
| Embodiment 6 | 0.13 | 0.30 |
| Comparative example 1 | 0.12 | 0.27 |
| Comparative example 2 | 0.27 | 0.55 |
It was found from the result of above-mentioned table 5, the implementation of the tartaric acid and fumaric acid as stabilizer is used in wet granulate
Example 1 to 6 is less than 0.25%, and stability is improved compared with the comparative example 2 for not adding stabilizer, is sold with the market
The Tamiflu (comparative example 1) using Oseltamivir phosphate stability it is similar.
According to the above results, compared using the situation of the organic acid as stabilizer with the situation of unused organic acid
Its stability dramatically increases, and shows similar stably with the Tamiflu (comparative example 1) as preparation on the market.This
Outside, it is known that using organic acid as stabilizer in use, because in wet granulate technique put into organic acid the step of difference produce
Raw stability difference is not too large.
Test example 4：Granule stability is evaluated by organic acid content
[table 6]
Weigh appropriate amount has the composition of above-mentioned table 6 and Austria obtained from the method for embodiment 5 prepares granule
Si Tawei granules are simultaneously put into HDPE bottles, after being placed six months under 40 DEG C, the acceleration environment of 75% relative humidity, root
" Oseltamivir phosphate capsule (Oseltamivir phosphate are respectively discussed according to the pharmaceuticals for being embodied in American Pharmacopeia (USP)
Capsule impurity analysis method in) " measures impurity, and calculates the content of impurity C and total unknown impuritie.Show in table 7 below
Go out the result.
[table 7]
| Impurity C (weight %) | Total impurities (weight %) | |
| Embodiment 7 | 0.20 | 0.40 |
| Embodiment 8 | 0.16 | 0.33 |
| Embodiment 9 | 0.15 | 0.33 |
| Embodiment 10 | 0.21 | 0.39 |
| Embodiment 11 | 0.26 | 0.53 |
| Embodiment 12 | 0.32 | 0.59 |
It was found from the result of above-mentioned table 7, shown when the weight rate of tartaric acid is about 0.25% (embodiment 11) with
The similar stability of above-mentioned comparative example 2 (negative control group) is understood the tartaric acid as embodiment 12 without effect
Stability reduces on the contrary when weight rate is about 7.5%.When consider as above-mentioned test example 1 under the conditions of weakly acidic pH Austria
Si Tawei stability is most excellent, and as test example 4 organic acid weight rate scope also critically important this point when, can
The ratio for knowing the preferably organic acid in the granule of Oseltamivir is about 0.3~6 weight %.
Test example 5：By pellet moisture evaluation stability (loss on drying)
To be formed with table 8 below identical by Oseltamivir (INIST ST companies, South Korea), pregelatinized starch and crosslinking carboxylic
Methylcellulose is received after mixing, is bonded with the slurry that PVP is dissolved into 70% ethanol and formed, and press
Time is dried after obtaining particle by moisture, is taken using 20 mesh sieves sieve and is prepared wet granulate.By being embodied in KP mono-
As loss on drying test method(s) in test method measure moisture.
Added in each particle prepared and mix tartaric acid, cross-linked carboxymethyl cellulose is received, talcum and stearoyl
Alcohol fumaric acid sodium and prepare Oseltamivir granule.
[table 8]
The Oseltamivir granule that weighs the composition using above-mentioned table 8 of appropriate amount and prepare simultaneously is put into HDPE bottles,
After placing surrounding under the conditions of 60 DEG C, " Oseltamivir phosphate capsule is respectively discussed according to the pharmaceuticals for being embodied in American Pharmacopeia (USP)
Impurity analysis method in (Oseltamivir phosphate Capsule) " measures impurity, and calculates impurity C and total unknown
The content of impurity.The result is shown in table 9 below.
[table 9]
| Impurity C (%) | Total impurities (%) | |
| Embodiment 13 | 0.22 | 0.59 |
| Embodiment 14 | 0.25 | 0.68 |
| Embodiment 15 | 0.46 | 0.86 |
| Embodiment 16 | 1.13 | 1.64 |
It was found from above-mentioned table 9, the moisture of Oseltamivir particle brings influence on stability.Understand as embodiment 16
Grain moisture is about more than 4.5% then to generate impurity and unstable, and understands that the pellet moisture as embodiment 13 to 15 is about
Less than 3.5 is then more stable.
Test example 6：Dissolution is evaluated by formulation
About 75mg a great deal of is taken from the granule of above-described embodiment 13 using as Oseltamivir, and be filled into No. two it is bright
Capsule is prepared in glue capsule (suheung capsules).In addition, about 75mg a great deal oves are taken from the granule of above-described embodiment 13
To be pressed as Oseltamivir, and using rotary tablet machine (SEJONG companies, MRC-18) under conditions of hardness about 10
Piece and prepare tablet.
By the use of following experimental conditions to being produced as the granule of so obtained embodiment 13, capsule, tablet and control
The about 75mg of productCapsule carries out dissolution test, and calculates average dissolution rate (weight %).This is shown in table 10 below
As a result.
<Dissolution testing conditions>
Dissolution test method：The method of dissolution second (slurry processes) of Pharmacopoeia Coreana
Dissolution fluid：0.1N- hydrochloric acid solutions
Dissolution liquid measure：900mL
Dissolution fluid temperature：37.5℃
Starch speed：50rpm
Test specimen number：6
The sample extraction time：5 minutes, 10 minutes, 15 minutes and 20 minutes
[table 10]
It can confirm from the result of above-mentioned table 10, show that the dissolution rate of Oseltamivir at 20 minutes was 90 in all formulations
More than weight %, show the dissolution state similar with the Tamiflu as reference product.
The present invention is illustrated centered on preferred embodiment so far.One of ordinary skill in the art will be understood that
It can implement the present invention in a manner of through deformation in the range of the intrinsic propesties of the present invention is not departed from.Therefore, it is above-mentioned disclosed
Embodiment should not consider from limited viewpoint, but should consider from illustrative viewpoint.The scope of the present invention is presented
In claims rather than foregoing explanation, existing in the scope equal with the claims had any different should be interpreted that
Point is comprising in the present invention.
Claims (15)
1. a kind of oral solid formulation, comprising：
Oseltamivir or its pharmaceutically acceptable salt；And
Organic acid.
2. oral solid formulation according to claim 1, wherein, the organic acid is organic with 1 to 5 carbon atom
Acid.
3. oral solid formulation according to claim 2, wherein, the organic acid be with 1 to 5 carbon atom and with
The organic acid of two carboxylic acid functionals.
4. oral solid formulation according to claim 1, wherein, the organic acid be selected from by tartaric acid, fumaric acid and its
It is combined the group of composition.
5. oral solid formulation according to claim 1, wherein, the Oseltamivir or its pharmaceutically acceptable salt are
Oseltamivir free alkali or Oseltamivir phosphate.
6. oral solid formulation according to claim 1, wherein, the Oseltamivir or its pharmaceutically acceptable salt are
Oseltamivir free alkali, the Oseltamivir free alkali have the particle mean size size d of the particle of particle the middle and low grade 90%(0.9)
For the particle size below 200 μm.
7. oral solid formulation according to claim 1, wherein, relative to solid pharmaceutical preparation total content, the organic acid
Content is 0.3 weight % to 6 weight %.
8. oral solid formulation according to claim 1, wherein, the oral solid formulation contains particle, the particle
Include Oseltamivir or its pharmaceutically acceptable salt and pharmaceutically acceptable additive.
9. oral solid formulation according to claim 8, wherein, the water containing below 3.5 weight % in the particle
Point.
10. oral solid formulation according to claim 8, wherein, the pharmaceutically acceptable additive is selected from by dilute
The group of agent, disintegrant, adhesive, lubricant and its any combination composition is released, described adhesive is hydrophilic adhesive.
11. oral solid formulation according to claim 10, wherein, the hydrophilic adhesive be selected from by PVP,
Hydroxypropyl cellulose, hydroxypropyl methyl cellulose, light anhydrous silicic acid, alumina silicate, calcium silicates, calcium monohydrogen phosphate, calcium carbonate and its
It is combined the adhesive of the group of composition.
12. oral solid formulation according to claim 1, wherein, the oral solid formulation is granule, tablet, glue
Wafer or dry syrup.
13. oral solid formulation according to claim 1, wherein, the oral solid formulation be capsule and comprising
Oseltamivir free alkali as active component.
14. a kind of method for preparing the oral solid formulation according to any one of claim 1 to 13, methods described bag
Include：
The granulation step of particle is prepared, the particle includes Oseltamivir or its pharmaceutically acceptable salt, diluent, disintegrant
And adhesive；
The whole grain step of whole grain is carried out to the particle；
By the particle after whole grain and disintegrant and the rear blend step of mix lubricant；And
Formulation step optionally is carried out to the mixture being obtained by mixing after,
Wherein, organic acid is added in the granulation step or rear blend step.
15. according to the method for claim 14, wherein, the granulation step includes following technique：By the way that department difficult to understand will be included
His Wei or its pharmaceutically acceptable salt, diluent and disintegrant mixture and the slurry containing adhesive with reference to and carry out
Granulation, and addition and mixed organic acid in the mixture and/or slurry.
Applications Claiming Priority (3)
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| KR10-2015-0045687 | 2015-03-31 | ||
| KR1020150045687A KR20160117070A (en) | 2015-03-31 | 2015-03-31 | An oral solid formulation containing oseltamivir and a process for the preparation thereof |
| PCT/KR2016/003021 WO2016159572A1 (en) | 2015-03-31 | 2016-03-25 | Solid oral formulation containing oseltamivir, and preparation method therefor |
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| Country | Link |
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| KR (1) | KR20160117070A (en) |
| CN (1) | CN107567332B (en) |
| WO (1) | WO2016159572A1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN114340614A (en) * | 2019-09-27 | 2022-04-12 | 广东东阳光药业有限公司 | Oseltamivir preparation |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2018004261A1 (en) * | 2016-06-30 | 2018-01-04 | 한미약품 주식회사 | Oseltamivir-containing solid preparation for oral administration and method for preparing same |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101389323A (en) * | 2006-02-20 | 2009-03-18 | 中外制药株式会社 | Pharmaceutical composition comprising oseltamivir phosphate |
| CN102166206A (en) * | 2011-02-12 | 2011-08-31 | 李春娟 | Liquid oseltamivir phosphate composition |
| KR20140087846A (en) * | 2012-12-31 | 2014-07-09 | 주식회사 삼양바이오팜 | Pharmaceutical composition comprising temozolomide with improved stability and process for manufacturing the same |
| CN104138355A (en) * | 2014-08-06 | 2014-11-12 | 广东东阳光药业有限公司 | Oseltamivir phosphate dry suspension and preparation method thereof |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR100678829B1 (en) * | 2004-12-06 | 2007-02-05 | 한미약품 주식회사 | Oral micro-emulsion composition comprising tacrolimus |
| CN1820744B (en) * | 2006-04-04 | 2011-01-26 | 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 |
| KR101832842B1 (en) * | 2012-01-13 | 2018-02-27 | 한미약품 주식회사 | Pharmaceutical composition with an improved stability comprising eperisone or a pharmaceutically acceptable salt thereof and specific acidifying agent |
-
2015
- 2015-03-31 KR KR1020150045687A patent/KR20160117070A/en active Application Filing
-
2016
- 2016-03-25 CN CN201680011569.5A patent/CN107567332B/en active Active
- 2016-03-25 WO PCT/KR2016/003021 patent/WO2016159572A1/en active Application Filing
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101389323A (en) * | 2006-02-20 | 2009-03-18 | 中外制药株式会社 | Pharmaceutical composition comprising oseltamivir phosphate |
| CN102166206A (en) * | 2011-02-12 | 2011-08-31 | 李春娟 | Liquid oseltamivir phosphate composition |
| KR20140087846A (en) * | 2012-12-31 | 2014-07-09 | 주식회사 삼양바이오팜 | Pharmaceutical composition comprising temozolomide with improved stability and process for manufacturing the same |
| CN104138355A (en) * | 2014-08-06 | 2014-11-12 | 广东东阳光药业有限公司 | Oseltamivir phosphate dry suspension and preparation method thereof |
Non-Patent Citations (1)
| Title |
|---|
| 郭慧玲: "《高等院校"十二五"规划教材 医药类 药剂学》", 28 February 2014 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114340614A (en) * | 2019-09-27 | 2022-04-12 | 广东东阳光药业有限公司 | Oseltamivir preparation |
| CN114340614B (en) * | 2019-09-27 | 2024-01-16 | 广东东阳光药业股份有限公司 | Oseltamivir preparation |
| 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 |
| 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 |
Also Published As
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| KR20160117070A (en) | 2016-10-10 |
| CN107567332B (en) | 2021-06-01 |
| WO2016159572A1 (en) | 2016-10-06 |
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