CN101427993A - Prostaglandin microemulsion gel rubber preparation and method of producing the same - Google Patents
Prostaglandin microemulsion gel rubber preparation and method of producing the same Download PDFInfo
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- CN101427993A CN101427993A CNA2008102289044A CN200810228904A CN101427993A CN 101427993 A CN101427993 A CN 101427993A CN A2008102289044 A CNA2008102289044 A CN A2008102289044A CN 200810228904 A CN200810228904 A CN 200810228904A CN 101427993 A CN101427993 A CN 101427993A
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Abstract
The invention relates to prostaglandin microemulsion-gel preparation and a preparation method thereof. The preparation comprises prostaglandin E1 or the derivative thereof, oil, emulsifier, assistant for emulsifying agent, gel substrate and water, and also possibly comprises a permeation accelerator, a preparation stabilizer, an antioxidant and antiseptics. The preparation has the advantages of good percutaneous permeability, no stimulation to skin and mucous membrane, simple preparation technique and stable quality, the preparation can be used for treating diseases such as ulcer of limbs caused by erectile dysfunction and chronic arterial occlusion and rest pain of limbs caused by microcirculatory disturbance.
Description
Technical field
The present invention relates to prostaglandin microemulsion gel rubber preparation and preparation method thereof, belong to medical technical field.
Background technology
PGE1 (PGE1) has another name called Alprostadil, and its chemical name is: 11 α, 15 (the S)-two hydroxyls-anti-prostenoic acid of 9-ketone-13-.
Chemical structural formula is:
Molecular formula: C
20H
34O
5
Molecular weight: 354.48
PGE1 is an important physical active substance in the human body, has blood vessel dilating, and anticoagulant is regulated the inflammatory cell activity, reduces gastric secretion, stimulates multiple physiological and pharmacological effects such as small intestinal, uterus wriggling.Be widely used in treatment various cardiovascular and cerebrovascular diseases, male erectile dysfunction, serious peripheral blood vessel, adult respiratory distress syndrome etc. clinically, but also diseases such as adjuvant treating hepatitis, hyperlipidemia, diabetes, renal insufficiency, bronchial asthma, pancreatitis.Have the advantages that dosage is little, evident in efficacy, toxic and side effects is little.
Therefore PGE1 adopts the injection system administration usually in the gastrointestinal tract metabolism that easily is decomposed.The PGE1 dosage form of having gone on the market both at home and abroad comprises at present: freeze-dried powder injection, injectable emulsion, ointment, urethral suppository and local injection agent etc.In recent years, the development of the local administration preparation of PGE1 rapidly.Prostaglandin E
1Corpus cavernosum injection agent and urethra administration suppository evident in efficacy, but local injection medication and insert caused pain, injury and inconvenience and limited its clinical practice.Prostaglandin E
1The emulsifiable paste onset is rapid, and is easy to use, but can cause local excitation symptom such as scorching hot, rubescent, pain.
At present the patent of relevant PGE1 local administration preparation can be divided three classes according to the difference of dosage form: 1. ointment, as CN1449270A, CN1354677A and CN1551784A etc.; 2. local injection agent is as CN1182592A and CN1492761A; 3. urethral bougie is as CN1331973A.
Microemulsion is that particle diameter is that the emulsion droplet of 10～100nm is dispersed in the colloidal dispersion system that forms in the another kind of liquid.Microemulsion as a kind of novel drug-supplying system have good stability, advantages such as solvability is strong, viscosity is low, preparation is simple, easily industrialization, the sterilization of available filtration method.Over nearly 20 years, microemulsion gets more and more people's extensive concerning in the pharmaceutics field, has been used for the research of multiple route of administration such as transdermal, oral, injection, mucosa delivery.Aspect transdermal drug delivery system, the application of microemulsion more and more widely.Compare with general preparation such as hydrogel, Emulsion, liposome etc., it has higher drug loading and stronger transdermal ability.
CN101125145A discloses a kind of local using prostaglandin micro emulsion and preparation method thereof, said preparation is made up of PGE1 or derivatives thereof, oil phase, emulsifying agent, co-emulsifier and water, has advantages such as Thermodynamically stable, preparation technology are simple, good penetrability.But because microemulsion system viscosity is low, mobile strong, it is not too convenient to use as the transdermal drug carrier.Therefore, the present invention joins gel-type vehicle in the microemulsion on the basis of CN101125145A, has further made micro emulsion gel.Micro emulsion gel is semi-solid, smears, stores and transport all very convenient as preparation capable of permeating skin.
The present invention has adopted the adjuvant of good biocompatibility, prepares prostaglandin E
1The or derivatives thereof micro emulsion gel has increased the Transdermal absorption of medicine, shortens the onset time of medicine, has eliminated the local injection medication and has inserted caused pain, injury and inconvenience, has reduced the zest of local application, is prostaglandin E
1A kind of desirable preparation of or derivatives thereof local application.
Summary of the invention
The present invention relates to a kind of prostaglandin microemulsion gel rubber preparation and preparation method thereof, said preparation is made up of PGE1 or derivatives thereof, oil, emulsifying agent, co-emulsifier, gel-type vehicle and water, also may contain penetration enhancer, preparation stabilization agent, antioxidant and antiseptic, its mass fraction is: PGE1 or derivant 0.0005%-5%, preferred 0.1%-1%; Oil phase 1%-30%, preferred 6%-20%; Emulsifying agent 1%-40%, preferred 5%-30%; Co-emulsifier 1%-40%, preferred 5%-20%; Gel-type vehicle 0.1%-20%, preferred 0.5%-15%; Penetration enhancer 0%-20%, preferred 0%-10%; Stabilizing agent 0%-30%, preferred 0%-20%; Antioxidant 0%-10%, preferred 0%-5%; Antiseptic 0%-5%, preferred 0%-1%; Water 30%-90%, preferred 50%-75%.
Derivatives of prostaglandins of the present invention is represented by general formula (I):
In the formula, R
1Expression hydrogen atom, C
1-10Alkyl or C
3-10Cycloalkyl
R
1C
1-10Alkyl represent straight chain shape or catenate alkyl, for example methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, the tert-butyl group, amyl group, isopentyl, 2-ethyl propyl, hexyl, isohesyl, 1-ethyl-butyl, heptyl, different heptyl, octyl group, nonyl, decyl etc.
R
1C
3-10Cycloalkyl for example cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl etc.
Oil of the present invention is one or more combinations in medium chain triglyceride, isopropyl myristate, isopropyl palmitate, isopropyl laurate, three sad caprins, ethyl oleate, Ethyl linoleate, soybean oil, Oleum Cocois, Oleum Ricini, Semen Maydis oil, olive oil, Oleum Arachidis hypogaeae semen, safflower oil, Semen Lini oil, Oleum Gossypii semen, Oleum sesami, Oleum Camelliae, fish oil, the oleic acid, preferred medium chain triglyceride, isopropyl myristate, isopropyl palmitate, oleic acid, ethyl oleate and soybean oil.
Emulsifying agent of the present invention is one or more combinations in tween, span, poloxamer, phospholipid of natural soybean, natural egg yolk lecithin, native phosphatidylcholine or semi-synthetic phosphatidylcholine and derivant, Myrj 45, sucrose fatty acid ester, Polyethylene Glycol-vitamin e succinate, Polyethylene Glycol-phospholipid, polyethylene glycol hydroxystearate, polyoxyethylene castor oil and the derivant thereof, preferred tween, poloxamer, phospholipid of natural soybean, natural egg yolk lecithin, sucrose fatty acid ester and polyoxyethylene castor oil.
Co-emulsifier of the present invention is one or more combinations in ethanol, normal propyl alcohol, propylene glycol, isopropyl alcohol, glycerol, n-butyl alcohol, n-octyl alcohol, n-heptanol, carbitol, PEG400, the triacetyl glycerine, preferred alcohol, normal propyl alcohol, propylene glycol, isopropyl alcohol, glycerol and PEG400.
Gel-type vehicle of the present invention is one or more combinations in carbomer, cellulose derivative, xanthan gum, arabic gum, tragakanta, carrageenin, gelatin, sodium alginate, the poloxamer, preferred carbomer, methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, xanthan gum, sodium alginate and poloxamer.
Penetration enhancer of the present invention is one or more combinations in pyrrolidinone compounds, azone, oleic acid, terpenoid, carbitol, carbamide, the amide-type, preferred N-Methyl pyrrolidone, azone, oleic acid, Mentholum, Borneolum Syntheticum, limonene, carbitol and carbamide.
Stabilizing agent of the present invention is one or more combinations in oleic acid, enuatrol, the cholesterol.
Antioxidant of the present invention is one or more the mixture in vitamin E, vitamin C, disodiumedetate, sodium sulfite, dibenzylatiooluene, butylated hydroxyarisol, the L-cysteine, preferred vitamin C, sodium sulfite and disodiumedetate.
Antiseptic of the present invention is one or more the mixture in phenol, chlorobutanol, benzyl alcohol, parabens, benzoic acid and salt, sorbic acid and salt, the bromination cetylamine, preferred phenol, parabens, benzoic acid and sorbic acid.
The preparation method of prostaglandin microemulsion gel rubber preparation of the present invention is as follows:
With PGE1 or derivatives thereof, oil, emulsifying agent, co-emulsifier, gel-type vehicle, the mixed microemulsion that gets of water, gel-type vehicle is added in the microemulsion, after the stirring swelling, promptly get micro emulsion gel; Perhaps PGE1 or derivatives thereof, oil, emulsifying agent, co-emulsifier are mixed obtaining oil phase, again water and gel-type vehicle are mixed and made into water-soluble bloated body, will promptly get micro emulsion gel behind oil phase and the water-soluble bloated body mix homogeneously; Perhaps PGE1 or derivatives thereof, oil, emulsifying agent, co-emulsifier are mixed and obtain oil phase, in addition water is divided into two parts in the ratio of 1:0.2～5, make microemulsion behind a adding oil phase, another part is mixed and made into water-soluble bloated body with gel-type vehicle, will make micro emulsion gel behind microemulsion and the water-soluble bloated body mix homogeneously.
Wherein, the method for preparing microemulsion also comprises high pressure homogenize emulsion process and supersound method.
Prostaglandin microemulsion gel rubber preparation of the present invention, outward appearance are translucent or are transparent and light blue opalescence, pH value are arranged is 3.0-9.0, and the emulsion droplet mean diameter is less than 100nm, and 90% particle diameter accumulated value is not more than 200nm.
Micro emulsion gel of the present invention may be a kind of temperature sensitive gel, is the colloidal sol of low-viscosity when being lower than 30 ℃, and is full-bodied gel when being higher than 30 ℃.
Description of drawings
Fig. 1: the particle size distribution figure of the micro emulsion gel that embodiment 1-4 makes, corresponding A, B, C, D respectively
Fig. 2: the accumulation penetration curve of the microemulsion gel preparation of the present invention's preparation
The specific embodiment
PGE1 0.2g
Refined soybean oil 10g
Lecithin 3g
Poloxamer 188 7g
Glycerol 10g
Vitamin C 0.2g
Methylcellulose 1g
Water for injection 68.6g
Preparation method: refined soybean oil, lecithin mix homogeneously are got oil phase, PGE1 is added in the oil phase dissolve; Methylcellulose is dispersed in the water, and swelling is spent the night, and adds poloxamer 188, glycerol and vitamin C again, and mix homogeneously gets water; Oil phase is joined aqueous phase, stir, after 0.22 μ m microporous filter membrane aseptic filtration, promptly get the PGE1 microemulsion gel preparation.
PGE1 0.5g
Ethyl oleate 8g
Polyoxyethylene castor oil 10g
Isopropyl alcohol 6g
Carbomer 0.5g
Triethanolamine 0.55g
Propyl p-hydroxybenzoate 0.05g
Water for injection 74.4g
Preparation method: ethyl oleate, polyoxyethylene castor oil mix homogeneously are got oil phase, PGE1 is added in the oil phase dissolve; Carbomer is dispersed in the water, and swelling is spent the night, and adds isopropyl alcohol again, and mix homogeneously gets water; Oil phase is joined aqueous phase, stir microemulsion; Triethanolamine is joined in the microemulsion, promptly get the PGE1 microemulsion gel preparation behind the mix homogeneously.
PGE1 0.8g
Isopropyl palmitate 15g
Tween 80 12g
1,2-propylene glycol 10g
Azone 5g
Disodiumedetate 0.05g
Hydroxypropyl cellulose 3g
Water for injection 54.15g
Preparation method: isopropyl palmitate, azone mix homogeneously are got oil phase, PGE1 is added in the oil phase dissolve; Hydroxypropyl cellulose is dispersed in the water, and swelling is spent the night, and adds Tween 80,1 again, 2-propylene glycol and disodiumedetate, and mix homogeneously gets water; Oil phase is joined aqueous phase, stir, after 0.22 μ m microporous filter membrane aseptic filtration, promptly get the PGE1 microemulsion gel preparation.
PGE1 0.5g
Refined soybean oil 15g
Polysorbate60 18g
Sorbester p18 3g
PEG400 6g
Butylated hydroxyarisol 0.02g
Hydroxypropyl methylcellulose 2g
Water for injection 55.48g
Preparation method: refined soybean oil, sorbester p18 mix homogeneously are got oil phase, PGE1 is added in the oil phase dissolve; Hydroxypropyl methylcellulose is dispersed in the water, and swelling is spent the night, and adds Tween 80, PEG400 and butylated hydroxyarisol again, and mix homogeneously gets water; Oil phase is joined aqueous phase, stir, after 0.22 μ m microporous filter membrane aseptic filtration, promptly get the PGE1 microemulsion gel preparation.
PH and mean diameter result that embodiment 5 measures the microemulsion that is made by above embodiment are as follows:
Particle size distribution figure sees accompanying drawing 1.
The test of embodiment 6 transdermal test in vitro
Get the male mice in kunming that body weight is 18-22g, shave except that belly wool with shaver, take off skin of abdomen after drawing neck to put to death, remove subcutaneous fat, clean skin with normal saline, it is standby that filter paper blots the back.Tried thing and be respectively embodiment 3 micro emulsion gel that makes and 20% ethanol water that contains 0.5% PGE1.Adopt improved Franz diffusion cell to carry out the transdermal test, skin is fixed between supply pool and the reception tank, stratum corneum side is to supply pool, and skin corium is towards reception tank.Add 0.5g in the supply pool and tried thing, add the 13.2ml normal saline in the reception tank, 37 ± 0.5 ℃ of circulator baths respectively at 1,2,3,4,6 hour 3ml that takes a sample, are added the fresh acceptable solution of equivalent simultaneously in reception tank from reception tank.After sample is centrifugal, use high effective liquid chromatography for measuring content.
The accumulation transit dose of the micro emulsion gel of the present invention's preparation has good percutaneous permeation apparently higher than the medicine alcoholic solution.The results are shown in Figure of description 2.
The test of embodiment 7 skin irritations
Observe animal intact skin and damaged skin and repeatedly give the local irritation that is produced behind prostaglandin microemulsion gel rubber preparation reaction.Get 9 of rabbit and be divided into 3 groups at random, 3 every group, first group is carried out the intact skin irritant experiment, and second group is carried out the damaged skin irritant experiment, and the 3rd group is blank group.First and second group adopts consubstantiality left and right sides self matching type relatively, and the left side gives the PGE1 micro emulsion gel, and the right side gives blank, and dosage is 0.5g, and blank group left side is an intact skin, and the right side is a damaged skin.Be administered once every day, and administration time is 4h, after administration finishes, removes and tried drug combination warm water cleaning medicine-feeding part and observe.Behind administration 1h and before the rechallenge, under natural light, observe every day and situation and time of origin and regression times such as record medicine-feeding part erythema, edema, pigmentation, petechia, pachylosis or epidermatic atrophy, and erythema and red and swollen situation are estimated.Successive administration is defined as 21 days, every day with method continuously in the administration of same position.After the last administration, 30-60min and 24,48 and 72h observes and the record coating part has or not situations such as erythema and edema after removing medicine.
The PGE1 micro emulsion gel to rabbit integrity skin and breakage skin repeatedly the irritation test result show, observe at 72h during the administration and after the drug withdrawal, all show as nonirritant, do not have any other variation smearing the position, the average response value is all less than 0.4.
Claims (6)
1, a kind of prostaglandin microemulsion gel rubber preparation, it is characterized in that forming by PGE1 or derivatives thereof, oil, emulsifying agent, co-emulsifier, gel-type vehicle and water, also may contain penetration enhancer, preparation stabilization agent, antioxidant and antiseptic, its mass fraction is: PGE1 or derivant 0.0005%-5%, oil phase 1%-30%, emulsifying agent 1%-40%, co-emulsifier 1%-40%, gel-type vehicle 0.05%-20%, penetration enhancer 0%-20%, stabilizing agent 0%-30%, antioxidant 0%-10%, antiseptic 0%-5%, water 30%-90%.
2, prostaglandin microemulsion gel rubber preparation according to claim 1 is characterized in that:
Described derivatives of prostaglandins is represented by general formula (I):
In the formula, R
1Expression hydrogen atom, C
1-10Alkyl or C
3-10Cycloalkyl
3, prostaglandin microemulsion gel rubber preparation according to claim 1 is characterized in that:
Described oil is one or more combinations in medium chain triglyceride, isopropyl myristate, isopropyl palmitate, isopropyl laurate, three sad caprins, ethyl oleate, Ethyl linoleate, soybean oil, Oleum Cocois, Oleum Ricini, Semen Maydis oil, olive oil, Oleum Arachidis hypogaeae semen, safflower oil, Semen Lini oil, Oleum Gossypii semen, Oleum sesami, Oleum Camelliae, the fish oil;
Described emulsifying agent is one or more combinations in tween, span, poloxamer, phospholipid of natural soybean, natural egg yolk lecithin, native phosphatidylcholine or semi-synthetic phosphatidylcholine and derivant, Myrj 45, sucrose fatty acid ester, Polyethylene Glycol-vitamin e succinate, Polyethylene Glycol-phospholipid, polyethylene glycol hydroxystearate, polyoxyethylene castor oil and the derivant thereof;
Described co-emulsifier is one or more combinations in ethanol, normal propyl alcohol, propylene glycol, isopropyl alcohol, glycerol, n-butyl alcohol, n-octyl alcohol, n-heptanol, carbitol, Polyethylene Glycol, the triacetyl glycerine.
Described gel-type vehicle is one or more combinations in carbomer, cellulose derivative, xanthan gum, arabic gum, carrageenin, gelatin, sodium alginate, the poloxamer.
Described penetration enhancer is one or more combinations in pyrrolidinone compounds, azone, oleic acid, terpenoid, carbitol, carbamide, the amide-type.
Described stabilizing agent is one or more combinations in oleic acid, enuatrol, the cholesterol.
Described antioxidant is one or more the mixture in vitamin E, vitamin C, disodiumedetate, sodium sulfite, dibenzylatiooluene, butylated hydroxyarisol, the L-cysteine.
Described antiseptic is one or more the mixture in phenol, chlorobutanol, benzyl alcohol, parabens, benzoic acid and salt, sorbic acid and salt, the bromination cetylamine.
4, the preparation method of the described prostaglandin microemulsion gel rubber preparation of claim 1, it is characterized in that: with PGE1 or derivatives thereof, oil, emulsifying agent, co-emulsifier, gel-type vehicle, the mixed microemulsion that gets of water, gel-type vehicle is added in the microemulsion, after the stirring swelling, promptly get micro emulsion gel; Perhaps PGE1 or derivatives thereof, oil, emulsifying agent, co-emulsifier are mixed obtaining oil phase, again water and gel-type vehicle are mixed and made into water-soluble bloated body, will promptly get micro emulsion gel behind oil phase and the water-soluble bloated body mix homogeneously; Perhaps PGE1 or derivatives thereof, oil, emulsifying agent, co-emulsifier are mixed and obtain oil phase, in addition water is divided into two parts in the ratio of 1:0.2～5, make microemulsion behind a adding oil phase, another part is mixed and made into water-soluble bloated body with gel-type vehicle, will make micro emulsion gel behind microemulsion and the water-soluble bloated body mix homogeneously.
5, prostaglandin microemulsion gel rubber preparation according to claim 1 is characterized in that: the said preparation outward appearance is translucent or is transparent and light blue opalescence, pH value are arranged is 3.0-9.0, and the emulsion droplet mean diameter is less than 100nm, and 90% particle diameter accumulated value is not more than 200nm.
6, prostaglandin microemulsion gel rubber preparation according to claim 1 is characterized in that: described micro emulsion gel may be a kind of temperature sensitive gel.
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Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103961356A (en) * | 2013-01-24 | 2014-08-06 | 上海医药工业研究院 | Freeze-dried alprostadil composition for injection and preparation method thereof |
| CN105342984A (en) * | 2014-08-21 | 2016-02-24 | 中国人民解放军总医院 | Injectable temperature-sensitive gel preparation for treating acute pancreatitis |
| US20160067263A1 (en) * | 2013-05-15 | 2016-03-10 | Topokine Therapeutics, Inc. | Methods and compositions for topical delivery of prostaglandins to subcutaneous fat |
| US9849179B2 (en) | 2013-05-10 | 2017-12-26 | Topokine Therapeutics, Inc. | Methods for topical delivery of prostaglandins to subcutaneous fat |
| US9861641B2 (en) | 2011-12-19 | 2018-01-09 | Topokine Therapeutics, Inc. | Methods for reducing body fat using tafluprost and analogs thereof |
| CN107669513A (en) * | 2017-08-24 | 2018-02-09 | 山西医科大学 | A kind of olive oil with skin care bacteriostasis/VE micro emulsion gels and preparation method thereof |
| CN108367046A (en) * | 2015-12-18 | 2018-08-03 | 普罗因韦特创新股份公司 | Preparation for controlling cyclostage and ovulation and method |
| US10188661B2 (en) | 2014-06-27 | 2019-01-29 | Topokine Therapeutics, Inc. | Topical dosage regimen |
| US10335418B2 (en) | 2011-01-19 | 2019-07-02 | Topokine Therapeutics, Inc. | Methods and compositions for treating metabolic syndrome |
| CN110585117A (en) * | 2019-09-16 | 2019-12-20 | 五邑大学 | Thermo-sensitive gel preparation of phloretin and preparation method and application thereof |
| CN112089684A (en) * | 2020-10-30 | 2020-12-18 | 华东医药（西安）博华制药有限公司 | Levoornidazole/ornidazole oil-in-water emulsion temperature-sensitive gel suppository and preparation method thereof |
| CN112263542A (en) * | 2020-10-19 | 2021-01-26 | 澳美制药厂有限公司 | Desonide nanoemulsion gel composition and preparation method thereof |
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| US10335418B2 (en) | 2011-01-19 | 2019-07-02 | Topokine Therapeutics, Inc. | Methods and compositions for treating metabolic syndrome |
| US9861641B2 (en) | 2011-12-19 | 2018-01-09 | Topokine Therapeutics, Inc. | Methods for reducing body fat using tafluprost and analogs thereof |
| CN103961356A (en) * | 2013-01-24 | 2014-08-06 | 上海医药工业研究院 | Freeze-dried alprostadil composition for injection and preparation method thereof |
| CN103961356B (en) * | 2013-01-24 | 2018-03-23 | 上海医药工业研究院 | Alprostadil freeze-dried composition of injection and preparation method thereof |
| US10556012B2 (en) | 2013-05-10 | 2020-02-11 | Topokine Therapeutics, Inc. | Compositions and methods for topical delivery of prostaglandins to subcutaneous fat |
| US9849179B2 (en) | 2013-05-10 | 2017-12-26 | Topokine Therapeutics, Inc. | Methods for topical delivery of prostaglandins to subcutaneous fat |
| US9820993B2 (en) * | 2013-05-15 | 2017-11-21 | Topokine Therapeutics, Inc. | Methods and compositions for topical delivery of prostaglandins to subcutaneous fat |
| US20160067263A1 (en) * | 2013-05-15 | 2016-03-10 | Topokine Therapeutics, Inc. | Methods and compositions for topical delivery of prostaglandins to subcutaneous fat |
| US10869874B2 (en) | 2013-05-15 | 2020-12-22 | Topokine Therapeutics, Inc. | Methods and compositions for topical delivery of prostaglandins to subcutaneous fat |
| US10188661B2 (en) | 2014-06-27 | 2019-01-29 | Topokine Therapeutics, Inc. | Topical dosage regimen |
| CN105342984A (en) * | 2014-08-21 | 2016-02-24 | 中国人民解放军总医院 | Injectable temperature-sensitive gel preparation for treating acute pancreatitis |
| CN108367046A (en) * | 2015-12-18 | 2018-08-03 | 普罗因韦特创新股份公司 | Preparation for controlling cyclostage and ovulation and method |
| CN107669513A (en) * | 2017-08-24 | 2018-02-09 | 山西医科大学 | A kind of olive oil with skin care bacteriostasis/VE micro emulsion gels and preparation method thereof |
| CN110585117A (en) * | 2019-09-16 | 2019-12-20 | 五邑大学 | Thermo-sensitive gel preparation of phloretin and preparation method and application thereof |
| CN112263542A (en) * | 2020-10-19 | 2021-01-26 | 澳美制药厂有限公司 | Desonide nanoemulsion gel composition and preparation method thereof |
| CN112263542B (en) * | 2020-10-19 | 2023-09-01 | 澳美制药厂有限公司 | Decne nano emulsion gel composition and its preparation method |
| CN112089684A (en) * | 2020-10-30 | 2020-12-18 | 华东医药（西安）博华制药有限公司 | Levoornidazole/ornidazole oil-in-water emulsion temperature-sensitive gel suppository and preparation method thereof |
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Owner name: LI SHUBIN Free format text: FORMER OWNER: SHENYANG ONEUPLEAD PHARM ACEUTICAL TECHNOLOGY CO., LTD. Effective date: 20110627 |
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Effective date of registration: 20110627 Address after: Hunnan New Century Road 110179 Shenyang city of Liaoning Province, No. 5 Tsinghua Tongfang Century Towers, B block 806 Applicant after: Li Shubin Address before: 110179 Liaoning city of Shenyang province Shenyang Hunnan New Long Street No. 10 -1 independent intellectual property park on the third floor Applicant before: Shenyang Wan'ai Pulide Medical Technology Co.Ltd |
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Application publication date: 20090513 |