CN108338969A - A kind of low concentration tropane class drug eye drops and preparation method thereof - Google Patents
A kind of low concentration tropane class drug eye drops and preparation method thereof Download PDFInfo
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
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- 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
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Abstract
The invention belongs to field of pharmaceutical technology, and in particular to a kind of low concentration tropane class drug eye drops, including following constituent：Tropane class drug 0.0005~0.5%；With clathration and irritating solute 0~10% can be reduced；With the solute 0.01~5% for increasing liquid viscosity；Acid-base modifier, amount are subject to pH and are adjusted to 4.0~6.5；Osmotic pressure regulator, amount are subject to osmotic pressure and are adjusted to 280~330mOsm/L；Bacteriostatic agent 0.01~0.05%；Surplus is water for injection；Preparation method includes the following steps：S1, it is weighed according to the ratio with clathration and irritating solute can be reduced be dissolved in the water, add tropane class drug, it is placed in ultrasonic oscillation cleaning machine, ultrasonic mixing 30 minutes, makes tropane class drug that can simultaneously be reduced irritating solute with clathration and include；S2, ethyl hydroxy benzoate, sodium chloride, sodium hyaluronate are weighed according to the ratio be dissolved in 40~75 DEG C of water for injection；S3, S2 is mixed with S1 acquired solutions；S4, filtering, sterilizing, packing to get.
Description
Technical field
The invention belongs to field of pharmaceutical technology, and in particular to a kind of low concentration tropane class drug eye drops and its preparation side
Method.
Background technology
Atropine sulfate ophthalmic solution record in《Chinese Hospitals preparation specification》The Western medicine preparation second edition, respectively 0.5%,
The preparation specification of 1% and 2% 3 concentration, composition are：
Preparation method：Ethyl hydroxy benzoate is dissolved in suitable hot water for injection, adds sodium chloride to make it dissolve, lets cool, is added
After atropine sulfate dissolving, filtering, from filter plus water for injection makes into 1000mL, stirs evenly, 100 DEG C of flowing steam sterilizations 30 divide
Clock, it is aseptic subpackaged to get.
Act on purposes：Mydriasis.For checking eyeground and ulcer of the cornea, keratitis, iridocyclitis.The sulfuric acid of the prescription
Atropine eye drops is 0.5% (w/v) to 2% (w/v) since main ingredient concentration is high, on the one hand can be drawn during Clinical practice
Follicular conjunctivitis is played, the local anaphylaxises such as eyelid skin eczema and eyes-affinity hyperemia erosion, on the other hand, liquid passes through lacrimal passage
Into after oral cavity, mouth parched and tongue scorched, flush can be caused, or even can also cause the symptoms such as body temperature raising, lead to patient compliance
It is bad, it influences to treat.
Invention content
One aspect of the present invention technical problems to be solved are to provide a kind of low concentration tropane class drug eye drops, to enhance
Curative effect of medication reduces adverse reaction.
In order to solve the above-mentioned technical problem, the technical scheme is that：
A kind of low concentration tropane class drug eye drops, including following constituent：
Tropane class drug 0.0005~0.5% (w/v)；With clathration and irritating solute 0~10% can be reduced
(w/v)；With the solute 0.01~5% (w/v) for increasing liquid viscosity；Acid-base modifier, amount is adjusted to 4.0 with pH~
Subject to 6.5；Osmotic pressure regulator, amount are subject to osmotic pressure and are adjusted to 280~330mOsm/L；Bacteriostatic agent 0.01~0.05%
(w/v)；Surplus is water for injection；The ratio of the content of each component is w/v；
The tropane class drug be atropine sulfate, hyoscine, belladonna alkaloids, coca alkaloids, anisodamine, after
Horse tropine, atropine or other using atropine as downstream product made of intermediate or Atropine derivatives；
It is described that there is clathration and irritating solute can be reduced as hydroxypropyl-β-cyclodextrin, beta-cyclodextrin and ring paste
It is one or more in smart analog derivative；
The solute with increase liquid viscosity is polyethylene glycol, polyvinyl alcohol, carbomer, sodium hyaluronate, methyl
It is one or more in cellulose and glycerine；
Acid-base modifier be disodium hydrogen phosphate-phosphate sodium dihydrogen buffer solution, potassium dihydrogen phosphate-dipotassium hydrogen phosphate buffer solution,
It is one or more in boric acid-borate buffer solution, citric acid, sodium citrate and acetic acid；
The osmotic buffering agent is sodium chloride or glucose；
The bacteriostatic agent be selected from ethyl hydroxy benzoate, methyl hydroxybenzoate, Nipasol, phenylmercuric acetate, anesin, thimerosal,
It is one or more in benzalkonium chloride and benzalkonium bromide.
In low concentration tropane class drug eye drops provided by the invention, it is preferable that it includes following each component：Sulfuric acid Ah
Tropine 0.0005~0.5% (w/v), sodium hyaluronate 0.01~0.35% (w/v), beta-cyclodextrin 0~10% (w/v), sodium chloride
PH is adjusted to 4.0~6.5 by 0.75~0.90% (w/v), ethyl hydroxy benzoate 0.01~0.05% (w/v) with phosphate buffer, remaining
Amount is water for injection.
In low concentration tropane class drug eye drops provided by the invention, it is preferable that it includes following each component：Sulfuric acid Ah
Tropine 0.0008~0.3% (w/v), sodium hyaluronate 0.05~0.30% (w/v), 0.3~2% (w/v) sodium chloride 0.80~
PH is adjusted to 5.0~6.5 by 0.90% (w/v), ethyl hydroxy benzoate 0.02~0.05% (w/v) with phosphate buffer, and surplus is note
It penetrates and uses water.
In low concentration tropane class drug eye drops provided by the invention, it is preferable that it includes following each component：Sulfuric acid Ah
Tropine 0.01% (w/v), sodium hyaluronate 0.15% (w/v), 0.5% (w/v) sodium chloride 0.85% (w/v), ethyl hydroxy benzoate
PH is adjusted to 6.0 by 0.03% (w/v) with phosphate buffer, and surplus is water for injection.
The ratio of each component is w/v in the present invention.
Another aspect of the present invention problem to be solved is to provide a kind of preparation side of low concentration tropane class drug eye drops
Method includes the following steps：
S1, it is weighed according to the ratio with clathration and irritating solute can be reduced be dissolved in water for injection, added
Tropane class drug, is placed in ultrasonic oscillation cleaning machine, ultrasonic mixing 30 minutes, make tropane class drug by with clathration simultaneously
Irritating solute inclusion can be reduced, solution 1 is obtained；
S2, ethyl hydroxy benzoate is weighed according to the ratio be dissolved in 40~75 DEG C of water for injection, obtain solution 2；
S3, sodium chloride is weighed according to the ratio be dissolved in solution 2, it is cooling, obtain solution 3；
S4, sodium hyaluronate is weighed according to the ratio be completely dissolved in solution 3, obtain solution 4；
S5, solution 1 is added in solution 4, mixing obtains solution 5；
S6, solution 5 is filtered, from filter plus water for injection is rinsed filter, and surplus adds water for injection to supply, and stirs
It is even, 121 DEG C of steam sterilizings 12 minutes, it is aseptic subpackaged to get.
In the preparation method of low concentration tropane class drug eye drops provided by the invention, it is preferable that described in step S2
Water for injection is 50 DEG C.
This preparation is clinically used to prevent and treat myopia.Since main ingredient concentration is relatively low, extremely for 0.01% (g/mL)
0.5% (g/mL), and the auxiliary material sodium hyaluronate for increasing eye drip fluid viscosity, improved atropine sulfate eye drip are added in prescription
It is short in eye retention time that liquid not only overcomes former eye drops, the shortcomings that cannot being contacted for a long time with eye, also overcomes sulfuric acid atropic
Product eye ointment works, and slow, dosage is bad grasps, is easy the shortcomings of pollution.This preparation strong, surface-active with liquid adhesion strength
Height can increase the features such as contact area and time of liquid and eyeball, and liquid forms Reticular breathable film in eyeball surface, can keep away
Exempt from atropine sulfate burst release drug and flow into nasolacrimal duct and absorb, but can slow release drug in a long time, to
Enhance curative effect of medication, reduces the incidence of adverse reaction.
Specific implementation mode
The specific implementation mode of the present invention is described further below.It should be noted that for these implementations
The explanation of mode is used to help understand the present invention, but does not constitute limitation of the invention.In addition, invention described below
Involved technical characteristic can be combined with each other as long as they do not conflict with each other in each embodiment.
Embodiment 1
Present embodiments provide a kind of low concentration tropane class drug eye drops comprising following each component：Atropine sulfate
0.02% (w/v), sodium hyaluronate 0.35% (w/v), sodium chloride 0.75% (w/v), ethyl hydroxy benzoate 0.01% (w/v), use phosphoric acid
PH is adjusted to 4.6 by buffer solution, and surplus is water for injection.
The preparation method of the low concentration tropane class drug eye drops includes the following steps：
S1, ethyl hydroxy benzoate is weighed according to the ratio be dissolved in 75 DEG C of water for injection, obtain solution 1；
S2, sodium chloride is weighed according to the ratio be dissolved in solution 1, it is cooling, obtain solution 2；
S3, sodium hyaluronate is weighed according to the ratio be completely dissolved in solution 2, obtain solution 3；
S4, sulfuric acid is weighed according to the ratio tropine is taken to be dissolved in solution 3, obtain solution 4；
S5, solution 4 is filtered, from filter plus water for injection is rinsed filter, and surplus adds water for injection to supply, and stirs
It is even, 121 DEG C of steam sterilizings 12 minutes, it is aseptic subpackaged to get.
Embodiment 2
Present embodiments provide a kind of low concentration tropane class drug eye drops comprising following each component：Atropine sulfate
0.05% (w/v), sodium hyaluronate 0.01% (w/v), beta-cyclodextrin 0.3% (w/v), sodium chloride 0.90% (w/v), ethyl hydroxy benzoate
PH is adjusted to 6.2 by 0.05% (w/v) with phosphate buffer, and surplus is water for injection.
The preparation method of the low concentration tropane class drug eye drops includes the following steps：
S1, beta-cyclodextrin is weighed according to the ratio be dissolved in water for injection, then weigh atropine sulfate addition, be placed in ultrasonic wave
It shakes in cleaning machine, ultrasonic mixing 30 minutes makes atropine sulfate be included completely by beta-cyclodextrin, obtains solution 1；
S2, ethyl hydroxy benzoate is weighed according to the ratio be dissolved in 40 DEG C of water for injection, obtain solution 2；
S3, sodium chloride is weighed according to the ratio be dissolved in solution 2, it is cooling, obtain solution 3；
S4, sodium hyaluronate is weighed according to the ratio be completely dissolved in solution 3, obtain solution 4；
S5, solution 1 is added in solution 4, obtains solution 5；
S6, solution 5 is filtered, from filter plus water for injection is rinsed filter, and surplus adds water for injection to supply, and stirs
It is even, 121 DEG C of steam sterilizings 12 minutes, it is aseptic subpackaged to get.
Embodiment 3
Present embodiments provide a kind of low concentration tropane class drug eye drops comprising following each component：Atropine sulfate
0.0009% (w/v), sodium hyaluronate 0.05% (w/v), beta-cyclodextrin 2% (w/v), sodium chloride 0.86% (w/v), ethyl hydroxy benzoate
PH is adjusted to 5.8 by 0.05% (w/v) with phosphate buffer, and surplus is water for injection.
The preparation method of the low concentration tropane class drug eye drops includes the following steps：
S1, beta-cyclodextrin is weighed according to the ratio be dissolved in water for injection, then weigh atropine sulfate addition, be placed in ultrasonic wave
It shakes in cleaning machine, ultrasonic mixing 30 minutes makes atropine sulfate be included completely by beta-cyclodextrin, obtains solution 1；
S2, ethyl hydroxy benzoate is weighed according to the ratio be dissolved in 45 DEG C of water for injection, obtain solution 2；
S3, sodium chloride is weighed according to the ratio be dissolved in solution 2, it is cooling, obtain solution 3；
S4, sodium hyaluronate is weighed according to the ratio be completely dissolved in solution 3, obtain solution 4；
S5, solution 1 is added in solution 3, mixing obtains solution 5；
S6, solution 5 is filtered, from filter plus water for injection is rinsed filter, and surplus adds water for injection to supply, and stirs
It is even, 121 DEG C of steam sterilizings 12 minutes, it is aseptic subpackaged to get.
Embodiment 4
Present embodiments provide a kind of low concentration tropane class drug eye drops comprising following each component：Atropine sulfate
0.1% (w/v), sodium hyaluronate 0.25% (w/v), beta-cyclodextrin 0.5% (w/v), sodium chloride 0.75% (w/v), ethyl hydroxy benzoate
PH is adjusted to 5.0 by 0.02% (w/v) with phosphate buffer, and surplus is water for injection.
The preparation method of the low concentration tropane class drug eye drops includes the following steps：
S1, beta-cyclodextrin is weighed according to the ratio be dissolved in water for injection, then weigh atropine sulfate addition, be placed in ultrasonic wave
It shakes in cleaning machine, ultrasonic mixing 30 minutes makes atropine sulfate be included completely by beta-cyclodextrin, obtains solution 1；
S2, ethyl hydroxy benzoate is weighed according to the ratio be dissolved in 50 DEG C of water for injection, obtain solution 2；
S3, sodium chloride is weighed according to the ratio be dissolved in solution 2, it is cooling, obtain solution 3；
S4, sodium hyaluronate is weighed according to the ratio be completely dissolved in solution 3, obtain solution 4；
S5, solution 1 is added in solution 4, mixing obtains solution 5；
S6, solution 5 is filtered, from filter plus water for injection is rinsed filter, and surplus adds water for injection to supply, and stirs
It is even, 121 DEG C of steam sterilizings 12 minutes, it is aseptic subpackaged to get.
Embodiment 5
Present embodiments provide a kind of low concentration tropane class drug eye drops comprising following each component：Atropine sulfate
0.01% (w/v), sodium hyaluronate 0.3% (w/v), beta-cyclodextrin 1% (w/v), sodium chloride 0.75% (w/v), ethyl hydroxy benzoate
PH is adjusted to 4.5 by 0.03% (w/v) with phosphate buffer, and surplus is water for injection.
The preparation method of the low concentration tropane class drug eye drops includes the following steps：
S1, beta-cyclodextrin is weighed according to the ratio be dissolved in water for injection, then weigh atropine sulfate addition, be placed in ultrasonic wave
It shakes in cleaning machine, ultrasonic mixing 30 minutes makes atropine sulfate be included completely by beta-cyclodextrin, obtains solution 1；
S2, ethyl hydroxy benzoate is weighed according to the ratio be dissolved in 50 DEG C of water for injection, obtain solution 2；
S3, sodium chloride is weighed according to the ratio be dissolved in solution 2, it is cooling, obtain solution 3；
S4, sodium hyaluronate is weighed according to the ratio be completely dissolved in solution 3, obtain solution 4；
S5, solution 1 is added in solution 4, mixing obtains solution 5；
S6, solution 5 is filtered, from filter plus water for injection is rinsed filter, and surplus adds water for injection to supply, and stirs
It is even, 121 DEG C of steam sterilizings 12 minutes, it is aseptic subpackaged to get.
Embodiment 6
Present embodiments provide a kind of low concentration tropane class drug eye drops comprising following each component：Atropine sulfate
0.5% (w/v), sodium hyaluronate 0.3% (w/v), beta-cyclodextrin 1.5% (w/v), sodium chloride 0.75% (w/v), ethyl hydroxy benzoate
PH is adjusted to 5.5 by 0.03% (w/v) with phosphate buffer, and surplus is water for injection.
The preparation method of the low concentration tropane class drug eye drops includes the following steps：
S1, beta-cyclodextrin is weighed according to the ratio be dissolved in water for injection, then weigh atropine sulfate addition, be placed in ultrasonic wave
It shakes in cleaning machine, ultrasonic mixing 30 minutes makes atropine sulfate be included completely by beta-cyclodextrin, obtains solution 1；
S2, ethyl hydroxy benzoate is weighed according to the ratio be dissolved in 65 DEG C of water for injection, obtain solution 2；
S3, sodium chloride is weighed according to the ratio be dissolved in solution 2, it is cooling, obtain solution 3；
S4, sodium hyaluronate is weighed according to the ratio be completely dissolved in solution 3, obtain solution 4；
S5, solution 1 is added in solution 3, mixing obtains solution 5；
S6, solution 5 is filtered, from filter plus water for injection is rinsed filter, and surplus adds water for injection to supply, and stirs
It is even, 121 DEG C of steam sterilizings 12 minutes, it is aseptic subpackaged to get.
Embodiment 7
Present embodiments provide a kind of low concentration tropane class drug eye drops comprising following each component：Atropine sulfate
0.0007% (w/v), sodium hyaluronate 0.28% (w/v), beta-cyclodextrin 4% (w/v), sodium chloride 0.75% (w/v), ethyl hydroxy benzoate
PH is adjusted to 4.0 by 0.04% (w/v) with phosphate buffer, and surplus is water for injection.
The preparation method of the low concentration tropane class drug eye drops includes the following steps：
S1, beta-cyclodextrin is weighed according to the ratio be dissolved in water for injection, then weigh atropine sulfate addition, be placed in ultrasonic wave
It shakes in cleaning machine, ultrasonic mixing 30 minutes makes atropine sulfate be included completely by beta-cyclodextrin, obtains solution 1；
S1, ethyl hydroxy benzoate is weighed according to the ratio be dissolved in 62 DEG C of water for injection, obtain solution 2；
S2, sodium chloride is weighed according to the ratio be dissolved in solution 2, it is cooling, obtain solution 3；
S3, sodium hyaluronate is weighed according to the ratio be completely dissolved in solution 3, obtain solution 4；
S4, solution 1 is added in solution 4, mixing obtains solution 5；
S5, solution 5 is filtered, from filter plus water for injection is rinsed filter, and surplus adds water for injection to supply, and stirs
It is even, 121 DEG C of steam sterilizings 12 minutes, it is aseptic subpackaged to get.
Embodiment 8
Present embodiments provide a kind of low concentration tropane class drug eye drops comprising following each component：Atropine sulfate
0.0005% (w/v), sodium hyaluronate 0.35% (w/v), beta-cyclodextrin 3% (w/v), sodium chloride 0.75% (w/v), ethyl hydroxy benzoate
PH is adjusted to 6.5 by 0.01% (w/v), asparagine 0.01% (w/v) with phosphate buffer, and surplus is water for injection.
The preparation method of the low concentration tropane class drug eye drops includes the following steps：
S1, beta-cyclodextrin is weighed according to the ratio be dissolved in water for injection, then weigh atropine sulfate addition, be placed in ultrasonic wave
It shakes in cleaning machine, ultrasonic mixing 30 minutes makes atropine sulfate be included completely by beta-cyclodextrin, obtains solution 1；
S2, ethyl hydroxy benzoate is weighed according to the ratio be dissolved in 75 DEG C of water for injection, obtain solution 2；
S3, sodium chloride is weighed according to the ratio be dissolved in solution 2, it is cooling, obtain solution 3；
S4, sodium hyaluronate is weighed according to the ratio be completely dissolved in solution 3, obtain solution 4；
S5, solution 1 is added in solution 4, mixing obtains solution 5；
S6, solution 5 is filtered, from filter plus water for injection is rinsed filter, and surplus adds water for injection to supply, and stirs
It is even, 121 DEG C of steam sterilizings 12 minutes, it is aseptic subpackaged to get.
Test example
1. clinical test
1.1 diagnostic criteria
According to the diagnostic criteria of ophthalmology branch of Chinese Medical Association ophthalmic dioptrics group in October, 1985 formulation (under normality adjusting
Distant vision reduces, and near vision is normal, and inspection shadow is that Myopia is ametropia, and the near-sighted shape of distant vision can be improved using negative spherical lens
State).
The selection of 1.2 cases
1.2.1 the general information of case
This research object is selected from Hong Hui hospitals of Yunnan Province (the 4th affiliated hospital of Kunming Medical University) children's ophthalmology outpatient service
In July, 2015~2016 year are diagnosed as myopia and meet the patient 500 of inclusion criteria January, be divided into eight treatment groups (A, B,
C, D, E, F, G and H group), blank control group (J groups) of an experimental comparison group (I groups), every group each 50.A groups：With implementation
1 gained eye drops of example (i.e. content of atropine sulfate is 0.02%) eye droppings, primary before sleeping every night, eyes alternating；B groups：With implementation
2 gained eye drops of example (i.e. content of atropine sulfate is 0.05%) eye droppings, primary before sleeping every night, eyes alternating；C groups：With implementation
3 gained eye drops of example (i.e. content of atropine sulfate is 0.0009%) eye droppings, primary before sleeping every night, eyes alternating；D groups：With reality
Apply 4 gained eye drops of example (i.e. content of atropine sulfate is 0.1%) eye droppings, twice a week, eyes alternating；E groups：With embodiment 5
Gained eye drops (i.e. content of atropine sulfate is 0.01%) eye droppings, primary before sleeping every night, eyes alternating；F groups：With embodiment 6
Eye drops (i.e. content of atropine sulfate is 0.5%) eye droppings of gained, twice a week, eyes alternating；G groups：With 7 gained of embodiment
Eye drops (i.e. content of atropine sulfate be 0.0007%) eye droppings, primary before sleeping every night, eyes alternating；H groups：With embodiment 8
Eye drops (i.e. content of atropine sulfate 0.0005) eye droppings of gained, primary before sleeping every night, eyes alternating；I groups：1% atropine
Eye gel point eyes, once every 2 weeks, eyes alternating；J groups：Mirror is worn in conventional optometry.Patient man 277, female 223, age 7~13
Year.
1.2.2 the inclusion criteria of case
(1) meet near-sighted diagnostic criteria；
(2) 7-16 Sui students；
(3) U.S. Dolly eye drops eye drip Mydriasis Test ＆ Optometry equivalent concave-sphere ＞ -1.00D, astigmatism≤- 1.00D, intraocular pressure after 30 minutes
＜ 21mmHg, anterior ocular segment and funduscopy are normal, most preferably correct defects of vision >=1.0, near vision >=1.0.
(4) it can be treated as required；
(5) patient parent signs informed consent form.
1.2.3 case exclusion criteria
(1) there is aobvious oblique, eye traumas, other eye disease and family's glaucoma Genetic history patient；
(2) there are the pathological myopia of ocular complications and the myopia of Familial Occurrence；
(3) mixed astigmatism；
(4) it is not resistant to photophobia caused by atropine mydriasis and receives other to control with the relevant drug of myopia and physics
Treat patient；
(5) allergic constitution, other severe total Diseases such as have congenital heart disease.
1.3 reagents and instrument and equipment
1% eye gel for atropine sulfate, trade name：Enlightening is kind, manufacturer：Shenyang Sinqi Eye Pharmaceutical Co., Ltd., rule
Lattice：2.5 gram：25 milligrams, main component：Atropine sulfate is 1.0%, is 4.0% containing hypromellose, and boronic acid containing is
0.5%, borax 1.0%, chloride containing benzene first hydroxylamine is 0.01%.
Eye drops made from embodiment 1 to 8 is pressed respectively, is voluntarily prepared by Pharmacy of No.2 People's Hospital, Yunnan Prov..
Inspection apparatus：It is IOL Master optical bios measuring instruments (Zeiss), rafractive (Topcon RM8900), comprehensive
Close optometry unit (Topcon CV3000), automatic intraocular pressure instrument (Topcon CT80), standard logarithmic visual acuity chart, slit-lamp microscope,
Hand-held ophthalmoscope.
2. research method
2.1 determine near-sighted type
All infant elder generation microcoria retinoscopy optometries, then with retinoscopy optometry after U.S. Dolly putting drops in eyes 30 minutes.Record inspection
It looks into as a result, the refractive diopter equivalent concave-sphere number of degrees (D) indicate, equivalent concave-sphere presses the concave-sphere number of degrees+mean of cylindrical diopter/2.
2.2 therapy
Patient is first given before medication and parent links up the therapeutic effect and side effect of various concentration atropine eye drops and gel,
Will have agreed to and can the patient of medication as required be included in GP TH.A groups：With 1 gained eye drops of embodiment, (i.e. atropine sulfate contains
Amount is 0.02%) eye droppings, primary before sleeping every night, eyes alternating；B groups：With 2 gained eye drops of embodiment, (i.e. atropine sulfate contains
Amount is 0.05%) eye droppings, primary before sleeping every night, eyes alternating；C groups：With 3 gained eye drops of embodiment, (i.e. atropine sulfate contains
Amount is 0.0009%) eye droppings, primary before sleeping every night, eyes alternating；D groups：With 4 gained eye drops (i.e. atropine sulfate of embodiment
Content is 0.1%) eye droppings, twice a week, eyes alternating；E groups：With 5 gained eye drops of embodiment, (i.e. content of atropine sulfate is
0.01%) eye droppings, primary before sleeping every night, eyes alternating；F groups：With eye drops (the i.e. content of atropine sulfate of 6 gained of embodiment
For 0.5%) eye droppings, twice a week, eyes alternating；G groups：With the eye drops of 7 gained of embodiment, (i.e. content of atropine sulfate is
0.0007%) eye droppings, primary before sleeping every night, eyes alternating；H groups：With the eye drops of 8 gained of embodiment, (i.e. atropine sulfate contains
0.0005) eye droppings is measured, primary before sleeping every night, eyes alternating；I groups：1% atropine eye gel point eyes, once every 2 weeks, eyes are handed over
It replaces；J groups：Mirror is worn in conventional optometry.Check is primary per March by all patients, follow-up 1 year.
2.3 observation index
Monthly monitor treatment group and experimental comparison group intraocular pressure；Observe the diopter after each group patient March, June and December and
Axis oculi changes；Advise patient and parent to record the eye droppings time on calendar, at the same give near vision variation after charting point atropine,
Photophobia continuous days.The value that data are inspection shadow after U.S. Dolly eyedrops mydriasis is recorded, retinoscopy optometry is responsible for by professional.
3.3 statistical analysis technique
For statistical analysis using SPSS17.0 software packages, enumeration data, which compares, in general analysis of clinical uses χ2Card side
It examines, measurement data is indicated with mean ± standard deviation, and each group uses self pair sample t-test, P before and after treatment<0.05 is poor
It is different statistically significant.
3, clinical data
A groups 46, B groups 47, C groups 46, D groups 45, E groups 47, F groups 47, G groups 46, H groups 45, I groups 38
With the 47 observation treatments for completing 1 year of J groups.
3.1 efficiency analysis
3.1.1 the variation of diopter
Before treatment, the not statistically significant (P of A, B, C, D, E, F, G, H, I and J group diopter comparing difference>0.05).1 year
Afterwards, A, B, C, D, E, F, I, J, six groups of patient's diopters have increases to a certain degree, respectively (- 4.32 ± 0.25) D, (- 4.46
±1.03)D、(-4.72±0.11)D、(-4.35±0.12)D、(-4.69±0.91)D、(-4.12±0.19)D、(-4.65±
0.07) D, (- 4.75 ± 0.17) D, (- 3.92 ± 0.31) D and (- 4.61 ± 0.19) D.It is shown in Table 1.
1 six groups of patient's diopter (D) variations of table
Statistical result showed, statistical result showed, C, E, G, H group and the variation of A, B, D, F, I group diopter have statistics poor
Different, C, E, G, H group mypia progression are very fast, illustrate extremely low concentration (0.0005%, 0.0007%, 0.009%, 0.01%) atropine
It is relatively poor to control mypia progression effect；A, comparison diopter variation no difference of science of statistics between B, D, F, I group group, 0.02%,
0.05%, 0.1%, 0.5%, 1% 5 kind of various concentration atropine under the different medicine frequencies of this experiment to near-sighted control effect
No significant difference；All experimental groups (0.02%, 0.05%, 0.1%, 0.5% and 1% concentration atropine ocular fluid) are to mypia progression
Control be superior to blank control group (non-medication group)
3.1.2 the variation of axis oculi
Before treatment, the not statistically significant (P of B, D group axis oculi comparing difference>0.05).After 1 year, A, B, C, D, E, F, G, H, I
Have with six groups of patient's axis oculi of J and increases to a certain degree, respectively (24.59 ± 0.30) mm, (24.65 ± 0.30) mm, (24.56
±0.10)mm、(24.62±0.15)mm、(24.62±0.11)mm、(24.46±0.33)mm、(24.63±0.21)mm、
(24.43 ± 0.16) mm, (24.55 ± 0.42) mm and (24.86 ± 0.35) mm.It is shown in Table 2.
2 six groups of patient's axis oculi (mm) variations of table
Statistical result showed, C, E, G, H group and the variation of A, B, D, F, I group axis oculi have significant difference, C, E, G, H group axis oculi
Increase comparatively fast, illustrates extremely low concentration (0.0005%, 0.0007%, 0.009%, 0.01) atropine control axis oculi progress effect phase
It is slightly poor to higher concentration group；A, between B, D, F, I group group compare axis oculi change no difference of science of statistics, 0.01%, 0.02%,
0.05%, 0.1%, 0.5%, 1% 5 kind of various concentration atropine under the different medicine frequencies of this experiment to axis oculi control effect
No significant difference；All experimental groups (0.01%, 0.02%, 0.05%, 0.1%, 0.5% and 1% concentration atropine ocular fluid) are right
The control of axis oculi progress is superior to blank control group (non-medication group)
3.2 safety analysis
The variation of intraocular pressure：In all treatment A, B, C, D, E, F, G, H, I and J groups, intraocular pressure apparent increase is not found
Patient, before and after treatment, the not statistically significant (P of each group intraocular pressure comparing difference>0.05) 3, are shown in Table.
3 each group patient intraocular pressure (mmHg) of table changes
3.3 Analysis on Compliance
Compliance statistic analysis result shows that A groups (0.02%) complete observation 46 (92%), B groups (0.05%) are completed
Observe 47 (94%), C groups (0.0009%) complete 46, D groups (0.1%) completion observation 45 (90%), E groups (0.01%)
Complete observation 46 (92%), F groups (0.5%) complete observation 47 (94%), G groups (0.0007%) completion observation 45
(90%), H groups (0.0005%) complete observation 47 (94%), I groups (1%) complete observation 38 (76%), J groups 47
(94%).Compliance no difference of science of statistics between low concentration atropine group is complied between 1% concentration atropine group and low concentration group
Property has significant difference.1% atropine group compliance is substantially reduced.
4 each group of table exits observation reason and compares (example)
Near vision variation, photophobia continuous days after patient and parent's charting point atropine are given, are occurred regarding being closely stranded
Difficult and photophobia infant statistical result showed：Simple eye near vision averagely needs 3.1 days up to 1.0 after 0.5% atropine of point, photophobia symptom
Disappearing needs 3.0 days；Simple eye near vision averagely needs 4.5 days up to 1.0 after 1% atropine of point, and photophobia symptom, which disappears, to be needed 4.4 days.And
0.0005%, 0.0007%, 0.009%, 0.01%, 0.02%, 0.05%, 0.1% concentration group infant do not tell apparent photophobia and
Being blurred.Illustrate that atropine concentration is lower, sense of discomfort is lower after medication, near vision is impacted smaller.
In short, 0.01%, 0.02%, 0.05%, 0.1%, 0.5%, 1% 6 kind of atropine ocular fluid have and subtract in various degree
The effect that slow myopia increases, but 1% atropine treatment group is because of side effects such as apparent photophobia, being blurreds makes its compliance also most
Difference can also learn Children Normal and live to have an impact, so widespread adoption is difficult to even with the method that interruption uses
It realizes；0.0005%, malaise symptoms are most light after 0.0007%, 0.009%, 0.01% 4 group of medication.0.02%, 0.05%,
0.1%, 0.5% concentration atropine compliance is preferable, and the near-sighted drug effect of control is also preferable, is conducive to larger scale clinical use.
Embodiments of the present invention are explained in detail above, but the present invention is not limited to described embodiments.It is right
For those skilled in the art, in the case where not departing from the principle of the invention and spirit, these embodiments are carried out more
Kind change, modification, replacement and modification, still fall in protection scope of the present invention.
Claims (6)
1. a kind of low concentration tropane class drug eye drops, which is characterized in that including following constituent：
Tropane class drug 0.0005~0.5% (w/v)；With clathration and 0~10% (w/ of irritating solute can be reduced
v)；With the solute 0.01~5% (w/v) for increasing liquid viscosity；Acid-base modifier, amount are adjusted to 4.0~6.5 with pH and are
It is accurate；Osmotic pressure regulator, amount are subject to osmotic pressure and are adjusted to 280~330mOsm/L；Bacteriostatic agent 0.01~0.05% (w/v)；
Surplus is water for injection；
The tropane class drug is atropine sulfate, hyoscine, belladonna alkaloids, coca alkaloids, anisodamine, rear horse support
Product, atropine or other using atropine as downstream product made of intermediate or Atropine derivatives；
It is described that there is clathration and irritating solute can be reduced as hydroxypropyl-β-cyclodextrin, beta-cyclodextrin and cyclodextrin
It is one or more in derivative；
The solute with increase liquid viscosity is polyethylene glycol, polyvinyl alcohol, carbomer, sodium hyaluronate, Methyl cellulose
It is one or more in element and glycerine；
Acid-base modifier is disodium hydrogen phosphate-phosphate sodium dihydrogen buffer solution, potassium dihydrogen phosphate-dipotassium hydrogen phosphate buffer solution, boric acid-
It is one or more in borate buffer solution, citric acid, sodium citrate and acetic acid；
The osmotic buffering agent is sodium chloride or glucose；
The bacteriostatic agent is selected from ethyl hydroxy benzoate, methyl hydroxybenzoate, Nipasol, phenylmercuric acetate, anesin, thimerosal, benzene and pricks
It is one or more in oronain and benzalkonium bromide.
2. low concentration tropane class drug eye drops according to claim 1, which is characterized in that it includes following each component：
Atropine sulfate 0.0005~0.5% (w/v), sodium hyaluronate 0.01~0.35% (w/v), beta-cyclodextrin 0~10% (w/v),
Sodium chloride 0.75~0.90% (w/v), ethyl hydroxy benzoate 0.01~0.05% (w/v), pH is adjusted to 4.0 with phosphate buffer~
6.5, surplus is water for injection.
3. low concentration tropane class drug eye drops according to claim 2, which is characterized in that it includes following each component：
Atropine sulfate 0.0008~0.3% (w/v), sodium hyaluronate 0.05~0.30% (w/v), 0.3~2% (w/v) sodium chloride
PH is adjusted to 5.0~6.5 by 0.80~0.90% (w/v), ethyl hydroxy benzoate 0.02~0.05% (w/v) with phosphate buffer, remaining
Amount is water for injection.
4. low concentration tropane class drug eye drops according to claim 3, which is characterized in that it includes following each component：
Atropine sulfate 0.01% (w/v), sodium hyaluronate 0.15% (w/v), 0.5% (w/v) sodium chloride 0.85% (w/v), oxybenzene second
PH is adjusted to 6.0 by ester 0.03% (w/v) with phosphate buffer, and surplus is water for injection.
5. according to the preparation method of Claims 1 to 4 any one of them low concentration tropane class drug eye drops, feature exists
In including the following steps：
S1, it is weighed according to the ratio with clathration and irritating solute can be reduced be dissolved in water for injection, add tropane
Class drug is placed in ultrasonic oscillation cleaning machine, ultrasonic mixing 30 minutes, and tropane class drug is made with clathration and to be subtracted
Few irritating solute inclusion, obtains solution 1；
S2, ethyl hydroxy benzoate is weighed according to the ratio be dissolved in 40~75 DEG C of water for injection, obtain solution 2；
S3, sodium chloride is weighed according to the ratio be dissolved in solution 2, it is cooling, obtain solution 3；
S4, sodium hyaluronate is weighed according to the ratio be completely dissolved in solution 3, obtain solution 4；
S5, solution 1 is added in solution 4, mixing obtains solution 5；
S6, solution 5 is filtered, from filter plus water for injection is rinsed filter, and surplus adds water for injection to supply, and stirs evenly,
121 DEG C of steam sterilizings 12 minutes, it is aseptic subpackaged to get.
6. the preparation method of low concentration tropane class drug eye drops according to claim 5, which is characterized in that in step S2
The water for injection is 50 DEG C.
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