CN108853012B - The eye drip aqueous solution increased for treating intraocular pressure - Google Patents
The eye drip aqueous solution increased for treating intraocular pressure Download PDFInfo
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- CN108853012B CN108853012B CN201810621622.4A CN201810621622A CN108853012B CN 108853012 B CN108853012 B CN 108853012B CN 201810621622 A CN201810621622 A CN 201810621622A CN 108853012 B CN108853012 B CN 108853012B
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- aqueous solution
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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
- A61K9/0048—Eye, e.g. artificial tears
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
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- 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
- A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/56—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/61—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule the organic macromolecular compound being a polysaccharide or a derivative thereof
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- 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
- A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6949—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/06—Antiglaucoma agents or miotics
Abstract
The invention belongs to pharmaceutical formulating arts, it is particularly used for the eye drip aqueous solution that treatment intraocular pressure increases, eye drip aqueous solution and substantially the container made of polyethylene is constituted, the eye drip aqueous solution includes: the inclusion compound and stabilizer being stably dispersed in aqueous phase solution, the inclusion compound includes the inclusion material of PGF2 alpha analog and the inclusion PGF2 alpha analog, the inclusion material include: a) 95wt% or more molecular weight be (1.1~1.5) × 106Sodium hyaluronate；B) it is (0.6~1.0) × 10 that remaining, which is molecular weight,6Sodium hyaluronate.PGF2 alpha analog is formed inclusion compound by inclusion technique using the inclusion material of innovation by the present invention, it solves PGF2 alpha analog and deposits the unstable and easily packaged big key problem of holder absorption two, eye drip aqueous solution of the present invention is substantially free of preservative and nonionic surfactant, and it can be stored in the container made of polyethylene substantially, photostability, thermostabilization are higher.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, and in particular to the eye drip aqueous solution increased for treating intraocular pressure.
Background technique
PGF2 alpha analog is widely used in treatment glaucoma and intraocular hypertension, and the drug that side effect is low, it is known that include
Latanoprost, Isopropyl Unoprostone, travoprost, bimatoprost and tafluprost.
However PGF2 alpha analog is unstable in illumination, hot conditions, such as Alcon withBrand sales
Travoprost eye drops is protected from light packaging using aluminium foil bag；Pfizer withThe latanoprost of brand sales drips
Ocular fluid, it is necessary to about 5 DEG C at a temperature of refrigerate.In addition, also just like United States Patent (USP) US6011062, US5688819,
US5849792, US4599553 etc. are described using nonionic surfactant (GREMAPHOR GS32, polyoxyethylene caster
Oily derivative, Sorbitan alcohol ester etc.) enhancing PGF2 alpha analog stability.
But the scheme of enhancing PGF2 alpha analog stability disclosed above is not fully satisfactory, moreover, PGF2 α class
It is mostly not soluble in water like object, PGF2 alpha analog can be made miscible with water although surfactant is added, PGF2 alpha analog drop
Eye agent during storage still can there is a situation where contents to be decreased obviously, which is found by experiment that uses with eye drops
It is related with the prescription of eye drops to pack material.Because PGF2 alpha analog is low-down for treating the concentration of glaucoma, such as
Concentration of the travoprost in ophthalmic composition is only 0.001-0.004%.As lipophilic substance, PGF2 alpha analog example
As travoprost is easy resin (plastics) container for being generally used for storing ophthalmic solution or bottle absorption, especially polyethylene system
The container made, it is thus possible to further decrease drug concentration very low in ophthalmic solution.
That is, the two big key problems that PGF2 alpha analog eye-drops preparations faces at present are: PGF2 alpha analog
The easily packaged holder absorption of unstable and PGF2 alpha analog.And it is directed to above-mentioned problem, not yet occur at present completely satisfactory
Scheme.
Therefore, it needs to develop a kind of at least PGF2 alpha analog eye-drops preparations containing following characteristics at present:
It is substantially free of preservative and nonionic surfactant；
Its photostability, thermal stability are higher；
Its contained PGF2 alpha analog keeps good solubility, stability and bioavailable degree in the formulation.
Summary of the invention
The present invention is intended to provide it is a kind of with PGF2 alpha analog for effective therapeutic component, and be substantially free of preservative and non-
Ionic surface active agent, and being capable of storage-stable increasing in the container being made of substantially polyethylene for treating intraocular pressure
Eye drip aqueous solution.
In order to achieve the above object, the invention adopts the following technical scheme:
The eye drip aqueous solution that the present invention relates to a kind of to increase for treating intraocular pressure, by eye drip aqueous solution and substantially
The container made of polyethylene is constituted, and the eye drip aqueous solution includes: the inclusion compound that is stably dispersed in aqueous phase solution and steady
Determine agent, the inclusion compound includes the inclusion material of PGF2 alpha analog and the inclusion PGF2 alpha analog, the inclusion material
Include: a) 95wt% or more molecular weight be (1.1~1.5) × 106Sodium hyaluronate；B) it is (0.6~1.0) that remaining, which is molecular weight,
×106Sodium hyaluronate.
Preferably, it is (1.2~1.5) × 10 that the inclusion material, which includes 95wt% or more molecular weight,6Sodium hyaluronate and
Molecular weight is (0.6~0.8) × 106Sodium hyaluronate.
Preferably, the content that material is included in the eye drip aqueous solution is 0.001-18% (w/v).
Preferably, the stabilizer is selected from ethylenediamine tetra-acetic acid and its esters, sodium nitrite, ascorbic acid, L- Vitamin C
Sour stearate, sodium hydrogensulfite, α thioglycerol, arabo-ascorbic acid, cysteine hydrochloride, citric acid, D-α-tocopherol acetate, two
Symclosene potassium, 2,6-di-tert-butyl-4-methylphenol, soybean lecithin, sodium thioglycolate, thiomalic acid sodium, natural dimension life
Plain E, sodium pyrosulfite, butylhydroxy fennel obtain ether, 1,3-BDO, [3- (3, the 5- di-t-butyl -4- oxybenzenes of pentaerythrite four
One of base)] propionic ester, propylgallate, 2-mercaptobenzimidazole and hydroxyquinoline sulfate.
It is highly preferred that the stabilizer is natrium adetate.
It is highly preferred that the content of stabilizer is 0.005-0.2% (w/v) in the eye drip aqueous solution.
Preferably, the content of PGF2 alpha analog is 0.0001-0.01% (w/v) in the eye drip aqueous solution.
Preferably, the PGF2 alpha analog is selected from Latanoprost, Isopropyl Unoprostone, travoprost, compares horse
The mixture of one or more of forefront element and tafluprost.
It is highly preferred that the PGF2 alpha analog is travoprost.
Eye drip aqueous solution of the invention can also delay comprising for the customary adjuvant in eye-drops preparations as conventional use of
Electuary, pH adjusting agent and tonicity agent.Suitable buffer includes but is not limited to sodium dihydrogen phosphate dihydrate, borax, citric acid
Or boric acid.Tonicity agent includes but is not limited to glycerol, sorbierite, mannitol or other sugar alcohols.
The pH of eye drip aqueous solution of the invention is preferably 4~8, and more preferable 5~7, " pH adjusting agent " described herein can be with
Using conventional pH adjusting agent, such as sodium hydroxide or hydrochloric acid.
" container being substantially made of polyethylene " described herein refer to container install eye drops medical fluid part it is basic or
It is entirely free of the other materials in addition to polyethylene, such as does not contain polypropylene, polystyrene and nylon substantially or entirely.
The present invention is another object is that increasing the water solubility of PGF2 alpha analog in eye drip aqueous solution and improving its stability
Method comprising use containing 95wt% or more molecular weight as (1.1~1.5) × 106Sodium hyaluronate and molecular weight be (0.6
~1.0) × 106The inclusion material application inclusion technique of sodium hyaluronate PGF2 alpha analog is included into the step of forming inclusion compound.
It " is substantially free of preservative " herein and refers to that being entirely free of preservative or solution in eye drip aqueous solution contains detection
Less than concentration preservative or do not provide anti-corrosion effect concentration preservative.
The invention has the following advantages that
PGF2 alpha analog is formed inclusion compound by inclusion technique using the inclusion material of innovation by the present invention, is solved
For PGF2 alpha analog there are the unstable and easily packaged big key problem of holder absorption two, eye drip of the present invention is aqueous molten
Liquid is substantially free of preservative and nonionic surfactant, and can be stored in the container made of polyethylene substantially,
More importantly the photostability of eye drip aqueous solution of the present invention, thermostabilization are higher, and PGF2 alpha analog is in aqueous solution
In solubility and bioavilability with higher, achieve significant progress compared with prior art.
Specific embodiment
The specific embodiment of form by the following examples makees further specifically above content of the invention
It is bright.But the range that this should not be interpreted as to the above-mentioned theme of the present invention is only limitted to following embodiment.
Embodiment 1, the eye drip aqueous solution containing different molecular weight sodium hyaluronate inclusion
Prescription:
Water for injection 1000ml, with sodium hydroxide and/or salt acid for adjusting pH to 6.5
Wherein, inclusion material is 1.25 × 10 by 95wt% or more molecular weight6Sodium hyaluronate and 5wt% molecular weight be
0.68×106Sodium hyaluronate composition.
Preparation method:
Take the inclusion material of recipe quantity in 60~90 DEG C of 800ml sterilized water for injection, recipe quantity is added in stirring and dissolving
Natrium adetate, biphosphate sodium-hydrate, disodium hydrogen phosphate and sodium chloride, dissolve, filtration, encapsulating, sterilizing；Separately take place
The hydrochloric acid or sodium hydrate regulator solution pH to 6.5 of 1mol/L is added in the travoprost just measured, finally plus sterilized water for injection
To 1000ml, filtering, it is aseptic subpackaged to get.
Test example one, different molecular weight sodium hyaluronate improve solubility, the stability of travoprost as inclusion material
The test example absorbed with inhibition by density polyethylene container
1.1 improve the solubility test of travoprost
By 0.04g travoprost, (two kinds of SH press the weight of 95:1 with the sodium hyaluronate by 0.05g different molecular weight respectively
Than composition) the inclusion material compatibility of composition, add and inject water to 100ml, be made medical fluid sample, half sample it is directly filling in
In medicinal eye drop bottle, the other half sample is after 0.22 μm of filtering with microporous membrane, and encapsulating is in medicinal eye drop bottle.And with it is existing
Conventional inclusion material Crodaret, hydroxypropyl-β-cyclodextrin compare, investigate the solubility to travoprost
It influences, as a result as shown in table 1 below.
Influence result of the table 1 to the solubility of travoprost
By upper table 1 it is found that using two kinds of molecular weight for (1.1~1.5) × 106It is (0.6~1.0) × 10 with molecular weight6's
Sodium hyaluronate, which include to travoprost, forms inclusion compound, content essentially unchangedization before and after medical filtration, and solubilizing effect is excellent
In conventional solubilizer Crodaret and hydroxypropyl-β-cyclodextrin.And when the Hyaluronic Acid for using unimodal molecular weight
Sodium hydrotropy, content is decreased obviously after medical filtration, and the slightly aobvious muddiness of medical fluid is found in process for preparation, is clarified after filtering
Liquid, should be caused by main ingredient is not completely dissolved and is retained by filter membrane.
1.2 improve the test of travoprost stability
Each group sample is prepared by 1.1, carries out the shadow of 60 DEG C of hot tests and 4500Lx ± 500Lx illumination illumination respectively
It investigates within the factor of sound 10 days, testing result is as shown in the following table 3~4.
Each sample testing result at table 20 days
Test result after 3 60 DEG C of table high temperature 10 days
4 4500Lx of table ± 500Lx illumination, 10 days test results of illumination
By upper table 3,4 it is found that with 1.25 × 106SH+0.68×106SH carries out 60 DEG C as the sample that inclusion material obtains
High temperature and after exposure experiments to light 10 days, less, and the miscellaneous and total miscellaneous ascensional range of list of travoprost is small for the pH variation of sample, and normal
The hydroxypropyl-β-cyclodextrin inclusion of rule is compared, and it is more significant to improve stabilizing effect；And use unimodal molecular weight sodium hyaluronate into
Row inclusion, the pH amplitude of variation of sample is larger, and the miscellaneous and total miscellaneous ascensional range of list of travoprost is obvious.
Inhibit travoprost by density polyethylene container absorption test at 1.3 5 DEG C, 25 DEG C and 40 DEG C
The medical fluid 2.5ml medical fluid that Example 1 is prepared is filled into low density polyethylene (LDPE) (LDPE) resistance bacterium multi-dose medicine
With the main part of eye drop bottle, body and corking are combined by dedicated unit, reach sealing.The inner bulk of the multi-dose container
Product is about 5ml, container package in the aluminum-polyethylene foil that paper is coated with and is stored in refrigerator or incubator, in 5 DEG C, 25
DEG C and 40 DEG C at store 20 weeks, by HPLC measure travoprost residual concentration, as a result as shown in table 5~7.
55 DEG C of test results of table
6 25 DEG C of test results of table
7 40 DEG C of test results of table
By upper table 5~7 it is found that using 1.25 × 106SH+0.68×106SH includes travoprost formation inclusion compound can
Travoprost is significantly inhibited by LDPE holder absorption.
The above-described embodiments merely illustrate the principles and effects of the present invention, and is not intended to limit the present invention.It is any ripe
The personage for knowing this technology all without departing from the spirit and scope of the present invention, carries out modifications and changes to above-described embodiment.Cause
This, institute is complete without departing from the spirit and technical ideas disclosed in the present invention by those of ordinary skill in the art such as
At all equivalent modifications or change, should be covered by the claims of the present invention.
Claims (8)
1. for treating the eye drip aqueous solution that intraocular pressure increases, which is characterized in that by eye drip aqueous solution and by polyethylene system
At container constitute, the eye drip aqueous solution includes: the inclusion compound and stabilizer being stably dispersed in aqueous phase solution, the packet
The inclusion material that object includes PGF2 alpha analog and the inclusion PGF2 alpha analog is closed, the inclusion material includes:
A) 95wt% or more molecular weight is (1.1~1.5) × 106Sodium hyaluronate；
B) it is (0.6~1.0) × 10 that remaining, which is molecular weight,6Sodium hyaluronate；
The content of PGF2 alpha analog is 0.0001-0.01% (w/v) in the eye drip aqueous solution, and the PGF2 alpha analog is song
Lie prostrate forefront element.
2. eye drip aqueous solution as described in claim 1, which is characterized in that the inclusion material includes 95wt% or more molecule
Amount is (1.2~1.5) × 106Sodium hyaluronate and molecular weight be (0.6~0.8) × 106Sodium hyaluronate.
3. eye drip aqueous solution as claimed in claim 1 or 2, which is characterized in that include material in the eye drip aqueous solution
Content is 0.001-18% (w/v).
4. eye drip aqueous solution as described in claim 1, which is characterized in that the stabilizer be selected from ethylenediamine tetra-acetic acid and its
Salt, sodium nitrite, ascorbic acid, L-ascorbyl stearate, sodium hydrogensulfite, α thioglycerol, arabo-ascorbic acid, salt
Sour cysteine, citric acid, D-α-tocopherol acetate, potassium dichloroisocyanurate, 2,6-di-tert-butyl-4-methylphenol, soybean lecithin, mercapto
Guanidine-acetic acid sodium, thiomalic acid sodium, natural VE, sodium pyrosulfite, butylhydroxy fennel obtain ether, 1,3-BDO, Ji Wusi
Alcohol four [3- (3,5- di-t-butyl -4- hydroxyphenyl)] propionic ester, propylgallate, 2-mercaptobenzimidazole and sulfuric acid hydroxyl quinoline
One of quinoline.
5. eye drip aqueous solution as claimed in claim 4, which is characterized in that the stabilizer is natrium adetate, the drop
The content of stabilizer is 0.005-0.2% (w/v) in eye aqueous solution.
6. a kind of aqueous solution product of eye drip, which is characterized in that it is made of eye drip aqueous solution and the container made of polyethylene,
The eye drip aqueous solution includes:
The travoprost of 0.0001-0.01% (w/v)；
The stabilizer of 0.005-0.2% (w/v)；
The inclusion material of 0.001-18% (w/v), the inclusion material include 95wt% or more molecular weight be (1.1~1.5) ×
106Sodium hyaluronate and molecular weight be (0.6~1.0) × 106Sodium hyaluronate；With
Conventional use of buffer, pH adjusting agent and tonicity agent in optional ophthalmic solution, and be free of preservative.
7. a kind of aqueous solution product of eye drip, which is characterized in that it is made of eye drip aqueous solution and the container made of polyethylene,
The eye drip aqueous solution includes:
The travoprost of 0.0001-0.01% (w/v)；
The natrium adetate of 0.005-0.2% (w/v)；
The inclusion material of 0.001-18% (w/v), wherein the inclusion material include 95wt% or more molecular weight be (1.2~
1.5)×106Sodium hyaluronate and molecular weight be (0.6~0.8) × 106Sodium hyaluronate；With
Conventional use of buffer, pH adjusting agent and tonicity agent in optional ophthalmic solution, and be free of preservative.
8. a kind of method for increasing its stability of the water solubility and improvement of PGF2 alpha analog in eye drip aqueous solution, feature exist
In, including use containing 95wt% or more molecular weight as (1.1~1.5) × 106Sodium hyaluronate and molecular weight be (0.6~
1.0)×106The inclusion material application inclusion technique of sodium hyaluronate PGF2 alpha analog is included into the step of forming inclusion compound, institute
The content for stating PGF2 alpha analog in eye drip aqueous solution is 0.0001-0.01% (w/v), and the PGF2 alpha analog is song Fu Qianlie
Element.
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| CN201810621622.4A CN108853012B (en) | 2018-06-15 | 2018-06-15 | The eye drip aqueous solution increased for treating intraocular pressure |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103977011A (en) * | 2013-02-07 | 2014-08-13 | 沈阳兴齐眼药股份有限公司 | Travoprost and timolol-containing ophthalmic gel and preparation method thereof |
| CN107854469A (en) * | 2016-09-21 | 2018-03-30 | 刘力 | Topical ophthalmic or the husky star medicine of ear or nose use or external preparation for skin and combinations thereof |
| CN107913246A (en) * | 2016-10-09 | 2018-04-17 | 刘力 | The medical composite for eye of local administration |
-
2018
- 2018-06-15 CN CN201810621622.4A patent/CN108853012B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103977011A (en) * | 2013-02-07 | 2014-08-13 | 沈阳兴齐眼药股份有限公司 | Travoprost and timolol-containing ophthalmic gel and preparation method thereof |
| CN107854469A (en) * | 2016-09-21 | 2018-03-30 | 刘力 | Topical ophthalmic or the husky star medicine of ear or nose use or external preparation for skin and combinations thereof |
| CN107913246A (en) * | 2016-10-09 | 2018-04-17 | 刘力 | The medical composite for eye of local administration |
Non-Patent Citations (1)
| Title |
|---|
| PhXA41降低眼压的研究;杨世能;《国外医学·眼科学分册》;19931028;第310-311页 |
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Inventor after: Du Zhibo Inventor after: He Xing Inventor after: Zhu Chengbo Inventor after: Yang Yanqiu Inventor after: Peng Wei Inventor before: Du Zhibo Inventor before: He Xing Inventor before: Zhu Chengbo Inventor before: Yang Yanqiu Inventor before: Peng Chi |