CN101537010A - Eyedrop preparation and preparation method thereof - Google Patents
Eyedrop preparation and preparation method thereof Download PDFInfo
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- CN101537010A CN101537010A CN200910038429A CN200910038429A CN101537010A CN 101537010 A CN101537010 A CN 101537010A CN 200910038429 A CN200910038429 A CN 200910038429A CN 200910038429 A CN200910038429 A CN 200910038429A CN 101537010 A CN101537010 A CN 101537010A
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Abstract
The invention discloses a doxycycline eyedrop preparation and a preparation method thereof. The doxycycline eyedrop preparation comprises 0.03 to 0.5 wt percent of doxycycline, distilled water, hydroxypropyl-beta-cyclodextrin and an antioxidant and has a pH value of 5.0 to 6.0, wherein the weight ratio of doxycycline to hydroxypropyl-beta-cyclodextrin is 1: (1 to 50). The doxycycline eyedrop preparation can improve the dissolubility, the dissolving rate and the stability of doxycycline medicines.
Description
Technical field
The invention belongs to field of pharmaceutical technology, relate to a kind of eye drip preparation and preparation method thereof.
Background technology
Xerophthalmia be because of tear matter and (or) general name of the ophthalmic uncomfortable that the unusual and tear kinetics of amount causes unusually, a class disease of eye table infringement, be one of modal eye surface diseases.Clinical manifestation be dry and astringent, burn, thing sense, gargalesthesia, blurred vision, furious and asthenopia etc.Severe forms of dry eye can also cause serious harm visions such as keratitis, cornea rebirth blood vessel, corneal ulcer, and its influence to people's quality of life more and more receives publicity.Its generation and blepharitis and meibomian gland dysfunction have confidential relation.
Present researchs and proposes, and xerophthalmia may be the non-infectious diseases associated with inflammation of a class in itself, thereby antiinflammatory becomes a new direction of xerophthalmia treatment.The generation of xerophthalmia and blepharitis and meibomian gland dysfunction have confidential relation.Discover, contain a large amount of corynebacteriums, coagulase negative staphylococcus and propionibacterium in the tarsal glands.Known propionibacterium can produce wax lipase and triglyceride enzyme, and coagulase negative staphylococcus can also produce cholesteryl esterase.The existence of these enzymes can change the composition of tarsal glands lipid, can cause the fusing point of tarsal glands secretions to rise on the one hand, makes the viscosity of tarsal glands lipid increase, and causes tarsal glands ductal strictures even obstruction, causes meibomian gland dysfunction; On the other hand, can produce free fatty, destroy the stability of tear film, cause xerophthalmia.Doxycycline (doxycycline, have another name called doxycycline, doxycycline) have a broad spectrum antibacterial function, oral doxycycline can suppress to cause the bacterial growth of chronic blepharitis and meibomian gland dysfunction effectively, and can suppress the generation and the activity thereof of coagulase negative staphylococcus and propionibacterium lipase effectively, thereby chronic blepharitis and meibomian gland dysfunction all had excellent curative, thereby play the effect of treatment xerophthalmia.Simultaneously, the prolonged application of anti-inflammatory drug glucocorticoid commonly used has bigger side effect at present, can cause severe complications such as cataract, glaucoma.Studies show that in recent years, previously the doxycycline that uses as antibiotic can suppress the people's corneal epithelial cell of In vitro culture and the expression of conjunctival epithelial cell inflammation-related factor.Process experiment showed, that the doxycycline eye drop can alleviate the inflammatory reaction of xerophthalmia lagophthalmos table, and can suppress the inductive cornea rebirth blood vessel formation of a chemical injury effectively.For example, it is eye drop of 0.1wt%～0.5wt% doxycycline hyclate and preparation method thereof that Chinese patent 200410027807.0 promptly discloses content, and this preparation method is: doxycycline hyclate, osmotic pressure regulator are dissolved in the distilled water; Add distilled water to volume required, regulating pH value is 5.5～6.0; Membrane filtration degerming, packing promptly get described eye drop.
Yet doxycycline is a kind of yellowish toner or yellow crystalline powder under drying regime, odorless, tasteless, bitter in the mouth, little have draw moistly, stable under the room temperature, it is rotten to meet light, but almost insoluble in chloroform; Unstable in neutrality and alkaline solution, antibacterial activity reduces rapidly, but activity increases in acid solution; Character instability when being made into aqueous solution sees that light easily decomposes, and 1% pH value of water solution is 2-3, and zest is bigger.
The complex compound that contains polyfunctional group and 5 asymmetric carbon atoms in the doxycycline molecule wherein contains structures such as phenol-ketone, keto-enol and phthalein amine.Its structure is made up of unsettled carbocyclic ring and diketone, so be subject to factor affecting such as light, heat, water and decompose.The decomposition reaction of doxycycline hydrochloride mainly comprises the hydrolysis of base catalysis, occurs in the isomerization reaction on C1 and the C6 position, and oxidation reaction etc.
At present among the eye preparation of listing, traditional ophthalmic preparation is still occupied an leading position, and wherein eye drop occupies approximately 70%, and wherein 62.4% is solution-type, and 8.7% is suspension type; Also have a spot of ointment to account for 17.4%.But eye drop generally has only the bioavailability of 1-10% because factor affecting such as the drain of tear, the time of staying be short, and Eye ointments be owing to can cause that generally the visual field is fuzzy, and the compliance of sufferer is relatively poor.
The drainage of tear and eye irriate are the main reason that causes administration near the eyes to run off caused nictation.The effect of gel systems is the viscosity that increases preparation, reduces flowability, extends contact time to reach improved effect.
Situ-gel be meant before medication for liquid condition, splash into a kind of preparation that forms gel behind the fornix owing to the change of environment.Relatively with the bioadhesive gel, situ-gel can provide dosage more accurately, and gel is coated with more equably, so better compliance and repeatability are arranged.Different according to the mechanism that forms gel, mainly be divided into responsive to temperature type, ion-sensitive type, pH responsive type and mixed type.
Summary of the invention
One of purpose of the present invention provides a kind of doxycycline eye drip preparation, and this eye drip preparation nature is stable, good absorbing effect.
A kind of doxycycline eye drip preparation contains the 0.03-0.5wt% doxycycline, distilled water, also contains HP-, antioxidant, and pH is 5.5-6.0, and wherein the weight ratio of doxycycline and HP-is 1: 1-50.
Preferably, described antioxidant is selected from one or more the combination in sodium sulfite, sodium sulfite, sodium pyrosulfite, the sodium thiosulfate.
Described eye drip preparation is preferably the temperature-sensitive situ-gel eye drop, and this situ-gel eye drop also contains poloxamer, and the content of this poloxamer in preparation is 16-30wt%.More preferably, described poloxamer is poloxamer 407 and poloxamer 188, and the amount ratio of poloxamer 407 and poloxamer 188 is 25: 1～3: 2.
Another object of the present invention provides the preparation method of the plain eye drip preparation of above-mentioned west ring.
A kind of method for preparing the described doxycycline eye drip of claim 1 preparation may further comprise the steps:
(1) with ultrasonic method, paddling process or polishing doxycycline, distilled water and HP-are mixed with doxycycline-hydroxypropyl-beta-cyclodextrin inclusion aqueous solution, use 0.45 μ m filtering with microporous membrane, get solution A;
(2) add an amount of antioxidant, the pH value of regulator solution is 5.5-6.0, adds distilled water to required weight, membrane filtration degerming.
Between step (1) and (2), also include following steps:
Take by weighing the poloxamer of weight portion, slowly be distributed in an amount of distilled water, deepfreeze is preserved, and until the solution that forms the clarification homogeneous, gets solution B, and solution A and solution B are fully mixed; Perhaps take by weighing the poloxamer of weight portion according to above-mentioned doxycycline eye drip preparation, slowly be distributed in the solution A, deepfreeze is preserved, until the solution that forms the clarification homogeneous.
The described medicine acceptable carrier that is fit to make gel for eye use is the stable less again irritating substrate of eye-gel preparation that makes doxycycline, but prolong drug strengthens drug absorption in the holdup time of eye, improves bioavailability, reduce the medication number of times, heighten the effect of a treatment and drug safety.The present invention is preferred through a large amount of experiments, has chosen the preferred gel-type vehicle of the present invention from numerous macromolecular materials, poloxamer.
The invention has the advantages that, utilize HP-to prepare the clathrate of medicine, improve medicine dissolution, dissolution rate, and improve medicine stability.And utilize the responsive to temperature character of poloxamer aqueous solution and the combination of different model poloxamer, prepared ocular in-situ gel preparation with suitable phase transition temperature, make it form gel with liquid state administration and at anterior corneal surface at ambient temperature, compare with Eye ointments, do not cause blurred vision, make things convenient for patient's medication, improved compliance, compare with eye drop, reduced the loss of medicine, improve local bioavailability thereby delay the medicine elimination simultaneously.
Description of drawings
Fig. 1 is the phased soln figure of the hydroxypropyl-beta-cyclodextrin inclusion of doxycycline monohydrate;
Fig. 2 is the X ray diffracting spectrum of doxycycline monohydrate, HP-, the two physical mixture and clathrate.
The specific embodiment
Cyclodextrin is a series of member cyclic oligosaccharides that starch forms after the effect of cyclodextrin glucose base translocase.Because cyclodextrin and derivant itself thereof are water solublity, to the human body safety and low toxicity, and can not cause immunoreation, so caused the more and more concerns of people, extensive use in inclusion technique.
The cyclodextrin inclusion of medicine, its characteristics are: the dissolubility that can increase medicine; Increase stability of drug; Make volatile liquid, solid or oily liquids powdered; Reduce the zest and the toxic and side effects of medicine; Cover bitterness and improve drug bioavailability.The various inclusions that medicine is made often will take place in recent years.α, beta cyclodextrin are comparatively commonly used on medicinal.
Cyclodextrin divides another name: α-CD, β-CD, γ-CD by 6,7,8 or the cyclic compound that links by α-1,4 glycosidic bond of more a plurality of D-glucopyranose units.
The hole size of β-CD is between between all the other the two, and void shape is prism-shaped, and the dissolubility in water is 18.5g/L, separate out crystallization from water the easiliest, along with the rising dissolubility of temperature in the water increases, so enclose is good, and toxicity is little, is beneficial to absorb and decomposition.But, the part group that β-CD can only the enclose medicine, and stability is not good, improper to a lot of medicines, should not produce effect so reach; In addition, β-CD is subjected to the less character restriction of autolysis degree, and its solubilising power is limited.
Semisynthetic β-CDYan Shengwu mainly is that its molecular structure is carried out necessary modification.β-CD water solublity is less, and reason is that there are 7 primary hydroxyls and 14 secondary hydroxyls in the two ends in hole, and intermolecular or intramolecularly hydrogen base has stoped the hydration of hydrone.With methyl and, groups such as hydroxypropyl, ethoxy introduce in β-CD molecule and carry out alkylated reaction with hydroxyl, just can destroy the formation of β-CD intramolecular hydrogen bond, and water solublity is changed.
(HP-β-CD) is hydrophilic β-CDYan Shengwu to HP-, compares with β-CD, and following change has taken place physicochemical properties: 1, become amorphism from crystallinity.2, dissolution properties changes.The dissolubility of HP-β-CD in water be greater than 50%, and dissolve in the aqueous solution of alcohol.3, HP-β-CD participates in the organism intracellular metabolite hardly not by gastric acid and α-Dian Fenmeishuixie, does not also accumulate.Basically all excrete with stool after oral with complete morphology.4, β-CD and medicine form complex has slow releasing function to medicine, and HP-β-CD and medicine form complex and medicine is had shortly release effect, make medicine release rapidly in vivo.5, β-CD has haemolysis, and parenterai administration also has certain zest.H P-β-CD surface activity is low, does not have hemolytic and zest basically.6, β-CD and H P-β-CD are to some difference of selectivity of object medicine.
In many pieces of bibliographical informations, H P-β-CD has following effect: raising medicine dissolution, raising dissolution rate, raising oral drugs bioavailability, minimizing medicine are to gastrointestinal stimulation, the bad smell of covering medicine, raising medicine stability, and the part document is mentioned improve powder property and the targeting etc. of H P-β-CD.
HP-is the derivant of beta-schardinger dextrin-, giant's tubular molecular structure, and very easily water-soluble, the enclose amount is big, and toxicity is low, can be applicable to dosing eyes.Through test, after doxycycline and HP-were carried out enclose by certain weight ratio, dissolubility was improved, and stability also is greatly improved.
Embodiment 1
The described eye drip preparation of present embodiment is eye drop, in 100g, contains doxycycline 0.10g, HP-1.00g, sodium sulfite 0.10g, pH 5.5-6.0.
Preparation method: get doxycycline hydrochloride (containing doxycycline 0.10g), HP-1.00g, add a small amount of distilled water to moistening, in mortar, fully grind 3h, add an amount of distilled water diluting, get light yellow clear and bright doxycycline inclusion complex in solution, add sodium sulfite 0.10g, add distilled water to 100g, adjusting pH value in the process is 5.0-6.0 (the pH regulator agent can be sodium hydrogen phosphate, sodium dihydrogen phosphate, sodium hydroxide or sodium bicarbonate), the membrane filtration degerming gets the doxycycline eye drop.
The described eye drip preparation of present embodiment is eye drop, in 100g, contains doxycycline 0.10g, HP-1.00g, sodium sulfite 0.10g, pH 5.5-6.0.
Preparation method: get HP-1.00g, be dissolved in the 10g distilled water, get HP-solution; Get doxycycline (containing doxycycline monohydrate 0.10g), be scattered in about 5.0g distilled water, slowly be added drop-wise in stirring in the HP-solution, ultrasonic 3h gets light yellow clear and bright doxycycline inclusion complex in solution.By phased soln and X-ray diffraction analysis, as Fig. 1 and Fig. 2.Wherein, (D) doxycycline monohydrate hydroxypropyl-beta-cyclodextrin inclusion (1: 24 w/w) of Fig. 1 (A) doxycycline monohydrate (B) HP-(C) doxycycline monohydrate and HP-physical mixture (1: 24 w/w).
From Fig. 1 as seen, HP-can obviously improve the dissolubility of doxycycline monohydrate in water; From the X-ray diffraction analysis result as seen, tangible medicine characteristic peak is arranged in doxycycline monohydrate and the HP-physical mixture, then do not have in the two clathrate, deducibility doxycycline monohydrate and HP-form clathrate.
Add sodium thiosulfate 0.10g in the doxycycline inclusion complex in solution, add distilled water to 100g, adjusting pH value in the process is 5.5-6.0, and the membrane filtration degerming gets the doxycycline eye drop.
Embodiment 3
The described eye drip preparation of present embodiment for the temperature-sensitive situ-gel eye drop, in 100g, contains doxycycline 0.03g, HP-0.90g, poloxamer 407 16.00g, sodium sulfite 0.10g, pH 5.5-6.0.
Preparation method: get HP-0.90g, be dissolved in the 10g distilled water, get HP-solution; Get doxycycline (containing doxycycline monohydrate 0.03g), be scattered in about 1.5g distilled water, slowly be added drop-wise in stirring in the HP-solution, ultrasonic 3h gets light yellow clear and bright doxycycline inclusion complex in solution, is solution A.
Get poloxamer 407 16.00g, slowly be dispersed in the 50g distilled water, deepfreeze is preserved 12-24h, and the solution until forming the clarification homogeneous is solution B.
Above solution A is fully mixed with solution B, add sodium sulfite 0.10g, add distilled water to 100g, adjusting pH value in the process is 5.0-6.0, and the membrane filtration degerming gets doxycycline ophthalmic temperature sensitivity in situ gel eye drop.Phase transition temperature is 29-30 ℃.
Embodiment 4
Eye drip preparation of the present invention, be the temperature-sensitive situ-gel eye drop, in 100g, contain doxycycline 0.50g, HP-25.00g, poloxamer 407 20.00g, poloxamer 188 3.00g, sodium sulfite 0.10g, pH5.5-6.0.
Preparation method: get HP-25.00g, be dissolved in the 40g distilled water, get HP-solution; Get doxycycline (containing doxycycline monohydrate 0.50g), be scattered in about 5g distilled water, slowly be added drop-wise in stirring in the HP-solution, magnetic agitation 10h gets light yellow clear and bright doxycycline inclusion complex in solution.
Get poloxamer 407 20.00g, poloxamer 188 3.00g, slowly be dispersed in the above doxycycline inclusion complex in solution, deepfreeze is preserved 12-24h, until the solution that forms the clarification homogeneous.Add sodium sulfite 0.10g, add distilled water to 100g, adjusting pH value in the process is 5.0-6.0, and the membrane filtration degerming gets doxycycline ophthalmic temperature sensitivity in situ gel eye drop.Phase transition temperature is 27-28 ℃, and after the dilution of simulation tear (gel-tear volume ratio is about 40: 7), phase transition temperature is 36-37 ℃.
Embodiment 5
Eye drip preparation of the present invention, be the temperature-sensitive situ-gel eye drop, in 100g, contain doxycycline 0.10g, HP-3.00g, poloxamer 407 25.00g, poloxamer 188 10.00g, sodium sulfite 0.10g, pH5.5-6.0.
Preparation method: get HP-3.00g, be dissolved in the 10g distilled water, get HP-solution; Get doxycycline (containing doxycycline monohydrate 0.10g), be scattered in about 5g distilled water, slowly be added drop-wise in stirring in the HP-solution, magnetic agitation 10h gets light yellow clear and bright doxycycline inclusion complex in solution, is solution A.
Get poloxamer 407 25.00g, poloxamer 188 10.00g, slowly be dispersed in the 45g distilled water, deepfreeze is preserved 12-24h, and the solution until forming the clarification homogeneous is solution B.
Above solution A is fully mixed with solution B, add sodium sulfite 0.10g, add distilled water to 100g, adjusting pH value in the process is 5.0-6.0, and the membrane filtration degerming gets doxycycline ophthalmic temperature sensitivity in situ gel eye drop.Phase transition temperature is 29-30 ℃, and after the dilution of simulation tear (gel-tear volume ratio is about 40: 7), phase transition temperature is 36-37 ℃.
Embodiment 6
Eye drip preparation of the present invention, be the temperature-sensitive situ-gel eye drop, in 100g, contain doxycycline 0.1g, HP-5.00g, poloxamer 407 25.00g, poloxamer 188 10.00g, sodium sulfite 0.10g, pH 5.0-6.0.
Preparation method: get HP-5.00g, be dissolved in the 10g distilled water, get HP-solution; Get doxycycline (containing doxycycline monohydrate 0.10g), be scattered in about 5g distilled water, slowly be added drop-wise in stirring in the HP-solution, magnetic agitation 10h gets light yellow clear and bright doxycycline inclusion complex in solution, is solution A.
Get poloxamer 407 25.00g, poloxamer 188 2.00g, slowly be dispersed in the 40g distilled water, deepfreeze is preserved 12-24h, and the solution until forming the clarification homogeneous is solution B.
Above solution A is fully mixed with solution B, add sodium sulfite 0.10g, add distilled water to 100g, adjusting pH value in the process is 5.0-6.0, and the membrane filtration degerming gets doxycycline ophthalmic temperature sensitivity in situ gel eye drop.Phase transition temperature is 25-26 ℃, and after the dilution of simulation tear (gel-tear volume ratio is about 40: 7), phase transition temperature is 33-34 ℃.
Embodiment 7: the inhibiting curative effect assessment of doxycycline gel corneal new vessels
Purpose research is local drips with the therapeutic effect of doxycycline gel for eye use to rat corneal neovascularization.
14 of method female sd inbred rats, operation is implanted bFGF slow release diaphragm to the corneal pocket top, and operative incision is folded, and otch is not sewed up, and art is complete to be added with 0.5% tobramycin eye ointment.Rat is divided into treatment group (0.1% doxycycline gel) and matched group (excipient) at random.Treatment is organized 0.1% doxycycline and is dripped gel, drips 50ul every day four times at every turn, postoperative continuous use 6 days; The matched group excipient, drips 50ul at every day four times at every turn.Heart perfusion prepared Chinese ink makes angle Gong Yuan, conjunctiva blood vessel, and cornea rebirth blood vessel becomes black fully.Enucleate eyeball, 4% paraformaldehyde is fixed, and takes out the eyeball that fixes after 24 hours, and operating microscope lower edge angle Gong Yuan takes off cornea, according to the radial cornea of cutting off in CNV vitellarium, paves the back slit lamp and takes a picture down.Dynamic observe cornea with slit lamp microscope and take pictures back 7 days of treatment.Use Image Pro-Plus 5.1 image processing softwares (MediaCybernetics company, USA) length and the area of measurement CNV, length of vessel is as the criterion to the orthotropic blood vessel of slow releasing tablet with angle Gong Yuan, and the statistical analysis between each group adopts independent sample t test or Mann-Whitney U test.Significant difference is defined as P＜0.05.All statistical analysiss all adopt SPSS 13.0 software kits (SPSS Inc., Chicago, IL, USA).
The result
The size of the slow releasing tablet of table 1 liang experimental group with and to the data of limbus of corneae distance
*
*Recorded in the 7th day in test
*The result describes with arithmetical average ± standard deviation
The area vasculosa area of table 2 liang test group and average length of vessel
*Mann-Whitney?U?test
The size of bFGF slow releasing tablet and slow releasing tablet are to the difference not statistically significant (table 1) of the distance of limbus of corneae between treatment group and the matched group.Between treatment group and the matched group, the difference of blood vessel area and length of vessel has statistical significance (table 2).
Local the dripping of conclusion can be suppressed cornea rebirth blood vessel with the doxycycline gel.
Claims (8)
1, a kind of doxycycline eye drip preparation, contain the 0.03-0.5wt% doxycycline, distilled water, it is characterized in that: also contain group-beta-cyclodextrin, antioxidant in the hydroxyl, pH is 5.0-6.0, and wherein the weight ratio of doxycycline and HP-is 1: 1-50.
2, doxycycline eye drip preparation according to claim 1 is characterized in that: described antioxidant is selected from one or more the combination in sodium sulfite, sodium sulfite, sodium pyrosulfite, the sodium thiosulfate.
3, doxycycline eye drip preparation according to claim 1, it is characterized in that: described eye drip preparation is the temperature-sensitive situ-gel eye drop, and this situ-gel eye drop also contains poloxamer, and the content of poloxamer in preparation is 16-30wt%.
4, doxycycline eye drip preparation according to claim 3 is characterized in that: described poloxamer is poloxamer 407 and/or poloxamer 188.
5, doxycycline eye drip preparation according to claim 4 is characterized in that: described poloxamer is poloxamer 407 and poloxamer 188, and the amount ratio of poloxamer 407 and poloxamer 188 is 25: 1～3: 2.
6, according to each described doxycycline eye drip preparation of claim 1-5, it is characterized in that: described doxycycline is to be present in the preparation with doxycycline monohydrate or doxycycline hydrochloride.
7, a kind of method for preparing the described doxycycline eye drip of claim 1 preparation is characterized in that: mainly may further comprise the steps:
(1) with ultrasonic method, paddling process or polishing doxycycline, distilled water and HP-are mixed with doxycycline-hydroxypropyl-beta-cyclodextrin inclusion aqueous solution, use 0.45 μ m filtering with microporous membrane, get solution A;
(2) add an amount of antioxidant, the pH value of regulator solution is 5.0-6.0, adds distilled water to required weight, membrane filtration degerming.
8, preparation method according to claim 7 is characterized in that: between step (1) and (2), also include following steps:
Take by weighing the poloxamer of weight portion by each described doxycycline eye drip preparation of claim 3-5, slowly be distributed in an amount of distilled water, deepfreeze is preserved, until the solution that forms the clarification homogeneous, solution B; Solution A and solution B are fully mixed; Perhaps take by weighing the poloxamer of weight portion by each described doxycycline eye drip preparation of claim 3-5, slowly be distributed in the solution A, deepfreeze is preserved, until the solution that forms the clarification homogeneous.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103142463A (en) * | 2013-03-05 | 2013-06-12 | 宁夏康亚药业有限公司 | Eye medicament composition as well as preparation method and application thereof |
| WO2016046442A1 (en) * | 2014-09-23 | 2016-03-31 | Agencia Pública Empresarial Sanitaria Hospital Alto Guadalquivir | Composition of doxycycline in liposomes for the prevention, improvement and/or treatment of ocular pathologies |
| CN106822154A (en) * | 2017-03-01 | 2017-06-13 | 福建农林大学 | A kind of anti-keratitis konjaku glucomannan eyedrops its preparation method |
| CN107106627A (en) * | 2014-10-10 | 2017-08-29 | 彼得·F·卡罗 | Anti-oxidant eyedrops |
| CN109568262A (en) * | 2019-01-04 | 2019-04-05 | 华南农业大学 | A kind of Doxycycline Temperature-sensitive in situ gel uterus perfusion and preparation method thereof for sow |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100340241C (en) * | 2004-06-28 | 2007-10-03 | 中山大学中山眼科中心 | Eye drop and its preparing method and use |
| MX2007005000A (en) * | 2007-04-25 | 2009-02-25 | Parfarm S A | Novel injectable wide spectrum antibacterial formulation for bovine cattle. |
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2009
- 2009-04-07 CN CN2009100384299A patent/CN101537010B/en not_active Expired - Fee Related
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103142463A (en) * | 2013-03-05 | 2013-06-12 | 宁夏康亚药业有限公司 | Eye medicament composition as well as preparation method and application thereof |
| WO2016046442A1 (en) * | 2014-09-23 | 2016-03-31 | Agencia Pública Empresarial Sanitaria Hospital Alto Guadalquivir | Composition of doxycycline in liposomes for the prevention, improvement and/or treatment of ocular pathologies |
| CN107106627A (en) * | 2014-10-10 | 2017-08-29 | 彼得·F·卡罗 | Anti-oxidant eyedrops |
| CN106822154A (en) * | 2017-03-01 | 2017-06-13 | 福建农林大学 | A kind of anti-keratitis konjaku glucomannan eyedrops its preparation method |
| CN109568262A (en) * | 2019-01-04 | 2019-04-05 | 华南农业大学 | A kind of Doxycycline Temperature-sensitive in situ gel uterus perfusion and preparation method thereof for sow |
| CN109568262B (en) * | 2019-01-04 | 2021-12-24 | 华南农业大学 | Doxycycline temperature-sensitive in-vivo gel uterus perfusate for sows and preparation method thereof |
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| CN101537010B (en) | 2011-07-27 |
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