CN104138355A - Oseltamivir phosphate dry suspension and preparation method thereof - Google Patents
Oseltamivir phosphate dry suspension and preparation method thereof Download PDFInfo
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- CN104138355A CN104138355A CN201410384632.2A CN201410384632A CN104138355A CN 104138355 A CN104138355 A CN 104138355A CN 201410384632 A CN201410384632 A CN 201410384632A CN 104138355 A CN104138355 A CN 104138355A
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- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
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Abstract
The invention provides an oseltamivir phosphate dry suspension. The oseltamivir phosphate dry suspension comprises oseltamivir phosphate, filler not prone to reacting with the oseltamivir phosphate and other pharmaceutically acceptable accessories, wherein the filler is one or more of maltitol, xylitol and mannitol or is the composition of one or more of the maltitol, the xylitol and the mannitol and sorbitol, the content of the sorbitol in the whole composition is X, and X large than or equal to 0% and less than or equal to 75%. Meanwhile, the invention provides a preparation method of the oseltamivir phosphate dry suspension. Preferably, the preparation method is a step-by-step wet preparation method. The oseltamivir phosphate dry suspension is good in stability, low in cost, simple in preparation technology and capable of being produced in an industrial mode easily.
Description
Technical field
The present invention relates to field of medicine and chemical technology, more specifically, relate to oseltamivir phosphate dry suspension and preparation method thereof.
Background technology
Oseltamivir phosphate, chemistry (-)-(3R, 4R, 5S)-4-acetamide-5-amino-3-(1-ethyl propoxyl group) hexamethylene-1-carboxylic acid, ethyl ester phosphate by name.Chemical structural formula is as follows:
By Switzerland Roche Holding Ag research and development, released, oseltamivir phosphate has the activity of very strong inhibition neuraminidase, and all effective to A, Type B influenza virus, the information disclosures such as its character and preparation method are in WO 1998007685 A1 and WO 1996026933 A1.
The oseltamivir phosphate at present dosage form of listing has granule, capsule and dry suspension etc.Granule or dry suspension are suitable for being mixed with before use liquid preparation, are convenient to old man, child and are not suitable for the crowd of swallowing take.Conventionally during opening granule or dry suspension and being packaged to and being used to complete, need to be kept at specific condition, easily be subject to preserving the impact of the conditions such as humidity, temperature, illumination.Medicine stability will affect the safety of medicine during use, therefore guarantees that medicine stability is during use very important.
The reduced form sugar alcohol of oseltamivir phosphate easily and in compositions reacts, in order to overcome this technical problem prior art CN 101389323 A, in order to reach the object of stable composition, require the excipient adding to be selected from 25 ℃, more than one of the Saccharide and saccharide alcohols that 70% time equilibrium moisture content of relative humidity is 1 % by weight, containedly in this Saccharide and saccharide alcohols as the glucose of impurity and the content of mannose, with respect to this Saccharide and saccharide alcohols, be respectively below 0.01 % by weight, need to very high prescription be proposed to the sugar alcohol adding, therefore very high to the control criterion of adjuvant, be not easy control or reach, cost also can harshly because of the prescription of adjuvant become higher in addition, therefore be not suitable for suitability for industrialized production, cost-saving.
Summary of the invention
Summary of the invention
The inventor finds to use separately sorbitol can make oseltamivir phosphate dry suspension very unstable as filler, is mainly to produce impurity because the reducing sugar in sorbitol easily reacts with oseltamivir phosphate.In order to address this problem, unexpectedly, the present invention finds to use difficult a kind of sugar alcohol or multiple sugar alcohol mixtures (as mannitol, maltose alcohol or xylitol etc.) of reacting with oseltamivir phosphate in compositions, do not needing the reducing sugar level of various interpolation sugar alcohols to be proposed under the harsh prerequisite requiring, both can, so that oseltamivir phosphate dry suspension becomes stable, while making to prepare, be more prone to granulating simultaneously.
Use after specific a kind of sugar alcohol or multiple sugar alcohol mixtures, it is stable that dry suspension becomes, its reason is to be difficult for comparing with the reducing sugar in sorbitol with a kind of sugar alcohol or the reducing sugar in multiple sugar alcohol mixtures of oseltamivir phosphate reaction, is difficult for reacting with oseltamivir phosphate.
Therefore,, when solving the problem of oseltamivir phosphate dry suspension stability, provide oseltamivir phosphate dry suspension a kind of economy, easy, that suitability for industrialized is produced.
First aspect present invention provides a kind of oseltamivir phosphate dry suspension, comprises oseltamivir phosphate, difficult a kind of sugar alcohol or multiple sugar alcohol mixtures and other the pharmaceutically acceptable adjuvants reacting with oseltamivir phosphate.
Second aspect present invention provides the method for the described oseltamivir phosphate dry suspension of preparation.
Term definition
" % " of the present invention refers to mass percent.
" v/v " of the present invention refers to volume ratio, i.e. the percentage composition of the volume of described component in cumulative volume.
Detailed Description Of The Invention
A kind of oseltamivir phosphate dry suspension that first aspect present invention provides, comprises oseltamivir phosphate, difficult filler and other the pharmaceutically acceptable adjuvants reacting with oseltamivir phosphate.
Oseltamivir phosphate dry suspension provided by the invention can be respectively by powder formulation mixing preparation method, the method that the direct preparation method of wet method or wet method are prepared is step by step prepared and is obtained, gained dry suspension is comprised of the medicine-containing particle that contains oseltamivir phosphate, wherein the selected filler that is difficult for reacting with oseltamivir phosphate can be selected from maltose alcohol, xylitol, the compositions of one or more in mannitol and sorbitol, the content of described sorbitol in whole compositions is X, 0%<X≤75% wherein, the mixture of preferred mannitol-sorbitol, wherein the content of sorbitol in the mixture of mannitol-sorbitol is X, 0%<X≤75% wherein, more preferably the mixture of mannitol-sorbitol, wherein the content of sorbitol in the mixture of mannitol-sorbitol is X, wherein 0%<X≤40%.Adopt described filler can obtain the good oseltamivir phosphate dry suspension of stability.
Oseltamivir phosphate dry suspension provided by the invention can be that the method preparation of preparing step by step by wet method obtains, gained dry suspension is comprised of the granules of accessories of the medicine-containing particle that contains oseltamivir phosphate and non-phosphoric acid Oseltamivir, wherein the selected filler that is difficult for reacting with oseltamivir phosphate is selected from maltose alcohol, one or more of xylitol or mannitol, or be selected from maltose alcohol, xylitol, the compositions of one or more in mannitol and sorbitol, the content of described sorbitol in whole compositions is X, 0%<X≤75% wherein, more preferably the mixture of mannitol-sorbitol, wherein the content of sorbitol in the mixture of mannitol-sorbitol is X, 0%<X≤40% wherein.Adopt described preparation method and select the described filler that is difficult for reacting with oseltamivir phosphate to prepare oseltamivir phosphate dry suspension, can obtain the good oseltamivir phosphate dry suspension of stability.
In described dry suspension, the content in whole dry suspension of oseltamivir phosphate can be approximately 1.0%～10.0%, preferably approximately 1.0%～7.0%, be more preferably approximately 3.0%～5.0%.
The content summation of the described difficult filler reacting with oseltamivir phosphate in dry suspension can be approximately 80.0%～95.0%, preferred approximately 85.0%～90.0%.
The acceptable adjuvant of described other pharmacy can be selected from one or more in suspending agent, pH adjusting agent, antiseptic and coloring agent.
Described suspending agent can be selected from xanthan gum, hydroxypropyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidone-K30, gelatin, carboxymethyl starch sodium and hypromellose, preferably xanthan gum.The content of suspending agent in dry suspension can be approximately 0.01%～5.0%, preferred approximately 0.01%～2.0%.
Described pH adjusting agent can be selected from mixture (as mixing of the mixture of citric acid and sodium citrate, monohydrate potassium and sodium citrate), dihydrogen citrate alkali metal salt (as sodium salt, potassium salt), sodium lactate, the sodium succinate of citric acid and hydrate thereof and the acceptable salt of its pharmacy, the mixture of optimization citric acid sodium dihydrogen or monohydrate potassium and sodium citrate.The content of pH adjusting agent in dry suspension can be approximately 0.01%～5.0%, preferred approximately 0.5%～3.5%.
Described antiseptic can be selected from one or more in sorbic acid, potassium sorbate, calcium sorbate, benzoic acid, sodium benzoate, methyl parahydroxybenzoate, ethylparaben, propyl p-hydroxybenzoate, butyl p-hydroxybenzoate, preferred sodium benzoate.The content of antiseptic in dry suspension can be approximately 0.01%～3.0%, preferred approximately 0.01%～1.0%.
Described coloring agent is selected from titanium dioxide, and the content in dry suspension can be approximately 0.1%～2.5%, and preferred approximately 0.1%～2.0%.
In certain embodiments, described oseltamivir phosphate dry suspension comprises oseltamivir phosphate, difficult filler and other the pharmaceutically acceptable adjuvants reacting with oseltamivir phosphate, wherein said filler is selected from the combination of one or more and sorbitol in maltose alcohol, xylitol, mannitol, the content of described sorbitol in whole sugar alcohol combination mixture is X, wherein 0%<X≤75%.In certain embodiments, the preferred maltose alcohol of described filler or mannitol, the mixture of preferred mannitol-sorbitol, wherein the content of sorbitol in the mixture of mannitol-sorbitol is X, wherein 0%<X≤75%; More preferably the mixture of mannitol-sorbitol, wherein the content of sorbitol in the mixture of mannitol-sorbitol is X, wherein 0%<X≤40%.
In certain embodiments, oseltamivir phosphate dry suspension provided by the present invention by comprise contain oseltamivir phosphate and suitably the medicine-containing particle of adjuvant and the granules of accessories that does not contain oseltamivir phosphate form, wherein said medicine-containing particle comprises one or more of oseltamivir phosphate, difficult filler, coloring agent and the suspending agent reacting with oseltamivir phosphate; Not the granules of accessories of phosphoric acid Oseltamivir comprise the filler that is difficult for reacting with oseltamivir phosphate, suspending agent,
pone or more of H regulator and antiseptic.The selection of wherein said difficult filler, coloring agent, suspending agent, suspending agent, pH adjusting agent and the antiseptic reacting with oseltamivir phosphate and content are as aforementioned.Alternatively, the granules of accessories of wherein said not phosphoric acid Oseltamivir also comprises sweeting agent.Alternatively, described by contain oseltamivir phosphate and suitably adjuvant medicine-containing particle and do not contain the oseltamivir phosphate dry suspension that the granules of accessories of oseltamivir phosphate forms and also comprise correctives.
Described sweeting agent can be selected from one or more in glucide, glycyrrhizic acid, glycyrrhizic acid dipotassium, Stevia rebaudiana (Bertoni) Hemsl extract, saccharin sodium, saccharin sodium dihydrate, aspartame, sucralose, cyclamate, preferably sucralose, glycyrrhizic acid, saccharin sodium, saccharin sodium dihydrate or glycyrrhizic acid dipotassium.The content of sweeting agent in dry suspension can be approximately 0.01%～5.0%, preferably approximately 0.1%～2.5%.
Described correctives can be selected from malted maize dextrin, other fragrance materials (as peach flavor, apple essence, flavoring pineapple essence and flavoring banana essence etc.), preferably peach flavor.The content of correctives in dry suspension can be approximately 0.1%～5.0%, preferred approximately 0.1%～1.0%.
In certain embodiments, described oseltamivir phosphate dry suspension comprises oseltamivir phosphate approximately 3.0%～5.0%, is difficult for the filler approximately 80.0%～95.0% reacting with oseltamivir phosphate, pH adjusting agent approximately 0.01%～5.0%, antiseptic approximately 0.01%～3.0% and the coloring agent approximately 0.1%～2.5% of suspending agent approximately 0.01%～5.0%, approximately 0.01%～5.0%.
In certain embodiments, described oseltamivir phosphate dry suspension comprises mixture approximately 80.0%～95.0%, xanthan gum approximately 0.01%～5.0%, sodium citrate approximately 0.01%～3.5%, monohydrate potassium approximately 0.01%～1.5%, sodium benzoate approximately 0.01%～3.0% and the titanium dioxide approximately 0.01%～2.5% of oseltamivir phosphate approximately 3.0%～5.0%, mannitol-sorbitol, wherein the content of sorbitol in the mixture of mannitol-sorbitol is X, wherein 0%<X≤75%.
In certain embodiments, described oseltamivir phosphate dry suspension comprises medicine-containing particle and granules of accessories, and wherein medicine-containing particle comprises oseltamivir phosphate approximately 3.0%～5.0%, difficult filler approximately 35.0%～50.0%, suspending agent approximately 0.01%～2.5% and the coloring agent approximately 0.1%～2.5% reacting with oseltamivir phosphate; Wherein granules of accessories comprises difficult filler approximately 35.0%～50.0%, suspending agent approximately 0.01%～2.5%, pH adjusting agent approximately 0.01%～5.0% and the antiseptic approximately 0.01%～3.0% reacting with oseltamivir phosphate.Alternatively, described oseltamivir phosphate dry suspension can further contain correctives, and the content of described correctives in dry suspension is approximately 0.1%～5.0%, and the content of described correctives in dry suspension is approximately 0.1%～1.0% in certain embodiments.
In certain embodiments, described oseltamivir phosphate dry suspension comprises medicine-containing particle, granules of accessories and correctives, and wherein medicine-containing particle comprises oseltamivir phosphate approximately 3.0%～5.0%, maltose alcohol approximately 35.0%～50.0%, xanthan gum approximately 0.01%～1.0% and titanium dioxide approximately 0.1%～2.0%; Wherein granules of accessories comprises maltose alcohol approximately 35.0%～50.0%, xanthan gum approximately 0.01%～1.0%, sodium citrate approximately 0.5%～2.5%, monohydrate potassium approximately 0.1%～1.0%, sodium benzoate approximately 0.01%～1.0% and saccharin sodium dihydrate approximately 0.1%～2.5%; Wherein the content of correctives in dry suspension is approximately 0.1%～1.0%, and correctives is apple essence.
In certain embodiments, described oseltamivir phosphate dry suspension comprises medicine-containing particle, granules of accessories and correctives, and wherein medicine-containing particle comprises oseltamivir phosphate approximately 3.0%～5.0%, mannitol approximately 35.0%～50.0%, xanthan gum approximately 0.01%～1.0% and titanium dioxide approximately 0.1%～2.0%; Wherein granules of accessories comprises mannitol approximately 35.0%～50.0%, xanthan gum approximately 0.01%～1.0%, sodium citrate approximately 0.5%～2.5%, monohydrate potassium approximately 0.1%～1.0%, sodium benzoate approximately 0.01%～1.0% and saccharin sodium dihydrate approximately 0.1%～2.5%; Wherein the content of correctives in dry suspension is approximately 0.1%～1.0%, and correctives is flavoring banana essence.
In certain embodiments, described oseltamivir phosphate dry suspension comprises medicine-containing particle, granules of accessories and correctives, wherein medicine-containing particle comprises oseltamivir phosphate approximately 3.0%～5.0%, mannitol-sorbitol mixture approximately 35.0%～50.0%, xanthan gum approximately 0.01%～1.0% and titanium dioxide approximately 0.1%～2.0%, wherein the content of sorbitol in the mixture of mannitol-sorbitol is X, wherein 0%<X≤75%; Wherein granules of accessories comprises mannitol-sorbitol mixture approximately 35.0%～50.0%, xanthan gum approximately 0.01%～1.0%, sodium citrate approximately 0.5%～2.5%, monohydrate potassium approximately 0.1%～1.0%, sodium benzoate approximately 0.01%～1.0% and saccharin sodium dihydrate approximately 0.1%～2.5%, wherein the content of sorbitol in the mixture of mannitol-sorbitol is X, wherein 0%<X≤75%; Wherein the content of correctives in dry suspension is approximately 0.1%～1.0%, and correctives is peach flavor.
Oseltamivir dry suspension provided by the invention is selected from maltose alcohol by employing, xylitol, the combination filler of one or more in mannitol and sorbitol can play good stablizing effect to whole dry suspension, or can also adopt and only be selected from maltose alcohol, xylitol, one or more in mannitol, alternatively further with the combination of sorbitol, and employing separates the method for granulating, use the reducing sugar in medicine and sugar alcohol, and other adjuvant, as sodium benzoate, saccharin sodium etc., be spaced from each other, the probability of contact is lower, the impurity producing still less.Oseltamivir phosphate dry suspension provided by the invention, in preservation process, the impurity of oseltamivir phosphate dry suspension is very stable, has guaranteed the safety of medication.
Second aspect present invention provides the method for the described oseltamivir phosphate dry suspension of preparation.The method of preparing described oseltamivir phosphate can be the method that powder formulation mixing preparation method, the direct preparation method of wet method and wet method are prepared step by step.Preferably wet method is divided one-step preparation method.
Described powder formulation mixing preparation method is that oseltamivir phosphate, adjuvant are crossed to screen cloth by recipe quantity, mix homogeneously, encapsulation.
The direct preparation method of described wet method refers to the conventional wet granulation method of employing, oseltamivir phosphate, adjuvant are pressed to the direct mixed once of recipe quantity even, cross screen cloth, then add 20%-60% ethanol water to granulate, wet granular is crossed screen cloth, oven drying, adopts screen cloth to sieve after dry end, encapsulation.
The method that described wet method is prepared step by step refers to by the method for wet granulation and completes according to the following steps dry suspension preparation:
1) medicine-containing particle that preparation contains oseltamivir phosphate and suitable adjuvant;
2) preparation does not contain the granules of accessories of oseltamivir phosphate;
3) by the above-mentioned medicine-containing particle making and granules of accessories mix homogeneously.
Described 1) step comprises:
A) oseltamivir phosphate and suitable adjuvant premixing in granulator is even;
B) add appropriate 20%-60% alcoholic solution, granulate;
C) cross screen cloth granulate, and dry on fluid bed, finally cross screen cloth granulate.
Described 1) adjuvant described in step comprises difficult filler, suspending agent and the coloring agent reacting with oseltamivir phosphate.
In certain embodiments, oseltamivir phosphate addition is approximately 3.0%～5.0% at whole dry suspension; The filler addition that is difficult for reacting with oseltamivir phosphate is approximately 35%～50% at whole dry suspension; Suspending agent addition is approximately 0.01%～2.5% at whole dry suspension; Adding of colorants is approximately 0.1%～2.5% at whole dry suspension.
In certain embodiments, oseltamivir phosphate addition is approximately 3.0%～5.0% at whole dry suspension; The filler addition that is difficult for reacting with oseltamivir phosphate is approximately 35%～50% at whole dry suspension; Suspending agent addition is approximately 0.01%～1.0% at whole dry suspension; Adding of colorants is approximately 0.1%～2.0% at whole dry suspension.
In certain embodiments, the difficult filler reacting with oseltamivir phosphate is maltose alcohol, xylitol or mannitol.
In certain embodiments, the filler that is difficult for reacting with oseltamivir phosphate is one or more and the combination in any of sorbitol being selected from maltose alcohol, xylitol, mannitol, while wherein containing sorbitol in multiple sugar alcohol mixtures, the content of sorbitol in whole sugar alcohol mixtures is X, wherein 0%<X≤75%.
In certain embodiments, suspending agent is xanthan gum, and coloring agent is titanium dioxide.
Described 2) step comprises:
A) premixing in granulator of suitable adjuvant is even;
B) add appropriate 20%-60% alcoholic solution, granulate;
C) cross screen cloth granulate, and dry on fluid bed, finally cross screen cloth granulate.
Described 2) described in step, adjuvant comprises difficult filler, suspending agent, pH adjusting agent and the antiseptic reacting with oseltamivir phosphate.
In certain embodiments, difficult filler addition of reacting with oseltamivir phosphate is approximately 35%～50% at whole dry suspension; Suspending agent addition is approximately 0.01%～2.5% at whole dry suspension; PH adjusting agent addition is approximately 0.01%～5.0% at whole dry suspension; Antiseptic addition is approximately 0.01%～2.0% at whole dry suspension.
In certain embodiments, difficult filler addition of reacting with oseltamivir phosphate is approximately 35%～50% at whole dry suspension; Suspending agent addition is approximately 0.01%～1.0% at whole dry suspension; PH adjusting agent addition is approximately 0.5%～3.5% at whole dry suspension; Antiseptic addition is approximately 0.01%～1.0% at whole dry suspension.
In certain embodiments, the difficult filler reacting with oseltamivir phosphate is maltose alcohol, xylitol or mannitol.
In certain embodiments, the filler that is difficult for reacting with oseltamivir phosphate is the combination in any that is selected from the two or more sugar alcohols in maltose alcohol, xylitol, mannitol and sorbitol, while wherein containing sorbitol in multiple sugar alcohol mixtures, the content of sorbitol in whole sugar alcohol mixtures is X, wherein 0%<X≤75%.
In certain embodiments, suspending agent is xanthan gum, and pH adjusting agent is the compositions of sodium citrate and monohydrate potassium, and antiseptic is sodium benzoate.
Also added in certain embodiments sweeting agent, sweeting agent addition is approximately 0.01%～5.0% at whole dry suspension; Sweeting agent addition is approximately 0.1%～2.5% at whole dry suspension in certain embodiments; Sweeting agent is saccharin sodium dihydrate in certain embodiments.
Further, the method that described wet method is prepared step by step, additional correctives in the suspensoid that can also in the end make.
In certain embodiments, correctives is apple essence, flavoring banana essence or peach flavor.
By the method that adopts wet method to prepare step by step, by separately granulating, use the reducing sugar in medicine and sugar alcohol, and other adjuvant, as sodium benzoate, saccharin sodium etc., being spaced from each other, the probability of contact is lower, and the impurity of generation is still less.Therefore can obtain more stable oseltamivir phosphate dry suspension, make the impurity of oseltamivir phosphate dry suspension in preservation process very stable, guarantee the safety of medication.
The above three kinds of preparation method all can optionally add suitable correctives to the granule that preparation method is made separately, and mix homogeneously.
The specific embodiment
In order to make those skilled in the art understand better technical scheme of the present invention, below further disclose some unrestricted embodiment the present invention is described in further detail.
In the present embodiment, percentage composition described in specific embodiment is in mass ratio.
The reagent that the present embodiment is used all can be buied from the market or can obtain by method preparation described in the invention.
In the present embodiment, sorbitol is to buy from Roquette Freres, meets the adjuvant standard of U.S. USP-NF, and wherein the limit of reducing sugar is to be less than 0.3% (in sucrose)
Embodiment 1
Prescription:
| Component | Content |
| Oseltamivir phosphate | 3.5％ |
| Mannitol | 49.6％ |
| Sorbitol | 34.1％ |
| Xanthan gum | 4.5％ |
| Titanium dioxide | 2.5％ |
| Sodium citrate | 4.0％ |
| Monohydrate potassium | 0.8％ |
| Sodium benzoate | 1.0％ |
| Add up to | 100.0％ |
Preparation method:
By recipe quantity, take respectively appropriate oseltamivir phosphate and adjuvant; add successively 3.5% oseltamivir phosphate, 34.1% Sorbitol, 49.6% mannitol, 2.5% titanium dioxide, 4.0% sodium citrate, 0.8% monohydrate potassium, 1.0% sodium benzoate and 4.5% xanthan gum; mix homogeneously in granulator; granulator blade rotating speed 150rpm; cutter rotating speed 3000rpm, then crosses 30 eye mesh screen 3 times.
Embodiment 2
Prescription:
| Component | Content |
| Oseltamivir phosphate | 3.8％ |
| Mannitol | 70.8％ |
| Sorbitol | 23.5％ |
| Hydroxypropyl cellulose | 0.1％ |
| Titanium dioxide | 0.5％ |
| Sodium citrate | 1.0％ |
| Monohydrate potassium | 0.2％ |
| Sodium benzoate | 0.1％ |
| Add up to | 100.0％ |
Preparation technology:
By recipe quantity, take respectively appropriate oseltamivir phosphate and adjuvant; add successively 3.8% oseltamivir phosphate, 23.5% Sorbitol, 70.8% mannitol, 0.5% titanium dioxide, 1.0% sodium citrate, 0.2% monohydrate potassium, 0.1% sodium benzoate and 0.1% hydroxypropyl cellulose; mix homogeneously in granulator; granulator blade rotating speed 150rpm; cutter rotating speed 3000rpm, then crosses 30 eye mesh screen 3 times.
Embodiment 3
Prescription:
| Component | Content |
| Oseltamivir phosphate | 3.6％ |
| Maltose alcohol | 53.3％ |
| Sorbitol | 37.8％ |
| Hypromellose | 0.9％ |
| Titanium dioxide | 1.3％ |
| Monobasic sodium citrate | 2.6％ |
| Sodium benzoate | 0.5％ |
| Add up to | 100.0％ |
Preparation method:
By recipe quantity, take respectively appropriate oseltamivir phosphate and adjuvant; add successively 3.6% oseltamivir phosphate, 37.8% Sorbitol, 53.3% mannitol, 1.3% titanium dioxide, 2.6% disodium citrate, 0.5% sodium benzoate and 0.9% hypromellose; mix homogeneously in granulator; granulator blade rotating speed 150rpm; cutter rotating speed 3000rpm, then crosses 30 eye mesh screen 3 times.
Embodiment 4
Prescription:
| Component | Content |
| Oseltamivir phosphate | 3.9％ |
| Xylitol | 62.1％ |
| Sorbitol | 22.0％ |
| Sodium carboxymethyl cellulose | 4.3％ |
| Titanium dioxide | 2.0％ |
| Sodium succinate | 4.6％ |
| Potassium sorbate | 1.1％ |
| Add up to | 100.0％ |
Preparation method:
By recipe quantity, take respectively appropriate oseltamivir phosphate and adjuvant, add successively 3.9% oseltamivir phosphate, 22.0% Sorbitol, 62.1% mannitol, 2.0% titanium dioxide, 4.6% sodium succinate, 1.1% potassium sorbate and 4.3% sodium carboxymethyl cellulose, mix homogeneously, granulator blade rotating speed 150rpm, cutter rotating speed 3000rpm, cross 40 eye mesh screen 3 times, adopt peristaltic pump to add 25% ethanol water to granulate, peristaltic pump rotating speed 50rpm, liquid feeding and pelletization granulator blade rotating speed 150rpm, cutter rotating speed 3000rpm, wet granular is crossed 18 eye mesh screens, approximately 55 ℃, baking oven is dry, after dry end, adopt 30 eye mesh screens to sieve.
Embodiment 5
Prescription:
| Component | Content |
| Oseltamivir phosphate | 3.0％ |
| Mannitol | 70.5％ |
| Maltose alcohol | 19.0％ |
| Sorbitol | 5.15％ |
| Xanthan gum | 0.2％ |
| Titanium dioxide | 0.4％ |
| Sodium citrate | 1.3％ |
| Monohydrate potassium | 0.3％ |
| Sodium benzoate | 0.15％ |
| Add up to | 100.0％ |
Preparation method:
By recipe quantity, take respectively appropriate oseltamivir phosphate and adjuvant, add successively 3.0% oseltamivir phosphate, 5.15% Sorbitol, 70.5% mannitol, 19.0% maltose alcohol, 0.4% titanium dioxide, 1.3% sodium citrate, 0.3% monohydrate potassium, 0.15% sodium benzoate and 0.2% xanthan gum, mix homogeneously, granulator blade rotating speed 150rpm, cutter rotating speed 3000rpm, cross screen cloth 3 times, adopt peristaltic pump to add 50% ethanol water to granulate, peristaltic pump rotating speed 50rpm, liquid feeding and pelletization granulator blade rotating speed 150rpm, cutter rotating speed 3000rpm, wet granular is crossed 18 eye mesh screens, approximately 55 ℃, baking oven is dry, after dry end, adopt 30 eye mesh screens to sieve.
Embodiment 6
Prescription:
| Component | Content |
| Oseltamivir phosphate | 3.5％ |
| Mannitol | 23.9％ |
| Sorbitol | 67.9％ |
| Xanthan gum | 1.0％ |
| Titanium dioxide | 1.2％ |
| Sodium citrate | 1.8％ |
| Monohydrate potassium | 0.4％ |
| Sodium benzoate | 0.3％ |
| Add up to | 100.0％ |
Preparation method:
By recipe quantity, take respectively appropriate oseltamivir phosphate and adjuvant, add successively 3.5% oseltamivir phosphate, 67.9% Sorbitol, 23.9% mannitol, 1.2% titanium dioxide, 1.8% sodium citrate, 0.4% monohydrate potassium, 0.3% sodium benzoate and 1.0% xanthan gum, mix homogeneously, granulator blade rotating speed 150rpm, cutter rotating speed 3000rpm, cross 40 eye mesh screen 3 times, adopt peristaltic pump to add 20% ethanol water to granulate, peristaltic pump rotating speed 50rpm, liquid feeding and pelletization granulator blade rotating speed 150rpm, cutter rotating speed 3000rpm, wet granular is crossed 18 eye mesh screens, approximately 55 ℃, baking oven is dry, after dry end, adopt 30 eye mesh screens to sieve.
Embodiment 7
Prescription:
Preparation method:
1) medicine-containing particle preparation:
By recipe quantity, add respectively 4.1% oseltamivir phosphate, 37.2% mannitol, 12.3% Sorbitol, 0.41% titanium dioxide and 0.15% xanthan gum premix in the pot of granulating even, granulator blade rotating speed 150rpm, cutter rotating speed 3000rpm.Adopt peristaltic pump to add the alcoholic solution of appropriate amount 35% to granulate, peristaltic pump rotating speed 50rpm, liquid feeding and pelletization granulator blade rotating speed 150rpm, cutter rotating speed 3000rpm; Adopt 18 eye mesh screen granulate, pelletizing machine rotating speed 1442rpm; Adopt fluid bed drying, 55 ℃ of inlet temperature, 40 ℃ of temperature of charge, air intake frequency 25Hz.Adopt 30 eye mesh screen granulate, pelletizing machine rotating speed 1442rpm
2) granules of accessories preparation:
By recipe quantity, add respectively 32.63% mannitol, 11.23% Sorbitol, 1.0% sodium citrate, 0.3% monohydrate potassium, 0.2% saccharin sodium dihydrate, 0.53% sodium benzoate and 0.15% xanthan gum premix in granulator, granulator blade rotating speed 150rpm, cutter rotating speed 3000rpm; Adopt peristaltic pump to add the alcoholic solution of appropriate amount 35% to granulate, peristaltic pump rotating speed 50rpm, liquid feeding and pelletization granulator blade rotating speed 150rpm, cutter rotating speed 3000rpm; Adopt 18 eye mesh screen granulate, pelletizing machine rotating speed 1442rpm; Adopt fluid bed drying, 40 ℃ of inlet temperature, 40 ℃ of temperature of charge, air intake frequency 20～25Hz.Adopt again 30 eye mesh screen granulate, pelletizing machine rotating speed 1442rpm.
3) mix medicine-containing particle and granules of accessories
By the medicine-containing particle of above-mentioned preparation and the granules of accessories rotating speed mix homogeneously with 10rpm in tempering tank.
Embodiment 8
Prescription:
Preparation method:
4) medicine-containing particle preparation:
By recipe quantity, add respectively 4.1% oseltamivir phosphate, 36.2% sorbitol, 13.5% maltose alcohol, 0.41% titanium dioxide and 0.15% hydroxypropyl cellulose premix in the pot of granulating even, granulator blade rotating speed 150rpm, cutter rotating speed 3000rpm.Adopt peristaltic pump to add the alcoholic solution of appropriate amount 35% to granulate, peristaltic pump rotating speed 50rpm, liquid feeding and pelletization granulator blade rotating speed 150rpm, cutter rotating speed 3000rpm; Adopt 18 eye mesh screen granulate, pelletizing machine rotating speed 1442rpm; Adopt fluid bed drying, 55 ℃ of inlet temperature, 40 ℃ of temperature of charge, air intake frequency 25Hz.Adopt 30 eye mesh screen granulate, pelletizing machine rotating speed 1442rpm
5) granules of accessories preparation:
By recipe quantity, add respectively 31.63% sorbitol, 11.43% maltose alcohol, 1.3% monobasic sodium citrate, 1.13% sodium benzoate and 0.15% maltose alcohol premix in granulator, granulator blade rotating speed 150rpm, cutter rotating speed 3000rpm; Adopt peristaltic pump to add the alcoholic solution of appropriate amount 35% to granulate, peristaltic pump rotating speed 50rpm, liquid feeding and pelletization granulator blade rotating speed 150rpm, cutter rotating speed 3000rpm; Adopt 18 eye mesh screen granulate, pelletizing machine rotating speed 1442rpm; Adopt fluid bed drying, 40 ℃ of inlet temperature, 40 ℃ of temperature of charge, air intake frequency 20～25Hz.Adopt again 30 eye mesh screen granulate, pelletizing machine rotating speed 1442rpm.
6) mix medicine-containing particle and granules of accessories
By the medicine-containing particle of above-mentioned preparation and the granules of accessories rotating speed mix homogeneously with 10rpm in tempering tank.
Embodiment 9
Prescription:
Preparation method:
7) medicine-containing particle preparation:
By recipe quantity, add respectively 3.65% oseltamivir phosphate, 31.5% mannitol, 13.2% Sorbitol, 2.5% titanium dioxide and 0.22% xanthan gum premix in the pot of granulating even, granulator blade rotating speed 150rpm, cutter rotating speed 3000rpm.Adopt peristaltic pump to add the alcoholic solution of appropriate amount 60% to granulate, peristaltic pump rotating speed 50rpm, liquid feeding and pelletization granulator blade rotating speed 150rpm, cutter rotating speed 3000rpm; Adopt 18 eye mesh screen granulate, pelletizing machine rotating speed 1442rpm; Adopt fluid bed drying, 55 ℃ of inlet temperature, 40 ℃ of temperature of charge, air intake frequency 25Hz.Adopt 30 eye mesh screen granulate, pelletizing machine rotating speed 1442rpm
8) granules of accessories preparation:
By recipe quantity, add respectively 22.95% mannitol, 11.2% Sorbitol, 4.0% sodium citrate, 0.9% monohydrate potassium, 4.5% saccharin sodium dihydrate, 1.2% sodium benzoate and 2.2% xanthan gum premix in granulator, granulator blade rotating speed 150rpm, cutter rotating speed 3000rpm; Adopt peristaltic pump to add the alcoholic solution of appropriate amount 60% to granulate, peristaltic pump rotating speed 50rpm, liquid feeding and pelletization granulator blade rotating speed 150rpm, cutter rotating speed 3000rpm; Adopt 18 eye mesh screen granulate, pelletizing machine rotating speed 1442rpm; Adopt fluid bed drying, 40 ℃ of inlet temperature, 40 ℃ of temperature of charge, air intake frequency 20～25Hz.Adopt again 30 eye mesh screen granulate, pelletizing machine rotating speed 1442rpm.
9) mix medicine-containing particle and granules of accessories
By the medicine-containing particle of above-mentioned preparation and the granules of accessories rotating speed mix homogeneously with 10rpm in tempering tank.
Embodiment 10
Prescription:
Preparation method:
10) medicine-containing particle preparation:
By recipe quantity, add respectively 3.8% oseltamivir phosphate, 32.14% mannitol, 12.26% Sorbitol, 1.4% titanium dioxide and 0.4% xanthan gum premix in the pot of granulating even, granulator blade rotating speed 150rpm, cutter rotating speed 3000rpm.Adopt peristaltic pump to add the alcoholic solution of appropriate amount 25% to granulate, peristaltic pump rotating speed 50rpm, liquid feeding and pelletization granulator blade rotating speed 150rpm, cutter rotating speed 3000rpm; Adopt 18 eye mesh screen granulate, pelletizing machine rotating speed 1442rpm; Adopt fluid bed drying, 55 ℃ of inlet temperature, 40 ℃ of temperature of charge, air intake frequency 25Hz.Adopt 30 eye mesh screen granulate, pelletizing machine rotating speed 1442rpm
11) granules of accessories preparation:
By recipe quantity, add respectively 26.9% mannitol, 18.10% Sorbitol, 1.96% sodium citrate, 0.48% monohydrate potassium, 1.2% saccharin sodium dihydrate, 0.46% sodium benzoate and 0.4% xanthan gum premix in granulator, granulator blade rotating speed 150rpm, cutter rotating speed 3000rpm; Adopt peristaltic pump to add the alcoholic solution of appropriate amount 25% to granulate, peristaltic pump rotating speed 50rpm, liquid feeding and pelletization granulator blade rotating speed 150rpm, cutter rotating speed 3000rpm; Adopt 18 eye mesh screen granulate, pelletizing machine rotating speed 1442rpm; Adopt fluid bed drying, 40 ℃ of inlet temperature, 40 ℃ of temperature of charge, air intake frequency 20～25Hz.Adopt again 30 eye mesh screen granulate, pelletizing machine rotating speed 1442rpm.
12) mix medicine-containing particle and granules of accessories
By the medicine-containing particle of above-mentioned preparation, granules of accessories and the 0.5% peach flavor rotating speed mix homogeneously with 10rpm in tempering tank.
Embodiment 11
Prescription:
Preparation method:
13) medicine-containing particle preparation:
By recipe quantity, add respectively 3.5% oseltamivir phosphate, 44.5% maltose alcohol, 1.4% titanium dioxide and 0.6% xanthan gum premix in the pot of granulating even, granulator blade rotating speed 150rpm, cutter rotating speed 3000rpm.Adopt peristaltic pump to add the alcoholic solution of appropriate amount 25% to granulate, peristaltic pump rotating speed 50rpm, liquid feeding and pelletization granulator blade rotating speed 150rpm, cutter rotating speed 3000rpm; Adopt 18 eye mesh screen granulate, pelletizing machine rotating speed 1442rpm; Adopt fluid bed drying, 55 ℃ of inlet temperature, 40 ℃ of temperature of charge, air intake frequency 25Hz.Adopt 30 eye mesh screen granulate, pelletizing machine rotating speed 1442rpm
14) granules of accessories preparation:
By recipe quantity, add respectively 45.0% maltose alcohol, 2.44% sodium lactate, 1.2% glucide, 0.46% methyl parahydroxybenzoate and 0.4% xanthan gum premix in granulator, granulator blade rotating speed 150rpm, cutter rotating speed 3000rpm; Adopt peristaltic pump to add the alcoholic solution of appropriate amount 25% to granulate, peristaltic pump rotating speed 50rpm, liquid feeding and pelletization granulator blade rotating speed 150rpm, cutter rotating speed 3000rpm; Adopt 18 eye mesh screen granulate, pelletizing machine rotating speed 1442rpm; Adopt fluid bed drying, 40 ℃ of inlet temperature, 40 ℃ of temperature of charge, air intake frequency 20～25Hz.Adopt again 30 eye mesh screen granulate, pelletizing machine rotating speed 1442rpm.
15) mix medicine-containing particle and granules of accessories
By the medicine-containing particle of above-mentioned preparation, granules of accessories and the 0.5% apple essence rotating speed mix homogeneously with 10rpm in tempering tank.
Embodiment 12
Prescription:
Preparation method:
16) medicine-containing particle preparation:
By recipe quantity, add respectively 3.7% oseltamivir phosphate, 42.3% mannitol, 1.1% titanium dioxide and 0.7% xanthan gum premix in the pot of granulating even, granulator blade rotating speed 150rpm, cutter rotating speed 3000rpm.Adopt peristaltic pump to add the alcoholic solution of appropriate amount 25% to granulate, peristaltic pump rotating speed 50rpm, liquid feeding and pelletization granulator blade rotating speed 150rpm, cutter rotating speed 3000rpm; Adopt 18 eye mesh screen granulate, pelletizing machine rotating speed 1442rpm; Adopt fluid bed drying, 55 ℃ of inlet temperature, 40 ℃ of temperature of charge, air intake frequency 25Hz.Adopt 30 eye mesh screen granulate, pelletizing machine rotating speed 1442rpm
17) granules of accessories preparation:
By recipe quantity, add respectively 47.0% mannitol, 2.06% sodium citrate sodium, 0.78% monohydrate potassium, 0.8% aspartame, 0.46% sodium benzoate and 0.8% xanthan gum premix in granulator, granulator blade rotating speed 150rpm, cutter rotating speed 3000rpm; Adopt peristaltic pump to add the alcoholic solution of appropriate amount 25% to granulate, peristaltic pump rotating speed 50rpm, liquid feeding and pelletization granulator blade rotating speed 150rpm, cutter rotating speed 3000rpm; Adopt 18 eye mesh screen granulate, pelletizing machine rotating speed 1442rpm; Adopt fluid bed drying, 40 ℃ of inlet temperature, 40 ℃ of temperature of charge, air intake frequency 20～25Hz.Adopt again 30 eye mesh screen granulate, pelletizing machine rotating speed 1442rpm.
18) mix medicine-containing particle and granules of accessories
By the medicine-containing particle of above-mentioned preparation, granules of accessories and the 0.3% flavoring banana essence rotating speed mix homogeneously with 10rpm in tempering tank.
Comparative example 1
Prescription:
| Component | Content |
| Oseltamivir phosphate | 3.75％ |
| Sorbitol | 89.2％ |
| Xanthan gum | 0.75％ |
| Titanium dioxide | 1.3％ |
| Sodium citrate | 2.7％ |
| Monohydrate potassium | 0.9％ |
| Sodium benzoate | 1.4％ |
| Add up to | 100.0％ |
Preparation method:
By recipe quantity, take respectively appropriate oseltamivir phosphate and adjuvant; add successively 3.75% oseltamivir phosphate, 89.2% mannitol, 1.3% titanium dioxide, 2.7% sodium citrate, 0.9% monohydrate potassium, 1.4% sodium benzoate and 0.75% xanthan gum; mix homogeneously in granulator; granulator blade rotating speed 150rpm; cutter rotating speed 3000rpm, then crosses 30 eye mesh screen 3 times.
Comparative example 2
Prescription:
| Component | Content |
| Oseltamivir phosphate | 3.3％ |
| Sorbitol | 90.6％ |
| Xanthan gum | 0.8％ |
| Titanium dioxide | 1.25％ |
| Monobasic sodium citrate | 2.6％ |
| Sodium benzoate | 1.45％ |
| Add up to | 100.0％ |
Preparation method:
By recipe quantity, take respectively appropriate oseltamivir phosphate and adjuvant, add successively 3.3% oseltamivir phosphate, 90.6% Sorbitol, 1.25% titanium dioxide, 2.6% monobasic sodium citrate, 1.45% sodium benzoate and 0.8% xanthan gum, mix homogeneously, granulator blade rotating speed 150rpm, cutter rotating speed 3000rpm, cross 40 eye mesh screen 3 times, adopt peristaltic pump to add 45% ethanol water to granulate, peristaltic pump rotating speed 50rpm, liquid feeding and pelletization granulator blade rotating speed 150rpm, cutter rotating speed 3000rpm, wet granular is crossed 18 eye mesh screens, approximately 55 ℃, baking oven is dry, after dry end, adopt 30 eye mesh screens to sieve.
Comparative example 3
Prescription:
Preparation method:
19) medicine-containing particle preparation:
By recipe quantity, add respectively 3.7% oseltamivir phosphate, 8.46% mannitol, 35.24% Sorbitol, 1.3% titanium dioxide and 0.5% xanthan gum premix in the pot of granulating even, granulator blade rotating speed 150rpm, cutter rotating speed 3000rpm.Adopt peristaltic pump to add the alcoholic solution of appropriate amount 25% to granulate, peristaltic pump rotating speed 50rpm, liquid feeding and pelletization granulator blade rotating speed 150rpm, cutter rotating speed 3000rpm; Adopt 18 eye mesh screen granulate, pelletizing machine rotating speed 1442rpm; Adopt fluid bed drying, 55 ℃ of inlet temperature, 40 ℃ of temperature of charge, air intake frequency 25Hz.Adopt 30 eye mesh screen granulate, pelletizing machine rotating speed 1442rpm
20) granules of accessories preparation:
By recipe quantity, add respectively 9.3% mannitol, 36.9% Sorbitol, 1.96% sodium citrate, 0.60% monohydrate potassium, 0.8% saccharin sodium dihydrate, 0.54% sodium benzoate and 0.4% xanthan gum premix in granulator, granulator blade rotating speed 150rpm, cutter rotating speed 3000rpm; Adopt peristaltic pump to add the alcoholic solution of appropriate amount 25% to granulate, peristaltic pump rotating speed 50rpm, liquid feeding and pelletization granulator blade rotating speed 150rpm, cutter rotating speed 3000rpm; Adopt 18 eye mesh screen granulate, pelletizing machine rotating speed 1442rpm; Adopt fluid bed drying, 40 ℃ of inlet temperature, 40 ℃ of temperature of charge, air intake frequency 20～25Hz.Adopt again 30 eye mesh screen granulate, pelletizing machine rotating speed 1442rpm.
21) mix medicine-containing particle and granules of accessories
By the peach flavor of the medicine-containing particle of above-mentioned preparation, granules of accessories and 0.3% rotating speed mix homogeneously with 10rpm in tempering tank.
Experimental example 1
In order to examine or check the stability of the prepared oseltamivir phosphate dry suspension of above embodiment 1-12 and comparative example 1-3, the present invention carries out accelerated test investigation with reference to 2010 editions second appendix X IX oseltamivir phosphate of Chinese Pharmacopoeia and pharmaceutical preparation stability test guideline to above-mentioned preparing product.Sampling observation after 0 day and 1st month, detects related substance project.The results are shown in Table 1
Experiment condition:
Embodiment 1-12 and comparative example 1-3 products obtained therefrom are adopted respectively to the encapsulation of HDPE bottle, at 30 ℃, under 65%RH condition, place.
Analyzing and testing condition:
Chromatographic column: Waters Xbridge C8,5 μ m, 4.6mm * 250mm
Detect wavelength: 207nm
Column temperature: 50 ℃
Flow velocity: 1.2mL/min
Sample size: 20 μ L
Running time: about 35min
Rear operation: 3min.
Gradient:
| Time (min) | Mobile phase A, v/v | Mobile phase B, v/v | Mobile phase C, v/v |
| 0～5.0 | 75 | 15 | 10 |
| 5.0～5.1 | 75→60 | 15→30 | 10 |
| 5.1～35 | 60 | 30 | 10 |
Mobile phase A: take potassium dihydrogen phosphate 6.80g, be dissolved in 1L ultra-pure water, mix, with potassium hydroxide, regulate pH to 6.0, with 0.45um water system membrane filtration, ultrasonic and get final product.
Mobile phase B: methanol
Mobile phase C: acetonitrile
Table 1: Accelerated stability test (30 ℃, 65%RH) testing result
Remarks:
ND represents not detect;
Through 1 month accelerated stability, investigate, known
In comparative example 1 and 2, in prescription, use separately sorbitol, as the filler of oseltamivir phosphate dry suspension, the more acceptable adjuvant of other pharmacy in addition.Because the reducing sugar in sorbitol is easy and oseltamivir phosphate reacts, the unknown impuritie of RRT=1.10 can significantly increase, and causes the safety of medication, the assorted also increase to some extent of the not notice of invitation of RRT=1.26 in addition.In comparative example 1 and 2, total mixing reaches respectively 1.07% and 1.08%, has a strong impact on medicine stability.
In comparative example 3, in prescription, use mannitol and sorbitol, wherein the content of sorbitol in the mixture of mannitol-sorbitol is approximately 80%, filler as oseltamivir phosphate dry suspension, the acceptable adjuvant of other pharmacy in addition, and the method preparation that adopts preferred wet method to prepare step by step again.But because the reducing sugar in sorbitol easily reacts with oseltamivir phosphate, the not notice of invitation that the unknown impuritie of RRT=1.10 also can significantly increase to 0.36%, RRT=1.26 is mixed and is also increased to 0.20%.In comparative example 3, total mixing reaches respectively 0.99%, has a strong impact on medicine stability.
In embodiment 1-6, in prescription, use sorbitol and mannitol, the compositions of one or more in maltose alcohol and xylitol, wherein the content of sorbitol in sugar alcohol composite is X, 0%<X≤75% wherein, filler as oseltamivir phosphate dry suspension, the acceptable adjuvant of other pharmacy in addition again, adopt the direct preparation method preparation of powder formulation mixing preparation method or wet method, reducing sugar and the oseltamivir phosphate that can effectively suppress in sorbitol react, the unknown impuritie of RRT=1.10 is obviously controlled, after within one month, accelerating, recruitment is below 0.20%, the not notice of invitation of RRT=1.26 is mixed and is also effectively controlled, and after within one month, accelerating, recruitment is below 0.15%, total assorted being controlled at below 0.7%.Therefore by the preparation method of embodiment 1-6, effectively stablized oseltamivir phosphate dry suspension.
In embodiment 7-12, use one or more the compositions in sorbitol and mannitol, maltose alcohol and xylitol in prescription, wherein the content of sorbitol in sugar alcohol composite is X, wherein 0%<X≤75%; Or use a kind of in mannitol, maltose alcohol or xylitol, as the filler of oseltamivir phosphate dry suspension, the more acceptable adjuvant of other pharmacy in addition, the method preparation that adopts wet method to prepare step by step.Reducing sugar and oseltamivir phosphate that prescription and preparation method by embodiment 7-12 can more effectively reduce in sorbitol react, and the unknown impuritie of RRT=1.10 is obviously controlled, and after within one month, accelerating, recruitment is below 0.10%; The not notice of invitation of RRT=1.26 is mixed and is also effectively controlled, and after within one month, accelerating, recruitment is below 0.05%; Total assorted being controlled at below 0.5%.Therefore, provide the oseltamivir phosphate dry suspension that a kind of stability is more superior.
Described in total upper embodiment, in the present embodiment, use separately the compositions of sorbitol or sorbitol and other sugar alcohols, wherein the content of sorbitol in sugar alcohol is greater than 75% as filler, these filleies easily react with oseltamivir phosphate, cause dry suspension unstable.Adopt a kind of in xylitol, mannitol or maltose alcohol; Or the arbitrary composition in mannitol, maltose alcohol and xylitol; Or one or more the compositions in sorbitol and mannitol, maltose alcohol and xylitol, wherein the content of sorbitol in sugar alcohol composite is X, 0%<X≤75% wherein, filler as oseltamivir phosphate dry suspension is difficult for reacting with oseltamivir phosphate, particularly adopt wet method just to prepare step by step and more can effectively reduce the degree that described filler reacts with oseltamivir phosphate, effectively stablized oseltamivir phosphate dry suspension.
Method of the present invention is described by preferred embodiment, and related personnel obviously can change methods and applications as herein described or suitably change and combination in content of the present invention, spirit and scope, realizes and apply the technology of the present invention.Those skilled in the art can use for reference content herein, suitably improve technological parameter and realize.Special needs to be pointed out is, all similar replacements and change apparent to those skilled in the artly, they are all deemed to be included in the present invention.
Claims (11)
1. an oseltamivir phosphate dry suspension, described dry suspension is comprised of the medicine-containing particle of phosphoric acid Oseltamivir, wherein said medicine-containing particle comprises oseltamivir phosphate, be difficult for filler and other pharmaceutically acceptable adjuvants of reacting with oseltamivir phosphate, the wherein said filler that is difficult for reacting with oseltamivir phosphate is selected from maltose alcohol, xylitol, the compositions of one or more in mannitol and sorbitol, the content of described sorbitol in whole compositions is X, 0%<X≤75% wherein, preferred 0%<X≤40%.
2. an oseltamivir phosphate dry suspension, described dry suspension is comprised of the medicine-containing particle of phosphoric acid Oseltamivir and the granules of accessories of non-phosphoric acid Oseltamivir, and wherein said medicine-containing particle comprises oseltamivir phosphate, difficult filler and other the pharmaceutically acceptable adjuvants reacting with oseltamivir phosphate; Described granules of accessories comprises the difficult filler reacting with oseltamivir phosphate and other pharmaceutically acceptable adjuvants, and the wherein said filler that is difficult for reacting with oseltamivir phosphate is selected from one or more of maltose alcohol, xylitol or mannitol; Or the compositions that is selected from one or more and sorbitol in maltose alcohol, xylitol, mannitol, the content of described sorbitol in whole compositions is X, wherein 0%<X≤75%, preferably 0%<X≤40%.
3. oseltamivir phosphate dry suspension according to claim 1 and 2, wherein said other pharmaceutically acceptable adjuvants comprise one or more in suspending agent, pH adjusting agent, antiseptic and coloring agent.
4. oseltamivir phosphate dry suspension according to claim 3, wherein said suspending agent is selected from xanthan gum, hydroxypropyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidone-K30, gelatin, carboxymethyl starch sodium and hypromellose, preferably xanthan gum; Described pH adjusting agent can be selected from mixture (as mixing of the mixture of citric acid and sodium citrate, monohydrate potassium and sodium citrate), dihydrogen citrate alkali metal salt (as sodium salt, potassium salt), sodium lactate, the sodium succinate of citric acid and hydrate thereof and the acceptable salt of its pharmacy, the mixture of optimization citric acid sodium dihydrogen or monohydrate potassium and sodium citrate; Described antiseptic can be selected from one or more in sorbic acid, potassium sorbate, calcium sorbate, benzoic acid, sodium benzoate, methyl parahydroxybenzoate, ethylparaben, propyl p-hydroxybenzoate, butyl p-hydroxybenzoate, preferred sodium benzoate; Described coloring agent is selected from titanium dioxide.
5. oseltamivir phosphate dry suspension according to claim 4, comprise oseltamivir phosphate approximately 3.0%～5.0%, be difficult for the filler approximately 80.0%～95.0% reacting with oseltamivir phosphate, preferred approximately 85.0%～90.0%, the mixture approximately 80.0%～95.0% of mannitol-sorbitol in certain embodiments, suspending agent approximately 0.01%～5.0%, preferred approximately 0.01%～2.0%, xanthan gum approximately 0.01%～5.0% in certain embodiments, pH adjusting agent approximately 0.01%～5.0%, preferred approximately 0.5%～3.5%, sodium citrate approximately 0.01%～3.5% and monohydrate potassium approximately 0.01%～1.5% in certain embodiments, antiseptic approximately 0.01%～3.0%, preferred approximately 0.01%～1.0%, sodium benzoate approximately 0.01%～3.0% and coloring agent approximately 0.1%～2.5% in certain embodiments, preferred approximately 0.1%～2.0%, titanium dioxide approximately 0.01%～2.5% in certain embodiments, wherein the content of sorbitol in the mixture of mannitol-sorbitol is X, 0%<X≤75% wherein, 0%<X≤40% in certain embodiments.
6. oseltamivir phosphate dry suspension according to claim 2, wherein said medicine-containing particle comprises oseltamivir phosphate approximately 3.0%～5.0%, be difficult for the filler approximately 35.0%～50.0%, suspending agent approximately 0.01%～2.5% and the coloring agent approximately 0.1%～2.5% that react with oseltamivir phosphate; Described granules of accessories comprises difficult filler approximately 35.0%～50.0%, suspending agent approximately 0.01%～2.5%, pH adjusting agent approximately 0.01%～5.0% and the antiseptic approximately 0.01%～3.0% reacting with oseltamivir phosphate; The filler that is wherein difficult for reacting with oseltamivir phosphate is selected from one or more of maltose alcohol, xylitol or mannitol; Or the compositions that is selected from one or more and sorbitol in maltose alcohol, xylitol, mannitol, the content of described sorbitol in whole compositions is X, wherein 0%<X≤75%, preferably 0%<X≤40%.
7. oseltamivir phosphate dry suspension according to claim 6; wherein said granules of accessories also comprises sweeting agent; be selected from one or more in glucide, glycyrrhizic acid, glycyrrhizic acid dipotassium, Stevia rebaudiana (Bertoni) Hemsl extract, saccharin sodium, saccharin sodium dihydrate, aspartame, sucralose, cyclamate; preferred sucralose, glycyrrhizic acid, saccharin sodium, saccharin sodium dihydrate or glycyrrhizic acid dipotassium; the content of sweeting agent in dry suspension is approximately 0.01%～5.0%, preferred approximately 0.1%～2.5%.
8. oseltamivir phosphate dry suspension according to claim 7, also include correctives, be selected from malted maize dextrin, other fragrance materials (as peach flavor, apple essence, flavoring pineapple essence and flavoring banana essence etc.), preferred peach flavor, the content of correctives in dry suspension can be approximately 0.1%～5.0%, preferred approximately 0.1%～1.0%.
9. oseltamivir phosphate dry suspension according to claim 8, wherein said medicine-containing particle comprises oseltamivir phosphate approximately 3.0%～5.0%, maltose alcohol or mannitol approximately 35.0%～50.0%, xanthan gum approximately 0.01%～1.0% and titanium dioxide approximately 0.1%～2.0%; Wherein said granules of accessories comprises maltose alcohol approximately 35.0%～50.0%, xanthan gum approximately 0.01%～1.0%, sodium citrate approximately 0.5%～2.5%, monohydrate potassium approximately 0.1%～1.0%, sodium benzoate approximately 0.01%～1.0% and saccharin sodium dihydrate approximately 0.1%～2.5%; The content of wherein said correctives in dry suspension is approximately 0.1%～1.0%, and correctives is apple essence.
10. oseltamivir phosphate dry suspension according to claim 8, wherein said medicine-containing particle comprises oseltamivir phosphate approximately 3.0%～5.0%, mannitol-sorbitol mixture approximately 35.0%～50.0%, xanthan gum approximately 0.01%～1.0% and titanium dioxide approximately 0.1%～2.0%, wherein the content of sorbitol in the mixture of mannitol-sorbitol is X, wherein 0%<X≤75%; Wherein said granules of accessories comprises mannitol-sorbitol mixture approximately 35.0%～50.0%, xanthan gum approximately 0.01%～1.0%, sodium citrate approximately 0.5%～2.5%, monohydrate potassium approximately 0.1%～1.0%, sodium benzoate approximately 0.01%～1.0% and saccharin sodium dihydrate approximately 0.1%～2.5%, wherein the content of sorbitol in the mixture of mannitol-sorbitol is X, wherein 0%<X≤75%; The content of wherein said correctives in dry suspension is approximately 0.1%～1.0%, and correctives is peach flavor.
11. 1 kinds of wet methods are prepared the method for oseltamivir phosphate dry suspension step by step, comprise the following steps:
1) medicine-containing particle that preparation contains oseltamivir phosphate and suitable adjuvant;
2) preparation does not contain the granules of accessories of oseltamivir phosphate;
3) by the above-mentioned medicine-containing particle making and granules of accessories mix homogeneously;
Wherein said 1) step is that oseltamivir phosphate and suitable adjuvant premixing in granulator is even; Add appropriate 20%-60% alcoholic solution, granulate; Cross screen cloth granulate, and dry on fluid bed, finally cross screen cloth granulate;
Wherein said 2) step is that the premixing in granulator of suitable adjuvant is even; Add appropriate 20%-60% alcoholic solution, granulate; Cross screen cloth granulate, and dry on fluid bed, finally cross screen cloth granulate;
Wherein 1) described suitable adjuvant comprises: be difficult for the filler, suspending agent and the coloring agent that react with oseltamivir phosphate;
Wherein 2) described suitable adjuvant comprises: be difficult for the filler, suspending agent, pH adjusting agent and the antiseptic that react with oseltamivir phosphate;
The wherein said filler that is difficult for reacting with oseltamivir phosphate is selected from one or more of maltose alcohol, xylitol or mannitol; Or the compositions that is selected from one or more and sorbitol in maltose alcohol, xylitol, mannitol, the content of described sorbitol in whole compositions is X, wherein 0%<X≤75%, preferably 0%<X≤40%.
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| CN104784122A (en) * | 2014-01-20 | 2015-07-22 | 广东东阳光药业有限公司 | Benproperine-contained solid preparation |
| WO2016088010A1 (en) * | 2014-12-01 | 2016-06-09 | Lupin Atlantis Holdings Sa | Oseltamivir compositions |
| CN107567332A (en) * | 2015-03-31 | 2018-01-09 | 韩美药品株式会社 | Oral solid formulation containing Oseltamivir and preparation method thereof |
| CN108403642A (en) * | 2018-04-27 | 2018-08-17 | 山西皇城相府药业股份有限公司 | A kind of Erythromycin Ethylsuccinate Suspension and preparation method thereof |
| CN108420792A (en) * | 2018-05-21 | 2018-08-21 | 天津双硕医药科技有限公司 | A kind of combination of oral medication containing Oseltamivir phosphate |
| CN112791054A (en) * | 2021-02-23 | 2021-05-14 | 北京阳光诺和药物研究股份有限公司 | Dry granulation method of dry suspension |
| CN113116827A (en) * | 2019-12-30 | 2021-07-16 | 上海复星星泰医药科技有限公司 | Oseltamivir phosphate granules and preparation method thereof |
| CN113603606A (en) * | 2021-08-25 | 2021-11-05 | 北京睿悦生物医药科技有限公司 | Preparation method of oseltamivir phosphate dry suspension impurity |
| CN113730358A (en) * | 2021-08-25 | 2021-12-03 | 海南海神同洲制药有限公司 | Preparation method of oseltamivir phosphate dry suspension |
| CN116211810A (en) * | 2023-03-21 | 2023-06-06 | 南京海鲸药业股份有限公司 | Preparation method of oseltamium phosphate Wei Ganhun suspension |
| CN117214369A (en) * | 2023-11-09 | 2023-12-12 | 山东百诺医药股份有限公司 | Liquid chromatography method for detecting related substances of oseltamium phosphate Wei Ganhun suspension |
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| CN104784122A (en) * | 2014-01-20 | 2015-07-22 | 广东东阳光药业有限公司 | Benproperine-contained solid preparation |
| WO2016088010A1 (en) * | 2014-12-01 | 2016-06-09 | Lupin Atlantis Holdings Sa | Oseltamivir compositions |
| US20170258749A1 (en) * | 2014-12-01 | 2017-09-14 | Lupin Atlantis Holdings Sa | Oseltamivir Compositions |
| CN107567332B (en) * | 2015-03-31 | 2021-06-01 | 韩美药品株式会社 | Oral solid preparation containing oseltamivir and preparation method thereof |
| CN107567332A (en) * | 2015-03-31 | 2018-01-09 | 韩美药品株式会社 | Oral solid formulation containing Oseltamivir and preparation method thereof |
| CN108403642A (en) * | 2018-04-27 | 2018-08-17 | 山西皇城相府药业股份有限公司 | A kind of Erythromycin Ethylsuccinate Suspension and preparation method thereof |
| CN108403642B (en) * | 2018-04-27 | 2020-12-29 | 山西皇城相府药业股份有限公司 | Erythromycin ethylsuccinate dry suspension and preparation method thereof |
| CN108420792A (en) * | 2018-05-21 | 2018-08-21 | 天津双硕医药科技有限公司 | A kind of combination of oral medication containing Oseltamivir phosphate |
| CN113116827A (en) * | 2019-12-30 | 2021-07-16 | 上海复星星泰医药科技有限公司 | Oseltamivir phosphate granules and preparation method thereof |
| CN113116827B (en) * | 2019-12-30 | 2022-09-23 | 上海复星星泰医药科技有限公司 | Oseltamivir phosphate granules and preparation method thereof |
| CN112791054A (en) * | 2021-02-23 | 2021-05-14 | 北京阳光诺和药物研究股份有限公司 | Dry granulation method of dry suspension |
| CN112791054B (en) * | 2021-02-23 | 2022-02-11 | 北京阳光诺和药物研究股份有限公司 | Dry granulation method of dry suspension |
| CN113603606A (en) * | 2021-08-25 | 2021-11-05 | 北京睿悦生物医药科技有限公司 | Preparation method of oseltamivir phosphate dry suspension impurity |
| CN113730358A (en) * | 2021-08-25 | 2021-12-03 | 海南海神同洲制药有限公司 | Preparation method of oseltamivir phosphate dry suspension |
| CN116211810A (en) * | 2023-03-21 | 2023-06-06 | 南京海鲸药业股份有限公司 | Preparation method of oseltamium phosphate Wei Ganhun suspension |
| CN117214369A (en) * | 2023-11-09 | 2023-12-12 | 山东百诺医药股份有限公司 | Liquid chromatography method for detecting related substances of oseltamium phosphate Wei Ganhun suspension |
| CN117214369B (en) * | 2023-11-09 | 2024-02-02 | 山东百诺医药股份有限公司 | Liquid chromatography method for detecting related substances of oseltamium phosphate Wei Ganhun suspension |
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Application publication date: 20141112 |