Summary of the invention
The object of the present invention is to provide a kind of oseltamivir phosphate pharmaceutical composition of novelty, expect its can face with before be mixed with liquid preparation, it is favourable that liquid preparation is taken medicine for old people, child and influenza patient with severe symptoms.It is extremely beneficial for oseltamivir phosphate is provided in the stability of facing when before being mixed with liquid preparation that the inventor finds to use special adjuvant.The present invention is based on this discovery and be accomplished.
Therefore, the invention provides following various aspects:
[1] a kind of solid composite medicament wherein comprises oseltamivir phosphate, the sodium alginate of treatment or prevention effective dose and the acceptable excipient of choosing wantonly of one or more pharmacy.
[2] according to the solid composite medicament of project 1, wherein the weight ratio of sodium alginate and oseltamivir phosphate is (0.01~100): 1, preferred (0.1~10): 1, preferred (0.1~5): 1.
[3] according to the solid composite medicament of project 1, the acceptable excipient of wherein said pharmacy is selected from filler, buffer agent, thickening agent, antiseptic, flavoring agent, sweeting agent.
[4] according to the solid composite medicament of project 3, wherein said filler is selected from sorbitol, mannitol, lactose, sucrose.
[5] according to the solid composite medicament of project 3, wherein said buffer agent is selected from sodium citrate, potassium citrate, sodium lactate, sodium succinate.
[6] according to the solid composite medicament of project 3, wherein said thickening agent is selected from xanthan gum (xanthan gam), sodium carboxymethyl cellulose.
[7] according to each solid composite medicament of project 1-6; Wherein comprise sorbitol and/or mannitol and/or the lactose of sodium alginate, 0.01~1000 weight portion (preferred 0.1~100 weight portion) of oseltamivir phosphate, 0.01~100 weight portion (preferred 0.1~10 weight portion) of 1 weight portion, the sodium citrate of 0.01~100 weight portion (preferred 0.01~10 weight portion), the xanthan gum of 0.01~100 weight portion (preferred 0.01~10 weight portion), and the saccharin sodium of the sodium benzoate of optional 0.001~10 weight portion (preferred 0.01~1 weight portion), optional 0.001~10 weight portion (preferred 0.01~1 weight portion).
[8] purposes of each solid composite medicament of project 1-7 in preparation liquid medicine for oral use.
[9] a kind of composition of liquid medicine; Each solid composite medicament or the composition that wherein comprised (this moment, each composition added up to 1 weight portion) of project 1-7 that wherein comprises 1 weight portion; And the water-bearing media of 2-100 weight portion (preferred 2-50 weight portion, preferred 5-20 weight portion).
[10] composition of liquid medicine of project 9, wherein said water-bearing media is selected from: water, syrup, glucose solution, sodium chloride solution, fruit drink, Ringer's mixture.
The present invention also provides the disease that a kind of treatment or flu-prevention virus caused or the method for illness, the perhaps method of treatment or flu-prevention, and said method comprises the following steps: a) to make said solid composite medicament form suspension with water-bearing media; And b) as required to the aqueous solution of patient's orally give gained.
In one aspect, the present invention also provides solid composite medicament or the composition of liquid medicine that has like the prescription of being put down in writing in this paper embodiment or the preparation example.And the used unit of weight of each composition can change weight portion in these embodiment or the preparation example.
Solid composite medicament of the present invention also can be described as granule or dry suspension, and this is known at pharmaceutical field.Oseltamivir phosphate granula of the present invention can be deployed into solution facing with preceding water or other water-bearing media; Thereby being particularly suitable for the inconvenient patient of child and swallowable capsule takes; Dosage can be selected to use according to patient's age and body weight easily; And its preparation technology is simple and easy to do, and is with low cost.
In one embodiment, solid composite medicament of the present invention comprises:
Oseltamivir phosphate 1 weight portion,
Sodium alginate 0.1~10 weight portion,
Sorbitol and/or mannitol and/or lactose 0.1~100 weight portion.
In one embodiment, solid composite medicament of the present invention comprises:
Oseltamivir phosphate 1 weight portion,
Sodium alginate 0.1~10 weight portion,
Sorbitol and/or mannitol and/or lactose 0.1~100 weight portion,
Sodium citrate 0.01~10 weight portion.
In one embodiment, solid composite medicament of the present invention comprises:
Oseltamivir phosphate 1 weight portion,
Sodium alginate 0.1~10 weight portion,
Sorbitol and/or mannitol and/or lactose 0.1~100 weight portion,
Sodium citrate 0.01~10 weight portion,
Xanthan gum 0.01~10 weight portion.
In one embodiment, solid composite medicament of the present invention comprises:
Oseltamivir phosphate 1 weight portion,
Sodium alginate 0.1~10 weight portion,
Sorbitol and/or mannitol and/or lactose 0.1~100 weight portion,
Sodium citrate 0.01~10 weight portion,
Xanthan gum 0.01~10 weight portion,
Sodium benzoate 0.01~1 weight portion,
Saccharin sodium 0.01~1 weight portion.
In one embodiment, solid composite medicament of the present invention comprises:
Oseltamivir phosphate 1 weight portion,
Sodium alginate 0.1~5 weight portion,
Sorbitol and/or mannitol and/or lactose 5~50 weight portions,
Sodium citrate 0.01~2 weight portion,
Xanthan gum 0.01~2 weight portion,
Sodium benzoate 0.01~1 weight portion,
Saccharin sodium 0.01~0.1 weight portion.
Those skilled in the art know that; Solid composite medicament of the present invention; Can be used as a kind of dry suspension and offer the patient, promptly the solid composite medicament of the present invention as dry suspension is to be solid state in preparation, storage, transportation, before the patient faces usefulness; To wherein adding entry or other suitable water-bearing media; Process suspension, just can directly take for the patient, this moment, the liquid preparation as suspension was particularly advantageous for particular patient (for example children's, old people or patient with severe symptoms) aspect the divided dose.But, it will be apparent to those skilled in the art that this suspension can be used as the multiple dose medicament and possibly need to preserve a couple of days, thus its to have acceptable clinically stability be necessary, for example placed at normal temperatures 10 days, should keep gratifying stability.
According to the present invention, said sodium alginate is to meet standard that for example American Pharmacopeia, British Pharmacopoeia or the European Pharmacopoeia of current edition put down in writing.These products are to obtain easily on the market.
According to the present invention, phrase " sorbitol and/or mannitol and/or lactose " be meant contain in the pharmaceutical composition of the present invention among sorbitol, mannitol and the lactose three any one, two kinds or three kinds.
The method for preparing of solid composite medicament of the present invention is well known to a person skilled in the art, each composition is simply mixed, and for example mixes through the equivalent incremental method; Fully after the mix homogeneously, in pack into vial or the plastic bottle, seal.In addition; Also is very easy by solid composite medicament of the present invention facing with preceding obtaining liq pharmaceutical composition; For example in above-mentioned solid composite medicament in vial or plastic bottle, quantitatively add entry or other water-bearing media, fully be mixed, take according to routine dose and get final product.Thus, solid composite medicament of the present invention and composition of liquid medicine can be used as the multiple dose use.The present invention finds that solid composite medicament water of the present invention is made into after the suspension, and it has good stable property, particularly can place at normal temperatures at least 10 days.
The specific embodiment
Embodiment 1: the preparation of oseltamivir phosphate solid composite medicament
Composition |
Weight |
Oseltamivir phosphate |
15g |
Sodium alginate |
15g |
Oseltamivir phosphate and sodium alginate are all pulverized 100 mesh sieves, accurately took by weighing oseltamivir phosphate, the sodium alginate of recipe quantity, mix homogeneously; Divide to install in the plastic bottle, every bottle of phosphoric acid Oseltamivir 600mg promptly gets.
Embodiment 2: the preparation of oseltamivir phosphate solid composite medicament
Composition |
Weight |
Oseltamivir phosphate |
15g |
Sodium alginate |
1.5g |
Oseltamivir phosphate and sodium alginate are all pulverized 100 mesh sieves, accurately took by weighing oseltamivir phosphate, the sodium alginate of recipe quantity, mix homogeneously; Divide to install in the plastic bottle, every bottle of phosphoric acid Oseltamivir 600mg promptly gets.
Embodiment 3: the preparation of oseltamivir phosphate solid composite medicament
Composition |
Weight |
Oseltamivir phosphate |
15g |
Sodium alginate |
150g |
Oseltamivir phosphate and sodium alginate are all pulverized 100 mesh sieves, accurately took by weighing oseltamivir phosphate, the sodium alginate of recipe quantity, mix homogeneously; Divide to install in the plastic bottle, every bottle of phosphoric acid Oseltamivir 600mg promptly gets.
Embodiment 4: the preparation of oseltamivir phosphate solid composite medicament
Composition |
Weight/g |
Oseltamivir phosphate |
15 |
Sodium alginate |
15 |
Sorbitol |
150 |
Sodium citrate |
3 |
Xanthan gum |
1 |
Oseltamivir phosphate and sodium alginate and other adjuvant are all pulverized 100 mesh sieves, accurately took by weighing oseltamivir phosphate, sodium alginate and other adjuvant of recipe quantity, mix homogeneously; Divide to install in the plastic bottle, every bottle of phosphoric acid Oseltamivir 600mg promptly gets.
Embodiment 5: the preparation of oseltamivir phosphate solid composite medicament
Composition |
Weight/g |
Oseltamivir phosphate |
15 |
Sodium alginate |
10 |
Sorbitol |
150 |
Sodium citrate |
3 |
Xanthan gum |
3 |
Sodium benzoate |
1 |
Saccharin sodium |
0.15 |
Oseltamivir phosphate and sodium alginate and other adjuvant are all pulverized 100 mesh sieves, accurately took by weighing oseltamivir phosphate, sodium alginate and other adjuvant of recipe quantity, mix homogeneously; Divide to install in the plastic bottle, every bottle of phosphoric acid Oseltamivir 600mg promptly gets.
Embodiment 6: the preparation of oseltamivir phosphate solid composite medicament
Oseltamivir phosphate |
15 |
Sodium alginate |
1.5 |
Sorbitol |
750 |
Mannitol |
750 |
Sodium citrate |
0.15 |
Xanthan gum |
0.15 |
Sodium benzoate |
0.15 |
Saccharin sodium |
0.15 |
Oseltamivir phosphate and sodium alginate and other adjuvant are all pulverized 100 mesh sieves, accurately took by weighing oseltamivir phosphate, sodium alginate and other adjuvant of recipe quantity, mix homogeneously; Divide to install in the plastic bottle, every bottle of phosphoric acid Oseltamivir 600mg promptly gets.
Embodiment 7: the preparation of oseltamivir phosphate solid composite medicament
Composition |
Weight/g |
Oseltamivir phosphate |
15 |
Sodium alginate |
150 |
Sorbitol |
500 |
Sodium citrate |
150 |
Xanthan gum |
0.15 |
Sodium benzoate |
1 |
Saccharin sodium |
0 |
Oseltamivir phosphate and sodium alginate and other adjuvant are all pulverized 100 mesh sieves, accurately took by weighing oseltamivir phosphate, sodium alginate and other adjuvant of recipe quantity, mix homogeneously; Divide to install in the plastic bottle, every bottle of phosphoric acid Oseltamivir 600mg promptly gets.
Embodiment 8: the preparation of oseltamivir phosphate solid composite medicament
Composition |
Weight/g |
Oseltamivir phosphate |
15 |
Sodium alginate |
75 |
Lactose |
75 |
Sodium citrate |
30 |
Xanthan gum |
30 |
Sodium benzoate |
15 |
Saccharin sodium |
1.5 |
Oseltamivir phosphate and sodium alginate and other adjuvant are all pulverized 100 mesh sieves, accurately took by weighing oseltamivir phosphate, sodium alginate and other adjuvant of recipe quantity, mix homogeneously; Divide to install in the plastic bottle, every bottle of phosphoric acid Oseltamivir 600mg promptly gets.
Embodiment 9: the preparation of oseltamivir phosphate solid composite medicament
Oseltamivir phosphate and sodium alginate and other adjuvant are all pulverized 100 mesh sieves, accurately took by weighing oseltamivir phosphate, sodium alginate and other adjuvant of recipe quantity, mix homogeneously; Divide to install in the plastic bottle, every bottle of phosphoric acid Oseltamivir 600mg promptly gets.
The preparation of comparative example 1, oseltamivir phosphate granula
Composition |
Weight |
Oseltamivir phosphate |
20g |
Sucrose |
568g |
Polyvidone k30 |
12g |
Total amount |
600g |
Oseltamivir phosphate and other adjuvant were all pulverized 100 mesh sieves, accurately took by weighing oseltamivir phosphate, polyvidone k30 and the sucrose of recipe quantity, by the equivalent method mix homogeneously that progressively increases; With 40v/v% ethanol water system soft material, cross 14 mesh sieves and granulate, wet granular is placed 45-60 ℃ of oven for drying after, through 14 mesh sieve granulate, remove fine powder with No. 5 sieve sieves after, mensuration granule drug content and moisture are confirmed loading amount; Above-mentioned granule branch is installed in the plastic bottle, and every bottle of phosphoric acid Oseltamivir 600mg promptly gets.
The preparation of comparative example 2, oseltamivir phosphate granula
Composition |
Weight |
Oseltamivir phosphate |
15g |
The oseltamivir phosphate branch that directly will pulverize 100 mesh sieves installs in the plastic bottle, and every bottle of phosphoric acid Oseltamivir 600mg promptly gets.
The preparation of comparative example 3, oseltamivir phosphate granula
Composition |
Weight/g |
Oseltamivir phosphate |
15 |
Sorbitol |
150 |
Sodium citrate |
3 |
Xanthan gum |
3 |
Sodium benzoate |
1 |
Saccharin sodium |
0.15 |
Oseltamivir phosphate and other adjuvant are all pulverized 100 mesh sieves, accurately took by weighing oseltamivir phosphate and other adjuvant of recipe quantity, mix homogeneously; Divide to install in the plastic bottle, every bottle of phosphoric acid Oseltamivir 600mg promptly gets.
Preparation example 1: the preparation of oseltamivir phosphate composition of liquid medicine (suspension)
Get embodiment 1-9 and comparative example 1-3 gained solid composite medicament respectively, 1: 5,1: 10,1: 20 the mixed of weight ratio of pressing solid and water (or water-bearing media) shakes up, and processes suspension.The numbering of the carrier of this suspension, configuration proportion and gained suspension is distinguished as follows:
Annotate above symbol, the for example composition of liquid medicine that is mixed with 1: 10 ratio of solid-to-liquid ratio with solid composite medicament and 30% sucrose solution of embodiment 1 of " Suc-1 " expression; The composition of liquid medicine that " sWat-c1 " expression is mixed with 1: 20 ratio of solid-to-liquid ratio with the solid composite medicament and the water of comparative example 1, other symbol also has similar meaning.
Test Example 1: oseltamivir phosphate liquid stabilising property investigation
Get the suspension of respectively filling a prescription that obtains in the preparation example 1, in 40 ℃ of calorstats, placed 15 days.To each sample,, investigate each sample oseltamivir phosphate remnants rate (%) in the time of 15 days respectively at 0 day (before 40 ℃ of calorstats are placed) and (after 40 ℃ of calorstats are placed) sampling in 15 days.The remaining rate of oseltamivir phosphate (%) is calculated as follows:
In this experiment, get each specimen and suitably dilute, filter; Then list of references [Hu Hairong, the content of measuring the oseltamivir phosphate crude drug etc., HPLC also detects its related substance; The West China pharmaceutical journal; 2009 the 6th phases] record the HPLC method [used basic chromatographic condition is: use the LunaC8 post, mobile phase is 0.05molL-1 potassium dihydrogen phosphate-acetonitrile-methanol (620: 245: 135), and flow velocity is 1.2mLmin-1; Column temperature is 50 ℃, and the detection wavelength is 207nm] measure in each sample the remaining percentage amounts of oseltamivir phosphate.The result of each sample remaining rate of oseltamivir phosphate (%) in the time of 15 days sees the following form.