CN106551898A - A kind of Vonoprazan fumarate compositionss and preparation method thereof - Google Patents
A kind of Vonoprazan fumarate compositionss and preparation method thereof Download PDFInfo
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- CN106551898A CN106551898A CN201610714831.4A CN201610714831A CN106551898A CN 106551898 A CN106551898 A CN 106551898A CN 201610714831 A CN201610714831 A CN 201610714831A CN 106551898 A CN106551898 A CN 106551898A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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Abstract
The present invention relates to a kind of Vonoprazan fumarate compositionss and preparation method thereof.The compositionss include Vonoprazan fumarate, solubilizing agent, buffer agent, pH adjusting agent, solvent, wherein, solubilizing agent can dramatically increase Vonoprazan fumarate dissolubility, compositionss good stability, buffer agent and pH adjusting agent, compositionss stability is added to significantly change.Meanwhile, present invention also offers the method for preparing above-mentioned Vonoprazan fumarate compositionss, the method simple economy, it is adaptable to industrialized production.
Description
Technical field
The present invention relates to a kind of Vonoprazan fumarate compositionss, and in particular to a kind of safe and stable containing substituted beta-ring
Vonoprazan fumarate compositionss of dextrin and preparation method thereof, belong to pharmaceutical technology field.
Background technology
Vonoprazan fumarate (Vonoprazan fumarate) once used code name TAK-438, was opened by Japanese Wu Tian companies
A kind of new gastric acid secretion inhibitor sent out, with quick-acting, powerful, lasting gastric acid secretion inhibitory action, and in parietal cell
In the final step of gastric acid secretion, by suppressing K+To H+-K+The combination of-ATP enzyme (proton pump), also has to gastric acid secretion
There is termination in advance.Vonoprazan fumarate is in 2014 in Japanese Initial Public Offering, trade name Takecab.
Vonoprazan fumarate chemical entitled 1- [5- (2- fluorophenyls) -1- (pyridin-3-yl sulfonyl) -1H- pyrroles -
3- yls]-N- methyl methylamine fumaric acid mono-salts, structural formula is as follows：
The listing dosage form of Vonoprazan fumarate is tablet at present, not yet has other dosage forms to disclose.As tablet belongs to mouth
Formulation, for, when dysphagia patients, child, old people's medication, compliance is poor；And for needing the acute of quick acting
Gastritis, patients w ith peptic ulcer disease, tablet do not reach the clinical demand of quick acting, therefore develop new Vonoprazan fumarate medicine agent
Type, such as injection, possess medication demand and are difficult with tablet for administration or reach the patient of curative effect providing therapeutic choice for more
It is significant.
Vonoprazan fumarate is the material for being slightly soluble in water, due to its water solublity it is poor, it is difficult to meet injection to medicine
The demand of dissolubility.Therefore, for the exploitation of injection type has larger challenge.
Prior art CN 201410154778.8 discloses the new type water-solubility acylate of Wo Nuolazan and described water-soluble
Property acylate injection and preparation method thereof, but this kind of new type water-solubility acylate and the active component for having listed
Vonoprazan fumarate is compared, and its effect does not obtain clinical experiment and the support of pharmaceutical practice, does not also have increase fumaric acid to irrigate
Water miscible technological means and effect that Nola praises, and the injection uses 100 DEG C of steam sterilizations 30 minutes, the method is not
Terminal sterilization, does not reach preferably sterilization effect.Therefore, Vonoprazan fumarate water solublity is improved by appropriate method, is opened
Send that to be suitable to the Vonoprazan fumarate compositionss and injection of injecting purposes and preparation method thereof significant.
The content of the invention
Summary of the invention
First aspect present invention provides a kind of compositionss of the Vonoprazan fumarate containing Chagerdβcyclodextrins, the replacement
Beta-schardinger dextrin-can increase Vonoprazan fumarate dissolubility in water.
Second aspect present invention provides a kind of Vonoprazan fumarate injection prepared by first aspect compositionss
Agent, safely and effectively, storage stability is good for the injection, to should not oral special population bring new medication to select, satisfaction urgency
Property gastritis, patients w ith peptic ulcer disease need the clinical demand of quick acting.
Third aspect present invention provides a kind of preparation method of Vonoprazan fumarate injection described in second aspect, the party
Method is simple, can be sterilized using terminal sterilization method, and good stability is safe, is suitable to industrialized production.
Fourth aspect present invention additionally provides a kind of Vonoprazan fumarate transfusion solution and preparation method thereof.
Term is defined
Term "comprising" or " including " are open language, i.e., including the content specified by the present invention, but be not precluded from which
Content in terms of him.
The design parameter of " terminal sterilization method "：Moist heat sterilization, 121 DEG C, 12min to 15min.
In the context of the present invention, regardless of whether using " about " or the wording such as " about ", all numbers being disclosed that
Word is approximation.Each digital numerical value is possible to the conjunction that less than 10% difference or those skilled in the art think occurs
The difference of reason, such as 1%, 2%, 3%, 4% or 5% difference.
Detailed description of the invention
Based on the deficiencies in the prior art, the present invention is through deeply investigation and studies, from Chagerdβcyclodextrins as solubilising
Agent forms clathrate with Vonoprazan fumarate, and one side Chagerdβcyclodextrins increase dissolving of the Vonoprazan fumarate in water
Property, stability of solution is good, and satisfaction is prepared into the dissolubility demand of injection；On the one hand, further prepared by the clathrate
Vonoprazan fumarate injection, bioavailability are high, and rapid-action, safety is good, good to the medication compliance of special population；Separately
On the one hand using the combination of Chagerdβcyclodextrins and Vonoprazan fumarate in the preparation technology of injection, stability of solution
By force, can be sterilized using terminal sterilization method, sterilizing is thorough.
The present invention provides a kind of Vonoprazan fumarate compositionss, containing Vonoprazan fumarate and solubilizing agent, wherein, institute
Solubilizing agent is stated for Chagerdβcyclodextrins, Tween 80, phospholipid, poloxamer or their combination in any.The solubilizing agent can
Increase Vonoprazan fumarate dissolubility in water.
The solubilizing agent in certain embodiments is Chagerdβcyclodextrins.
A kind of compositionss containing Vonoprazan fumarate Yu Chagerdβcyclodextrins, wherein the Chagerdβcyclodextrins are hydroxyl
Propyl-beta-cyclodextrin, sulfobutyl ether-beta-cyclodextrin, hydroxyethyl-β-cyclodextrin, methyl-B-cyclodextrin or their any group
Close.It is HP-β-CD in certain embodiments；It is sulfobutyl ether-beta-cyclodextrin in certain embodiments.
A kind of Vonoprazan fumarate compositionss, wherein, the compositionss are clathrate.
A kind of compositionss containing Vonoprazan fumarate Yu solubilizing agent, which can be prepared into Vonoprazan fumarate liquid
Preparation, the liquid preparation can be but not limited to spray, suspensoid, solution, injection.In certain embodiments, institute
Liquid preparation is stated for injection.
The present invention provides a kind of Vonoprazan fumarate clathrate, containing Vonoprazan fumarate and Chagerdβcyclodextrins,
The Chagerdβcyclodextrins can increase Vonoprazan fumarate dissolubility in water.
A kind of clathrate containing Vonoprazan fumarate Yu Chagerdβcyclodextrins, wherein the Vonoprazan fumarate with
The part by weight of Chagerdβcyclodextrins is 1:1 to 1:20.It is 1 in certain embodiments:3；It is 1 in certain embodiments:5；
It is 1 in some embodiments:10.
A kind of clathrate containing Vonoprazan fumarate Yu Chagerdβcyclodextrins, wherein the Chagerdβcyclodextrins are hydroxyl
Propyl-beta-cyclodextrin, sulfobutyl ether-beta-cyclodextrin, hydroxyethyl-β-cyclodextrin, methyl-B-cyclodextrin or their any group
Close.It is HP-β-CD in certain embodiments；It is sulfobutyl ether-beta-cyclodextrin in certain embodiments.
A kind of clathrate containing Vonoprazan fumarate Yu Chagerdβcyclodextrins, which can be prepared into fumaric acid Wo Nuola
Liquid preparation is praised, the liquid preparation can be but not limited to spray, suspensoid, solution, injection.In some embodiments
In, the liquid preparation is injection.
The present invention provides a kind of Vonoprazan fumarate injection, comprising Vonoprazan fumarate and Chagerdβcyclodextrins.
A kind of Vonoprazan fumarate injection, wherein the Chagerdβcyclodextrins are HP-β-CD, sulphur butyl
Ether-beta-schardinger dextrin-, hydroxyethyl-β-cyclodextrin, methyl-B-cyclodextrin or their combination in any.It is hydroxyl in certain embodiments
Propyl-beta-cyclodextrin；It is sulfobutyl ether-beta-cyclodextrin in certain embodiments.
A kind of Vonoprazan fumarate injection, wherein, the injection is instant liquid infusion agent.
A kind of Vonoprazan fumarate injection, wherein, the weight of the Vonoprazan fumarate is total relative to injection
The ratio of volume is 0.05% to 10% (W/V, g/mL).It is 0.4% in certain embodiments.
A kind of Vonoprazan fumarate injection, wherein, the weight of contained Chagerdβcyclodextrins is relative to injection totality
Long-pending ratio is 0.4% to 20% (W/V, g/mL).It is 0.8% in certain embodiments；It is 1.2% in certain embodiments；
It is 2% in certain embodiments.
A kind of Vonoprazan fumarate injection, wherein the weight ratio of the Vonoprazan fumarate and Chagerdβcyclodextrins
Example is 1:1 to 1:20.It is 1 in certain embodiments:3；It is 1 in certain embodiments:5；It is 1 in certain embodiments:10.
In some embodiments, a kind of Vonoprazan fumarate injection, its also comprising solvent, pH adjusting agent,
Buffer agent.Wherein, described solvent is water.Wherein, the pH adjusting agent comprising hydrochloric acid, acetic acid, sodium hydroxide, dibastic sodium phosphate,
Calcium Carbonate or magnesium hydroxide；In certain embodiments, pH adjusting agent is sodium hydroxide.Wherein, the buffer agent is acetic acid, a water
Citric acid, succinic acid, adipic acid, tartaric acid, ascorbic acid, malic acid, benzoic acid or their combination in any；In some enforcements
In example, described buffer agent is tartaric acid；In certain embodiments, described buffer agent is citric acid monohydrate.
A kind of Vonoprazan fumarate injection, wherein, the ratio of the weight of contained buffer agent relative to injection cumulative volume
Example is 0.1% to 3% (W/V, g/mL).It is 0.4% in certain embodiments.
A kind of Vonoprazan fumarate injection, wherein, the injection pH value range is 3.0 to 9.0, in some enforcements
It is 4.23 in example.
A kind of Vonoprazan fumarate injection, wherein, the injection pH value range is 3.0 to 6.0.
A kind of Vonoprazan fumarate injection, wherein, the injection pH value range is 4.0 to 5.0, in some enforcements
It is 4.14 in example.
In some embodiments, a kind of Vonoprazan fumarate injection, which includes：
1) Vonoprazan fumarate 0.05%-10%；
2) HP-β-CD 0.4%-20%；
3) citric acid monohydrate 0.1%-3%；
4) NaOH is appropriate；
5) purified water.
In some embodiments, a kind of Vonoprazan fumarate injection, which includes：
1) Vonoprazan fumarate 0.05%-10%；
2) HP-β-CD 0.4%-20%；
3) tartaric acid 0.1%-3%；
4) NaOH is appropriate；
5) purified water.
In some embodiments, a kind of Vonoprazan fumarate injection, which includes：
1) Vonoprazan fumarate 0.05%-10%；
2) sulfobutyl ether-beta-cyclodextrin 0.4%-20%；
3) citric acid monohydrate 0.1%-3%；
4) NaOH is appropriate；
5) purified water.
In some embodiments, a kind of Vonoprazan fumarate injection, which includes：
1) Vonoprazan fumarate 0.05%-10%；
2) sulfobutyl ether-beta-cyclodextrin 0.4%-20%；
3) tartaric acid 0.1%-3%；
4) NaOH is appropriate；
5) purified water.
Present invention also offers a kind of preparation method of above-mentioned Vonoprazan fumarate injection, methods described include by
Buffer agent, Chagerdβcyclodextrins are dissolved in purified water, adjust pH to 4.0-5.0 using pH adjusting agent, add fumaric acid Wo Nuola
Praise, after stirring and dissolving, add purified water constant volume, the whole solution ph of measurement, bottling to jump a queue, roll lid, terminal sterilization.
In some embodiments, above-mentioned Vonoprazan fumarate injection can be prepared in accordance with the following methods：
1) buffer agent of recipe quantity is dissolved in the purified water of recipe quantity 50%-90%, forms buffer solution；
2) Chagerdβcyclodextrins of recipe quantity are added in buffer solution, is stirred to being completely dissolved, is adjusted using pH adjusting agent
Section pH to 4.5；
3) Vonoprazan fumarate is added in system, after stirring and dissolving, add purified water constant volume, and measure whole pH value of solution
Value；
4) bottle, jump a queue, roll lid, 121 DEG C, 12min-15min terminal sterilizations.
On the other hand, the present invention provides a kind of Vonoprazan fumarate transfusion solution.
A kind of Vonoprazan fumarate transfusion solution, wherein, the weight of the Vonoprazan fumarate is relative to transfusion
The ratio of agent cumulative volume is 0.005% to 10% (W/V, g/mL).It is 0.0107% in certain embodiments；In some embodiments
In be 0.053%；It is 0.0053% in certain embodiments.
A kind of Vonoprazan fumarate transfusion solution, comprising Vonoprazan fumarate and buffer agent, wherein, the buffering
Agent is acetic acid, citric acid monohydrate, succinic acid, adipic acid, tartaric acid, ascorbic acid, malic acid, benzoic acid or their any group
Close.In certain embodiments, the buffer agent is tartaric acid.
A kind of Vonoprazan fumarate transfusion solution, wherein, the weight of contained buffer agent is total with solution relative to transfusion
The ratio of volume is 0.001% to 3% (W/V, g/mL).It is 0.0053% in certain embodiments；It is in certain embodiments
0.053%.
A kind of Vonoprazan fumarate transfusion solution, which also includes isoosmotic adjusting agent.Wherein, the isoosmotic adjusting agent is
Sodium Chloride, glucose, Mannitol, Sorbitol, glycerol etc..In certain embodiments, isoosmotic adjusting agent is Sodium Chloride；In some realities
Apply in example, isoosmotic adjusting agent is glucose.Wherein, adjust solution infiltration 260mosm/L is depressed into 320mosm/L.
A kind of Vonoprazan fumarate transfusion solution, wherein, the transfusion solution ph scope is 3.0 to 6.0.
It is 4.5 in some embodiments.
Present invention also offers a kind of preparation method of Vonoprazan fumarate transfusion solution, methods described include by etc.
Ooze regulator to be dissolved in purified water, add Vonoprazan fumarate, buffer agent, after stirring and dissolving, pH is adjusted using pH adjusting agent
To 3.0-6.0, purified water constant volume, the whole solution ph of measurement are added.
In some embodiments, above-mentioned Vonoprazan fumarate transfusion solution can be prepared in accordance with the following methods：
1) isoosmotic adjusting agent of recipe quantity is dissolved in the purified water of recipe quantity 50%-90%；
2) buffer agent of recipe quantity, stirring and dissolving are added；
3) Vonoprazan fumarate is added in system, after stirring and dissolving, adjust pH to 4.5 using pH adjusting agent；
4) purified water constant volume is added, and measures whole solution ph.
The Vonoprazan fumarate compositionss that the present invention is provided can increase dissolubility of the Vonoprazan fumarate in water,
Satisfaction is prepared into the demand of injection, and can be sterilized using terminal sterilization method, and sterilizing is thorough, improves injection safety；
The Vonoprazan fumarate injection of offer, is a kind of new dosage form, can meet fast for acute gastritiss, patients w ith peptic ulcer disease needs
The clinical demand that speed works, and an administration difficult problem for dysphagia patients, safe, good stability can be solved；The preparation of offer
Method is simple, is suitable to industrialized production.
The Vonoprazan fumarate transfusion solution that the present invention is provided, preparation method are simple, are suitable to industrialized production.
Specific embodiment
In order that those skilled in the art more fully understands technical scheme, some are disclosed further below non-
The present invention is described in further detail to limit embodiment.
Reagent used in the present invention can be buied from the market or can be by method system described in the invention
It is standby and obtain.
In the present invention, min represents minute, and h represents hour, and mg represents milligram, and g represents gram that mL represents milliliter, and W represents weight
Amount, V represent volume.
Embodiment 1：Using HP-β-CD (HP- β-CD) solubilising Vonoprazan fumarate.
The purified water of certain volume (accounting for the 75% of solution final volume) is added in beaker, hydroxy propyl-Beta-ring paste is added
Essence, is stirred dissolving with magnetic stirring apparatuss；After HP-β-CD dissolving, Vonoprazan fumarate, stirring, mesh are added
Vonoprazan fumarate dissolving situation is surveyed, is stirred to Vonoprazan fumarate and is completely dissolved；Purified water is added to be settled to 20mL.It is right
Solution carries out short-term stability Journal of Sex Research, and (stability places condition for sample is positioned over 40 DEG C of certain hours first, then sample is put
It is placed in 60 DEG C of certain hours).Prescription is shown in Table 1-1.
Table 1-1
1 result of embodiment：After stirring 20min, API is completely dissolved.Short-term stability result of study confirms that the solution is 40
DEG C place 80h, then by solution in 60 DEG C place 72h, solution remained stable.Results of stability is shown in Table 1-2.
Table 1-2
1 conclusion of embodiment：HP- β-CD are 10 with API mass ratioes：When 1, can effective solubilization API；And the solution for obtaining is 40
60 DEG C are continued at after DEG C placing 80 hours place and keep within 72 hours stable.
Embodiment 2：HP- β-CD solubilising the Vonoprazan fumarates of different amounts.
The purified water of certain volume (accounting for the 75% of solution final volume) is separately added into in two beakers, is separately added into not
With the HP- β-CD of consumption, dissolving is stirred with magnetic stirring apparatuss；After HP- β-CD dissolvings, Vonoprazan fumarate is added, is stirred
Mix, range estimation Vonoprazan fumarate dissolving situation is stirred to Vonoprazan fumarate and is completely dissolved；Purified water is added to be settled to
20mL.Prescription is shown in Table 2-1,2-2.
Table 2-1
Table 2-2
2 result of embodiment：When HP- β-CD consumptions are 240mg, i.e., it is 3 with API mass ratioes：When 1, API add to HP- β-
In CD solution, 60min is stirred, API is completely dissolved；When HP- β-CD consumptions are 400mg, i.e., it is 5 with API mass ratioes：When 1, API
Add into HP- β-CD solution, stir 20min, API is completely dissolved.
2 conclusion of embodiment：HP- β-CD are down to 3 with API ratios：1 remains to effective solubilization API.
Embodiment 3：Solubilization of the HP- β-CD to Vonoprazan fumarate in different buffer solution.
The purified water of certain volume (accounting for the 75% of solution final volume) is separately added into in two beakers, prescription is added
The citric acid monohydrate or tartaric acid of amount, magnetic stirrer dissolving, adjusts pH to 4.5 with 2% (w/w) NaOH solution；Add
HP- β-CD, magnetic stirrer dissolving；Vonoprazan fumarate, magnetic stirrer is added to estimate fumaric acid Wo Nuola
Dissolving situation is praised, is stirred to Vonoprazan fumarate and is completely dissolved；20mL, and pH value determination are settled to purified water.Prescription is shown in
Table 3-1,3-2.Solution short-term stability is studied (stability place condition for first by sample be positioned over 40 DEG C one timing
Between, then sample is positioned over into 60 DEG C of certain hours).
Table 3-1
Table 3-2
3 result of embodiment：Stirring 60min, API are dissolved completely in solution.Two sample end solution ph are respectively
4.22 with 4.23；Primary stability result of study shows that two solution place 24h at 40 DEG C, then at 60 DEG C of placement 24h, solution
In relevant content of material be basically unchanged.Relevant content of material is shown in Table 3-3,3-4.
3 conclusion of embodiment：HP- β-CD are 3 with API mass ratioes：When 1, the energy effective solubilization API in different buffer solution,
Buffer agent is had no significant effect to rate of dissolution；The solution of acquisition places 24h at 40 DEG C, 24h is placed then at 60 DEG C and keeps stable.
The table 3-3 β-CD of HP- containing citric acid monohydrate Vonoprazan fumarates (3：1) solution (pH4.22) stability data
The table 3-4 β-CD of HP- containing tartaric acid Vonoprazan fumarates (3：1) solution (pH4.23) stability data
Embodiment 4：Solubilization of the HP- β-CD to Vonoprazan fumarate in different buffer solution.
The purified water of certain volume (accounting for the 75% of solution final volume) is separately added into in four beakers, is separately added into not
With the HP- β-CD or tartaric acid or citric acid monohydrate of consumption, dissolving is stirred with magnetic stirring apparatuss；Tartaric acid or a water Fructus Citri Limoniae
PH value is adjusted to 4.5 with 2% (w/w) NaOH after acid dissolving；After HP- β-CD dissolvings, Vonoprazan fumarate, stirring, mesh are added
Vonoprazan fumarate dissolving situation is surveyed, is stirred to Vonoprazan fumarate and is completely dissolved；Purified water is added to be settled to 20mL, and
The whole solution ph of measurement.Prescription is shown in Table 4-1 and 4-2.
Table 4-1
Table 4-2
Embodiment 5：Sulfobutyl ether-beta-cyclodextrin (SBE- β-CD) solubilising Vonoprazan fumarate
The purified water of certain volume (accounting for the 75% of solution final volume) is separately added into in two beakers, is separately added into not
With the SBE- β-CD of consumption, dissolving is stirred with magnetic stirring apparatuss；After SBE- β-CD dissolvings, Vonoprazan fumarate is added,
Stirring, range estimation Vonoprazan fumarate dissolving situation, stirs to Vonoprazan fumarate and is completely dissolved；Purified water is added to be settled to
20mL.Prescription is shown in Table 5-1,5-2.
Table 5-1
Table 5-2
5 result of embodiment：When SBE- β-CD consumptions are 240mg, i.e., it is 3 with API mass ratioes：When 1, API is added to SBE-
In β-CD solution, 60min is stirred, API is completely dissolved；When SBE- β-CD consumptions are 400mg, i.e., it is 5 with API mass ratioes：When 1,
API is added into SBE- β-CD solution, stirs 20min, and API is completely dissolved.
5 conclusion of embodiment：When SBE- β-CD are 3 with API mass ratioes：1 and during the above, can effective solubilization API.
Embodiment 6：Solubilization of the SBE- β-CD to Vonoprazan fumarate in different buffer solution.
The purified water of certain volume (accounting for the 75% of solution final volume) is separately added into in two beakers, prescription is added
The citric acid monohydrate or tartaric acid of amount, magnetic stirrer dissolving, adjusts pH to 4.5 with 2% (w/w) NaOH solution；Add
SBE- β-CD, magnetic stirrer dissolving；Add Vonoprazan fumarate, magnetic stirrer, the fertile promise of range estimation fumaric acid
La Zan dissolves situation, stirs to Vonoprazan fumarate and is completely dissolved；20mL, and pH value determination are settled to purified water.Prescription
It is shown in Table 6-1,6-2.Solution short-term stability is studied (stability place condition for first by sample be positioned over 40 DEG C one timing
Between, then sample is positioned over into 60 DEG C of certain hours).
Table 6-1
Table 6-2
6 result of embodiment：Stirring 60min, API are dissolved completely in solution.Two sample end solution ph are respectively
4.14 (citric acid monohydrate) and 4.21 (tartaric acid)；Primary stability result of study shows that two solution place 24h at 40 DEG C,
Then at 60 DEG C of placement 24h, in solution, relevant content of material is basically unchanged.Relevant content of material is shown in Table 6-3,6-4.
6 conclusion of embodiment：SEB- β-CD are 3 with API mass ratioes：When 1, the energy effective solubilization API in different buffer solution,
And rate of dissolution is had no significant effect；The solution of acquisition places 24h at 40 DEG C, 24h is placed then at 60 DEG C and keeps stable.
Table 6-3 β-CD Vonoprazan fumarate solution (pH4.14) stability datas of SBE- containing citric acid monohydrate
Table 6-4 β-CD Vonoprazan fumarate solution (pH4.21) stability datas of SBE- containing tartaric acid
Embodiment 7：Stability of the SBE- β-CD Vonoprazan fumarates solution to sterilising conditions.
The purified water of certain volume (accounting for the 75% of solution final volume) is added in four beakers, different use are separately added into
SBE- β-the CD of amount or tartaric acid or citric acid monohydrate, are stirred dissolving with magnetic stirring apparatuss；Tartaric acid or citric acid monohydrate
PH value is adjusted to 4.5 with 2% (w/w) NaOH after dissolving；After SBE- β-CD dissolvings, Vonoprazan fumarate, stirring, range estimation are added
Vonoprazan fumarate dissolves situation, stirs to Vonoprazan fumarate and is completely dissolved；Purified water is added to be settled to target end body
Product, and measure whole solution ph.High-pressure steam sterilizing pan is sterilized, and sterilising conditions are 121 DEG C, 12min.Prescription is shown in Table 7-1
To 7-5.
Table 7-1 (No. 01)
Table 7-2 (No. 02)
Table 7-3 (No. 03)
Table 7-4 (No. 04)
Table 7-5 (No. 05)
7 result of embodiment：Before and after low concentration sample and enriched sample sterilizing, solution is clear, colourless solution.
After sterilizing, in solution, relevant content of material slightly increases；SBE- β-CD consumptions and buffer species are to relevant content of material in solution
Have no significant effect.Relevant content of material is shown in Table 7-5.
Table 7-6
7 conclusion of embodiment：5 prescription sample solutions kept stable after 121 DEG C of sterilizing 12min.
Embodiment 8：SBE- β-CD Vonoprazan fumarate solution Journal of Sex Research steady in a long-term
The purified water of certain volume (accounting for the 75% of solution final volume) is separately added into in two beakers, place is separately added into
SBE- β-the CD of side's amount, are stirred dissolving with magnetic stirring apparatuss；Tartaric acid stirring and dissolving is added in 02；Add the fertile promise of fumaric acid
La Zan, stirring, range estimation Vonoprazan fumarate dissolving situation are stirred to Vonoprazan fumarate and are completely dissolved；With 2% (w/w)
Sample solution 01,02 is adjusted pH value to 4.5 by NaOH solution；Add purified water to be settled to 60mL, and measure whole solution ph.It is high
Pressure steam sterilization pan is sterilized, and sterilising conditions are 121 DEG C, 15min.After sterilizing, sample is positioned under the conditions of 40 DEG C, respectively at
The relevant material situation of change of 1,3,6 months detection samples.Prescription is shown in Table 8-1,8-2.
Table 8-1 (No. 01)
Table 8-2 (No. 02)
8 experimental result of embodiment：
Table 8-3
Two samples are placed 6 months in 40 DEG C of conditions, impurity content only marginal increase.
8 conclusion of embodiment：SBE- β-CD Vonoprazan fumarate solution long-time stability are good.
Embodiment 9：Vonoprazan fumarate transfusion is prepared with solution
The purified water of certain volume (accounting for the 75% of solution final volume) is separately added into in two beakers, place is separately added into
The Sodium Chloride or glucose of side's amount, is stirred dissolving with magnetic stirring apparatuss；Add recipe quantity tartaric acid stirring and dissolving；Add rich
Horse acid Wo Nuolazan, stirring, range estimation Vonoprazan fumarate dissolving situation are stirred to Vonoprazan fumarate and are completely dissolved；With
Sample solution is adjusted pH value to 4.5 by 2% (w/w) NaOH solution；Add purified water to be settled to target final volume, and measure molten eventually
Liquid pH value.
Table 9-1 (No. 01)
Table 9-2 (No. 02)
Table 9-3 (No. 03)
Table 9-4 (No. 04)
9 experimental result of embodiment：In four samples Vonoprazan fumarate stirring half an hour after dissolve, acquisition it is molten
Liquid clear, it is colourless；Solution can moist heat sterilization or filtration sterilization.
By the above results as can be seen that embodiment 1- embodiment 7 prepares the fertile promise of fumaric acid using replacement-beta-schardinger dextrin-respectively
Compositionss or injection are praised in drawing, and in stability experiment, single miscellaneous and total miscellaneous content is basically unchanged, in influence factor's experiment, single
Miscellaneous and total miscellaneous only slight increase, variation tendency be not obvious, even across high pressure steam sterilization, single miscellaneous and total miscellaneous before and after sterilizing
Changes of contents is also less, meets the impurity content control standard of injection.Draw from stability experiment interpretation of result, it is of the invention
Dissolubility and stability of solution that Vonoprazan fumarate compositionss or injection have had.
The method of the present invention is described by preferred embodiment, related personnel substantially can present invention,
Method described herein and application are modified in spirit and scope or suitably change and combine, realize and apply the present invention
Technology.Those skilled in the art can use for reference present disclosure, be suitably modified technological parameter realization.Specifically, institute
There is similar replacement and change apparent to those skilled in the art, they are considered as being included in the present invention
It is interior.
In the description of this specification, reference term " one embodiment ", " some embodiments ", " some embodiments ",
" some embodiments ", " example ", " specific example ", or the description of " some examples " etc. mean to retouch with reference to the embodiment or example
Specific features, structure, material or the feature stated is contained at least one embodiment or example of the present invention.In this specification
In, what the schematic representation of above-mentioned term was not necessarily referring to is identical embodiment or example.And, the specific features of description,
Structure, material or feature can be combined in any one or more embodiments or example in an appropriate manner.Additionally, in not phase
Mutually in the case of contradiction, those skilled in the art can be by the different embodiments or example and difference described in this specification
The feature of embodiment or example is combined and combines.
Although embodiments of the invention have been shown and described above, it is to be understood that above-described embodiment is example
Property, it is impossible to limitation of the present invention is interpreted as, one of ordinary skill in the art within the scope of the invention can be to above-mentioned
Embodiment is changed, changes, replacing and modification.
Claims (14)
1. a kind of compositionss, comprising Vonoprazan fumarate and solubilizing agent, wherein, the solubilizing agent is Chagerdβcyclodextrins, tells
Temperature 80, phospholipid, poloxamer or their combination in any.
2. compositionss according to claim 1, wherein, the Chagerdβcyclodextrins are HP-β-CD, sulphur butyl
Ether-beta-schardinger dextrin-, hydroxyethyl-β-cyclodextrin, methyl-B-cyclodextrin or their combination in any.
3. a kind of Vonoprazan fumarate clathrate, containing Vonoprazan fumarate and Chagerdβcyclodextrins, wherein, the replacement
Beta-schardinger dextrin-be HP-β-CD, sulfobutyl ether-beta-cyclodextrin, hydroxyethyl-β-cyclodextrin, methyl-B-cyclodextrin or it
Combination in any.
4. clathrate according to claim 3, which is further prepared into Vonoprazan fumarate liquid preparation.
5. a kind of Vonoprazan fumarate injection, which includes Vonoprazan fumarate and Chagerdβcyclodextrins, wherein, it is described to take
For beta-schardinger dextrin-be HP-β-CD, sulfobutyl ether-beta-cyclodextrin, hydroxyethyl-β-cyclodextrin, methyl-B-cyclodextrin or
Their combination in any.
6. injection according to claim 5, wherein, the injection is instant liquid infusion agent.
7. injection according to claim 5, wherein, the weight of the Vonoprazan fumarate is relative to injection totality
Long-pending ratio is 0.05% to 10%.
8. injection according to claim 5, wherein, the weight of the Chagerdβcyclodextrins is relative to injection cumulative volume
Ratio be 0.4% to 20%.
9. injection according to claim 5, wherein, the weight ratio of Vonoprazan fumarate and the Chagerdβcyclodextrins
Example is 1:1 to 1:20.
10., according to the arbitrary described injection of claim 5-9, which further includes pH adjusting agent, buffer agent and solvent, its
In, the pH adjusting agent is hydrochloric acid, acetic acid, sodium hydroxide, dibastic sodium phosphate, Calcium Carbonate or magnesium hydroxide, and the buffer agent is second
Acid, citric acid monohydrate, succinic acid, adipic acid, tartaric acid, ascorbic acid, malic acid, benzoic acid or their combination in any.
11. injections according to claim 5, its pH value are 3.0 to 9.0.
12. injections according to claim 10, wherein, the weight of the buffer agent is relative to the cumulative volume of injection
Ratio is 0.1% to 3%.
13. injections according to claim 5, comprising sulfobutyl ether-beta-cyclodextrin, citric acid monohydrate, sodium hydroxide and
Purified water, or include HP-β-CD, citric acid monohydrate, sodium hydroxide and purified water.
A kind of 14. methods for preparing injection described in any one of claim 5-13, which includes：
1) purified water of certain volume is added in container, the buffer agent of recipe quantity, stirring and dissolving is added；
2) pH to 4.0 to 5.0 is adjusted with pH adjusting agent；
3) Chagerdβcyclodextrins, stirring and dissolving are added；
4) Vonoprazan fumarate is added, stirs to Vonoprazan fumarate and be completely dissolved；
5) use purified water constant volume；
6) solution in 5) is sterilized, sterilising conditions are 121 DEG C, 12～15min.
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| WO2018133009A1 (en) * | 2017-01-19 | 2018-07-26 | 广东东阳光药业有限公司 | Vonoprazan fumarate composition and preparation method thereof |
| CN113350271A (en) * | 2020-03-04 | 2021-09-07 | 广东东阳光药业有限公司 | Composition of proton pump inhibitor and preparation method thereof |
| CN113827574A (en) * | 2021-10-18 | 2021-12-24 | 沈阳药科大学 | Vonoprazan fumarate oral instant tablet and preparation method thereof |
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