CN102397242A - Hydrogel containing coenzyme Q10, and cataplasm prepared by hydrogel - Google Patents
Hydrogel containing coenzyme Q10, and cataplasm prepared by hydrogel Download PDFInfo
- Publication number
- CN102397242A CN102397242A CN2011102574844A CN201110257484A CN102397242A CN 102397242 A CN102397242 A CN 102397242A CN 2011102574844 A CN2011102574844 A CN 2011102574844A CN 201110257484 A CN201110257484 A CN 201110257484A CN 102397242 A CN102397242 A CN 102397242A
- Authority
- CN
- China
- Prior art keywords
- ubiquinone
- hydrogel
- present
- coenzyme
- nano
- 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 present invention relates to a hydrogel containing coenzyme Q10 and a cataplasm prepared by the hydrogel. The coenzyme Q10 of the present invention is prepared into nanoparticles, solid lipid nanoparticles, flexible nano-liposomes, nano-microemulsion, nano-micelles and the like. Especially that the flexible coenzyme Q10 nano-liposomes are preferably adopted in the hydrogel of the present invention. The coenzymes Q10 with various forms are adopted to prepare the hydrogel, the cataplasm prepared by the hydrogel, and other external application preparations or apparatuses. In the prior art, the coenzyme Q10 in the common external application preparation containing the coenzyme Q10 is easily oxidized and decomposed, and is preserved difficultly. With the present invention, the problems in the prior art are effectively solved; the skin penetration performance of the coenzyme Q10 is substantially increased. The hydrogel and the cataplasm prepared by the hydrogel can be applicable for dermal topical application and nursing of the coenzyme Q10, or percutaneous systematic administration of the coenzyme Q10, specifically for preparation into cosmetics, health products, or drugs and the like. The present invention further relates to a use of the coenzyme Q10 nano-preparation in preparation of the coenzyme Q10 hydrogel preparation.
Description
Technical field
The present invention relates to contain ubiquinone
10Hydrogel and contain the cataplasma of this hydrogel, ubiquinone wherein
10The form that exists be the nano-preparations carrier form that nanotechnologys such as nanoparticle, solid lipid nanoparticle, flexible nano liposome, nanometer microemulsion, nano-micelle are processed, preferably with the flexible nano liposome as ubiquinone among the present invention
10The preparations carrier form.
Background technology
With traditional medical substance; Process various pastes, the agent of mud Buddhist nunnery or various soft, the plaster of topical like plant tissue extract, animal tissue's extract, natural minerals etc.; The existing extensive application among the people in various countries; The rubber unguentum traditional like China, Egypt and babylonia " her Bai Shi Papyrus " also have the record of plaster in (BC1552).Modern transdermal patch is since emerging the 1980s, and development is rapid, and the transdermal patch of the existing at least 20 number of chemical medicines in the whole world obtains the listing approval of various countries pharmaceutical control and administration department so far.External preparation such as above-mentioned transdermal patch and rubber unguentum are generally the liposoluble system; Though such preparation is comparatively ripe on preparation technology at present; Can realize large-scale industrial production, also accepted by the people day by day that sales volume continues to enlarge in the application of medical field; But still there are many insoluble problems, it applied receive bigger restriction.Like a lot of patients these fat-soluble external preparation are produced anaphylaxis, use the back red swelling of the skin even fester; The patient who has is difficult to accept the indecency traditional oiliness plaster of outward appearance psychologically.In recent years, along with the development of material science, it is the Percutaneously administrable prepn of material with the water-soluble base that the pharmacists of Asian countries such as Japan and Korea S have developed a kind of, the domestic cataplasma of generally being called of China.One one of Pharmacopoeia of the People's Republic of China version in 2010 ranges the gel ointment in the emplastrum with cataplasma.This kind aqueous cataplasma sticks behind patient skin, and because of it contains a large amount of moisture content and does not contain or only contain a spot of liposoluble constituent basically, patient's toleration is good, is not prone to allergic phenomena, receives the welcome of extensive patients.The cataplasma product is not only very popular in the Asia, and begins to move towards the international market, and existing several cataplasma products obtain the listing approval of U.S. FDA.Also have the cataplasma of import to sell on the China market, compare with traditional rubber-emplastrum, it is more soft that cataplasma seems, also cleaner.
Except the problem in the clinical practice of ubi supra; Percutaneously administrable prepn also has bigger limitation in technology; Use traditional technological means; Some material is not easy to process Percutaneously administrable prepn, is inappropriate for transdermal administration in theory like molecular weight big (greater than 500 dalton), the higher chemical compound of fusing point, and the chemical compound of water solublity or fat-soluble difference etc. then also is difficult to be prepared as Percutaneously administrable prepn.Above-mentioned situation has hindered the application of these materials in fields such as transdermal administration and cosmetics.For this reason, people explore the carrier material of transdermal administration and medicine distribution and pharmacokinetics thereof in these carriers etc. again.Along with nano material and technology are introduced into pharmaceuticals industry; It is found that the unique effect of nanotechnology in the transdermal administration field; And developed several and be applicable to the nano-carrier form of transdermal administration, like nanoparticle, solid lipid nanoparticle, flexible nano liposome, nanometer microemulsion, nano-micelle etc.The carrier of these nano shape provides approach for breaking through macromole and the application limitation of water-insoluble drug in transdermal administration, and obtains positive achievement.The potential quantity that can be used for the medicine of transdermal administration has been expanded in the introducing of nanotechnology widely, like the water-insoluble ubiquinone of macromolecule
10
Ubiquinone
10Be a kind of bioactive substance that extensively is present on the cell mitochondrials such as animal, plant, microorganism, can conveying electronic in various biological oxidation-reductions, be the natural anti-oxidation system that cell self produces, have the important physical effect.Existing bibliographical information, ubiquinone
10Can be applicable to treat diseases such as vitamin C deficiency, heart disease, viral hepatitis, congenital reproducibility anemia, emphysema, bronchial asthma, parkinson.The zoopery result shows also have antitumor action.The mankind itself can be raw material composite part ubiquinone voluntarily with tyrosine
10, but it just begins continuous minimizing at the intravital content of people after the age surpasses 20 years old.Exogenous ubiquinone
10Application, can remedy self the source deficiency.
Along with to ubiquinone
10The extension of the deep and industrial chain of research is except having broad prospect of application at field of medicaments, present ubiquinone
10Food, health product and cosmetic field have been widely used in developed country.In cosmetic application, ubiquinone
10Effect mainly be crease-resistant effect, its mechanism of action is ubiquinone
10Promotion face, hand epithelial cell respiratory chain are transmitted and ARP produces; Thereby promotion skin metabolism; The skin tension pressure that elimination is brought by aging, malnutrition, illumination, disease etc. suppresses the skin lipid peroxidating simultaneously, skin is risen nourish and anti-aging effects.Campaign is the result show, ubiquinone
10It is more remarkable than VE, VB2 that the Skin Cell lipid peroxidation is suppressed effect.
But because ubiquinone
10Contain unsaturated double-bond in the molecular structure, therefore extremely unstable, be prone to by airborne oxygen and light oxidation and decomposition, be heated or run into then accelerated decomposition of metal ion, the result often causes ubiquinone in the product
10Content descends, and is very big to the influence of product quality and result of use.For the ubiquinone in the cosmetics for external use
10, because in use, the relative contact of itself and air and surrounding is long-pending bigger, oxidation with decompose more violent.How to prevent or slow down ubiquinone
10Oxidation in the external preparation be decomposed into problem demanding prompt solution.
Nano-drug preparation is the current developing dosage form of new generation that is in, and the size of Nano medication carrier for active principle particle is its primary characteristic, also is the important foundation of nano effect that nano-drug preparation appears.The particle size range of version Pharmacopoeia of the People's Republic of China regulation nanosphere in 2000, nanocapsule is 10～1000nm.Big quantity research shows; When the particle diameter of drug particles is between 10～1000nm; Nano medication has demonstrated and the conventional formulation evident difference in the characteristic aspect of physicochemical property, pharmacokinetics (PK) and pharmacodynamics (PD), and these have constituted the material base of the special biological effect of Nano medication.
Liposome is as the existing nearly 40 years history of the research of pharmaceutical carrier, and technology of preparing is comparative maturity.Liposome comprises the number of plies of lipoids bilayer according to its structure, be divided into particle diameter at the small unilamellar vesicle between 20～80nm, particle diameter at large unilamellar vesicle between 100～1000nm and the multilamelar liposome of particle diameter between 1～5 μ m.Wherein nanometer liposome refers generally to small unilamellar vesicle.Liposome is made up of lecithin and cholesterol usually.Method for preparing commonly used comprises injection method, film dispersion method, ultrasonic dispersing method, reverse phase evaporation and surfactant treatment method etc.Medicine or be dissolved in the intravital water of lipid, or absorption or be dissolved on the bimolecular lipid membrane or in the film.The nanometer liposome drug-loading system has and strengthens drug targeting property, prolong drug action time, improves medicine stability, reduces characteristics such as adverse effect.
If adopt Nano capsule technology preparation ubiquinone
10Nanometer liposome can not only strengthen its stability, prevents oxidative degradation, and can improve its water solublity, promotes ubiquinone
10Absorption.External existing bibliographical information is with ubiquinone
10Bioavailability and result of use have been significantly improved after processing liposome.
Before the present invention, the people has been arranged with ubiquinone
10Processed common nanometer liposome.Like " food industry science and technology " the 2nd phase in 2006 the 164th page to 168 pages " ubiquinones
10The preparation of nanometer liposome " in promptly introduced the method for preparing nanometer liposome.This article adopts thin film-ultrasonic method and ethanol injection-ultrasonic method to prepare ubiquinone
10Nanometer liposome.Wherein adopt the prepared ubiquinone of ethanol injection-ultrasonic method
10The carrying capacity of nanometer liposome can be up to 45%.Here cite this article, with as preparing ubiquinone among the present invention
10One of alternative approach of nanometer liposome.In addition; " Nano medication " (chief editor: Yang Xiang is good; Publishing house of Tsing-Hua University; October in 2007 the 1st edition) also introduced the common method of preparation nanometer formulation in, medicine and cosmetic field are engaged in the those of ordinary skill of nanometer formulation preparation and can be consulted this book and when the preparation nanometer formulation, use book as guidance.
With ubiquinone
10But process the preparation of external, thereby bring into play its pharmacological action, more existing researchs before the present invention.
US2006182787A1 has described a kind of material that is used for skin or skin trauma place, and it contains polycondensation compound substrate and a kind of water absorbent polymer, and this water absorption chemical compound can ooze out material and a kind of skin-care substances of at least a promotion wound healing.In a kind of therein scheme, this suction chemical compound comprises at least 90% cross-linked acrylic acid in mass, and the acrylic acid that in these acrylic acid, has 30mol% at least is neutral acrylic acid.
EP1588703A1 has described ubiquinone
10Thereby be used for the mankind and other animals and slow down tired purposes.Ubiquinone wherein
10Can be used by human body in many ways,, also can directly be used for skin as oral.It can be made into exterior-applied formulations such as cream, plaster, gel, spray.Cream wherein can be made into w/o type.
Summary of the invention
The present invention relates to contain ubiquinone
10The compositions that exists of a kind of independent or two or more mixing of nanoparticle, solid lipid nanoparticle, flexible nano liposome, nanometer microemulsion, nano-micelle and contain said composition form ubiquinone
10Hydrogel and the cataplasma of processing with this hydrogel.This contains ubiquinone
10Hydrogel and the cataplasma that contains this hydrogel of one or more mixture of nanoparticle, solid lipid nanoparticle, flexible nano liposome, nanometer microemulsion, nano-micelle can be applicable to human body skin or mucosa; Like positions such as hand, arm, abdominal part, face, oral mucosas; As fatigue preparations, skin wound care formulations or uses such as beautifying skin thin film or pad pasting; Especially be suitable for being used in face and cervical region, have the skin aging of slowing down, effect such as crease-resistant as beauty mask.
The present invention especially preferably uses and contains ubiquinone
10The flexible nano liposome is prepared into hydrogel and contains the cataplasma of this hydrogel.
Nanoparticle described in the present invention is meant the solid particle of particle diameter between 10～1000nm, comprises nanocapsule and nanosphere.Nanoparticle is made up of natural, semisynthetic and synthetic macromolecular material.Generally directly be prepared as the medicament nano granule through nanometer sedimentation or superfine technique.
Solid lipid nanoparticle described in the present invention is meant that phospholipid relies on hydrophobic association to act on a kind of molecular assembly assembly of spontaneous formation in the water; Be the multilamellar vesicle structure; Every layer is the lipoid bimolecular film, and interlayer and liposome kernel are water, is oil phase between bimolecular film.
Flexible nano liposome described in the present invention is meant surfactant; Join having self deformation of height, can penetrating the lipoid plastid in one the skin duct of having only himself big decimal branch efficiently of processing in the lipid materials of preparation liposome like sodium cholate, sodium deoxycholate etc., have efficient permeability, high degree of flexibility and hydrophilic.The similar biomembrane of this flexible nano liposome; It is a kind of multi-functional targeted drug carrier; More active component is retained in the skin, reduces active component and get into sanguimotor amount, form drug-reservoir at epidermis and intradermal; Form a slow release model, medicine is played a role to skin or corresponding position enduringly.Such characteristic is particularly suitable for being applied to the present invention.
Nanometer microemulsion described in the present invention is meant that particle diameter is that the emulsion droplet of 10～100nm is dispersed in the dispersion system of colloid that forms in the another kind of liquid, is transparent or semitransparent; It is spherical mostly its emulsion droplet is; Size is more even, through pressure sterilizing or centrifugally can not make it layering, belongs to the thermodynamically metastable fixed system.
Nano-micelle described in the present invention; Be meant by parents' polymer and in selective solvent, microphase-separated take place and a kind of self-assembled structures with hydrophobic cores and hydrophilic shell that forms, the motive force between them has hydrophobic interaction, electrostatic interaction, hydrogen bond action and metal complexation etc.Because of its possess hydrophilic property shell and hydrophobic cores, thus the spontaneous formation macromolecule micelle in back in water, dissolved, and accomplish solubilising and parcel to medicine.Can it be divided into spherical, bar-shaped, vesicle shape, tubulose, two-dimentional micelle and compound big micelle etc. according to form.
The inventor is at the preparation ubiquinone
10Find in hydrogel and the process, for ubiquinone with larger molecular weight and utmost point low aqueous solubility with this preparing gel cataplasma
10, adopt traditional Percutaneously administrable prepn method for preparing and technology to be difficult to reach application purpose, ubiquinone
10The phenomenon of in system, luming is very serious, not only influences the outward appearance of medicine, the more important thing is that prepared hydrogel and cataplasma can not effectively discharge ubiquinone
10So the inventor attempts ubiquinone
10Use after being loaded into suitable carrier formulation after adopting nanotechnology to handle, as process with ubiquinone
10For pharmaceutical carriers such as the nanoparticle of active component, solid lipid nanoparticle, flexible nano liposome, nanometer microemulsion, nano-micelles, then these carrier formulations are applied to prepare hydrogel, obtained unforeseeable effect.Not only made ubiquinone
10The product that in whole system, is evenly distributed, and improved the useful load and the stability of medicine greatly.Thereafter to these by stripping or transdermal experiment that made hydrogel of said medicine carrier formulation and cataplasma are done, also obtain promising result, can satisfy the preparation ubiquinone fully
10Hydrogel and contain the requirement of the cataplasma of this hydrogel.In various nanometer dosage forms according to the invention, promptly in nanoparticle, solid lipid nanoparticle, flexible nano liposome, nanometer microemulsion, the nano-micelle, preferred ubiquinone
10The flexible nano liposome.
Ubiquinone
10Nanoparticle, solid lipid nanoparticle, flexible nano liposome, nanometer microemulsion, nano-micelle etc. have shown common ubiquinone in the present invention
10Not available physics of micropowder or suspension and chemical characteristic, thus can merge preferably with system, and make the effective ingredient ubiquinone
10The hydrogel and the cataplasma that are evenly distributed and effectively discharge; Its reason is the combined effect of the peculiar quantum size effect of nanoparticle, small-size effect, skin effect and macro quanta tunnel effect etc.; In addition, different nano shape preparations also have its unique function and characteristic:
Ubiquinone
10Nanoparticle is owing to have the peculiar skin effect of nanometer materials, strengthened the dispersibility in water-based material and has been applied to the present invention with the compatibility of water-based material.
The outer surface of solid lipid nanoparticle has stronger hydrophilic, can merge well with aqueous gel substrate, thereby in hydrogel and cataplasma stable existence.
The flexible nano liposome is a kind of lipoid aggregation, and its main component is phospholipid and surfactant, has some particular performances, comprises high deformation property, highly hydrophilic, efficient permeability, high stability etc.These characteristics make the flexible nano liposome become the preferred version among the present invention.Adopt ubiquinone
10The flexible nano liposome prepares hydrogel and cataplasma, can make ubiquinone
10In system, be evenly distributed, and after carrying out the suitable pharmaceutical proportioning, have controlled transdermal performance, can carry out the deep layer release, be suitable for whole body administration and local skin administration, especially be fit to be prepared into used for cosmetic and nourish in the local deep layer of skin through skin.
In the big quantity research that the inventor did, the inventor finds that the flexible nano liposome is particularly suitable for the present invention.The first is owing to the biphase hydrophilic interface that is inside and outside the flexible nano liposome, and the two sides in the intermediate layer at its inside and outside two interfaces then is lipophilic layer, ubiquinone
10Can be embedded in this intermediate layer and stable existence; Hydrophilic outer surface is then compatible with aqueous gel very good; Can make whole flexible nano liposome be able in preparation and storage process, be difficult for taking place comparatively stably to be present in the aquogel system such as destructive variations such as the flexible nano liposome break.In addition, the flexible nano liposome makes it have morphotropism preferably because of in its system, having introduced surfactant, can penetrating aperture size have only himself diameter number/one's skin duct, like sweat pore, such characteristic just is suitable for ubiquinone
10See through epiderm skin.If be made into cosmetics, can also play the effect that is penetrated into deep skin, like the entering subcutaneous tissue, thereby bring into play the not available effect unique of general cosmetics.Therefore, in the present invention, preferred ubiquinone
10The flexible nano liposome prepares hydrogel and cataplasma.
Except active component is handled; Thereby make its corresponding existence form compatible with system; And have medicine useful load and a release performance that meets application target; In aqueogel and cataplasma preparation, the selection of adjuvant and proportioning thereof have decisive influence to the performance of the aqueogel that contains active component.Particularly, mainly be the aqueous binder material that constitutes the hydrogel main body, whole system is had the most key effect.The inventor compares test to the adjuvant material and analyzes, and from numerous alternative materials, filtered out and be applicable to hydrophilic binder agent material of the present invention, and to studying with the technology of its preparation hydrogel.
The inventor finds that the polyacrylic binder with following structural formula can be applied among the present invention preferably:
Wherein preferred m: n≤1: 1, the polyacrylic binder shown in the said structure formula, the H on the part carboxylic acid wherein is neutralized the back and is replaced by alkali metal such as Na, and the H as 50% is neutralized and is replaced by alkali metal, and such structure has following advantage:
A. stronger viscosity.The content of PAA reduces can improve its viscosity;
B. with alcohols material good affinity is arranged.As polyvalent alcohols materials such as glycerol are had good affinity;
C. lower pH value.Because of the pH value of aqueous solution of polymer is low, when being used for acid unguentum, be easy to carry out the adjustment of pH value.
Preferably, the molecular weight of above-mentioned polyacrylic acid (sodium) is greater than 1,000, and 000.Be applicable to that commercially available prod of the present invention is Viscomate NP-700 or Viscomate NP-600 Japanese clear and electrician company.
In addition, the hydrophilic adhesive in this hydrogel matrix can also be selected gelatin, polyvinyl alcohol, polyvinylpyrrolidone etc. for use.They can be singly with or with above-mentioned polyacrylic acid (sodium), mix like NP-700 or NP-600 and to use.The polyvinylpyrrolidone that is adopted among the present invention can be selected from the Kolidone of BASF AG, and like PVP-K30, PVP-K90 etc., the polyvinyl alcohol that is adopted among the present invention can be selected PVA2124 for use.Especially when polyvinyl alcohol or polyvinylpyrrolidone and polyacrylic acid (sodium) composition mixed adhesive substrate, can prepare more good quality production of performance in the present invention.
Except the aqueous cohesive material, the hydrogel among the present invention and contain in the hydrogel matrix of cataplasma of this hydrogel and also can contain wetting agent, solubilizing agent, thickening agent, excipient, penetrating agent, cross-linking agent etc.
Thereby the wetting agent described in the present invention is meant the moisture substantially constant that can keep over a period to come in this hydrogel and keeps the constant material of its physicochemical property; The wetting agent that wherein the most often uses is polyhydric alcohol; Like glycerol, Polyethylene Glycol, sorbitol, propylene glycol, glycerin, wetting agent also can be selected from pyrrolidone sodium carboxylate, trimethyl glycine, chitin and derivant thereof, Aloe, pantothenylol, collagen protein, hyaluronic acid etc.
Solubilizing agent described in the present invention is for increasing the material of the dissolubility of medicine in aquogel system, and in the present invention, both being meant to increase free ubiquinone
10, also refer to be embedded in the ubiquinone in the nano-carrier
10Be dispersion and the dissolving of nano-carrier in system.Comprise cationic, anionic and nonionic surfactant.Wherein anionic surfactant comprises soap kind, like hard soap; Hydrosulphate is like stearyl alcohol sodium sulfate; Azochlorosulfonate acid compound is like dioctyl succinate sodium sulfonate etc.; Nonionic surfactant mainly contains polyoxyethylene sorbitan fatty acid ester class, Tweens; Polyoxyethylene fatty acid ester class, polyoxyethylene aliphatic alcohol ether class etc.
Excipient described in the present invention is the material that helps to keep hydrogel physical space characteristic and shape, and excipient commonly used is an inorganic matter, like micropowder silica gel, calcium carbonate, Kaolin, kieselguhr, kaolin etc.
Penetrating agent described in the present invention is claimed transdermal enhancer again; Can effectively promote hydrogel and the active component in the cataplasma among the present invention to get into skin surface and see through skin and get into blood of human body circulation material, can be divided into three types of nonpolar, polarity and surface activitys according to general classification.Nonpolar type of penetrating agent wherein commonly used has higher fatty acids, like oleic acid, lauric acid, linoleic acid etc.; High fatty alcohol is like oleyl alcohol, lauryl alcohol, hexadecanol etc.; Terpenes is like cineole, menthol etc.; Polarity class penetrating agent commonly used has monobasic or polyalcohols, like methanol, ethanol, glycerol, isopropyl alcohol; Phenol is like thymol; Sulfoxide is like dimethyl sulfoxide, dodecyl methyl sulfoxide etc.; Surface activity class penetrating agent comprises cationic; Anionic is like sodium laurylsulfate etc.; Amphoteric ion type is like dodecyl dimethyl propyl group ammonium sulfate etc.; Nonionic is like tween 80, sad single glyceride etc.Preferred penetrating agent is azone, propylene glycol, Borneolum Syntheticum and Oleum menthae among the present invention.
Antioxidant described in the present invention is not limited only to the low Reducing agent of oxidizing potential, also comprises the material that can delay pharmaceutical preparation is produced Oxidation.Can be divided into water soluble antioxidant and oil-soluble inhibitor according to qualitative classification; Preferred oil soluble antioxidant of the present invention, the following oil-soluble inhibitor that can select altogether that is: hydroquinone, propyl gallate, ascorbyl palmitate, the nor-pair of hydrogen guaiaretic acid, to hydroxyl tert-butyl group methoxybenzene, toluene di-tert-butyl phenol, Jiao's property gallate-based and ester thereof, alpha-tocopherol, phenyl-1-naphthylamine, lecithin etc.The preferred alpha-tocopherol of the present invention (vitamin E).
Cross-linking regulator described in the present invention is for can selecting organic acid for use in order to regulate the material of the polyacrylic acid crosslinked speed and the degree of cross linking, like citric acid, edetate sodium (EDTA), tartaric acid, oleic acid, gluconic acid in the present invention; Aluminum salt is like aluminium hydroxide etc.
In addition, each several part of the present invention comprise among the embodiment water if no special instructions, be deionized water.
Effective active composition among the present invention is a ubiquinone
10, the inventor finds ubiquinone
10Process that nanoparticle, solid lipid nanoparticle, flexible nano liposome, nano-micelle, nanometer microemulsion are applied to hydrogel of the present invention and during the cataplasma processed by this hydrogel, can effectively solve ubiquinone
10In water, be difficult to dissolve and then can not prepare the ubiquinone of character homogeneous
10The difficult problem of hydrogel.Furthermore, with ubiquinone
10Be prepared as the form of loading, can alleviate ubiquinone greatly with above-mentioned carrier
10In air, be prone between the storage life in the time of in the process that is prepared as hydrogel and cataplasma and before using by the problem of oxygen and light oxidation and decomposition.In addition, cross-linking agent commonly used in aqueogel contains metal ion, and these metal ions possibly quicken ubiquinone
10The oxidation process, from but preparation loses effect, and with ubiquinone
10Process nanoparticle, solid lipid nanoparticle, flexible nano liposome, nano-micelle and nanometer microemulsion etc. and then can effectively prevent or reduce its destruction.When this hydrogel or the cataplasma that contains this hydrogel were used for human body skin, these were included in the ubiquinone in the carrier material
10Can in the interaction of carrier and skin and external environment, discharge, absorb or directly act on the epidermis cell keratodermatitis under through skin, thereby bring into play its biochemical effect, like resisting fatigue, promotion wound healing, crease-resistant, nourishes rough skin etc.Preferably, with ubiquinone
10Process the flexible nano liposome, can not only bring above-mentioned serial effect, more because ubiquinone
10Special and the superior permeance property of flexible nano liposome can strengthen ubiquinone
10The transdermal amount, bring into play more significant physiological effect, especially the deep layer of skin is nourished and beauty functions.
To carry out more detailed explanation to the present invention below.
Binder polymer in the hydrogel among the present invention calculates with the dry weight before absorbing water, and its percentage composition in the gross weight of whole its matter of hydrogel is 3%～60%; Be preferably 4%～10%; More preferably 5%～8%.
In whole hydrogel matrix, in its gross weight, ubiquinone
10Percentage composition be 0.01%～10%; Be preferably 0.03%～1%; More preferably 0.05～0.35%.Has plenty of ubiquinone if contain in the hydrogel
10Solid lipid nanoparticle, flexible nano liposome, nanometer microemulsion, nano-micelle then need to convert content wherein into pure ubiquinone according to corresponding drug loading and envelop rate
10Content.
In hydrogel of the present invention, wherein the percentage composition of water in the gross weight of hydrogel matrix is 15%～80%, and be preferred 35%～70%, more preferably 45%～68%.
In hydrogel of the present invention, the wetting agent that contains is 15%～35%, and wetting agent can use preferably from sorbic acid, glycerol, propylene glycol, glycerin, Polyethylene Glycol in independent or two or more mixing.
In hydrogel of the present invention, can also contain antioxidant, its percentage composition that accounts for the hydrogel matrix gross weight is 0.1～10%, and is preferred 0.15%～2%, more preferably 0.3%～1.2%.The antioxidant that can select for use comprises the reproducibility vitamin, like vitamin E, and vitamin C etc., preferred vitamin E.
When the binding agent in the hydrogel of the present invention is selected the poly acrylic acid-poly PAA for use, can also use cross-linking agent, wherein said cross-linking agent is selected from bivalence or trivalent metal ion, and aluminum salt especially is like aluminium hydroxide, aluminum chloride, dihydroxyaluminum aminoacetate etc.The ratio of its content and poly acrylic acid-poly PAA is about 1: 100～and 1: 5, especially preferred about 1: 10.
Also can contain a spot of cross-linking regulator in the hydrogel matrix among the present invention, it accounts for 0.05%～1% of whole hydrogel matrix.Cross-linking regulator commonly used is tartaric acid, EDTA etc.
After preparing hydrogel through suitable dry run; As be statically placed under the workshop indoor environment of dry cleansing of certain clean order of magnitude; So that preparations shaping, and make moisture wherein reach predetermined requirement, promptly can process aqueogel of the present invention; Also can the hydrogel of above-mentioned undried be coated and carry out drying behind the suitable back lining materials again and process and use more conveniently, also more be prone to the cataplasma of preserving.In the present invention, as a kind of product of application, preferably this hydrogel is directly processed cataplasma.And this cataplasma meets the skin surface of human body after can passing through suitable cutting, as processes the facial film shape, and perhaps wrist strap form can let user use more convenient like this and result of use is better.Because the hydrogel in this cataplasma promptly adopts said method prepared, therefore, it forms the substrate hydrogel in this cataplasma as follows:
Binder polymer in this cataplasma hydrogel matrix calculates with the dry weight before absorbing water, and its percentage composition in the gross weight of whole hydrogel matrix is 3%～60%; Be preferably 4%～10%; More preferably 5%～8%.
In whole hydrogel matrix, in its gross weight, ubiquinone
10Percentage composition be 0.01%～10%; Be preferably 0.03%～1%; More preferably 0.05～0.35%.Has plenty of ubiquinone if contain in the hydrogel
10Solid lipid nanoparticle, flexible nano liposome, nanometer microemulsion, nano-micelle then need to convert content wherein into pure ubiquinone according to corresponding drug loading
10Content.
In hydrogel of the present invention, wherein the percentage composition of water in the gross weight of hydrogel matrix is 15%～80%, and be preferred 35%～70%, more preferably 45%～68%.
In hydrogel of the present invention, the wetting agent that contains is 15%～35%, and wetting agent can be selected from sorbic acid, glycerol, propylene glycol, glycerin, Polyethylene Glycol, can independent or two or more mixing use.
In hydrogel of the present invention, can also contain antioxidant, its percentage composition that accounts for the hydrogel matrix gross weight is 0.1～10%, and is preferred 0.5%～2%, more preferably 0.8%～1.2%.The antioxidant that can select for use is the reproducibility vitamin, like vitamin E, and vitamin C etc.
When the binding agent in the hydrogel of the present invention is selected the poly acrylic acid-poly PAA for use, also possibly need use cross-linking agent, wherein said cross-linking agent can be selected from bivalence or trivalent metal ion, and aluminum salt especially is like aluminium hydroxide, aluminum chloride, dihydroxyaluminum aminoacetate etc.The ratio of its content and poly acrylic acid-poly PAA is about 1: 100～and 1: 5, especially about 1: 10.
Also can contain a spot of cross-linking regulator in the hydrogel matrix among the present invention, it accounts for 0.05%～1% of whole hydrogel matrix.Cross-linking regulator commonly used is tartaric acid, EDTA etc.
For the present invention further is described, the inventor has carried out explanation further with following embodiment to the foregoing invention content, and these embodiment are in order more clearly to describe the present invention rather than to restriction that the present invention carried out.
The specific embodiment
Embodiment 1
Preparation contains ubiquinone
10The hydrogel of nanoparticle and contain the cataplasma of this hydrogel
Present embodiment contains Q with preparation
10Hydrogel that gathers peptide-chitosan complexes nanoparticle and cataplasma be that example comes preparation is contained ubiquinone
10The hydrogel of nanoparticle and the cataplasma that contains this hydrogel describe.
Prepare ubiquinone in the present embodiment
10The method of gathering peptide-chitosan complexes nanoparticle can consult CN101530394B.
At first prepare this and contain ubiquinone
10Gather peptide-chitosan complexes nanoparticle.The main adjuvant of used preparation nanoparticle is for gathering (L-glutamic acid-γ-benzyl esters)-polyethyleneglycol block copolymer (PBLG-b-PEG) among the present invention, and its preparation method is following:
Under the room temperature with PBLG-b-PEG block copolymer and the 3mg ubiquinone of 2.5mg
10Mixture is dissolved in the 25mL dimethyl formamide: in the mixed solvent of oxolane=7: 3; Put into bag filter after the dissolving fully; Bag filter is inserted in the beaker that the 1000mL deionized water is housed and was dialysed 72 hours, and whenever changes once new deionized water at a distance from 3 hours, to remove organic solvent.After the dialysis, not embedding medicinal is removed in centrifugalize in deionized water, and it is the membrane filtration of 0.45 μ m that diameter is used in the supernatant, obtains the about 40mL of polypeptide drug-loaded micelle solution.
Measure the above-mentioned ubiquinone that has prepared
10Gather peptide amphipathic nature block polymer self-assembled nanometer solution 20mL; With itself and concentration is that the acetum 40mL of 2.25mg/mL mixes; Simultaneously an amount of chitosan is dissolved in the acetum that concentration is 1.5mg/mL, processing chitosan concentration is the solution 20mL of 1.5mg/mL, then with ubiquinone
10Gather the acetum of peptide and the acetum of chitosan and mix stirring, dripping concentration while stirring is the sodium tripolyphosphate solution 50mL of 0.75mg/mL, makes the embedding ubiquinone
10Chitosan-gather peptide composite nano-granule solution.
Through analyzing the above-mentioned ubiquinone that makes
10The particle diameter major part of nanoparticle is between 200～300nm, and average carrying drug ratio is about 3.5%, and average envelop rate is 55%.
Contain above-mentioned ubiquinone for preparation below
10The general process of nanoparticle hydrogel:
Appropriate amount of deionized water is placed large beaker, add sorbitol, carbomer, tartaric acid, EDTA mixing successively.Again with above-mentioned ubiquinone
10Nanoparticle solution adds in the large beaker, adds vitamin E, span 20, polysorbas20, NP-700, glycerol, propylene glycol, dihydroxyaluminum aminoacetate then successively, uses motor stirrer under room temperature, to stir 1 hour, makes and contains ubiquinone
10Hydrogel.
Using medical scraper or other specific purpose tools to coat non-woven fabrics and place after compound with antiadhesion barrier and place humidity above-mentioned hydrogel is about 40% cleaning work room air drying 24 hours under room temperature.Package encapsulation behind the cross cutting as requested then.
Contain ubiquinone among the embodiment 1
10Each component percentage quality proportioning table of hydrogel
Need to prove the ubiquinone described in the present embodiment
10Gathering peptide-chitosan complexes nanoparticle is not to refer to pure nanoparticle, but the mixed system that behind the preparation nanoparticle, is obtained comprises ubiquinone
10The ubiquinone that nanoparticle is sealed
10, free ubiquinone
10, the filmogen (lipid) that added etc., therefore, ubiquinone
10Actual content also need be through detecting and calculating and could confirm.Below the nano material that adopts among each embodiment all have the situation similar with present embodiment, will not explain in addition.
In the present embodiment, employed ubiquinone
10The carrying capacity of gathering peptide-chitosan complexes nanoparticle is 3.5%, and envelop rate is about 55%.The computing formula of carrying capacity and envelop rate is as follows respectively:
If no special instructions, the computing formula of this carrying capacity and envelop rate is equally applicable to following each embodiment.Above-mentioned formula is simplified processing, can obtain the computational envelope ubiquinone
10And free ubiquinone
10The computing formula of content, expression is as follows respectively:
Seal ubiquinone
10Lipid content * carrying capacity in content-product (%)
Can calculate by above-mentioned formula and to learn ubiquinone in the present embodiment
10Gather the ubiquinone of sealing that contains in peptide-chitosan complexes nanoparticle
10The quality percentage composition be 0.01%, and the ubiquinone of free state in this hydrogel
10Content be 0.008%, ubiquinone in this hydrogel then
10Total content be about 0.018%.
Embodiment 2
Preparation contains ubiquinone
10The hydrogel of flexible nano liposome and contain the cataplasma of this hydrogel.
Present embodiment is that the main film material metric system is equipped with ubiquinone with Ovum Gallus domesticus Flavus lecithin
10The flexible nano liposome; Its preparation method is following: take by weighing 2.25g Ovum Gallus domesticus Flavus lecithin, 0.36g cholesterol, 1.62g Tween 80 respectively, place the 250mL round-bottomed flask, add the 20mL ether and make its dissolving; Then this round-bottomed flask is connected with the rotation decompression evaporator; Reduction vaporization 30 minutes to remove organic solvent wherein, is deposited on bottle wall until the dried lipid film; In round-bottomed flask, add the 5mL ether then, rock round-bottomed flask until being deposited on the dissolving that comes off fully of dried lipid film on the flask walls.Accurately take by weighing the 30mg ubiquinone again
10With the 0.36g sodium cholate, add the 10mL deionized water, rock dissolving, be poured into the above-mentioned ubiquinone that is loaded with
10Round-bottomed flask in, make its uniform mixing, with the liposome turbid liquor that obtains supersound process 5min in the probe-type Ultrasound Instrument.Other gets a clean 250mL round-bottomed flask, pours above-mentioned lipid soln into, and round-bottomed flask is connected with rotary evaporator, and reduction vaporization 30min with the filtering with microporous membrane of 0.45 μ m, promptly obtains ubiquinone again
10The flexible nano liposome turbid liquor.Through detecting, its envelop rate is about 45%, and drug loading is about 5.6%, and mean diameter is 130nm, and particle size distribution is narrower.
According to method in embodiment 1 prepare ubiquinone thereafter,
10Hydrogel and cataplasma.The component of above-mentioned hydrogel and catablasm base material hydrogel and the quality percentage composition following:
Ubiquinone in the present embodiment
10The envelop rate of flexible nano liposome is 45%, and carrying capacity is 5.6%.Then can know, be embedded in the ubiquinone in the nanometer flexible lipidosome in the said hydrogel of present embodiment through the computing formula of carrying capacity
10Percentage composition be 0.043%, the Q of free state
10The percentage mass content be 0.052%, then total Q
10The quality percentage composition be 0.101%.
Embodiment 3～7
Hydrogel described in the embodiment 3～7 and contain the ubiquinone of selecting for use in the cataplasma of this hydrogel
10Identical among flexible nano liposome and the embodiment 2.
Ubiquinone described in the foregoing description 3～7
10The ubiquinone that is in embedding state and free state that is contained in the flexible nano liposome
10Content carry out through above-mentioned company respectively, the result is following:
| Ubiquinone 10Content | Embodiment 3 | Embodiment 4 | Embodiment 5 | Embodiment 6 | Embodiment 7 |
| The embedding ubiquinone 10Content | 0.05％ | 0.05％ | 0.05％ | 0.063％ | 0.063％ |
| Free ubiquinone 10Content | 0.061％ | 0.061％ | 0.061％ | 0.077％ | 0.077％ |
| Total ubiquinone 10Content | 0.111％ | 0.111％ | 0.111％ | 0.14％ | 0.14％ |
Claims (10)
1. aqueogel, in weight percentage, it contains 3%～60% hydrophilic polymer binding agent, 0.01%～25% ubiquinone
10, 15%～80% water, wherein ubiquinone
10Dosage form for nanoparticle, solid lipid nanoparticle, flexible nano liposome, nanometer microemulsion, nano-micelle.
2. the aqueogel described in the claim 1 is characterized in that hydrophilic polymer binding agent wherein is a polyacrylic acid.
3. the described aqueogel of claim 2 is characterized in that polyacrylic acid is wherein neutralized by part for the carboxyl on its polymerization single polymerization monomer, and it has following general structure:
M≤n wherein promptly in this polyacrylic acid, has to be not less than 50% carboxyl and to be neutralized by alkali.
4. claim 2,3 described aqueogels is characterized in that wherein polyacrylic molecular weight greater than 10,000,000.
5. the aqueogel described in the claim 1 is characterized in that hydrophilic polymer binding agent wherein is the mixture that polyvinyl alcohol, gelatin, polyvinylpyrrolidone and polyacrylic acid are formed.
6. the described aqueogel of claim 1 is characterized in that ubiquinone wherein
10Nanometer formulation is its flexible nano liposome.
7. the aqueogel described in one of claim 2～5 is characterized in that polyacrylic binder wherein is a cross linked polyacrylate, and the cross-linking agent that wherein contains is 1: 100～1: 5 with the ratio of polyacrylic quality.
8. the described aqueogel of claim 7 is characterized in that the ratio of cross-linking agent and polyacrylic quality is 1 in the polyacrylic binder wherein: 10.
9. a cataplasma is characterized in that its substrate is the aqueogel described in the claim 1～8.
10. ubiquinone
10Nanoparticle, ubiquinone
10Solid lipid nanoparticle, ubiquinone
10Flexible nano liposome, ubiquinone
10Nanometer microemulsion, ubiquinone
10Micelle is at the preparation ubiquinone
10Purposes in the aqueogel.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011102574844A CN102397242A (en) | 2011-09-02 | 2011-09-02 | Hydrogel containing coenzyme Q10, and cataplasm prepared by hydrogel |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011102574844A CN102397242A (en) | 2011-09-02 | 2011-09-02 | Hydrogel containing coenzyme Q10, and cataplasm prepared by hydrogel |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN102397242A true CN102397242A (en) | 2012-04-04 |
Family
ID=45880141
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2011102574844A Pending CN102397242A (en) | 2011-09-02 | 2011-09-02 | Hydrogel containing coenzyme Q10, and cataplasm prepared by hydrogel |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102397242A (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103126965A (en) * | 2013-03-01 | 2013-06-05 | 珠海海狮龙生物科技有限公司 | Novel crystal pad pasting and preparation method |
| CN106924176A (en) * | 2017-03-20 | 2017-07-07 | 荆楚理工学院 | A kind of TAM flexible nano-liposomes gel and preparation method thereof |
| CN108992713A (en) * | 2018-09-06 | 2018-12-14 | 武汉市思泰利医疗器械发展有限公司 | A kind of corrosion-resistant stoma leakproof cream and preparation method thereof |
| CN109528693A (en) * | 2018-12-20 | 2019-03-29 | 武汉科福新药有限责任公司 | A kind of rapamycin cataplasm and preparation method thereof |
| CN112646228A (en) * | 2020-12-21 | 2021-04-13 | 嘉兴学院 | Tannin crosslinked chitosan/gelatin liquid-absorbing hemostatic antibacterial sponge and preparation method thereof |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2004352637A (en) * | 2003-05-28 | 2004-12-16 | Kanae Technos:Kk | Sheetlike pack material |
| CN101530394A (en) * | 2009-04-17 | 2009-09-16 | 上海应用技术学院 | Polypeptide-chitosan composite nanoparticles loaded with coenzyme Q10 and preparation method thereof |
| CN101590028A (en) * | 2009-04-16 | 2009-12-02 | 中国人民解放军第二军医大学 | Comprise hydrogel patch of tulobuterol and preparation method thereof |
| WO2010117199A2 (en) * | 2009-04-06 | 2010-10-14 | 한국생명공학연구원 | Coenzyme q10 nanoparticles, preparation method thereof and composition containing said nanoparticles |
-
2011
- 2011-09-02 CN CN2011102574844A patent/CN102397242A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2004352637A (en) * | 2003-05-28 | 2004-12-16 | Kanae Technos:Kk | Sheetlike pack material |
| WO2010117199A2 (en) * | 2009-04-06 | 2010-10-14 | 한국생명공학연구원 | Coenzyme q10 nanoparticles, preparation method thereof and composition containing said nanoparticles |
| CN101590028A (en) * | 2009-04-16 | 2009-12-02 | 中国人民解放军第二军医大学 | Comprise hydrogel patch of tulobuterol and preparation method thereof |
| CN101530394A (en) * | 2009-04-17 | 2009-09-16 | 上海应用技术学院 | Polypeptide-chitosan composite nanoparticles loaded with coenzyme Q10 and preparation method thereof |
Non-Patent Citations (3)
| Title |
|---|
| JAE-YOON SHIN ET AL: "Assembly of Coenzyme Q10 nanostructure resembling nascent discoidal high density lipoprotein particle", 《BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS》, vol. 388, no. 2, 30 July 2009 (2009-07-30), pages 217 - 221, XP 026522057, DOI: doi:10.1016/j.bbrc.2009.07.140 * |
| VARAPORN B. JUNYAPRASERT ET AL: "Q10-loaded NLC versus nanoemulsions: Stability, rheology and in vitro skin permeation", 《INTERNATIONAL JOURNAL OF PHARMACEUTICS》, vol. 377, 22 May 2009 (2009-05-22) * |
| 夏书芹等: "辅酶Q_(10)纳米脂质体配方与工艺优化研究", 《食品科学》, vol. 28, no. 03, 31 December 2007 (2007-12-31) * |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103126965A (en) * | 2013-03-01 | 2013-06-05 | 珠海海狮龙生物科技有限公司 | Novel crystal pad pasting and preparation method |
| CN106924176A (en) * | 2017-03-20 | 2017-07-07 | 荆楚理工学院 | A kind of TAM flexible nano-liposomes gel and preparation method thereof |
| CN106924176B (en) * | 2017-03-20 | 2020-08-11 | 荆楚理工学院 | Tamoxifen flexible nano liposome gel and preparation method thereof |
| CN108992713A (en) * | 2018-09-06 | 2018-12-14 | 武汉市思泰利医疗器械发展有限公司 | A kind of corrosion-resistant stoma leakproof cream and preparation method thereof |
| CN109528693A (en) * | 2018-12-20 | 2019-03-29 | 武汉科福新药有限责任公司 | A kind of rapamycin cataplasm and preparation method thereof |
| CN109528693B (en) * | 2018-12-20 | 2022-03-01 | 武汉科福新药有限责任公司 | Rapamycin cataplasm and preparation method thereof |
| CN112646228A (en) * | 2020-12-21 | 2021-04-13 | 嘉兴学院 | Tannin crosslinked chitosan/gelatin liquid-absorbing hemostatic antibacterial sponge and preparation method thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Dymek et al. | Liposomes as biocompatible and smart delivery systems–The current state | |
| CN110403833B (en) | Compositions and methods for enhancing topical application of alkaline benefit agents | |
| CN106132401B (en) | Compositions and methods for enhancing topical application of acidic benefit agents | |
| Fan et al. | Effect of different preparation methods on physicochemical properties of salidroside liposomes | |
| Firthouse et al. | Formulation and evaluation of miconazole niosomes | |
| WO2005060935A1 (en) | Drug-containing nanoparticle, process for producing the same and parenterally administered preparation from the nanoparticle | |
| CN107411983A (en) | A kind of water-soluble fullerene topical composition | |
| JP2011063606A (en) | alpha-LIPOIC ACID NANOPARTICLE AND PROCESS FOR PREPARATION OF THE SAME | |
| CN101237856A (en) | Compositions for drug delivery | |
| CN103893122B (en) | A kind of madecassoside liposome and preparation method and application | |
| CN102397242A (en) | Hydrogel containing coenzyme Q10, and cataplasm prepared by hydrogel | |
| CN1957924A (en) | Nano liposome of tea plant oil, and preparation method | |
| KR102611992B1 (en) | Nanocapsule coated with chitosan and use thereof | |
| Oommen et al. | Niosome entrapped β-cyclodextrin methotrexate complex as a drug delivery system | |
| Conte et al. | New therapeutic potentials of nanosized phytomedicine | |
| CN102772802A (en) | Oleanolic acid nanoliposome modified by chitosan and polyethylene glycol and preparation method thereof | |
| WO2004082668A1 (en) | Coenzyme q10-containing proliposome and preparation thereof | |
| CN112022919A (en) | Percutaneous-absorption artemisia vulgaris oil carrier gel and preparation method thereof | |
| CN104887630A (en) | A lipidosome-covered dehydrogenated silibinin phospholipid complex and a preparing method thereof | |
| CN104983590B (en) | A kind of nano liposomes powder of Chitosan Coating and preparation method thereof | |
| CN101088523A (en) | Nanometer solid lipid particle of active skullcap components and its prepn process and prepn | |
| WO2004067012A1 (en) | Limposomes containing asiaticoside and the uses thereof | |
| CN108670945A (en) | A kind of nanogel preparation and preparation method thereof with double slow releasing functions | |
| CN109498733B (en) | Dragon's blood nano suspension and preparation method thereof | |
| CN101088505B (en) | Nanometer breviscapine polymer particle preparation and its preparation process |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| ASS | Succession or assignment of patent right |
Owner name: JIANGSU KANGBEIDE PHARMACEUTICAL CO., LTD. Free format text: FORMER OWNER: HENAN KANGBEIDE PHARMACEUTICAL CO., LTD. BEIJING TECHNOLOGY DEVELOPMENT CENTER Effective date: 20130604 |
|
| C41 | Transfer of patent application or patent right or utility model | ||
| COR | Change of bibliographic data |
Free format text: CORRECT: ADDRESS; FROM: 100089 HAIDIAN, BEIJING TO: 211500 NANJING, JIANGSU PROVINCE |
|
| TA01 | Transfer of patent application right |
Effective date of registration: 20130604 Address after: Zhongshan science and Technology Park, Zhongxin road along the Yangtze River Industrial Development Zone in Nanjing City, Jiangsu Province, No. 709 211500 Applicant after: JIANGSU KBD PHARMACEUTICAL CO., LTD. Address before: 100089 Beijing Haidian District Zizhuyuan Road No. 98 Building No. 116 room 205 Applicant before: Henan Kangbeide Pharmaceutical Co.,Ltd. Beijing Technology Development Center |
|
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| CB02 | Change of applicant information |
Address after: Zhongxin Road, Nanjing Industrial Development Zone along the Yangtze River in Jiangsu province 211500 Zhongshan science and Technology Park No. 709 Applicant after: Jiangsu Kang times pharmaceutical Limited by Share Ltd Address before: Zhongxin Road, Nanjing Industrial Development Zone along the Yangtze River in Jiangsu province 211500 Zhongshan science and Technology Park No. 709 Applicant before: JIANGSU KBD PHARMACEUTICAL CO., LTD. |
|
| COR | Change of bibliographic data | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20120404 |
|
| RJ01 | Rejection of invention patent application after publication |