CN106963730A - Highly stable nepafenac medical composite for eye - Google Patents
Highly stable nepafenac medical composite for eye Download PDFInfo
- Publication number
- CN106963730A CN106963730A CN201611233627.7A CN201611233627A CN106963730A CN 106963730 A CN106963730 A CN 106963730A CN 201611233627 A CN201611233627 A CN 201611233627A CN 106963730 A CN106963730 A CN 106963730A
- Authority
- CN
- China
- Prior art keywords
- composition
- nepafenac
- pharmaceutical composition
- eye
- sodium chloride
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- 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
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
-
- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
-
- 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
-
- 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
- A61K9/10—Dispersions; Emulsions
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Dispersion Chemistry (AREA)
- Ophthalmology & Optometry (AREA)
- Inorganic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to a kind of highly stable nepafenac medical composite for eye.Specifically, this ophthalmically acceptable pharmaceutical composition includes：A) 0.09 0.11% (w/v) nepafenac；B) 0.4 0.6% (w/v) carbomer；C) nonionic surfactant；D) tension regulator, presenting in an amount at least sufficient to makes the osmotic pressure molality of composition for 250 350mOsm/kg；E) pH adjusting agent, presenting in an amount at least sufficient to makes the pH of composition be 7.0 7.8；And f) water, wherein composition optionally contains the composition selected from preservative and intercalating agent.There is nepafenac medical composite for eye of the present invention the excellent technique effect such as stability with height to be particularly the stability shown in terms of some/certain specific impurities.
Description
Technical field
The present invention relates to a kind of ophthalmic pharmaceutical formulation for treating non-infectious inflammation, more particularly to a kind of nepafenac are ophthalmically acceptable
Preparation.
Background technology
The clinical practice of NSAIDs (non-steroidal antiinflammatory drugs, NSAIDS) is
There is last 100 yearses history, be widely used in from glucocorticoid after clinic, the application of this kind of medicine was once once being reduced.But, due to sugar
Cortin can cause dependence, can not be discontinued immediately in short term, and long-term prescription can cause many serious adverse reactions again, thus right
NSAIDS research is paid attention to again again.In recent decades, it is clinically main to apply antihistamine, Congestant, mast cell
The diseases such as the drug therapy ocular allergies such as stabilizer, corticosteroid, because there are various serious adverse reactions in said medicine, and
NSAIDs has anti-inflammatory, antiallergy and analgesic effect, and the adverse reaction without corticosteroid, and therefore, it is in ophthalmology
Application be increasingly subject to pay attention to.As NSAIDS is in the extensive use of ophthalmology and being incremented by for usage amount, the validity of such medicine
The attention of oculist has been obtained with security.
External eyes caused by non-infectious inflammation and anterior disease of eye such as blepharitis, conjunctivitis, keratitis, sclerotitis, shallow-layer
Sclerotitis, iridocyclitis, post-operation inflammatory etc., show as more anterior chamber's scintillation, conjunctival congestion, shed tears, photophobia, anterior chamber's cellulose
The inflammation sex expressions such as property is oozed out, myosis, iris hyperemia.Due to the presence of human body " blood-ocular barrier ", to the non-infectious of eye
It is difficult to work that inflammation, which carries out systemic medication, and treatment external eyes and anterior ocular segment inflammation are only in eye local topical NSAIDs
Effective way.The mechanism of action of NSAIDs is by suppressing epoxidase, preventing the biosynthesis of prostaglandin and release
Put, prevent inflammatory mediator to Ocular irritation and infringement, play stronger antiallergy, alleviate itch, anti-inflammatory and analgesic effect；And
NSAIDS, which also has, suppresses the effect that operation induces miosis, pupil can be maintained to expand in operation.The non-steroid of ophthalmology commonly used at present
Body anti-inflammatory agent has Indometacin Eye Drops, Diclofenac sodium gutta, ketorolac tromethamine eye drops, pranoprofen eye drip
Liquid, Flurbiprofen eye drops etc., clinically using than wide, but excitant is larger, intraocular penetration power is poor mostly, raw
Thing availability is relatively low, adverse reaction is more, is clinically difficult to reach good therapeutic effect.Therefore, clinically it is highly desirable to treatment
Imitate, the new varieties Non-steroid anti-inflammatory medicine for external use for ophthalmology that few side effects, intraocular penetration power are strong, property is stable.
Nepafenac is as NSAIDS of new generation, and its chemical constitution is conducive to the medicine to readily penetrate through cornea and is distributed in its work
With target position, thus help to reduce accumulation of the medicine in anterior corneal surface, reduce the generation of eyeball surface complication.Nepafenac is passed through
After dosing eyes, cornea can be quickly passed through, and is converted into the presence of ocular tissue's hydrolase amfenac (a kind of NSAIDs)；And
Amfenac blocks the synthesis of prostaglandin, to play its anti-inflammatory analgesic further through prostaglandin H synthetase (Cycloxygenase) is suppressed
Effect.Nepafenac adds the bioconversion organized within the eye because it is in the bioactivity and permeability of eye, make its
Preocular and rear portion have unique targeted inhibition effect to prostate.Prostaglandin is to cause one of medium of intraocular inflammation, energy
Cause blood, aqueous barrier collapse, blood vessel dilatation, vasopermeability increase and leukocyte chemotaxis etc..In addition, prostaglandin can also lead to
Cross non-cholinergic mechanism and shrink iris sphincter muscle, trigger in ophthalmic surgical procedures and postoperative miosis reaction.Nepafenac eye
It is FDA's approval in 2005 with suspension (Nepafenac, trade name Nevanac, Alcon company)
The first ophthalmically acceptable NSAIDS precursor medicinal preparations of listing, are mainly used in treatment cataract operation associated pain and inflammation.EMA is also
The newly-increased indication of nepafenac (nepafenac is developed by Alcon companies) is have approved, can be used for mitigating diabetic
There is the risk of macular edema after pain and inflammation after cataract operation, and reduction Operation of Cataract in Diabetics, have
Research shows that nepafenac is a kind of up-and-coming medicine in macular cystoid edema (CME) treatment.
Nepafenac is compared with traditional NSAIDs, with that penetration is strong, targeting is strong, toxic side effect is small etc. is excellent
Point.The country has been approved by Ai Erkang (China) ophthalmic product Co., Ltd application nepafenac eye drops clinical register, and (clinic is
Batch), but not yet list.Nepafenac is configured into eye-drops preparations needs to reach a series of particular requirements such as：1. it is antibacterial, it is most of
Eye-drops preparations needs to reuse because being multiple-unit container, easily contaminated during use, so to add bacteriostatic agent, presses down
Pathogen can be killed or suppressed its growth, breeding by microbial inoculum；2. suitable acid-base value, the thorn of pH7.4 eye drops to eyes
Swash property minimum, without uncomfortable sensation during pH6~8, normal eyes can tolerate pH5~9, and have obvious if pH ＜ 5 or pH ＞ 11.4
Excitant.Need on the premise of nepafenac is maintained, the suitable pH value of adjustment decoction；3. suitable osmotic pressure, eye drops
Osmotic pressure should be close with tear, equivalent to 0.9% sodium chloride solution.Eyes are adaptable in the case of no wound
Osmolarity ranges are equivalent to 0.6~2.0% sodium chloride solution.It is hypertonic to be dehydrated eye, it is hypotonic to make ocular edema.It is hypertonic or hypotonic
Lacrimal secretion can be also stimulated, eye drops is diluted and rush Xian；4. suitable viscosity, the viscosity relationship of eye-drops preparations exists to medicine
Holdup time, drug bioavailability in conjunctival sac and the excitant to eye, it is sticky selected by formulation viscosity to adjust
Agent will have suitable light transmittance, index of refraction；5. formula and technique will also reach：Bacteriostatic agent used and other auxiliary materials not with Nai Pafen
Physical and chemical reaction occurs for amine, affects the treatment；Auxiliary material used is conducive to the stabilization of nepafenac, preparation is preserved for a long time；Prescription and
Preparation technology will ensure in preparation without visible foreign matters；To eye low irritant, it is to avoid tear is largely secreted.
Nepafenac is also referred to as 2- amino -3- Benzoylbenzene guanidine-acetic acids.Nepafenac and 3- benzoylphenyl second
Other acid amides and ester derivant treatment ophthalmic inflammation of acid and the topical use of pain are disclosed in US patents 5475034.According to '
034 patent, the composition containing 3- Benzoylbenzene acetic acid derivatives can be formulated as the ophthalmic compositions that various parts can be applied
Thing, such as solution, suspension, gel or ointment.Said composition optionally containing preservative such as BZK and thickener such as carbomer,
Hydroxyethyl cellulose or polyvinyl alcohol.
Those skilled in the art still expect there is the new method for preparing nepafenac eye-drops preparations.
The content of the invention
It is an object of the invention to provide a kind of new nepafenac eye-drops preparations, this nepafenac eye-drops preparations is expected
With excellent property.
The composition of the present invention is the aqueous suspension composition of nepafenac.Said composition contains 0.09-0.11% (w/
V) nepafenac.Said composition is substantially by nepafenac, carbomer, nonionic surfactant, tension regulator, pH-
Conditioning agent, purified water and optional preservative and intercalating agent composition.
Specifically, the invention provides a kind of ophthalmically acceptable pharmaceutical composition, including：A) 0.09-0.11% (w/v)
Nepafenac；B) 0.4-0.6% (w/v) carbomer；C) nonionic surfactant；D) tension regulator, presenting in an amount at least sufficient to makes
The osmotic pressure molality of composition is 250-350mOsm/kg；E) pH adjusting agent, presenting in an amount at least sufficient to makes the pH of composition be
7.0-7.8；And f) water, wherein composition optionally contains the composition selected from preservative and intercalating agent.
According to the pharmaceutical composition of the present invention, wherein composition includes 0.1% (w/v) nepafenac.
According to the pharmaceutical composition of the present invention, wherein composition includes 0.5% (w/v) carbomer；For example, the carbomer is
The acrylate copolymer being crosslinked with allyl sucrose or Allyl pentaerythritol.
According to the pharmaceutical composition of the present invention, wherein nonionic surfactant is tyloxapol；For example, said composition
Include 0.01% (w/v) tyloxapol.
According to the pharmaceutical composition of the present invention, wherein tension regulator is selected from metal chloride salt and mannitol or maltose
Alcohol；For example, the tension regulator includes sodium chloride and mannitol；For example, said composition includes 0.3-0.5% (w/v) sodium chloride
With 2-3% (w/v) mannitol or maltitol；For example, said composition includes 0.4% (w/v) sodium chloride and 2.4% (w/v) wheat
Bud sugar alcohol；For example, said composition includes 0.4% (w/v) sodium chloride and 2.4% (w/v) mannitol.
According to the pharmaceutical composition of the present invention, wherein pH adjusting agent is selected from hydrochloric acid and sodium hydroxide；For example, this its make combination
The pH of thing is 7.3-7.7.
According to the pharmaceutical composition of the present invention, wherein composition contains preservative and intercalating agent；For example, the preservative is selected from
Halogenation zephiran；Polyquaternium -1 and chlorine dioxide；For example, the preservative is BZK；For example, said composition is included
0.005% BZK.
According to the pharmaceutical composition of the present invention, wherein intercalating agent is selected from disodium ethylene diamine tetraacetate；Ethylenediamine tetra-acetic acid three
Sodium；Tetrasodium ethylenediamine tetraacetate；And calcium disodium edathamil.
According to the pharmaceutical composition of the present invention, wherein composition includes 0.001-0.1% (w/v) Ca-EDTA two
Sodium or disodium ethylene diamine tetraacetate.
According to the present invention pharmaceutical composition, including：A) 0.1% (w/v) nepafenac；B) 0.5% (w/v) card ripple
Nurse；C) 0.01% (w/v) tyloxapol；D) 0.4% (w/v) sodium chloride；E) 2.4% (w/v) mannitol；F) pH adjusting agent, its
Amount is enough to make the pH of composition to be 7.3-7.7；G) 0.005% (w/v) BZK；H) 0.01% disodium ethylene diamine tetraacetate；
And i) purified water.
According to the pharmaceutical composition of any embodiment of the present invention, mannitol therein is replaced by the maltitol of isoconcentration
Change.
According to the pharmaceutical composition of any embodiment of the present invention, disodium ethylene diamine tetraacetate therein is by the second of isoconcentration
Ethylenediamine tetraacetic acid (EDTA) calcium disodium is replaced.
According to the pharmaceutical composition of any embodiment of the present invention, mannitol therein is replaced by the maltitol of isoconcentration
And disodium ethylene diamine tetraacetate therein is replaced by the calcium disodium edathamil of isoconcentration.
According to the present invention pharmaceutical composition, including：A) 0.1% (w/v) nepafenac；B) 0.5% (w/v) card ripple
Nurse；C) 0.01% (w/v) tyloxapol；D) 0.4% (w/v) sodium chloride；E) 2.4% (w/v) maltitol；F) pH adjusting agent,
Presenting in an amount at least sufficient to makes the pH of composition be 7.3-7.7；G) 0.005% (w/v) BZK；H) 0.01% Ca-EDTA two
Sodium；And i) purified water.
The present invention is further illustrated below.
Active component in pharmaceutical composition of the present invention is that principal component is nepafenac (Nepafenac), and it is changed
Scientific name：Nepafenac, molecular formula：C15H14N2O2, molecular weight：254.3, CAS accession number：
78281-72-8, its chemical structural formula is as follows：
Unless otherwise instructed, the concentration of all the components is represented with % weight/volumes unit (%w/v).
Nepafenac is known compound.It can be prepared by known methods.See, for example, the He of US patents 5475034
4313949.The composition of the present invention contains 0.09-0.11% nepafenacs, preferably 0.1% nepafenac.
In addition to nepafenac, suspension composite of the invention also contains carbomer and increased as thickener or physical stability
Strong agent.Make to share and be also known as " carboxy vinyl polymer " or carboxypolymethylene in carbomer of the invention.They from Noveon,
Inc. (Cleveland, Ohio) is commercially available, with trade name(carbopol) is sold.Carbopol polymer is crosslinking
Acrylic polymer.They are crosslinked with allyl sucrose or Allyl pentaerythritol.Carbopol copolymer is the poly- of acrylic acid
Compound, it is modified with C10-30 alkyl acrylates and is crosslinked with Allyl pentaerythritol.For excellent in the present composition
The carbomer of choosing be with allyl sucrose or Allyl pentaerythritol crosslinking acrylate copolymer, its withCity
Selling to obtain.The concentration of carbomer is usually 0.4-0.6% in the present composition, and preferably 0.5%.
The composition of the present invention also contains the acceptable nonionic surfactant of ophthalmology.Known much ophthalmology are subjected to
Nonionic surfactant.Suitable nonionic surfactant includes but is not limited to tyloxapol；Polyoxyethylene loses
Water sorb ester such as polysorbate 20, polysorbate 60 and polyoxyethylene sorbitan monoleate；GREMAPHOR GS32 CremophorEL；Poly- second
The rilanit special of epoxide such as HC0-40；And poloxamer.Most preferred surfactant is tyloxapol.In tyloxapol
In the case of, the usual content of surfactant is 0.001-0.05%, preferably 0.01%.
In addition to nepafenac, carbomer and nonionic surfactant, composition of the invention also contains ophthalmology
Acceptable tension regulator.The acceptable tension regulator of ophthalmology includes but is not limited to metal chloride salt and nonionic
Power conditioning agent such as mannitol.It is preferred that metal chloride salt be human tears in it is visible those, such as sodium chloride, potassium chloride, chlorine
Change calcium and magnesium chloride.The amount of contained tension regulator is to be enough to make the osmotic pressure quality mole of composition dense in the present composition
Degree is about 250-350mOsm/kg, preferably 270-315mOsm/kg amount.The most preferably combination of sodium chloride and mannitol.For it
Middle tension regulator is the most preferred embodiment of the combination of sodium chloride and mannitol, and the amount of sodium chloride is preferably 0.3-
0.5%, the amount of mannitol is 2-3%, and the amount of most preferred sodium chloride is 0.4%, and the amount of most preferred mannitol is 2.4%.
The pH of the composition of the present invention is 7.0-7.8.Preferably, the pH of composition is 7.3-7.7, most preferably 7.5.Combination
Thing contains the acceptable pH adjusting agent of ophthalmology, to obtain required pH.The acceptable pH adjusting agent of ophthalmology is known, including but not
It is limited to hydrochloric acid (HCl) and sodium hydroxide (NaOH).
The composition of the present invention optionally contains the acceptable preservative ingredient of ophthalmology.The acceptable preservative ingredient of ophthalmology is
It is known, including but not limited to halogenation zephiran (benzalkonium halide) such as BZK, polyquaternium -1
And chlorine dioxide (polyquaternium-1).Most preferably BZK and polyquaternium -1.In the case of BZK, prevent
The content of rotten agent is preferably 0.001-0.01%, and most preferably 0.005%.
Intercalating agent is also optionally included in the suspension composite of the present invention.Suitable intercalating agent includes ethylenediamine tetra-acetic acid
Disodium；Sodium versenate；Calcium disodium edathamil；Tetrasodium ethylenediamine tetraacetate.It is preferred that ethylenediamine tetra-acetic acid two
Sodium.If including intercalating agent, its usual content is 0.001-0.1%.In calcium disodium edathamil or ethylenediamine tetra-acetic acid
In the case of disodium, intercalating agent preferably exists with 0.01% concentration.
Following examples are intended to elaboration and are not intended to limit the present invention.
Embodiment
Embodiments below is prepared for the ophthalmically acceptable pharmaceutical composition in suspension formation, and to their some pharmacy
Property is investigated.
Hereinafter, when determining the external corneal osmosis rate of medical composite for eye preparation, according to Ke et al.,
Inflammation, 24 (4)：371-384 (2000) methods described, using the rabbit corneal of fresh separated in perfusion bath, is evaluated
Corneal osmosis rate.
After measured, pharmaceutical composition ophthalmically acceptable obtained by following embodiment, their corneal osmosis rate average is 17.8
In the range of~20.1 (nM/min), do not occur difference, such as embodiment 1~3 and the medicine group of embodiment 21~24 between each sample
The corneal osmosis rate average of compound is in the range of 18.4~19.3 (nM/min).
After measured, pharmaceutical composition ophthalmically acceptable obtained by following embodiment, their osmotic pressure molality exists
In the range of 270-315mOsm/kg.
Determine the HPLC methods of active component and impurity 7- benzoyl -1,3- Indolin-2-one contents in composition such as
Under：
The preparation of need testing solution：Precision measures medical composite for eye 10ml prepared by the present invention, adds to 20ml measuring bottles
In, plus acetonitrile 8ml, ultrasonication dissolves medicine, with dilution in acetonitrile to scale, shaken up, and is used as need testing solution (about 500 μ
g/ml)；
The preparation of contrast solution：Precision measures need testing solution 1ml, puts in 100ml measuring bottles, with dilution in acetonitrile to scale,
Shake up, be used as contrast solution (about 5 μ g/ml)；
The preparation of impurity reference substance solution：Precision weighs impurity compound in right amount, plus acetonitrile dissolves and concentration is made for 5 μ
G/ml solution, is used as impurity reference substance solution；
The preparation of reference substance solution：Precision weighs nepafenac reference substance in right amount, plus it is 500 that acetonitrile, which dissolves and concentration is made,
μ g/ml solution, is used as reference substance solution；
Chromatographic condition is with determining：It is filler with octadecylsilane chemically bonded silica, chromatographic column specification is 5 μm, 200mm ×
4.6mm；Mobile phase is 0.01mol/L formic acid aqueous ammoniums：Acetonitrile (65：35), flow velocity is 1ml/min, Detection wavelength 240nm,
30 DEG C of column temperature；Number of theoretical plate is calculated by nepafenac peak is not less than 3000；The μ l of contrast solution 20 are taken to inject liquid chromatograph, regulation
Detection sensitivity, the peak height for making principal component chromatographic peak is about the 10%~15% of full scale, then precision measure need testing solution with
Each 20 μ l of contrast solution, impurity reference substance solution, reference substance solution, are injected separately into liquid chromatograph, record chromatogram；For miscellaneous
Matter 7- benzoyl -1,3- Indolin-2-ones, using content of the external standard method by the calculated by peak area impurity；For it is other not
Know impurity, use the chromatogram response that contrast solution is provided with its own counter point by its content of calculated by peak area；For activity
Component content, the content of active component in calculated by peak area composition is pressed with reference substance solution concentration and response with external standard method.
It is well known that 7- benzoyl -1,3- Indolin-2-ones are typical miscellaneous in nepafenac bulk drug and preparation
Its content of quality supervision control is extremely important for drug quality evaluation.
Preparation stability：Place 2 months, combined when determining 0 month and at 2 months under the conditions of medical composite for eye is placed in into 45 DEG C
Impurity 7- benzoyl -1,3- Indolin-2-one contents and active component content, for same composition, calculate it in thing
Impurity 7- benzoyls -1,3- Indolin-2-one increases percentage when at 2 months relative to 0 month, and calculates it at 2 months
Active component remnants rates during relative to 0 month, calculating formula difference is as follows：
After measured：
Medical composite for eye made from following whole embodiments, their active component contents at 0 month are that theory contains
In the range of the 99~101% of amount (theoretical inventory when being prepared according to composition calculates what is obtained), show formulation process
In do not lose active component substantially；
Following whole embodiments are with medical composite for eye made from a collection of bulk drug, their impurity 7- benzene first at 0 month
Acyl group -1,3- Indolin-2-one content is in the range of 0.023~0.036%, each combination prepared using same bulk drug
The impurity content is 0.024% in impurity content no significant difference between thing, bulk drug；
Medical composite for eye made from following whole embodiments, they after the experience high-temperature treatment of 2 months, activity into
Divide remaining rate in the range of 94.6~98.8%, for example three medical composite for eye of gained of embodiment 1~3 are undergoing 2
After the high-temperature treatment of the moon, active component remnants rates are in the range of 97.6~98.8%, the work of other embodiments resulting composition
Property the remaining rate of composition in the range of 94.6~97.4%, it is more slightly worse than embodiment 1-3；
After the experience high-temperature treatment of 2 months, impurity 7- benzoyls -1,3- bis- of each composition of the gained of embodiment 1~3
Hydrogen indoles -2- ketone increases percentage in the range of 27~41%, embodiment 4~11 and each combination of the gained of embodiment 21~24
Impurity 7- benzoyls -1,3- Indolin-2-one of thing increases percentage in the range of 184~272%, such as embodiment
Impurity 7- benzoyls -1,3- Indolin-2-one of 4~6 each compositions of gained increases percentage in 213~236% models
In enclosing, show that other each compositions significantly compare in terms of impurity 7- benzoyls -1,3- Indolin-2-one increase percentage
The composition of embodiment 1~3 is poor, is entirely unacceptable；The remaining rate of above-mentioned active component content increases percentage with impurity
Show that their change is inconsistent, said from the synthesis result of medicine stability, the composition of embodiment 1~3 is significantly
Better than other compositions.
Embodiment 1：Ophthalmically acceptable pharmaceutical composition
Prescription：Nepafenac 0.1% (w/v), Carbopol974P：0.5% (w/v), sodium chloride 0.4% (w/v), malt
Sugar alcohol 2.4% (w/v), tyloxapol 0.01% (w/v), calcium disodium edathamil 0.01% (w/v), BZK
0.01% (w/v), NaOH/HCl are in right amount to pH7.5, Purified Water q. s to 100% (w/v).
Preparation method：Make to be micronized to can by the nepafenacs of 300 mesh and sodium chloride added to recipe quantity about 90% it is pure
Change in water, be stirred to dissolve/be suspended, add other auxiliary materials, be stirred to dissolve, extremely provided with the pH value of NaOH/HCl regulating liquid medicines
Value, adds water to full dose, stirs, be dispensed into eye-drop liquid bottle, produce.
Embodiment 2：Ophthalmically acceptable pharmaceutical composition
Prescription：Nepafenac 0.1% (w/v), Carbopol 974P：0.5% (w/v), sodium chloride 0.4% (w/v), wheat
Bud sugar alcohol 2.4% (w/v), tyloxapol 0.01% (w/v), calcium disodium edathamil 0.01% (w/v), BZK
0.0075% (w/v), NaOH/HCl are in right amount to pH7.5, Purified Water q. s to 100% (w/v).
Preparation method：Make to be micronized to can by the nepafenacs of 300 mesh and sodium chloride added to recipe quantity about 90% it is pure
Change in water, be stirred to dissolve/be suspended, add other auxiliary materials, be stirred to dissolve, extremely provided with the pH value of NaOH/HCl regulating liquid medicines
Value, adds water to full dose, stirs, be dispensed into eye-drop liquid bottle, produce.
Embodiment 3：Ophthalmically acceptable pharmaceutical composition
Prescription：Nepafenac 0.1% (w/v), Carbomer974P：0.5% (w/v), sodium chloride 0.4% (w/v), malt
Sugar alcohol 2.4% (w/v), tyloxapol 0.01% (w/v), calcium disodium edathamil 0.01% (w/v), BZK
0.005% (w/v), NaOH/HCl are in right amount to pH7.3-7.7, Purified Water q. s to 100% (w/v).
Preparation method：Make to be micronized to can by the nepafenacs of 300 mesh and sodium chloride added to recipe quantity about 90% it is pure
Change in water, be stirred to dissolve/be suspended, add other auxiliary materials, be stirred to dissolve, extremely provided with the pH value of NaOH/HCl regulating liquid medicines
Value, adds water to full dose, stirs, be dispensed into eye-drop liquid bottle, produce.
In the present invention, Carbomer 974P and Carbopol 974P are same substance.Tyloxapol is
tyloxapol。
Embodiment 4：Ophthalmically acceptable pharmaceutical composition
Prescription：Nepafenac 0.1% (w/v), Carbopol974P：0.5% (w/v), sodium chloride 0.4% (w/v), malt
Sugar alcohol 2.4% (w/v), tyloxapol 0.01% (w/v), BZK 0.01% (w/v), NaOH/HCl is pure in right amount to pH7.5
Change appropriate amount of water to 100% (w/v).
Preparation method：Make to be micronized to can by the nepafenacs of 300 mesh and sodium chloride added to recipe quantity about 90% it is pure
Change in water, be stirred to dissolve/be suspended, add other auxiliary materials, be stirred to dissolve, extremely provided with the pH value of NaOH/HCl regulating liquid medicines
Value, adds water to full dose, stirs, be dispensed into eye-drop liquid bottle, produce.
Embodiment 5：Ophthalmically acceptable pharmaceutical composition
Prescription：Nepafenac 0.1% (w/v), Carbopol 974P：0.5% (w/v), sodium chloride 0.4% (w/v), wheat
Bud sugar alcohol 2.4% (w/v), tyloxapol 0.01% (w/v), BZK 0.0075% (w/v), NaOH/HCl is in right amount extremely
PH7.5, Purified Water q. s to 100% (w/v).
Preparation method：Make to be micronized to can by the nepafenacs of 300 mesh and sodium chloride added to recipe quantity about 90% it is pure
Change in water, be stirred to dissolve/be suspended, add other auxiliary materials, be stirred to dissolve, extremely provided with the pH value of NaOH/HCl regulating liquid medicines
Value, adds water to full dose, stirs, be dispensed into eye-drop liquid bottle, produce.
Embodiment 6：Ophthalmically acceptable pharmaceutical composition
Prescription：Nepafenac 0.1% (w/v), BZK 0.005% (w/v), Carbomer 974P：0.5% (w/
V), tyloxapol 0.01% (w/v), maltitol 2.4% (w/v), sodium chloride 0.4% (w/v), NaOH/HCl is in right amount extremely
PH7.3-7.7, Purified Water q. s to 100% (w/v).
Preparation method：Make to be micronized to can by the nepafenacs of 300 mesh and sodium chloride added to recipe quantity about 90% it is pure
Change in water, be stirred to dissolve/be suspended, add other auxiliary materials, be stirred to dissolve, extremely provided with the pH value of NaOH/HCl regulating liquid medicines
Value, adds water to full dose, stirs, be dispensed into eye-drop liquid bottle, produce.
Embodiment 7：Ophthalmically acceptable pharmaceutical composition
Prescription：Nepafenac 0.1% (w/v), Carbopol974P：0.5% (w/v), sodium chloride 0.4% (w/v), Tai Luo
Sand pool 0.01% (w/v), calcium disodium edathamil 0.01% (w/v), BZK 0.01% (w/v), NaOH/HCl is suitable
Measure to pH7.5, Purified Water q. s to 100% (w/v).
Preparation method：Make to be micronized to can by the nepafenacs of 300 mesh and sodium chloride added to recipe quantity about 90% it is pure
Change in water, be stirred to dissolve/be suspended, add other auxiliary materials, be stirred to dissolve, extremely provided with the pH value of NaOH/HCl regulating liquid medicines
Value, adds water to full dose, stirs, be dispensed into eye-drop liquid bottle, produce.
Embodiment 8：Ophthalmically acceptable pharmaceutical composition
Prescription：Nepafenac 0.1% (w/v), Carbopol 974P：0.5% (w/v), sodium chloride 0.4% (w/v) is safe
Lip river Sha Bo 0.01% (w/v), calcium disodium edathamil 0.01% (w/v), BZK 0.0075% (w/v), NaOH/
HCl is appropriate to pH7.5, Purified Water q. s to 100% (w/v).
Preparation method：Make to be micronized to can by the nepafenacs of 300 mesh and sodium chloride added to recipe quantity about 90% it is pure
Change in water, be stirred to dissolve/be suspended, add other auxiliary materials, be stirred to dissolve, extremely provided with the pH value of NaOH/HCl regulating liquid medicines
Value, adds water to full dose, stirs, be dispensed into eye-drop liquid bottle, produce.
Embodiment 9：Ophthalmically acceptable pharmaceutical composition
Prescription：Nepafenac 0.1% (w/v), BZK 0.005% (w/v), Carbomer 974P：0.5% (w/
V), tyloxapol 0.01% (w/v), calcium disodium edathamil 0.01% (w/v), sodium chloride 0.4% (w/v), NaOH/
HCl is appropriate to pH7.3-7.7, Purified Water q. s to 100% (w/v).
Preparation method：Make to be micronized to can by the nepafenacs of 300 mesh and sodium chloride added to recipe quantity about 90% it is pure
Change in water, be stirred to dissolve/be suspended, add other auxiliary materials, be stirred to dissolve, extremely provided with the pH value of NaOH/HCl regulating liquid medicines
Value, adds water to full dose, stirs, be dispensed into eye-drop liquid bottle, produce.
Embodiment 10：Ophthalmically acceptable pharmaceutical composition
Prescription and preparation method respectively refer to embodiment 1,2,3, and different is only to replace calcium disodium edathamil therein
Disodium ethylene diamine tetraacetate is changed to, three samples are obtained.
Embodiment 11：Ophthalmically acceptable pharmaceutical composition
Prescription and preparation method respectively refer to embodiment 1,2,3, and different is only that maltitol therein is replaced with into mannitol,
Obtain three samples.
Embodiment 21：Ophthalmically acceptable pharmaceutical composition
Prescription：Nepafenac 0.1% (w/v), Carbopol974P：0.5% (w/v), sodium chloride 0.4% (w/v), sweet dew
Alcohol 2.4% (w/v), tyloxapol 0.01% (w/v), disodium ethylene diamine tetraacetate 0.01% (w/v), BZK 0.01%
(w/v), NaOH/HCl is in right amount to pH7.5, Purified Water q. s to 100% (w/v).
Preparation method：Make to be micronized to can by the nepafenacs of 300 mesh and sodium chloride added to recipe quantity about 90% it is pure
Change in water, be stirred to dissolve/be suspended, add other auxiliary materials, be stirred to dissolve, extremely provided with the pH value of NaOH/HCl regulating liquid medicines
Value, adds water to full dose, stirs, be dispensed into eye-drop liquid bottle, produce.
Embodiment 22：Ophthalmically acceptable pharmaceutical composition
Prescription：Nepafenac 0.1% (w/v), Carbopol 974P：0.5% (w/v), sodium chloride 0.4% (w/v) is sweet
Reveal alcohol 2.4% (w/v), tyloxapol 0.01% (w/v), disodium ethylene diamine tetraacetate 0.01% (w/v), BZK 0.01%
(w/v), NaOH/HCl is in right amount to pH7.5, Purified Water q. s to 100% (w/v).
Preparation method：Make to be micronized to can by the nepafenacs of 300 mesh and sodium chloride added to recipe quantity about 90% it is pure
Change in water, be stirred to dissolve/be suspended, add other auxiliary materials, be stirred to dissolve, extremely provided with the pH value of NaOH/HCl regulating liquid medicines
Value, adds water to full dose, stirs, be dispensed into eye-drop liquid bottle, produce.
Embodiment 23：Ophthalmically acceptable pharmaceutical composition
Prescription：Nepafenac 0.1% (w/v), Carbopol974P：0.5% (w/v), sodium chloride 0.4% (w/v), sweet dew
Alcohol 2.4% (w/v), tyloxapol 0.01% (w/v), NaOH/HCl is in right amount to pH7.5, Purified Water q. s to 100% (w/v).
Preparation method：Make to be micronized to can by the nepafenacs of 300 mesh and sodium chloride added to recipe quantity about 90% it is pure
Change in water, be stirred to dissolve/be suspended, add other auxiliary materials, be stirred to dissolve, extremely provided with the pH value of NaOH/HCl regulating liquid medicines
Value, adds water to full dose, stirs, be dispensed into eye-drop liquid bottle, produce.
Embodiment 24：Ophthalmically acceptable pharmaceutical composition
Prescription：Nepafenac 0.1% (w/v), BZK 0.005% (w/v), Carbomer 974P：0.5% (w/
V), tyloxapol 0.01% (w/v), disodium ethylene diamine tetraacetate 0.01% (w/v), mannitol 2.4% (w/v), sodium chloride
0.4% (w/v), NaOH/HCl are in right amount to pH7.3-7.7, Purified Water q. s to 100% (w/v).
Preparation method：Make to be micronized to can by the nepafenacs of 300 mesh and sodium chloride added to recipe quantity about 90% it is pure
Change in water, be stirred to dissolve/be suspended, add other auxiliary materials, be stirred to dissolve, extremely provided with the pH value of NaOH/HCl regulating liquid medicines
Value, adds water to full dose, stirs, be dispensed into eye-drop liquid bottle, produce.
The present invention is described by reference to certain preferred embodiments；It should be understood, however, that it can be specific with other
Form or its variant are implemented, without departing from its spirit and inner characteristic.The embodiment above is accordingly regarded as comprehensive
Illustrative and not restrictive, the scope of the present invention is by appended claims rather than is described above shown.
Claims (10)
1. ophthalmically acceptable pharmaceutical composition, including：A) 0.09-0.11% (w/v) nepafenac；B) 0.4-0.6% (w/v) blocks
Ripple nurse；C) nonionic surfactant；D) tension regulator, presenting in an amount at least sufficient to makes the osmotic pressure molality of composition be
250-350mOsm/kg；E) pH adjusting agent, presenting in an amount at least sufficient to makes the pH of composition be 7.0-7.8；And f) water, wherein composition is optional
Contain the composition selected from preservative and intercalating agent.
2. the pharmaceutical composition of claim 1, wherein composition include 0.1% (w/v) nepafenac.
3. the pharmaceutical composition of claim 1, wherein composition include 0.5% (w/v) carbomer；For example, the carbomer be with
Allyl sucrose or the acrylate copolymer of Allyl pentaerythritol crosslinking.
4. the pharmaceutical composition of claim 1, wherein nonionic surfactant are tyloxapols；For example, said composition bag
Containing 0.01% (w/v) tyloxapol.
5. the pharmaceutical composition of claim 1, wherein tension regulator are selected from metal chloride salt and mannitol；For example, this
Power conditioning agent includes sodium chloride and mannitol；For example, said composition includes 0.3-0.5% (w/v) sodium chloride and 2-3% (w/v)
Mannitol；For example, said composition includes 0.4% (w/v) sodium chloride and 2.4% (w/v) mannitol.
6. the pharmaceutical composition of claim 1, wherein pH adjusting agent are selected from hydrochloric acid and sodium hydroxide；For example, this its make composition
PH be 7.3-7.7.
7. the pharmaceutical composition of claim 1, wherein composition contain preservative and intercalating agent；For example, the preservative is selected from halogen
Change zephiran；Polyquaternium -1 and chlorine dioxide；For example, the preservative is BZK；For example, said composition is included
0.005% BZK.
8. the pharmaceutical composition of claim 1, wherein intercalating agent be selected from disodium ethylene diamine tetraacetate, sodium versenate,
Tetrasodium ethylenediamine tetraacetate.
9. the pharmaceutical composition of claim 7, wherein composition include 0.001-0.1% (w/v) disodium ethylene diamine tetraacetate.
10. ophthalmically acceptable pharmaceutical composition, including：A) 0.1% (w/v) nepafenac；B) 0.5% (w/v) carbomer；c)
0.01% (w/v) tyloxapol；D) 0.4% (w/v) sodium chloride；E) 2.4% (w/v) mannitol；F) pH adjusting agent, presents in an amount at least sufficient to
The pH for making composition is 7.3-7.7；G) 0.005% (w/v) BZK；H) 0.01% disodium ethylene diamine tetraacetate；And it is i) pure
Change water.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201611233627.7A CN106963730A (en) | 2016-12-22 | 2016-12-22 | Highly stable nepafenac medical composite for eye |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201611233627.7A CN106963730A (en) | 2016-12-22 | 2016-12-22 | Highly stable nepafenac medical composite for eye |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN106963730A true CN106963730A (en) | 2017-07-21 |
Family
ID=59334541
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201611233627.7A Pending CN106963730A (en) | 2016-12-22 | 2016-12-22 | Highly stable nepafenac medical composite for eye |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106963730A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107024550A (en) * | 2016-12-21 | 2017-08-08 | 广州仁恒医药科技股份有限公司 | The quality control method of nepafenac medical composite for eye |
| CN108042670A (en) * | 2017-12-29 | 2018-05-18 | 广州仁恒医药科技股份有限公司 | A kind of pharmaceutical composition containing nepafenac and preparation method thereof |
| CN114272207A (en) * | 2022-01-21 | 2022-04-05 | 山东诺明康药物研究院有限公司 | Nanocrystal suspension eye drops and preparation method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101068573A (en) * | 2004-12-02 | 2007-11-07 | 爱尔康公司 | Topical nepafenac formulations |
| CN107024550A (en) * | 2016-12-21 | 2017-08-08 | 广州仁恒医药科技股份有限公司 | The quality control method of nepafenac medical composite for eye |
-
2016
- 2016-12-22 CN CN201611233627.7A patent/CN106963730A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101068573A (en) * | 2004-12-02 | 2007-11-07 | 爱尔康公司 | Topical nepafenac formulations |
| CN107024550A (en) * | 2016-12-21 | 2017-08-08 | 广州仁恒医药科技股份有限公司 | The quality control method of nepafenac medical composite for eye |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107024550A (en) * | 2016-12-21 | 2017-08-08 | 广州仁恒医药科技股份有限公司 | The quality control method of nepafenac medical composite for eye |
| CN108042670A (en) * | 2017-12-29 | 2018-05-18 | 广州仁恒医药科技股份有限公司 | A kind of pharmaceutical composition containing nepafenac and preparation method thereof |
| CN114272207A (en) * | 2022-01-21 | 2022-04-05 | 山东诺明康药物研究院有限公司 | Nanocrystal suspension eye drops and preparation method thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US8389014B2 (en) | Gel useful for the delivery of ophthalmic drugs | |
| JP2001521885A (en) | Long-acting ophthalmic composition containing a water-soluble drug | |
| TW309426B (en) | ||
| JP7340139B2 (en) | Methods for improving the stability of low concentration atropine ophthalmic formulations | |
| WO2007058935A2 (en) | Ophthalmic composition for dry eye therapy | |
| EP1938799B1 (en) | Compositions for treating and preventing posterior segment ophthalmic disorders and use thereof | |
| CN102724965A (en) | Carboxyvinyl polymer-containing nanoparticle suspensions | |
| CN106963730A (en) | Highly stable nepafenac medical composite for eye | |
| CN106794254A (en) | Topical formulations and its application | |
| JP2021518352A (en) | Pharmaceutical composition containing timolol | |
| CN105106107A (en) | Eye gellan gum in-situ gel made of bendazac lysine and preparing method of eye gellan gum in-situ gel | |
| CN103977011B (en) | Travoprost and timolol-containing ophthalmic gel and preparation method thereof | |
| CN105943500B (en) | A kind of antimycotic solution of ophthalmically acceptable nano-micelle containing Chinese mugwort Saperconazole | |
| KR20140069210A (en) | Ophthalmic gel compositions | |
| CN102085175B (en) | Ophthalmic gel and preparation method thereof | |
| CN107024550A (en) | The quality control method of nepafenac medical composite for eye | |
| WO2012068998A2 (en) | Triamcinolone acetonide ophthalmic preparation and preparation method thereof | |
| EP3675872B1 (en) | Compositions providing improved eye comfort | |
| US20120028947A1 (en) | Ophthalmic Compositions | |
| GR1010024B (en) | Pharmaceutical brimonidine-containing preparation for ocular administration | |
| TWI805705B (en) | Methods of use and pharmaceutical compositions of a selective syk inhibitor | |
| CN100360132C (en) | Combination of medication for antivirus in use for eye region and preparation method | |
| KR100894385B1 (en) | Use of non-feminizing estrogens as retinoprotective agents for the treatment of glaucoma | |
| CN109200016A (en) | A kind of Benzydalysine eye drop and preparation method thereof and purposes | |
| CN103977008A (en) | Dorzolamide and timolol-containing ophthalmic gel and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| DD01 | Delivery of document by public notice |
Addressee: Zhou Shengan Document name: Notification of Acceptance of Patent Application |
|
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20170721 |
|
| WD01 | Invention patent application deemed withdrawn after publication |