CN108158983B - A kind of sodium hyaluronate eye drops and preparation method thereof - Google Patents
A kind of sodium hyaluronate eye drops and preparation method thereof Download PDFInfo
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- CN108158983B CN108158983B CN201810045146.6A CN201810045146A CN108158983B CN 108158983 B CN108158983 B CN 108158983B CN 201810045146 A CN201810045146 A CN 201810045146A CN 108158983 B CN108158983 B CN 108158983B
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- sodium hyaluronate
- eye drops
- water
- butylene glycol
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Classifications
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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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
- A61K31/728—Hyaluronic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- 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
- A61K9/0048—Eye, e.g. artificial tears
Abstract
The present invention relates to a kind of sodium hyaluronate eye drops and preparation method thereof, sodium hyaluronate eye drops disclosed in this invention include following component：Sodium hyaluronate 0.05 1.0% (w/v), 1,3 butanediols 0.2 1.5% (w/v) and water, 1,3 butanediols are matched with sodium hyaluronate under certain composition ratio, very low concentration has preferable bacteriostasis, and be conducive to be promoted the stability of sodium hyaluronate, stabilizer need not be added again, sodium hyaluronate eye drops can be made to have good stability at normal temperatures, sodium hyaluronate eye drops ingredient disclosed in this invention is simple, can multi-dose packing, stability is good, irritation is low, works well, and has certain market advantage.
Description
Technical field
Invention is related to a kind of eye drops and preparation method thereof containing sodium hyaluronate.
Background technology
Xerophthalmia (DryEye) i.e. angle xerosis of conjunctiva refers to tear matter caused by any reason or amount exception or dynamics
It is abnormal, cause tear film stability to decline, and with ophthalmic uncomfortable or the general name of a variety of diseases of ocular lesion tissue feature.Dry eyes
Growth trend year by year is also presented in incidence of the disease in China.
Sodium hyaluronate also known as Sodium Hyaluronate (SodiumHyaluronate, HA-Na) are by cockscomb extraction method or microorganism
The acid mucopolysaccharide macromolecular that fermentation method obtains is a kind of high viscoplasticity, has the large biological molecule of fabulous biocompatibility, its energy
It is enough obviously prolonged breakup time of tear film, has good protective effect to cornea conjunctiva.Sodium hyaluronate is that a kind of macromolecular is viscous more
Sugar causes molecular weight to reduce under the influence of some physics and chemical factor, should not long-term preservation at room temperature, meanwhile, be also conducive to
Bacterial growth is prepared into after eye drops repeatedly drips use and is easily contaminated long bacterium.To solve this problem, or in sodium hyaluronate eye drops
Middle addition bacteriostatic agent, the multi-dose sodium hyaluronate eye drops of such as Japanese Santen Pharmaceutical Co. Ltd.'s exploitation, the 0.1% of bacteriostatic agent
HA-Na5ml；Or unit dose package is used, the 0.1% and 0.3%HA- without preservative of such as Japanese Santen Pharmaceutical Co. Ltd.
Na0.4ml；Or special sterile device is used, such as the sea dew sodium hyaluronate eye drip of URSAPHARM Arzneimittel GmbH
Liquid 0.1%HA-Na 10ml.Sodium hyaluronate eye drops containing common bacteriostatic agent are unsuitable for being used for a long time, because bacteriostatic agent is long
Phase application can reduce cornea and conjunctiva epithelial cell existence activity, cause angle conjunctival damage, and can cause inflammation, be not particularly suited for quick
Touching group；Using single dose packing or the sodium hyaluronate eye drops of the not bacteriostatic agent of sterile device, production cost undoubtedly can be big
Width increases.
Invention content
The technical problem to be solved in the present invention is to provide a kind of multi-dose sodium hyaluronate eye drips without using conventional bacteriostatic agent
Liquid, the eye drops ingredient is simple, and cost is relatively low, and stability is good, and irritation is low, works well.
In order to solve the above technical problems, the invention discloses a kind of sodium hyaluronate eye drops, it includes following components：Glass
Glass acid sodium 0.05-1.0% (w/v), 1,3 butylene glycol 0.2-1.5% (w/v) and water.
Preferably comprise following component：Sodium hyaluronate 0.06-0.5% (w/v), 1,3 butylene glycol 0.3-0.8% (w/v) and
The water of surplus.
It more preferably include following component：Sodium hyaluronate 0.1% (w/v), 1,3 butylene glycol 0.5% (w/v) and surplus
Water.
Sodium hyaluronate eye drops disclosed in this invention can also add osmotic pressure regulator, the osmotic pressure regulator
It is one or more in sodium chloride, mannitol, glycerine.
It is preferred that prescription is：Sodium hyaluronate 0.1% (w/v), 1,3 butylene glycol 0.4% (w/v), glycerine 0.2% (w/v) and remaining
The water of amount.
Following steps preparation can be used in sodium hyaluronate eye drops disclosed in this invention：A. sodium hyaluronate, 1,3- fourths are weighed
The 3/5-4/5 of glycol addition water total amount is settled to water total amount after being stirred, and obtains liquid；B. liquid obtained by step a is passed through
0.22-0.45 μm of filtering with microporous membrane；C. liquid obtained by step b is dispensed, pressure sterilizing to obtain the final product；
The safety of 1,3-BDO is worth affirmative, and the moisturizer and solvent frequently as cosmetics use, to the mucous membrane of people
It has no stimulation with skin, in terms of moisturizing, since butanediol is small molecule moisturizing composition, so grabbing water ratio very little, this hair
Bright researcher has been surprisingly found that 1,3-BDO is matched with sodium hyaluronate under certain composition ratio, and very low concentration has
Preferable bacteriostasis, and be conducive to be promoted the stability of sodium hyaluronate, stabilizer need not be added again, you can make Hyaluronic Acid
Sodium eye drops has good stability at normal temperatures.Therefore, sodium hyaluronate eye drops ingredient disclosed in this invention is simple, can multi-dose
Packing, stability is good, and irritation is low, works well, and has certain market advantage.
Specific implementation mode
The above of the present invention is described in further detail again below by way of specific embodiment.But this should not be managed
Solution is limited only to example below for the range of the above-mentioned theme of the present invention.The case where not departing from above-mentioned technological thought of the invention
Under, the various replacements or change made according to ordinary skill knowledge and customary means should all be included in the model of the present invention
In enclosing.
Embodiment 1
Prescription：
| Material forms | Prescription matches |
| Sodium hyaluronate | 1.0g |
| 1,3 butylene glycol | 8.0g |
| Water | It is settled to 1000ml |
Preparation method：A. sodium hyaluronate is weighed, 1,3 butylene glycol is added water for injection 600ml (60-70 DEG C of temperature) and stirs
After mixing plus water is settled to 1000ml, obtains liquid；B. by liquid obtained by step a through 0.22 μm of filtering with microporous membrane；C. by step b
Gained liquid dispenses, and pressure sterilizing to obtain the final product.
Embodiment 2
Prescription：
| Material forms | Prescription matches |
| Sodium hyaluronate | 10.0g |
| 1,3 butylene glycol | 2.0g |
| Water | It is settled to 1000ml |
Preparation method：A. sodium hyaluronate is weighed, 1,3 butylene glycol is added water for injection 700ml (60-70 DEG C of temperature) and stirs
After mixing plus water is settled to 1000ml, obtains liquid；B. by liquid obtained by step a through 0.45 μm of filtering with microporous membrane；C. by step b
Gained liquid dispenses, and pressure sterilizing to obtain the final product.
Embodiment 3
Prescription：
| Material forms | Prescription matches |
| Sodium hyaluronate | 1.0g |
| 1,3 butylene glycol | 5.0g |
| Water | It is settled to 1000ml |
Preparation method：A. sodium hyaluronate is weighed, 1,3 butylene glycol is added water for injection 650ml (60-70 DEG C of temperature) and stirs
After mixing plus water is settled to 1000ml, obtains liquid；B. by liquid obtained by step a through 0.22 μm of filtering with microporous membrane；C. by step b
Gained liquid dispenses, and pressure sterilizing to obtain the final product.
Embodiment 4
Prescription：
| Material forms | Prescription matches |
| Sodium hyaluronate | 3.0g |
| 1,3 butylene glycol | 3.0g |
| Sodium chloride | 1.0g |
| Water | It is settled to 1000ml |
Preparation method：A. sodium hyaluronate, 1,3 butylene glycol, sodium chloride are weighed, water for injection 650ml (temperature 60-70 is added
DEG C) be stirred Hou Jiashui and be settled to 1000ml, obtain liquid；B. by liquid obtained by step a through 0.22 μm of filtering with microporous membrane；c.
By liquid packing obtained by step b, pressure sterilizing to obtain the final product.
Embodiment 5
Prescription：
| Material forms | Prescription matches |
| Sodium hyaluronate | 1.0g |
| 1,3 butylene glycol | 2.0g |
| Sodium chloride | 4.0g |
| Water | It is settled to 1000ml |
Preparation method：A. sodium hyaluronate, 1,3 butylene glycol, sodium chloride are weighed, water for injection 650ml (temperature 60-70 is added
DEG C) be stirred Hou Jiashui and be settled to 1000ml, obtain liquid；B. by liquid obtained by step a through 0.22 μm of filtering with microporous membrane；c.
By liquid packing obtained by step b, pressure sterilizing to obtain the final product.
Embodiment 6
Prescription：
Preparation method：A. sodium hyaluronate, 1,3 butylene glycol, glycerine are weighed, water for injection 650ml (60-70 DEG C of temperature) is added
It is stirred Hou Jiashui and is settled to 1000ml, obtain liquid；B. by liquid obtained by step a through 0.22 μm of filtering with microporous membrane；C. will
Liquid packing obtained by step b, pressure sterilizing to obtain the final product.
It compares group to prepare using identical preparation method, prescription is as follows
| Comparative example 1 | Comparative example 2 | Comparative example 3 | |
| Sodium hyaluronate | 1.0g | 1.0g | 1.0g |
| 1,3 butylene glycol | |||
| Sodium chloride | 6.0g | 5.0g | |
| Glycerine | 6.0g | ||
| Anesin | 2g | ||
| Water | It is settled to 1000ml | It is settled to 1000ml | It is settled to 1000ml |
Test result is as follows for the analysis of sodium hyaluronate eye drops prepared by above example of the present invention：
(1) sodium hyaluronate eye drops prepared by above example and comparative example carry out inhibitory effect inspection (reference《China
Pharmacopeia》2015
Four general rules of year version, 1121 inhibitory effect inspection technique measures), the sodium hyaluronate eye drops prepared by above example
Inhibitory effect
Reach A standards, be better than comparative example, concrete outcome is shown in Table 1.
1 inhibitory effect measurement result of table
(2) embodiment 1, the sodium hyaluronate eye drops prepared by 3,5,6 and reference preparation 1 (0.1%HA-Na5ml, Japan
Santen Pharmaceutical Co. Ltd.) and reference preparation 2 (0.1%HA-Na0.4ml, Japanese Santen Pharmaceutical Co. Ltd.) and comparative example 3 make
For reagent, the macrocyclic lagophthalmos irritant experiment of high frequency time is carried out, test method is as follows：It is same using Adult New Zealand White Rabbit
Body own control, every group of selection rabbit 5 are interior for 24 hours before experiment to make eyes inspection (packet to every rabbit under slit-lamp microscope
Include and use fluorescein sodium inspection), and record cornea, iris and conjunctiva situation.Because eye drops uses agent, every time by reagent
0.1mL instillations left side eye conjunctiva is intracapsular, and right side is compared with 0.9% physiological saline, and gently sleep eyelid 10s, daily eye drip 12 times, often
Minor tick 1h, be used continuously 30d, before being administered daily and last time be administered after 1,2,4,24,48,72h observe eye
Situation, and Eye irritation reaction scoring is carried out by table 2, by the requirement of table 2 by cornea, the rainbow of every rabbit of each observing time point
Film, conjunctiva and the stimulate the reaction score value of secretion are added to obtain total mark, then same group of integral summation divided by observing time are counted,
It can be obtained the sodium hyaluronate eye drip prepared by the mean scores test result display embodiment 1,3,5,6 of its eye irritation reaction
Liquid irritation is similar to reference preparation 2, is better than reference preparation 1 and comparative example 3.
Concrete outcome is shown in Table 3.
2 eye irritation evaluation criterion of table
| Score value | Evaluation |
| 0~3 | It is nonirritant |
| 4~8 | Slight stimulation |
| 9~12 | Moderate irritation |
| 13~16 | Severe irritation |
Eye irritation result after 3 each reagent multiple dosing of table
(3) stability result is shown：Embodiment and comparative example are placed in 40 DEG C of high temperature, and 75% condition of humidity is placed, and 0,6
The moon carries out sodium hyaluronate content and molecular weight detection, evaluates its stability.Colorimetric estimation glass is indicated with glucurone
Sour sodium content；With the Ubbelohde viscometer that capillary E internal diameters are 0.6~0.7mm, is measured according to viscosimetry, find out inherent viscosity
(n), by formula (n)=0.036M0.78, find out average molecular weight.6 months sodium hyaluronates are placed under Examples 1 to 6 acceleration environment
The change of molecular weight within 10%, stability is all preferable, is much better than comparative example.Concrete outcome see the table below 4.
4 stability test result of table
Claims (7)
1. a kind of sodium hyaluronate eye drops, which is characterized in that include the component of following weight by volume percentage concentration：Sodium hyaluronate
0.05-1%, 1,3 butylene glycol 0.2-1.5% and water.
2. sodium hyaluronate eye drops as described in claim 1, which is characterized in that comprising following weight by volume percentage concentration
Component：The water of sodium hyaluronate 0.06-0.5%, 1,3 butylene glycol 0.3-0.8% and surplus.
3. sodium hyaluronate eye drops as claimed in claim 2, which is characterized in that comprising following weight by volume percentage concentration
Component：The water of sodium hyaluronate 0.1%, 1,3 butylene glycol 0.5% and surplus.
4. sodium hyaluronate eye drops as described in claim 1, it is characterised in that：It includes osmotic pressure regulator, the infiltration
Pressure conditioning agent is one or more in sodium chloride, mannitol, glycerine.
5. sodium hyaluronate eye drops as claimed in claim 4, which is characterized in that comprising following weight by volume percentage concentration
Component：The water of sodium hyaluronate 0.1%, 1,3 butylene glycol 0.4%, glycerine 0.2% and surplus.
6. the preparation method of sodium hyaluronate eye drops as described in any one of claims 1-3, it is characterised in that comprise the following steps：
A. weigh sodium hyaluronate, 1,3-BDO be added water total amount 3/5-4/5 be stirred after be settled to water total amount,
Obtain liquid；
B. by liquid obtained by step a through 0.22-0.45 μm of filtering with microporous membrane；
C. liquid obtained by step b is dispensed, pressure sterilizing to obtain the final product.
7. the preparation method of sodium hyaluronate eye drops as described in claim 4 or 5, it is characterised in that comprise the following steps：
A. weigh sodium hyaluronate, 1,3 butylene glycol, osmotic pressure regulator be added the 3/5-4/5 of water total amount be stirred after it is fixed
Hold to water total amount, obtains liquid；
B. by liquid obtained by step a through 0.22-0.45 μm of filtering with microporous membrane；
C. liquid obtained by step b is dispensed, pressure sterilizing to obtain the final product.
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| CN108158983B true CN108158983B (en) | 2018-10-19 |
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| CN110179748B (en) * | 2019-06-25 | 2021-08-10 | 吉林省华恩生物科技有限公司 | Eye drops for relieving ocular inflammation and allergic symptoms and preparation method thereof |
| CN113712909A (en) * | 2020-05-25 | 2021-11-30 | 南京帝昌医药科技有限公司 | Compound diquafosol tetrasodium eye drops and preparation method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2006036655A (en) * | 2004-07-23 | 2006-02-09 | Fancl Corp | Dfa-containing torpent |
| CN103623003A (en) * | 2013-09-09 | 2014-03-12 | 苏州工业园区天龙制药有限公司 | Pearl eye drops for improving eyesight and preparation method thereof |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2006036655A (en) * | 2004-07-23 | 2006-02-09 | Fancl Corp | Dfa-containing torpent |
| CN103623003A (en) * | 2013-09-09 | 2014-03-12 | 苏州工业园区天龙制药有限公司 | Pearl eye drops for improving eyesight and preparation method thereof |
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