CN101632717A - In situ forming eye gel preparation for treating myopia and asthenopia and preparation method thereof - Google Patents
In situ forming eye gel preparation for treating myopia and asthenopia and preparation method thereof Download PDFInfo
- Publication number
- CN101632717A CN101632717A CN200910008680A CN200910008680A CN101632717A CN 101632717 A CN101632717 A CN 101632717A CN 200910008680 A CN200910008680 A CN 200910008680A CN 200910008680 A CN200910008680 A CN 200910008680A CN 101632717 A CN101632717 A CN 101632717A
- Authority
- CN
- China
- Prior art keywords
- preparation
- eye
- radix
- poloxamer
- parts
- 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
Abstract
The invention relates to an in situ forming eye gel preparation for treating myopia and asthenopia. The preparation takes total alkaloid from dactylicapnos scandens hutch as an effective active ingredient and also contains auxiliary material acceptable in pharmacy and water; the preparation also contains poloxamer serving as matrix which causes solution to generate phase change; taking 1000 parts of in situ forming eye gel by weight, 200-800 parts of dactylicapnos scandens hutch medical drug by weight, 50-300 parts of poloxamer by weight and 900-1100 parts of water by weight are prepared into solution whose pH value is 4.0-6.0. The preparation of the invention has accurate preparation ration, small irritation, long retention time in eyes and high bioavailability.
Description
Technical field
The present invention relates to a kind of treatment adolescent myopia, pseudomyopia and closely use the caused asthenopic ophthalmic preparation of vision continuously, being specifically related to a kind of Radix dactylicapni (Radix Dactylicapnotis) total alkaloids is situ forming eye gel preparation of main medicine and preparation method thereof.
Background technology
1, instant gel for eye (in Situ Forming Eye Gel) preparation technique background
Situ-gel (in-situ-gel) claims gel on the throne again, mean that macromolecular material is with solution or semi-solid state administration after, stimulate to external world at agents area to respond, the reversible conversion of dispersity or conformation takes place, the semisolid of formation or liquid preparation.In recent years, along with some " intelligent " macromolecule, particularly developing rapidly of some environment sensitive type macromolecular materials, the appearance of this novel drug-supplying system of situ-gel and further exploitation have been promoted.It is compared with traditional drug-supplying system, and in-situ gel preparation has significant advantage:
(1) response physics or chemistry is made in the change of contact environment, adjusted the physicochemical character (as transformation degree mutually etc.) and the medicine state (as release, delay etc.) in vivo of preparation according to the size of response value, to adapt to the timely and effective treatment of the state of an illness;
(2) with medicine dissolution or be dispersed in and promptly can be made into gel in the environmental sensitivity macromolecular material.It can take place closely to contact with site of action the long period, bioadhesive is preferably arranged, and can improve the absorption of medicine from the contact site, avoids first pass effect, improves bioavailability of medicament;
(3) has highly hydrophilic tridimensional network, with wherein medicine the elementary preparation of medicine-adjuvant (as Emulsion, liposome, nanoparticle etc.) is bound by wherein or its gap in, the release of medicine can be controlled, and wherein medicine or the elementary preparation of medicine-adjuvant can be stablized;
(4) have special physicochemical property, as the sol-gel transition process, under conditions in vitro, have certain fluidity, suitability for industrialized production is convenient in easily fill;
(5) be applicable to the medicine wide range of in-situ gel, situ-gel can be used for local action medicine, general action medicine, hydrophilic medicament, hydrophobic drug, acidic drug, cationic drug, macromolecular drug, cell tissue etc.;
(6) have the favorable tissue compatibility, and easy to use, easily accepted by the patient, can be from multiple route of administration administration.
The formation mechanism of situ-gel is the response that utilizes macromolecular material to stimulate to external world, makes polymer issue the reversible change of diffusing state estranged or conformation at physiological condition, finishes the change process between solution and gel.Can be divided into responsive to temperature type according to its mechanism of action, ion-sensitive type, pH responsive type and photaesthesia type etc.
The application of situ-gel in pharmaceutics can be applied to multiple different way of administration as required, for example can be used for dosing eyes, nasal-cavity administration, rectum and vagina administration, drug administration by injection, oral administration etc.
Situ-gel is the pharmacy work abroad always person's research emphasis, at home owing to the restriction of reasons such as adjuvant and economic benefit, research deep not enough.The medicament that situ-gel is applied to the dosing eyes approach is studied, even still belong to newer field abroad, real sophisticated product is few.At present the U.S. FDA approved this series products timolol maleate glue sample eye drop, belong to the ion-sensitive type gel, internist's clinical medicine handbook (Physicians Desk Reference, PDR) record, name is called TimololMalaeate Ophthalmic Gel Forming Solution (eye gelling soln).Also have 2 artificial tears's instant gel for eye that adopt poloxamer 407 preparations in addition in Australia and Japan's listing.Present domestic this type of launch that still do not have, this series products of part is still being studied and is being declared the stage, mainly be temperature, pH responsive type instant gel for eye, the title of using has gel for eye use, at body gel, gel-type eye drop, slow release eye drop etc., after pharmacopeia can examine, change the common name of this type of preparation into instant gel for eye.Domestic detailed prescription and the Technology that relates to this series products is detected in patent documentation: application number: 200510021579.0,200610050215.X, 200710106037.2,200710123151.6,200710123318.9,200710129822.X, ZL 200410064366.1,03135526.9,200510109453.9,02136580.6.Do not see that as yet other publication publishes.Except that patent documentation, other document of collecting mostly is the data of summary property or the information of the non-prescription of certain specific product and Technology aspect.
Whether certain medicine is fit to make the instant gel for eye dosage form, and the instant gel for eye that is fit to make which kind of mechanism type, need take into full account its multiple factors such as clinical practice, pharmaceutical properties, production equipment, condition and Financial cost, need screening study by prescription, technology.
2, the Radix dactylicapni (Radix Dactylicapnotis) medicinal substances extract is applied to the pharmaceutical preparation background:
Mainly containing the different corydaline of dextrorotation, protopine, different corydine, boldine dimethyl ether etc. in Bai nationality's medical herbs Radix dactylicapni (Radix Dactylicapnotis) (Dactylicapnos scandens Hutch), is the Radix dactylicapni (Radix Dactylicapnotis) total alkaloids through the Radix dactylicapni (Radix Dactylicapnotis) extract that extracts, refining processing obtains.The Radix dactylicapni (Radix Dactylicapnotis) total alkaloids is applied to pharmaceutical preparation, and its oral and ejection preparation is the spasmolysis and analgesia medicine, is used for gastroenteritis, digestive tract ulcer and digestive tract treatment of pain more.Aspect ophthalmic preparation, can be used for mydriasis, treatment myopia and asthenopia, its main effective ingredient is right isocorydine, claim dextrorotation different corydaline again, have the effect of regulating vision, can be used for treating adolescent myopia, pseudomyopia and closely use the caused eyestrain of vision continuously.
Ophthalmic preparation has multiple dosage form, as dosage forms such as eye drop, collyrium, intraocular injection solution, Eye ointments, eye ointment, gel for eye, eye mask agent, eye pill, ophthalmic intercalating agent and instant gel for eye agent.At present existing disclosed is that the ophthalmic preparation of raw material only has 2 kinds of eye drop and gel for eye with the Radix dactylicapni (Radix Dactylicapnotis) extract; the specific product name is called near-sighted happy collyrium and near-sighted happy gel for eye use; the happy collyrium of myopia has gone on the market and has obtained the herbal species protection in 2006, and near-sighted happy gel for eye use is not got permission listing as yet.Publication is as seen: near-sighted happy collyrium drug standard [" Drug Standard of Ministry of Public Health of the Peoples Republic of China " (standard numbering: WS3-B-3851-98)]; Number of patent application: 200610046146.5; Number of patent application: 200510094185.8.
3, the instant gel for eye dosage form is applied to the background of Radix dactylicapni (Radix Dactylicapnotis) medicinal substances extract
The Radix dactylicapni (Radix Dactylicapnotis) medicinal substances extract is that the ophthalmic preparation of main active only has 2 kinds of eye drop and gel for eye at present, and specific product is near-sighted happy collyrium and near-sighted happy gel for eye use.Near-sighted happy collyrium has stronger eye mucosa zest in the clinical use, can cause the eye sensation of pricking after splashing into ophthalmic, blinking fast of lacrimal secretion increase and eyelid quickened the loss of medicinal liquid, causes the ingredient problem that the time of staying is short within the eye, bioavailability is not high.For this reason, needing increases the eye dripping frequency, stronger to the zest of eyes, for use brings a lot of inconvenience.And near-sighted happy gel for eye use is common gel, lacks good spreadability, and using dosage is wayward, can cause eye discomfort, foreign body sensation etc. after gel is pleasing to the eye.The shortcoming of above dosage form has all limited its being extensive use of clinically.
The instant gel for eye agent combines eye drop and gel for eye use is the advantage of type for 2 kinds, has remedied deficiency separately.Inversion of phases takes place in the instant gel for eye physiological environment (temperature, ion, pH) different according to the inside and outside, externally exists with liquid form, splashes into ophthalmic and transfers gel at once to.Not only can solve the problem that the common eye drops ophthalmic holdup time is short, bioavailability is not high, also overcome common gel for eye use and lacked good spreadability, the uppity problem of dosage.Shang Weiyou is applied to the relevant report of Radix dactylicapni (Radix Dactylicapnotis) medicinal substances extract with the instant gel for eye dosage form, is not the pharmacological evaluation of instant gel for eye of main medicine and the report of clinical practice aspect with the Radix dactylicapni (Radix Dactylicapnotis) medicinal substances extract more.Whether be better than the eye drop dosage form in order to verify this novel form, we verify by animal pharmacokinetics experiment (seeing specific embodiment 21 for details) and animal eye mucous membrane irritation experiment (seeing specific embodiment 22 for details).The animal pharmacokinetics experimental result as seen, healthy rabbits splash into instant gel for eye respectively and the near-sighted happy collyrium that gone on the market after, gained pharmacokinetic parameters: Cmax is respectively 8.50 ± 1.68 and 4.03 ± 1.19 μ g/ml, AUC is respectively 79.94 ± 22.43,36.61 ± 9.40 μ g h/ml, and Tmax is respectively 5.8 ± 3.8 and 6.5 ± 3.2h.The aqueous humor peak concentration of drug of instant gel for eye is obviously greater than the happy collyrium of myopia, area under curve differs nearly 2 times, tool significance meaning, simultaneously, the individual variation of common near-sighted happy collyrium is bigger, the uppity problem of dosage of collyrium has been described, and instant gel for eye has well solved this problem.Animal eye mucous membrane irritation experimental result as seen, healthy rabbits splashes into the happy collyrium 0.1ml of commercially available product myopia respectively at left eye, right eye splashes into instant gel for eye 0.1ml.Passive closed eyelid 5-10 second after the administration, administration every day 3 times, successive administration 7 days.The result presses the eye irritant test evaluation criterion, and instant gel for eye group stimulation degree is a nonirritant, and near-sighted happy collyrium stimulation degree is slight zest.The zest of instant gel for eye is significantly less than near-sighted happy collyrium.It is that the instant gel for eye of main effective ingredient has remarkable advantages than eye drop that experimental result shows with Radix dactylicapni (Radix Dactylicapnotis) extract.
Use technical scheme provided by the invention, can produce with Radix dactylicapni (Radix Dactylicapnotis) extract under the eye drop working condition of routine is the situ forming eye gel preparation of main effective ingredient, can reach aseptic requirement easily.
Summary of the invention
In order to overcome strong, the ingredient shortcoming that the holdup time is short within the eye, bioavailability is low of zest that exists in actual use of eye drop that existing Radix dactylicapni (Radix Dactylicapnotis) extract makes, the present invention aim to provide a kind of quantitatively accurately, the eye of zest is little, the holdup time is long in eye, bioavailability is high treatment eyestrain and myopia is with novel form and preparation method thereof.
For achieving the above object, the technical solution used in the present invention is:
A kind of treatment myopia and asthenopic situ forming eye gel preparation are the effective active composition with the Radix dactylicapni (Radix Dactylicapnotis) total alkaloids, also contain acceptable accessories and water, and said preparation also contains the substrate that solution is undergone phase transition.
The described substrate that solution is undergone phase transition is poloxamer, and in 1000 parts of instant gel for eye weight, 200～800 parts of Radix dactylicapni (Radix Dactylicapnotis) medical materials; 50～300 parts of poloxamers; 900～1100 parts in water is made into pH value and is 4.0～6.0 solution.Adjuvant comprises pH regulator agent or osmotic pressure regulator or stabilizing agent or antibacterial or viscosifier and other acceptable accessories.
Aforesaid situ forming eye gel preparation, described pH regulator agent are one or more the mixture in sodium hydroxide, hydrochloric acid, boric acid, Borax, sulphuric acid, phosphoric acid salt, citric acid, the citrate; Osmotic pressure regulator is one or more the mixture in sodium chloride, glucose, glycerol, propylene glycol, the mannitol; Stabilizing agent is one or more the mixture in sulfites, thiourea, cysteine, ascorbic acid, calcium disodium edetate, the disodium edetate; Antibacterial is one or more the mixture in parabens, chlorobutanol, Sodium Mercurothiolate, benzalkonium chloride, the benzalkonium bromide; Viscosifier are one or more the mixture in hypromellose, hydroxypropyl second cellulose, polyvinyl alcohol, polyvinylpyrrolidone, hyaluronic acid sodium, sodium alginate, methylcellulose, chitosan, the sodium carboxymethyl cellulose.
The preparation method of aforementioned situ forming eye gel preparation contains and has the following steps:
(1) utilize the Radix dactylicapni (Radix Dactylicapnotis) medicinal material coarse powder to extract the Radix dactylicapni (Radix Dactylicapnotis) total alkaloids;
(2) with said extracted thing and pH regulator agent, osmotic pressure regulator, antibacterial, stabilizing agent, viscosifier, add suitable quantity of water, stirring and dissolving forms extract solution;
(3) substrate is added suitable quantity of water, form matrix solution;
(4) in extract solution, add matrix solution, stir evenly;
(5) add suitable quantity of water, aseptic filtration.
From result of the test as seen, rabbit splash into instant gel for eye respectively and the near-sighted happy collyrium that gone on the market after, gained pharmacokinetic parameters: Cmax is respectively 8.50 ± 1.68 and 4.03 ± 1.19 μ g/ml, AUC is respectively 79.94 ± 22.43,36.61 ± 9.40 μ g h/ml, and Tmax is respectively 5.8 ± 3.8 and 6.5 ± 3.2h.The aqueous humor peak concentration of drug of instant gel for eye is obviously greater than commercially available near-sighted happy collyrium, area under curve differs nearly 2 times, tool significance meaning, simultaneously, the individual variation of common near-sighted happy collyrium is bigger, and instant gel for eye has well solved this problem.
The animal eye mucosa delivery splashes into for 3 times every day, and successive administration 7 days is observed in different time points, and instant gel for eye group cornea does not have muddiness, and iris does not normally have hyperemia, and light reflex is normal, and conjunctiva is not seen hyperemia, edema and secretions; Press the eye irritant test evaluation criterion, its stimulation degree is a nonirritant.The happy collyrium group cornea of myopia, iris, all degree of taking a favourable turn hyperemia of conjunctiva, secretions increases; Press the eye irritant test evaluation criterion, its stimulation degree is slight zest.The zest of instant gel for eye is significantly less than the near-sighted happy collyrium that has gone on the market.
The specific embodiment
The present invention provides a kind of novel form, i.e. instant gel for eye for existing Radix dactylicapni (Radix Dactylicapnotis) extract for the eye medicinal of main effective ingredient.According to the character of Radix dactylicapni (Radix Dactylicapnotis) extract, this raw material is fit to make the responsive to temperature type instant gel for eye.
With Radix dactylicapni (Radix Dactylicapnotis) extract is the responsive to temperature type instant gel for eye of main effective ingredient, substrate is selected poloxamer for use, poloxamer can be a kind of model in the poloxamer 124,188,237,338,407 or the mixture of more than one models, is optimum selection with poloxamer 407 wherein.
Preparation temperature responsive type instant gel for eye, in 1000 parts of instant gel for eye weight, 200～800 parts of Radix dactylicapni (Radix Dactylicapnotis) medical materials; 50～300 parts of poloxamers; 900～1100 parts in water is made into pH value and is 4.0～6.0 solution.
One of preferred be, in 1000 parts of instant gel for eye weight, described Radix dactylicapni (Radix Dactylicapnotis) medical material is 450～550 parts, and poloxamer is 150～200 parts, and water is 950～1050 parts, is made into pH value and is 4.0～6.0 solution.
PH regulator agent, osmotic pressure regulator, stabilizing agent, antibacterial and viscosifier and other acceptable accessories also can have been added in the prescription.
The pH regulator agent comprises one or more the mixture in sodium hydroxide, hydrochloric acid, boric acid, Borax, sulphuric acid, phosphoric acid salt, citric acid, the citrate.Osmotic pressure regulator comprises one or more the mixture in sodium chloride, glucose, glycerol, propylene glycol, the mannitol.Stabilizing agent comprises one or more the mixture in sulfites, thiourea, cysteine, ascorbic acid, calcium disodium edetate, the disodium edetate.Antibacterial comprises one or more the mixture in parabens, chlorobutanol, Sodium Mercurothiolate, benzalkonium chloride, the benzalkonium bromide; Viscosifier are one or more the mixture in hypromellose, hydroxypropyl second cellulose, polyvinyl alcohol, polyvinylpyrrolidone, hyaluronic acid sodium, sodium alginate, methylcellulose, chitosan, the sodium carboxymethyl cellulose.
The weight proportion scheme of pH regulator agent, antibacterial, stabilizing agent, osmotic pressure regulator and viscosifier in the prescription: in 1000 parts of instant gel for eye weight, 0～100 part of pH regulator agent is preferably 1～50 part, more preferably 10～30 parts; 0～10 part of antibacterial is preferably 0.001～5 part, more preferably 0.05～2.5 part.0～10 part of stabilizing agent is preferably 0.01～5 part, more preferably 0.01～1 part.Osmotic pressure regulator is preferably 0～100 part, more preferably 0～10 part.0～10 part of viscosifier are preferably 0.01～5 part, more preferably 0.01～1 part.
Preparation method of the present invention comprises following scheme:
1. get the Radix dactylicapni (Radix Dactylicapnotis) medicinal material coarse powder, make solvent with 50%～100% ethanol, flood and carry out percolation or reflux, extract, after 24 hours, ethanol liquid is evaporated to thick paste, and is refining with chloroform-ethanol, gets the Radix dactylicapni (Radix Dactylicapnotis) total alkaloids;
2. get pH regulator agent, antibacterial, stabilizing agent, osmotic pressure regulator and viscosifier and said extracted thing, add an amount of water for injection, stir and make dissolving fully;
3. get poloxamer and add in the above-mentioned solution, stirring makes and is uniformly dispersed, and place at cold place, makes into clear solution;
4. add the injection water to 1000ml, aseptic filtration.
Below further describe the present invention by specific embodiment, and do not limit the present invention in any way, under the prerequisite that does not deviate from technical solution of the present invention, any change or change that those of ordinary skills that the present invention did are realized easily all will fall within the claim scope of the present invention.
Embodiment 1
Preparation: the extract of Radix dactylicapni (Radix Dactylicapnotis) 200g, poloxamer 407180g adds the injection water to 1000ml.
Preparation method:
1. get the Radix dactylicapni (Radix Dactylicapnotis) medicinal material coarse powder, make solvent with 50%～100% ethanol, flood and carry out percolation or reflux, extract, after 24 hours, ethanol liquid is evaporated to thick paste, and is refining with chloroform-ethanol, gets the Radix dactylicapni (Radix Dactylicapnotis) total alkaloids;
2. get sodium chloride and said extracted thing, add an amount of water for injection, stir and make dissolving fully;
3. get poloxamer in above-mentioned solution, stirring makes and is uniformly dispersed, and place at cold place, makes into clear solution;
4. add the injection water to 1000ml, aseptic filtration, promptly.
Embodiment 2
Preparation: the extract of Radix dactylicapni (Radix Dactylicapnotis) 500g, poloxamer 407 180g add the injection water to 1000ml.
Preparation method: with reference to embodiment 1.
Embodiment 3
Preparation: the extract of Radix dactylicapni (Radix Dactylicapnotis) 800g, poloxamer 407 180g add the injection water to 1000ml.
Preparation method: with reference to embodiment 1.
Embodiment 4
Preparation: the extract of Radix dactylicapni (Radix Dactylicapnotis) 500g, poloxamer 407 100g, hypromellose 5g, boric acid 15g, Borax 0.1g, chlorobutanol 2.5g, sodium chloride 0.6g, sodium sulfite 0.1g adds the injection water to 1000ml.
Preparation method: with reference to embodiment 1.
Embodiment 5
Preparation prescription: the extract of Radix dactylicapni (Radix Dactylicapnotis) 500g, poloxamer 407 250g, boric acid 15g, Borax 0.1g, chlorobutanol 10g, sodium chloride 0.6g, sodium sulfite 1g adds the injection water to 1000ml.
Preparation method: with reference to embodiment 1
Embodiment 6
Preparation prescription: the extract of Radix dactylicapni (Radix Dactylicapnotis) 500g, poloxamer 407 180g, sodium dihydrogen phosphate 20g, sodium hydrogen phosphate 6g, chlorobutanol 5g, sodium sulfite 5g adds the injection water to 1000ml.
Preparation method: with reference to embodiment 1.
Embodiment 7
Preparation prescription: the extract of Radix dactylicapni (Radix Dactylicapnotis) 500g, poloxamer 407 180g, sodium hydroxide 5g, citric acid 5g, benzalkonium chloride 0.05g, disodium edetate 0.1g adds the injection water to 1000ml.
Preparation method: with reference to embodiment 1.
Embodiment 8
Preparation prescription: the extract of Radix dactylicapni (Radix Dactylicapnotis) 500g, poloxamer 407 160g, sodium hydroxide 5g, citric acid 5g, benzalkonium chloride 0.05g, calcium disodium edetate 0.1g adds the injection water to 1000ml.
Preparation method: with reference to embodiment 1.
Embodiment 9
Preparation prescription: the extract of Radix dactylicapni (Radix Dactylicapnotis) 500g, poloxamer 407 180g, sodium hydroxide 5g, citric acid 5g, benzalkonium chloride 0.05g, cysteine 0.1g adds the injection water to 1000ml.
Preparation method: with reference to embodiment 1.
Embodiment 10
Preparation prescription: the extract of Radix dactylicapni (Radix Dactylicapnotis) 500g, poloxamer 407 180g, hydrochloric acid 0.1g, sodium citrate 5g, benzalkonium bromide 0.1g, ascorbic acid 0.1g adds the injection water to 1000ml.
Preparation method: with reference to embodiment 1.
Embodiment 11
Preparation prescription: the extract of Radix dactylicapni (Radix Dactylicapnotis) 500g, poloxamer 40 780g, hyaluronic acid sodium 1g, boric acid 15g, Borax 0.1g, ethyl hydroxybenzoate 10g, thiourea 0.1g, propylene glycol 10g adds the injection water to 1000ml.
Preparation method: with reference to embodiment 1.
Embodiment 12
Preparation prescription: the extract of Radix dactylicapni (Radix Dactylicapnotis) 500g, poloxamer 407 80g, hydroxypropyl second cellulose 10g, boric acid 15g, Borax 0.1g, ethyl hydroxybenzoate 10g, sodium sulfite 0.1g,, mannitol 10g adds the injection water to 1000ml.
Preparation method: with reference to embodiment 1.
Embodiment 13
Preparation prescription: the extract of Radix dactylicapni (Radix Dactylicapnotis) 500g, poloxamer 407 80g, polyvinyl alcohol 10g, boric acid 15g, Borax 0.1g, ethyl hydroxybenzoate 10g, sodium sulfite 0.1g, glucose 10g adds the injection water to 1000ml.
Preparation method: with reference to embodiment 1.
Embodiment 14
Preparation prescription: the extract of Radix dactylicapni (Radix Dactylicapnotis) 500g, poloxamer 407 80g, polyvinylpyrrolidone 10g, boric acid 15g, Borax 0.1g, chlorobutanol 3g, sodium sulfite 0.1g, sodium chloride 0.6g adds the injection water to 1000ml.
Preparation method: with reference to embodiment 1.
Embodiment 15
Preparation prescription: the extract of Radix dactylicapni (Radix Dactylicapnotis) 500g, poloxamer 407 80g, chitosan 10g, boric acid 15g, Borax 0.1g, chlorobutanol 3g, sodium sulfite 0.1g, sodium chloride 0.6g adds the injection water to 1000ml.
Preparation method: with reference to embodiment 1.
Embodiment 16
Preparation prescription: the extract of Radix dactylicapni (Radix Dactylicapnotis) 500g, poloxamer 407 80g, sodium alginate 10g, boric acid 15g, Borax 0.1g, chlorobutanol 3g, sodium sulfite 0.1g, sodium chloride 0.6g adds the injection water to 1000ml.
Preparation method: with reference to embodiment 1.
Embodiment 17
Preparation prescription: the extract of Radix dactylicapni (Radix Dactylicapnotis) 500g, poloxamer 407 80g, methylcellulose 10g, boric acid 15g, Borax 0.1g, chlorobutanol 3g, sodium sulfite 0.1g, sodium chloride 0.6g adds the injection water to 1000ml.
Preparation method: with reference to embodiment 1.
Embodiment 18
Preparation prescription: the extract of Radix dactylicapni (Radix Dactylicapnotis) 500g, poloxamer 407 80g, sodium carboxymethyl cellulose 10g, boric acid 15g, Borax 0.1g, chlorobutanol 3g, sodium sulfite 0.1g, sodium chloride 0.6g adds the injection water to 1000ml.
Preparation method: with reference to embodiment 1.
Embodiment 19
Preparation prescription: the extract of Radix dactylicapni (Radix Dactylicapnotis) 500g, poloxamer 407 180g, boric acid 15g, Borax 0.1g, benzalkonium chloride 0.05g, disodium edetate 0.1g adds the injection water to 1000ml.
Preparation method: with reference to embodiment 1
Embodiment 20: with poloxamer 407 is example, and the Radix dactylicapni (Radix Dactylicapnotis) extract of determining responsive to temperature type is the concentration of poloxamer in the instant gel for eye of main effective ingredient
Poloxamer solution along with the rising of temperature, can undergo phase transition the formation semi-solid gel being flowability liquid preferably below 20 ℃.It is closely related that poloxamer solution undergoes phase transition the concentration of the temperature that need reach and poloxamer solution, adjusts the concentration of poloxamer solution, and its phase transition temperature also can change accordingly.Along with the increase of poloxamer solution concentration, phase transition temperature reduces gradually.
2005 editions Chinese Pharmacopoeia regulations: room temperature is 10 ℃～30 ℃.About about 34 ℃ of the temperature of people's eye.It is liquid state at normal temperatures that situ forming eye gel preparation needs, and be transformed into the semi-solid gel state rapidly after splashing into ophthalmic, so the phase transition temperature of situ forming eye gel preparation should be at 30 ℃～34 ℃.This foundation is formed gelation temperature time dimension standard is: 3 of instant gel for eye getting the Radix dactylicapni (Radix Dactylicapnotis) extract of responsive to temperature type, must not be transformed into semi-solid gelling in 1 minute under 30 ℃ of conditions, being transformed into the semi-solid agglomerative time under 34 ℃ of conditions must not be above 30 second.
With reference to the prescription of embodiment 19, being mixed with poloxamer 407 weight respectively is 15%, 16%, 17%, 18% instant gel for eye solution with the liquor capacity ratio, investigates the phase transition temperature of above each solution respectively.The results are shown in following table:
The result shows that poloxamer 407 weight meet gelation temperature time dimension standard with liquor capacity than the solution that is 16～18%.
Embodiment 21: the animal pharmacokinetics test
Get 36 of healthy rabbits, the male and female dual-purpose is divided into 6 groups at random, every group of corresponding respectively corresponding sample point, 6 every group, male and female half and half.Splash into the sample and contrast medicine (commercially available product: near-sighted happy collyrium that 50 μ l embodiment 1 make respectively at the rabbit right and left eyes, Dali Bai-Nationality Autonomous Prefecture Chinese Medicine Pharmacy Co., Ltd.), with thumb and forefinger the rabbit eyelid is being pulled into cup-shaped, middle finger is pushed nasolacrimal duct, drip medicine at two, drip the eyelid that gently rubs one's eyes behind the medicine, let alone after one minute from overflowing.After administration 5,15,30,45,60 and 90min sampling.By each sampling time point, after the rabbit auricular vein is injected 1.5% pentobarbital sodium auricular vein general anesthesia (2ml/kg), get aqueous humor respectively at 9 positions in the limbus of corneae with the 10ml asepsis injector, draw the about 200 μ l of every aqueous humor and put in the centrifuge tube of being with plug, preserve in-20 ℃ of refrigerators, in order to measuring.By measuring the concentration of isocorydine in the rabbit aqueous humor, observe rabbit splash into behind the instant gel for eye blood drug level through the time process, investigate the drug release characteristic of instant gel for eye, estimate corresponding pharmacokinetic parameter.And compare with the near-sighted happy collyrium that has gone on the market.
Result of the test as seen, rabbit splash into instant gel for eye respectively and the near-sighted happy collyrium that gone on the market after, gained pharmacokinetic parameters: Cmax is respectively 8.50 ± 1.68 and 4.03 ± 1.19 μ g/ml, AUC is respectively 79.94 ± 22.43,36.61 ± 9.40 μ g h/ml, and Tmax is respectively 5.8 ± 3.8 and 6.5 ± 3.2h.The aqueous humor peak concentration of drug of instant gel for eye is obviously greater than commercially available near-sighted happy collyrium, area under curve differs nearly 2 times, tool significance meaning, simultaneously, the individual variation of common near-sighted happy collyrium is bigger, and instant gel for eye has well solved this problem.
Embodiment 22: the lagophthalmos irritation test
Get healthy nothing and hinder rabbit, test was fixed rabbit the same day, and every animal splashes into the happy collyrium 0.1ml of commercially available product myopia respectively at left eye, and right eye splashes into instant gel for eye 0.1ml.Passive closed eyelid 5-10 second after the administration, administration every day 3 times, successive administration 7 days.Perusal horn film, iris, conjunctival reaction situation after administration every day are estimated according to eye irritant reaction standards of grading.Whether continue after the drug withdrawal to observe had abnormal response to occur in 3 days.The results are shown in following table.
The rabbit eye mucosa repeatedly splashes into the scoring of administration irritant reaction:
Perusal as a result: the animal eye mucosa delivery, splash into for 3 times every day, successive administration 7 days is observed in different time points, and instant gel for eye group cornea does not have muddiness, and iris does not normally have hyperemia, and light reflex is normal, and conjunctiva is not seen hyperemia, edema and secretions; Press the eye irritant test evaluation criterion, its stimulation degree is a nonirritant.The happy collyrium group cornea of myopia, iris, all degree of taking a favourable turn hyperemia of conjunctiva, secretions increases; Press the eye irritant test evaluation criterion, its stimulation degree is slight zest.The zest of instant gel for eye is significantly less than the near-sighted happy collyrium that has gone on the market.
Claims (8)
1. treatment myopia and asthenopic situ forming eye gel preparation are the effective active composition with the Radix dactylicapni (Radix Dactylicapnotis) total alkaloids, also contain acceptable accessories and water, and it is characterized in that: said preparation also contains the substrate that solution is undergone phase transition.
2. situ forming eye gel preparation as claimed in claim 1 is characterized in that: the described substrate that solution is undergone phase transition is poloxamer.
3. situ forming eye gel preparation as claimed in claim 2 is characterized in that: in 1000 parts of described instant gel for eye weight, wherein the Radix dactylicapni (Radix Dactylicapnotis) medical material is 200～800 parts; 50～300 parts of poloxamers; 900～1100 parts in water is made into pH value and is 4.0～6.0 solution.
4. as claim 2 or 3 described situ forming eye gel preparation, it is characterized in that: described poloxamer is a kind of model in the poloxamer 124,188,237,338,407 or the mixture of more than one models.
5. situ forming eye gel preparation as claimed in claim 4 is characterized in that: described poloxamer is a poloxamer 407.
6. situ forming eye gel preparation as claimed in claim 2, it is characterized in that: in 1000 parts of described instant gel for eye weight, the Radix dactylicapni (Radix Dactylicapnotis) medical material is 450～550 parts, and poloxamer is 150～200 parts, water is 950～1050 parts, is made into pH value and is 4.0～6.0 solution.
7. situ forming eye gel preparation as claimed in claim 1 is characterized in that: described adjuvant comprises a kind of or several arbitrarily in pH regulator agent or osmotic pressure regulator or stabilizing agent or antibacterial or the viscosifier;
Described pH regulator agent is one or more the mixture in sodium hydroxide or hydrochloric acid or boric acid or Borax or sulphuric acid or phosphoric acid salt or citric acid or the citrate;
Described osmotic pressure regulator is one or more the mixture in sodium chloride or glucose or glycerol or propylene glycol or the mannitol;
Described stabilizing agent is one or more the mixture in sulfites or thiourea or cysteine or ascorbic acid or calcium disodium edetate or the disodium edetate;
Described antibacterial is one or more the mixture in parabens or chlorobutanol or Sodium Mercurothiolate or benzalkonium chloride or the benzalkonium bromide;
Described viscosifier are one or more the mixture in hypromellose or hydroxypropyl second cellulose or polyvinyl alcohol or polyvinylpyrrolidone or hyaluronic acid sodium or sodium alginate or methylcellulose or chitosan or the sodium carboxymethyl cellulose.
8. the preparation method of the arbitrary described situ forming eye gel preparation of claim 1 to 7 contains and has the following steps:
(1) utilize the Radix dactylicapni (Radix Dactylicapnotis) medicinal material coarse powder to extract the Radix dactylicapni (Radix Dactylicapnotis) total alkaloids;
(2) with said extracted thing and pH regulator agent, osmotic pressure regulator, antibacterial, stabilizing agent, viscosifier, add suitable quantity of water, stirring and dissolving forms extract solution;
(3) substrate is added suitable quantity of water, form matrix solution;
(4) in extract solution, add matrix solution, stir evenly;
(5) add suitable quantity of water, aseptic filtration.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200910008680A CN101632717A (en) | 2008-07-25 | 2009-02-12 | In situ forming eye gel preparation for treating myopia and asthenopia and preparation method thereof |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200810071453 | 2008-07-25 | ||
| CN200810071453.8 | 2008-07-25 | ||
| CN200910008680A CN101632717A (en) | 2008-07-25 | 2009-02-12 | In situ forming eye gel preparation for treating myopia and asthenopia and preparation method thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101632717A true CN101632717A (en) | 2010-01-27 |
Family
ID=41592154
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN200910008680A Pending CN101632717A (en) | 2008-07-25 | 2009-02-12 | In situ forming eye gel preparation for treating myopia and asthenopia and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101632717A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102961324A (en) * | 2012-11-16 | 2013-03-13 | 沈阳药科大学 | Gel for lysozyme eye and preparation method thereof |
| CN114712418A (en) * | 2022-04-08 | 2022-07-08 | 西安军科视光科技研究院有限责任公司 | Ophthalmic gel for treating myopia |
| WO2023019687A1 (en) * | 2021-08-16 | 2023-02-23 | 海南鑫开源医药科技有限公司 | Ion-sensitive ophthalmic in-situ gel, preparation method therefor and application thereof |
-
2009
- 2009-02-12 CN CN200910008680A patent/CN101632717A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102961324A (en) * | 2012-11-16 | 2013-03-13 | 沈阳药科大学 | Gel for lysozyme eye and preparation method thereof |
| CN102961324B (en) * | 2012-11-16 | 2014-06-25 | 沈阳药科大学 | Gel for lysozyme eye and preparation method thereof |
| WO2023019687A1 (en) * | 2021-08-16 | 2023-02-23 | 海南鑫开源医药科技有限公司 | Ion-sensitive ophthalmic in-situ gel, preparation method therefor and application thereof |
| CN114712418A (en) * | 2022-04-08 | 2022-07-08 | 西安军科视光科技研究院有限责任公司 | Ophthalmic gel for treating myopia |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Gupta et al. | Carbopol/chitosan based pH triggered in situ gelling system for ocular delivery of timolol maleate | |
| CN101564374A (en) | Medicinal in situ forming eye gel | |
| CN101564375A (en) | Chinese medicinal in situ forming eye gel | |
| US20210386731A1 (en) | Treatment of ocular inflammatory diseases using laquinimod | |
| CN109966245A (en) | A kind of brimonidine tartrate gellan gum type situ-gel eye drops and preparation method | |
| CN109260146A (en) | Ophthalmic solution sodium in situ forming eye type gel eyedrop and preparation method | |
| CN104688672B (en) | Puerarin gel eyedrop is preparing the application in treating retinopathy medicine | |
| CN105106107A (en) | Eye gellan gum in-situ gel made of bendazac lysine and preparing method of eye gellan gum in-situ gel | |
| CN101632717A (en) | In situ forming eye gel preparation for treating myopia and asthenopia and preparation method thereof | |
| CN103977011B (en) | Travoprost and timolol-containing ophthalmic gel and preparation method thereof | |
| CN101579305A (en) | Ready-to-use puerarin ophthalmic gel | |
| CN101797223B (en) | Huperzine A preparations for eyes and application thereof | |
| CN101543509B (en) | Ophthalmic gel containing chondroitin sulfate and method for preparing same | |
| CN100548273C (en) | Instant cordate houttuynia gel preparation for eye | |
| CN100569218C (en) | Benzydalysine eye drop and preparation method thereof | |
| CN103432065B (en) | Compound gel for treating glaucoma and preparation method thereof | |
| CN101278895A (en) | Instant type gel preparation for eye and method of producing the same | |
| CN100584332C (en) | Eye-drops preparations containing tetrandrine and its application for preparing medicine therewith | |
| CN102648894A (en) | Eye-purposed in-vivo gel preparation prepared from pH (Potential Of Hydrogen) sensitive type baicalin | |
| CN102579599B (en) | Decumbent corydalis tuber eye drop and preparation method thereof | |
| CN101579403A (en) | Ready-to-use Dactylicapnos scandens ophthalmic gel | |
| CN1397272A (en) | In-vivo gel preparatino able to be dropped in eyes and its preparing process | |
| CN113786380A (en) | Pilocarpine nitrate ophthalmic gel and preparation method thereof | |
| CN109125318B (en) | Application of butylphthalide in preparation of medicine for treating xerophthalmia | |
| CN104188897A (en) | Timolol maleate ion exchange resin compound insitu gel preparation and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C12 | Rejection of a patent application after its publication | ||
| RJ01 | Rejection of invention patent application after publication |
Open date: 20100127 |