CN105878245A - Preparation method of rebamipide aqueous suspension - Google Patents
Preparation method of rebamipide aqueous suspension Download PDFInfo
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- CN105878245A CN105878245A CN201510013954.0A CN201510013954A CN105878245A CN 105878245 A CN105878245 A CN 105878245A CN 201510013954 A CN201510013954 A CN 201510013954A CN 105878245 A CN105878245 A CN 105878245A
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Abstract
The invention discloses a preparation method of a rebamipide aqueous suspension. The preparation method comprises the following steps: (1) dissolving all adjuvant materials in injection water, so that an adjuvant material aqueous solution is obtained; (2) adding rebamipide to the adjuvant material aqueous solution obtained in the step (1), performing crushing and dispersing, so that primary liquid of the rebamipide aqueous suspension is obtained; (3) homogenizing the primary liquid of the rebamipide aqueous suspension under high pressure, so that the aqueous suspension containing the rebamipide is finally obtained; and (4) sterilizing the rebamipide aqueous suspension obtained in the step (3), and sub-packaging the rebamipide aqueous suspension in a sterile environment in containers for clinical use. Compared with the prior art, the preparation method has the advantages that the average grain size of the rebamipide in the rebamipide aqueous suspension prepared by the rebamipide aqueous suspension preparation method disclosed by the invention is less than 1[micron]m; and the grain size cannot change much after high-temperature sterilization and cannot increase after long-term storage.
Description
Technical field
The present invention relates to eye drop field, be exactly the system of a kind of rebamipide water slurry
Preparation Method.
Background technology
Rebamipide (Rebamipide): be a kind of quinolone compounds is odorless and has the white of bitterness
Color crystal powder, atomic is dissolved in methanol and ethanol, is practically insoluble in water, CAS registration number: 90098-04-7.
Rebamipide can improve gastric motility, the stomach causing gastric ulcer, acute gastritis or chronic gastritis acute exacerbation
Mucosa injury has remarkable result.Also have in increasing the effect of ophthalmic goblet cell density, increase eyes glutinous
The effect of liquid and the effect of increase lachrymal gland fluid.
Xerophthalmia is a kind of common chronic ophthalmic, owing to lacking nature tear and eye mucosa liquid, may result in cornea
Damage with conjunctival epithelium.If do not treated, xerophthalmia then has the wind causing corneal ulcer or DE
Danger.
Rebamipide is a kind of mucosa protection agent, and 1999 as gastric ulcer resistance medicine being administered orally first in Japan
City, is approved the most again for treating the mucosal lesion that gastritis causes.It can promote COX-2 (COX2)
Generation and induce the generation of prostaglandin, be also reactive oxygen free radical scavenger.
Rebamipide (Rebamipide) (2-(4-chIorobenzoyIamino)-3-[2 (1H)-quinolyl-4] propanoic acid) has
Having and increase the effect of goblet cell density in cornea and conjunctiva, it increases mucinous yield, and mucin is
A kind of mucus composition and be mucus and lacrimal secretion thing, and therefore, it is possible to protection cornea and conjunctiva or make it steady
Fixed.The clinical trial positive findings carried out in Japan shows, this product can improve cornea-knot caused by xerophthalmia
Membrane damage and subjective symptoms (including having sand sensation and blurred vision in ocular pain, eye).Rebamipide can
Can be more preferable than the therapeutic effect of present artificial tears.Xerophthalmia and some other eye part disease are along with the increasing at age
Growing and engender, therefore the annual whole world about 22,000,000 patients seek the help of professional.
Rebamipide is atomic is dissolved in methanol and ethanol, is practically insoluble in water, is dissolvable in water alkaline aqueous solution.But
The eye drop of high ph-values is not particularly suited for suffering from cornea and conjunctiva (keratoconjunctiva) and damages such as the trouble of xerophthalmia
Person.Even if additionally, in the case of the alkaline solution containing rebamipide, rebamipide crystal the most also can occur
Deposition, it is taken as that the exploitation aqueous ophthalmically acceptable product of rebamipide is difficult.
Rebamipide is to eyes and mucosal tissue irritating little and that malfunction shortcoming is few physiological neutral PH
Not there is in the range of value solubility enough and steady in a long-term, and therefore can not prepare the auspicious of aqueous solution form
Bar sends special dose, because rebamipide is acid compound.On the other hand, it is possible to use surfactant
Such as ionic surfactant and nonionic surfactant or solubilizing agent such as cyclodextrin derivative comes
Prepare rebamipide aqueous solution.But when being administered said preparation, this kind of surfactant and this kind of solubilizing agent can
Can have biotic component in the mucosa being dissolved in this solution and may interfere with the activity of rebamipide, this is
A kind of effect making mucosa stabilisation and protecting mucosa.
At present, it is the most all will to add the high molecular polymerization such as suspensoid, suspending agent after rebamipide superfine grinding
The solution of thing prepares rebamipide water slurry.But the rebamipide water slurry being prepared is average
Particle diameter all ＞ 10 μm, after high temperature sterilize, average particle diameter became is bigger and is layered；During additionally preserving,
Rebamipide fine particle can be gathered into granule or crystal grain increases, and it is thin that the particle of precipitation is not easy redispersion
Grain, instills in eyes and has grains of sand sense, have stimulation, patient to feel uncomfortable.
Summary of the invention
For drawbacks described above, present invention solves the technical problem that and be to provide a kind of rebamipide water slurry
Preparation method, prepared rebamipide water slurry, rebamipide mean diameter ＜ 1 μm, after high temperature sterilize
Change of size is little, and long term storage particle diameter will not increase.
In order to solve above technical problem, the preparation method of the rebamipide water slurry of the present invention, including
Following steps:
(1), all adjuvants are dissolved in water for injection, obtain adjuvant aqueous solution；
(2), by rebamipide add in the adjuvant aqueous solution of step (1) gained, carry out pulverizing and dividing
Dissipate, obtain rebamipide water slurry just liquid；
(3), the rebamipide water slurry of step (2) gained just liquid is carried out high pressure homogenize, finally again
Obtain the water slurry containing rebamipide；
(4) sterilizing, by the rebamipide water slurry of step (3) gained is carried out, more aseptic subpackaged to supplying
In the container of Clinical practice.
Preferably, in step (1), adjuvant used includes suspending agent, osmotic pressure regulator, counter wads a quilt with cotton
Solidifying agent and pH adjusting agent.
Preferably, in step (2), described rebamipide water slurry is to be made in following ratio:
In 100ml water slurry, rebamipide 2.0g, suspending agent 0.1～1.0g, osmotic pressure regulator 0.1-1.0g,
Deflocculant 0.01～0.5, pH adjusting agent 0.01-0.5g, remaining is water for injection.
Preferably, described suspending agent is polyvinylpyrrolidone, polyvinyl alcohol, sodium carboxymethyl cellulose, card
Ripple nurse, poloxamer or Tai Luoshamu.
Preferably, described polyvinylpyrrolidone model is K30 or K90.
Preferably, described osmotic pressure regulator is sodium chloride or potassium chloride.
Preferably, the osmotic pressure of described rebamipide water slurry controls at 260-320mOsm/kg.
Preferably, described deflocculant is dextran sulfate sodium, citric acid, sodium citrate, tartrate, phosphate
Or glycinate.
Preferably, the one during described pH adjusting agent is sodium hydroxide, hydrochloric acid, boric acid, phosphoric acid or sulphuric acid
Or it is multiple.
Preferably, the pH of described rebamipide water slurry controls at 5.0-7.0.
Preferably, in step (2), the instrument used by the just liquid preparation of described rebamipide water slurry is
High speed dispersor, high-speed shearing machine or high speed even breast machine.
Preferably, in the present invention, instrument revolution parameter used by the preparation of rebamipide water slurry just liquid is
10000-20000rmp, the duration of runs is 3-15 minute.
Preferably, in step (3), in described rebamipide water slurry, rebamipide can be with surely
Surely scattered state retains, and wherein rebamipide is broken up into particulate, its mean diameter ＜ 1 μm.
Preferably, in step (3), the sterilization method of described rebamipide water slurry be moist heat sterilization,
Dry heat sterilization or irradiation sterilization.
Preferably, in the present invention, the sterilising temp of rebamipide water slurry is 110-130 DEG C, sterilizing
Time is 5-30 minute.
In step (2), the instrument used by the just liquid preparation of described rebamipide water slurry is high speed dispersion
Machine, high-speed shearing machine or high speed even breast machine.Instrument used by the preparation of rebamipide water slurry just liquid in the present invention
Device revolution parameter is 10000-20000rmp, and the duration of runs is 3-15 minute.
It is 5-15MPa that mesohigh homogenizer low pressure of the present invention arranges parameter.
Mesohigh homogenizer low pressure operation number of times of the present invention is 1-5 time.
It is 50-60MPa that mesohigh homogenizer high pressure of the present invention arranges parameter.
Mesohigh homogenizer high-voltage operation number of times of the present invention is 8-18 time.
Used by the present invention, high pressure homogenizer divides secondary pressure, i.e. low pressure and high pressure.Low pressure energy makes rebamipide water
Suspension particle diameter becomes uniform, and general low pressure arranges ＜ 20MPa, and low pressure reaches 5MPa and just can play a role,
But need to run often.High pressure produces strong shearing, shock and cavitation rebamipide aqueous suspension
Liquid micronization, high voltage parameter scope is generally 30-150MPa, and high pressure reaches 50MPa number of run and closes
Fit and just can make rebamipide mean diameter ＜ 1 μm.
The preparation method of the rebamipide water slurry of the present invention, has following key technology details needs
Note:
1, the use of polyvinylpyrrolidone, not only makes mean diameter ＜ 1 μm of rebamipide, and makes
Water slurry more stable homogeneous, also will not become big through high temperature sterilize particle diameter；
2, the preliminary of rebamipide is pulverized and mixes the preliminary of mixed liquor by high-speed shearing machine, is all system
The water slurry of the stable homogeneous of standby mean diameter ＜ 1 μm is laid a solid foundation；
3, the deep layer of mixed liquor is pulverized and disperses extremely important by high pressure homogenizer, particularly high pressure homogenize pressure
Power sets and plays a decisive role pulverizing and dispersion effect, can ensure that the every a collection of water slurry average particle of preparation
Footpath all ＜ 1 μm, technique is sufficiently stable, and repeatability is the highest.
Compared with prior art, the preparation method of the rebamipide water slurry of the present invention, prepared Rui Bapai
Special water slurry, rebamipide mean diameter ＜ 1 μm, after high temperature sterilize, change of size is little, long term storage
Particle diameter will not increase.
Detailed description of the invention
In order to those skilled in the art better understood when technical scheme provided by the present invention, below knot
Conjunction specific embodiment is illustrated.
This case can be illustrated by below example and be fully understood so that be familiar with this skill
The personage of skill can complete it according to this, and the embodiment of right this case not can be by following and limited
It implements kenel.
Embodiment 1
| Rebamipide | 2.0g |
| PVP K30 | 0.75g |
| Sodium citrate | 0.15g |
| Potassium chloride | 0.2g |
| Sodium chloride | 0.7g |
| Hydrochloric acid | (pH value is adjusted to 6) in right amount |
| Sodium hydroxide | (pH value is adjusted to 6) in right amount |
| Pure water | In right amount |
| Total amount | 100mL |
The preparation method of the rebamipide water slurry that the present embodiment provides, comprises the steps:
(1) prescription requirements is pressed, with the good all adjuvants of electronic balance weighing, by Agitation Tank, by all auxiliary
Material is dissolved in purified water, obtains adjuvant aqueous solution；
(2) inserting in adjuvant aqueous solution by high-speed shearing machine cutting head, open cutter, revolution is adjusted to
12000-16000rmp, limit sheared edge adds rebamipide, and rebamipide is sheared 5-10 minute after adding again,
Obtain rebamipide water slurry just liquid；
(3), after rebamipide water slurry just liquid constant volume and regulation pH, high pressure homogenizer, low pressure are added
8-12MPa homogenizing 2-3 time, high pressure 50-55MPa homogenizing 10-15 time, obtain rebamipide water slurry；
(4) rebamipide water slurry is carried out 121 DEG C of moist heat sterilizations 20-30 minute, more aseptic subpackaged arrive
5-15mL is intended in nonrecoverable plastic containers.
Embodiment 2
| Rebamipide | 2.0g |
| PVP K30 | 0.75g |
| Sodium citrate | 0.15g |
| Potassium chloride | 0.2g |
| Sodium chloride | 0.7g |
| Hydrochloric acid | (pH value is adjusted to 6) in right amount |
| Sodium hydroxide | (pH value is adjusted to 6) in right amount |
| Pure water | In right amount |
| Total amount | 100mL |
The preparation method of the rebamipide water slurry that the present embodiment provides, comprises the steps:
(1) prescription requirements is pressed, with the good all adjuvants of electronic balance weighing, by Agitation Tank,
All adjuvants are dissolved in purified water, obtain adjuvant aqueous solution；
(2) high-speed shearing machine cutting head is inserted in adjuvant aqueous solution, open cutter, turn
Number is adjusted to 12000-16000rmp, and limit sheared edge adds rebamipide, after rebamipide adds
Shear again 5-10 minute, obtain rebamipide water slurry just liquid；
(3), after rebamipide water slurry just liquid constant volume and regulation pH, high pressure homogenizer is added,
Low pressure 8-12MPa homogenizing 2-3 time, high pressure 56-60MPa homogenizing 10-15 time, obtain rebamipide
Water slurry；
(4) rebamipide water slurry is carried out 121 DEG C of moist heat sterilizations 20-30 minute, then
Aseptic subpackaged it is intended in nonrecoverable plastic containers to 5-15mL.
Embodiment 3
| Rebamipide | 2.0g |
| PVP K90 | 0.75g |
| Sodium citrate | 0.15g |
| Potassium chloride | 0.2g |
| Sodium chloride | 0.7g |
| Hydrochloric acid | (pH value is adjusted to 6) in right amount |
| Sodium hydroxide | (pH value is adjusted to 6) in right amount |
| Pure water | In right amount |
| Total amount | 100mL |
Prepare with reference to embodiment 1 method.
Comparative example 1
With reference to embodiment 1 prescription
(1) prescription requirements is pressed, with the good all adjuvants of electronic balance weighing, by Agitation Tank, by all auxiliary
Material is dissolved in purified water, obtains adjuvant aqueous solution.
(2) inserting in adjuvant aqueous solution by high-speed shearing machine cutting head, open cutter, revolution is adjusted to
12000-16000rmp, limit sheared edge adds rebamipide, and rebamipide is sheared 5-10 minute after adding again,
Obtain rebamipide water slurry.
(3) rebamipide water slurry is carried out 121 DEG C of moist heat sterilizations 20-30 minute, more aseptic subpackaged arrive
5-15mL is intended in nonrecoverable plastic containers.
Comparative example 2
| Rebamipide | 2.0g |
| Sodium carboxymethyl cellulose | 0.5g |
| Sodium citrate | 0.15g |
| Potassium chloride | 0.2g |
| Sodium chloride | 0.7g |
| Hydrochloric acid | (pH value is adjusted to 6) in right amount |
| Sodium hydroxide | (pH value is adjusted to 6) in right amount |
| Pure water | In right amount |
| Total amount | 100mL |
Prepare with reference to embodiment 1 method.
Embodiment 1,2,3 and comparative example 1,2 are compared:
High temperature sterilize forward backward averaging particle diameter contrast test
| Embodiment 1 | Embodiment 2 | Embodiment 3 | Comparative example 1 | Comparative example 2 | |
| Mean diameter (μm) before sterilizing | 0.39 | 0.25 | 0.26 | 1.97 | 0.42 |
| Mean diameter (μm) after sterilizing | 0.48 | 0.39 | 0.43 | 5.19 | 2.26 |
Conclusion: embodiment 1-3 sample mean diameter after 121 DEG C of moist heat sterilizations has no notable change, comparative example
1-2 sample mean diameter after 121 DEG C of moist heat sterilizations has significant change.
Long-term stable experiment
By Chinese Pharmacopoeia version annex XIXC crude drug in 2010 and pharmaceutical preparation stability test guideline,
By embodiment 1-3 and comparative example 1-2 finished product, it is placed in the climatic chamber of 25 DEG C/60%RH, carries out steady
Qualitative investigation 36 months, in the 0th, 6,9,12,18,24, sampling in 36 months, entirely examine.Result:
Embodiment 1-3 finished product is placed 36 months under the conditions of 25 DEG C/60%RH, and outward appearance, content, particle diameter etc. are the most not
See notable change；And comparative example 1-2 finished appearance, particle diameter have significant change.
Described above to the disclosed embodiments, makes professional and technical personnel in the field be capable of or uses this
Invention.Multiple amendment to these embodiments will be apparent for those skilled in the art
, generic principles defined herein can without departing from the spirit or scope of the present invention,
Other embodiments realizes.Therefore, the present invention is not intended to be limited to the embodiments shown herein, and
It is to fit to the widest scope consistent with principles disclosed herein and features of novelty.
Claims (13)
1. the preparation method of a rebamipide water slurry, it is characterised in that comprise the steps:
(1), all adjuvants are dissolved in water for injection, obtain adjuvant aqueous solution；
(2), by rebamipide add in the adjuvant aqueous solution of step (1) gained, pulverize and disperse, obtain rebamipide water slurry just liquid；
(3), the rebamipide water slurry of step (2) gained just liquid is carried out high pressure homogenize again, finally obtain the water slurry containing rebamipide；
(4) sterilizing, by the rebamipide water slurry of step (3) gained is carried out, more aseptic subpackaged in the container for Clinical practice.
The preparation method of rebamipide water slurry the most according to claim 1, it is characterised in that in step (1), adjuvant used includes suspending agent, osmotic pressure regulator, deflocculant and pH adjusting agent.
The preparation method of rebamipide water slurry the most according to claim 2, it is characterized in that, in step (2), described rebamipide water slurry is to be made in following ratio: in 100ml water slurry, rebamipide 2.0g, suspending agent 0.1～1.0g, osmotic pressure regulator 0.1-1.0g, deflocculant 0.01～0.5, pH adjusting agent 0.01-0.5g, remaining is water for injection.
The preparation method of rebamipide water slurry the most according to claim 2, it is characterised in that described suspending agent is polyvinylpyrrolidone, polyvinyl alcohol, sodium carboxymethyl cellulose, carbomer, poloxamer or Tai Luoshamu.
The preparation method of rebamipide water slurry the most according to claim 4, it is characterised in that described polyvinylpyrrolidone model is K30 or K90.
The preparation method of rebamipide water slurry the most according to claim 2, it is characterised in that described osmotic pressure regulator is sodium chloride or potassium chloride, it is also possible to be two kinds and share.
The preparation method of rebamipide water slurry the most according to claim 6, it is characterised in that the osmotic pressure of described rebamipide water slurry controls at 260-320mOsm/kg.
The preparation method of rebamipide water slurry the most according to claim 2, it is characterised in that described deflocculant is dextran sulfate sodium, citric acid, sodium citrate, tartrate, phosphate or glycinate.
The preparation method of rebamipide water slurry the most according to claim 2, it is characterised in that described pH adjusting agent is one or more in sodium hydroxide, hydrochloric acid, boric acid, phosphoric acid or sulphuric acid.
The preparation method of rebamipide water slurry the most according to claim 9, it is characterised in that the pH of described rebamipide water slurry controls at 5.0-7.0.
The preparation method of 11. rebamipide water slurries according to claim 1, it is characterised in that in step (2), the instrument used by the just liquid preparation of described rebamipide water slurry is high speed dispersor, high-speed shearing machine or high speed even breast machine.
The preparation method of 12. rebamipide water slurries according to claim 1, it is characterized in that, in step (3), in described rebamipide water slurry, rebamipide can retain with the most scattered state, wherein rebamipide is broken up into particulate, its particle mean size ＜ 1 μm.
The preparation method of 13. rebamipide water slurries according to claim 1, it is characterised in that in step (3), the sterilization method of described rebamipide water slurry is moist heat sterilization, dry heat sterilization or irradiation sterilization.
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| CN201510013954.0A CN105878245B (en) | 2015-01-07 | 2015-01-07 | A kind of preparation method of Rebamipide water slurry |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107349181A (en) * | 2016-05-09 | 2017-11-17 | 四川科伦药物研究院有限公司 | Ophthalmology water slurry containing Rebamipide and PVP and preparation method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103429224A (en) * | 2011-03-24 | 2013-12-04 | 大塚制药株式会社 | Pharmaceutical composition for treating disease in oral cavity comprising rebamipide |
| CN103976946A (en) * | 2014-05-20 | 2014-08-13 | 广州艾格生物科技有限公司 | Rebamipide suspension eye drop containing water soluble high-molecular polymers and preparation method thereof |
-
2015
- 2015-01-07 CN CN201510013954.0A patent/CN105878245B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103429224A (en) * | 2011-03-24 | 2013-12-04 | 大塚制药株式会社 | Pharmaceutical composition for treating disease in oral cavity comprising rebamipide |
| CN103976946A (en) * | 2014-05-20 | 2014-08-13 | 广州艾格生物科技有限公司 | Rebamipide suspension eye drop containing water soluble high-molecular polymers and preparation method thereof |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107349181A (en) * | 2016-05-09 | 2017-11-17 | 四川科伦药物研究院有限公司 | Ophthalmology water slurry containing Rebamipide and PVP and preparation method thereof |
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| CN105878245B (en) | 2017-12-15 |
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