CN100430069C - Reversible heat gelling aquatic pharmaceutical composition of a Chinese medicine and compound prescription thereof - Google Patents
Reversible heat gelling aquatic pharmaceutical composition of a Chinese medicine and compound prescription thereof Download PDFInfo
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Abstract
The present invention relates to a traditional Chinese medicine aqueous medicine composition having property of reversible thermosetting gelation and a compound formula of the aqueous medicine composition, wherein the aqueous medicine composition is used for ophthalmology, nasal cavities, other cavities and dermatology and has a clinic treatment function. The medicine composition is composed of traditional Chinese medicines with different functions, the compound formulas of the traditional Chinese medicines, methylcellulose of certain concentration, polybasic acid salts, a pH modifying agent, etc., and has liquid of which the fluidity is high before medicine administration or coating. The present invention is characterized in that the aqueous medicine composition is fluxible liquid at a room temperature or a temperature which is lower than the room temperature, and the aqueous medicine composition is used for the parts of human bodies and other mammals, which need treating; when the value of the temperature rises or approaches to the value of a body temperature, the aqueous medicine composition can realize gelation in a short time. The aqueous medicine composition has the functions of extending the residence time of medicine effect ingredients on medication parts, enhancing the biology availability of the medicine effect ingredients and extending the duration time of medicine effects.
Description
Technical field:
The present invention relates to contain a kind of Chinese medicine and compound recipe composition thereof, the aqueous drug composition having property of reversible thermosetting gelation that is combined as substrate with methylcellulose and multivalence hydrochlorate belongs to field of traditional Chinese.It is characterized in that this aqueous pharmaceutical compositions is flowable liquid being lower than under room temperature or the room temperature, be used in when human body and other are mammiferous to need therapentic part, because temperature rises and to reach body temperature or near body temperature, but realize gelation in the short period, have thus and prolong the holdup time of efficacy component at agents area, increase availability biology of efficacy component, prolong the effect of duration of efficacy.
Background technology:
According to the investigation and the retrieval of related data, find present colloidal sol---the variation of gel is respectively temperature, pH value and ionic strength based on three kinds of different mechanism.The feature of these systems is: along with temperature, the variation of pH value and/or ion concentration can cause colloidal sol thus---the variation of gel.Wherein, disclosed in recent years multiple room temperature or below the room temperature for liquid, be the aqueous pharmaceutical compositions of semisolid or gelation under human temperature.The waterborne compositions that discloses Pluronic (trade name PLURONIC) in No. the 4188373rd, the United States Patent (USP) is adjusted the concentration of Pluronic because of the heat gelation, thus desirable colloidal sol---the heat gelling aquatic pharmaceutical composition of gel transition temperature.In addition, No. 4474751, United States Patent (USP) No. 4474752, has been put down in writing the medicament delivery system that adopts this heat gelling aquatic pharmaceutical composition in No. 4474753 and No. 4478822.But it is higher that this substrate is used concentration, when room temperature and the following temperature of room temperature certain viscosity arranged, and is applied to positions such as eye, nasal cavity and has any problem, and inconvenience, and the polymer that this system need be a large amount of are that some sensitive part such as eye institute is insupportable.
It is after medication that pH value changes the responsive type gel, because of the pH value effect of agents area forms gel.But the pH difference of substrate and agents area must cause the stimulation and the sense of discomfort of agents area, and is therefore not easy for patients to accept.Occurred simultaneously changing and temperature rises variation simultaneously at the aqueous pharmaceutical compositions (patent WO91/19481) of topical gelization because of pH.
The spy opens and discloses the colloidal sol that produces according to ionic strength among the clear 62-181228---and gel phase shifts aqueous pharmaceutical compositions.China has announced that in ZL86106631.5 gelling is used for the compositions of ophthalmology according to the ionic strength increase.Compare with the heat gelling aquatic pharmaceutical composition of front, causing colloidal sol---the material concentration that gel phase shifts has reduced by 10～100 times, and have in the storage and do not have the characteristics of the danger of gelation, but only be applicable to specific part (for example eye) with the ambient temperature rising.And this system will be applied to medicine and the clinical restriction that also is subjected to the carrier quality, does not still have the adjuvant carrier of medicinal specification at present, and its safety also needs further checking.
Therefore, comparatively speaking, the thermosensitive type gel is comparatively ideal at present.
Methylated cellulose aqueous solution adds Thermogelling and cools off and then recover collosol state, i.e. colloidal sol---and it is reversible that gel phase shifts, and this also is the characteristics of reversibly hot gel.
Chinese patent 93121431.9 discloses and has utilized methylcellulose (methoxyl group containing ratio scope is 26～33%) 0.2～2.0% (W/V), citric acid 1.2～2.3% (W/V) and Polyethylene Glycol 0.5～13% (W/V) can be realized being lower than and be liquid, the aqueous pharmaceutical compositions of gelation under human temperature under room temperature or the room temperature.
Methylated cellulose aqueous solution is subjected to the temperature of Thermogelling influenced by several factors, and comprising salt ionic concentration, this is a well known fact, is thought that by many editions pharmaceutics textbooks methylcellulose is as one of characteristic of medicinal materials.Japanese document has reported with certain speed heating methylated cellulose aqueous solution and has generated gel that the mutual relation of the degree of polymerization of methylcellulose and concentration and gelling temperature and ion add the variation of the gelling temperature that produces.Yet, cooperate waterborne compositions but without any record about near the methylcellulose of the gelation human temperature.
In addition, E.Heymann has measured the methylated cellulose aqueous solution (methylcellulose concentration 1.6%) that adopts methoxyl group containing ratio 35.4%, colloidal sol---the transition temperature of gel under different salt ionic concentration influences.But do not study near the gelation situation mammal body temperature, do not study the influence of applicable concrete salt yet.And the methoxyl group containing ratio of the methylcellulose of using in the document is higher, and the methoxyl group containing ratio that has surpassed the Chinese Pharmacopoeia regulation is 27～32% category, and its safety remains further to be verified.And according to our research, the colloidal sol of methylcellulose under different salt ionic concentrations influences---gel transition temperature may be relevant with what of methoxyl group containing ratio, therefore uses the methylcellulose of pharmacopeia regulation, its possibility of result difference.This has obtained the proof of experiment: the descendant is arranged according to the document, adopt methylcellulose (methoxyl group containing ratio 26～30%), salinity is that the methylated cellulose aqueous solution (methylcellulose concentration is 1.6%) of 0.2mol is not finished gelation near human temperature.
We are according to this characteristic of methylcellulose, use methylcellulose and salt up to specification, the applicable salt of human body is (better with multivalence hydrochlorate effect preferably to optimize effect, comprise citrate, tartrate and borate, phosphate, wherein ideal) with the above two effect, and the concentration of regulating methylcellulose and salt make this combination have near human temperature can fast gelation characteristics, and successfully be applied in the pharmaceutical preparation, still belong to for the first time.And with respect to patent 93121431.9, our compositions only comprises two kinds of Main Ingredients and Appearances---methylcellulose and multivalence hydrochlorate, and both all are wide material sources, quality controllable, the pharmaceutic adjuvant that safety is secure can be widely used in eye, positions such as multiple body cavity such as nasal cavity and skin.This compositions does not contain Polyethylene Glycol, has reduced component, has saved resource, has reduced cost, has guaranteed safety, has reduced the polymer content in the medicine yet, has relatively improved patient's compliance.And through evidence, in the medicine scope that we adopted, it becomes gel characteristic more superior.Under the same conditions, become gel time shorter, become gelling temp and gel hardness to be suitable for each position administration of people more.
Summary of the invention:
The present invention adopts the gelation material of establishing applicable to the safety at whole positions of needs treatment to develop and is liquid when optimizing room temperature or being lower than room temperature, the aqueous pharmaceutical compositions of gel under human temperature.The result of research obtains with keen determination repeatedly: methylcellulose, it is aqueous pharmaceutical compositions gelation under the local body temperature temperature of people of liquid in the time of can making room temperature or be lower than room temperature that the multivalence hydrochlorate cooperates with appropriate amount, and does not have sense of discomfort after the administration, so finished the present invention.
As the form of implementation of the reversibly hot gelified water soluble Pharmaceutical composition of Chinese medicine of the present invention and compound recipe thereof, limit according to the concentration range of following reason to methylcellulose and multivalence hydrochlorate.
The viscosity of methylcellulose records according to measuring the methylated cellulose aqueous solution of 2% (W/V) under 20 ℃ of conditions.The range of viscosities that is used for methylcellulose of the present invention is 3～4000mPas, preferred 5～400mPas, more preferably 10～50mPas.According to the Pharmacopoeia of People's Republic of China regulation, the methoxyl group containing ratio of pharmaceutic adjuvant methylcellulose is 27～32%, and the methoxyl group containing ratio that therefore can be used for methylcellulose of the present invention should be in this scope.Its working concentration is in the scope of 1.0～5.0% (W/V).When concentration is lower than 1.0% (W/V), be difficult to generate gel in the part, and when being higher than 5.0% (W/V), the viscosity of solution is too high, dosage is inaccurate during use, uses also inconvenient.Better with effect in 2.0%～4.0% (W/V) scope, effect is best in 3.0%～3.5% (W/V) scope.
The concentration of multivalence hydrochlorate is different and to be concrete Jie fixed according to the position of the kind of salt and application.To consider in the position of osmotic pressure that at eye and nasal cavity etc. the concentration of multivalence hydrochlorate can not make the osmotic pressure of preparation surpass and wait oozes osmotic pressure * 120%.So in these positions, tartrate (C
4H
4O
6M2H
2O), phosphate (MPO
412H
2O), citrate (MC
6H
5O
72H
2O) and borate (MB
4O
7.10H
2O) concentration range is decided to be 2.0～4.0% (W/V) respectively, 1.0～6.0% (W/V), and 2.0～4.0% (W/V) are in the scope of 1.0～3.0% (W/V).When being lower than 2.0%, 1.0%, 2.0%, 1.0% (W/V), concentration near human temperature, is difficult to generate gel, and concentration is when being higher than 4.0%, 6.0%, 4.0%, 3.0% (W/V), salinity increase cause the preparation osmotic pressure surpass human body endurable ± 20% grade oozes scope, to eye, the zest at positions such as nasal cavity increases, and patient's compliance is poor; And becoming gelling temp to reduce, viscosity increase at room temperature causes the characteristics of its gel on the throne to be difficult to performance, and stores difficulty.Working concentration is respectively at 2.5%～4.0% (W/V), 2.0%～5.0% (W/V), 2.5%～4.0% (W/V), effect is better in 1.2%～2.8% (W/V) scope, and respectively at 3.2%～3.8% (W/V), 3.0%～4.0% (W/V), 3.2%～3.8% (W/V), effect is best in 1.8%～2.5% (W/V) scope.
At the position that skin etc. is not subjected to osmotic pressure influence, the concentration range of multivalence hydrochlorate can be bigger.Consider actual application need, tartrate, phosphate, citrate and boratory concentration range are decided to be 2.0%～15%, 1.0%～10.0%, 2.0%～15%, 1.0%～4.0% (W/V) respectively.When being lower than 2.0%, 1.0%, 2.0%, 1.0% (W/V), concentration near human temperature, is difficult to generate gel, and concentration becomes gelling temp to reduce when too high, and viscosity increase at room temperature causes the characteristics of its gel on the throne to be difficult to performance, and store difficulty, cause unnecessary waste.Working concentration is respectively at 3.0%～12.0% (W/V), 2.0%～8.0% (W/V), 3.0%～12.0% (W/V), better in 1.5%～3.5% (W/V) scope, and respectively at 4.0%～10.0% (W/V), 3.0%～6.0% (W/V), 4.0%～10.0% (W/V), effect is best in 2.0%～3.0% (W/V) scope.
Find through test repeatedly, tartrate such as sodium tartrate, potassium, phosphate such as sodium phosphate, potassium, multivalence hydrochlorate such as citrate such as sodium citrate, potassium and borates such as sodium borate, potassium and methylcellulose compatibility all can reach good reversible heat-transformation gel characteristic.Wherein the zest of citrate and tartrate is slightly little, becomes gel effect good slightly, wherein is better with the citrate; Further, the zest of sodium salt is littler than potassium salt, and is therefore best with the sodium citrate effect.In application, can according to the requirement of concrete agents area with become gel effect to select the kind of multivalence hydrochlorate, and the concentration of regulating multivalence hydrochlorate and methylcellulose reaches near the optimum efficiency that becomes gel the body temperature.
In addition, room temperature or room temperature are following to be liquid owing to be desirably in, near gelation people's body temperature, so the gelling temperature of compositions be about 25 ℃～about 40 ℃ more suitable.
Be the substrate " solution-gel " of investigating this pharmaceutical composition characteristic, select concentration (methylcellulose concentration is 3.5%, and sodium citrate concentration is 3.5%) preparation one substrate of two kinds of components with temperature transition.This substrate, according to the assay method of pharmacopeia viscosity, is used the Ping Shi viscosimeter and is measured the viscosity variation of this substrate behind preservation 10,20,30min under 5,10,15,20,25,30,32,33,34 ℃ after two hours 0 ℃ of preservation.Discovery is since 30 ℃, and the viscosity of substrate begins significantly to increase, and increases rapidly with the rising of temperature and the prolongation of holding time.The substrate sample that viscosity is significantly increased is positioned over 0 ℃ of preservation again, and its viscosity is reduced to initial value again rapidly, illustrates that promptly substrate returns to solution state again.Result of the test illustrates that this substrate " solution-gel " is good with the characteristic of temperature transition.
We have declared patent (number of patent application: 200510043412.4), the reversibly hot gelified water soluble compositions that relates to chemicals with the effect of pharmacology Clinics and Practices, the present invention relates to be used for eye, the Chinese medicine of the treatment of nasal cavity and other body cavitys and dermatosis and the aqueous drug composition having property of reversible thermosetting gelation of compound recipe thereof.
The example of the Chinese medicine that is applied to people's eye that contains in the aqueous drug composition having property of reversible thermosetting gelation of Chinese medicine of the present invention and compound recipe thereof is as follows.Have and move back redly, the Chinese medicine of clearing heat for detumescence effect is Calamina (forging), succinum, Fel Ursi (Fel Ursi powder), Borneolum Syntheticum, Moschus, Margarita (Margarita hydrolyzed solution), artificial Calculus Bovis, Sal Ammoniacus, Carnis Rapanae thomasianae Octopus ocellatus Gray, Concha Haliotidis (forging), Thallus Laminariae (Thallus Eckloniae); Have heat-clearing and toxic substances removing, the Chinese medicine of effects of antiinflammation and bacteriostasis is Rhizoma Osmundae, Herba Taraxaci, Rhizoma Polygonati, Radix Bupleuri, the Radix Angelicae Dahuricae, Herba Houttuyniae, Semen Cuscutae, Herba Erodii, Fructus Lycii, Spica Prunellae, Rhizoma Cyperi, Flos Chrysanthemi Indici, Herba Violae, Herba Lophatheri, Flos Buddlejae, Flos Lonicerae, Radix Scutellariae, Radix Isatidis, Rhizoma Coptidis, Radix Stephaniae Tetrandrae, Radix Puerariae, Herba Centipedae, Radix Actinidiae Chinensis, Herba Asari, Periostracum Cicadae, Herba Equiseti Hiemalis, Rhizoma Atractylodis, Cortex Fraxini, Radix Gentianae Macrophyllae, Semen Cassiae, Fructus Atriplicis Sibiricae; Chinese medicine with the stagnant blood stasis removing effect of row is Oleum Curcumae, Flos Carthami, Radix Ginseng, Radix Angelicae Sinensis, Rhizoma Corydalis, Fructus Aurantii, Herba Senecionis Scandentis, Radix Salviae Miltiorrhizae, Radix Rubiae, Fructus Corni, Rhizoma Corydalis Decumbentis, Radix Clematidis, Flos Eriocauli, Rhizoma Et Radix Notopterygii; Chinese medicine with myosis or platycoria effect is the compound recipe that Semen Celosiae, Fructus Leonuri, Fructus Schisandrae Chinensis, Semen Arecae and above-mentioned flavour of a drug are formed through compatibility, the compound recipe that also can use other Chinese medicine that is applicable to ophthalmic and form through reasonable compatibility.
The example of the Chinese medicine that is applied to people's nasal cavity that the aqueous drug composition having property of reversible thermosetting gelation of Chinese medicine of the present invention and compound recipe thereof contains is as follows.Have diffusing wind dehumidifying, the Chinese medicine of clearing the nasal passage effect is Fructus Xanthii, Herba Schizonepetae, Flos Magnoliae, Herba Centipedae, Herba Asari, Bulbus Allii Macrostemonis, the Radix Angelicae Dahuricae, Flos Genkwa, Cortex Mori, Herba Ephedrae, Rhizoma Acori Graminei; Chinese medicine with antipyretic and antidote functions is Herba Andrographis, Herba Selaginellae Moellendorfii, Folium Hibisci Mutabilis, Herba Commelinae, Rhizoma Imperatae, Radix Scutellariae, Herba Taraxaci, Flos Lonicerae, Herba Solidaginis; Chinese medicine with the turbid effect of heat clearing awayization is hyocholic acid, oil of Herba Pogostemonis; Chinese medicine with diffusing wind-getting resuscitation effect is Mentholum, Borneolum Syntheticum, Oleum Eucalypti, and above-mentioned flavour of a drug also can use other Chinese medicine that is applicable to that nasal cavity is used and the warp compound recipe of compatibility composition rationally through the compound recipe of compatibility composition.
The body cavity that is applied to that contains in the aqueous drug composition having property of reversible thermosetting gelation of Chinese medicine of the present invention and compound recipe thereof is an auditory meatus, oral cavity or oral pit, and rectum, urethra, the example of the Chinese medicine of vagina is as follows.Is boric acid, dried Alumen, Alumen, Realgar as auditory meatus with the Chinese medicine that agent has sterilization, antiinflammatory, antisepsis; Chinese medicine with antipyretic and antidote functions is Cortex Phellodendri, Herba Violae, Herba Andrographis, Herba Taraxaci, Radix Scutellariae, Radix Et Rhizoma Rhei; Have blood circulation promoting and blood stasis dispelling as oral cavity or oral pit with agent, the Chinese medicine for the treatment of blood disorders analgesic effect is Radix Genkwa, Cortex Lycii; Have the dissipating blood stasis fire, the Chinese medicine that ends the toothache effect is Borneolum Syntheticum; Have heat-clearing and toxic substances removing, reducing swelling and alleviating pain, removing the necrotic tissue and promoting granulation, the Chinese medicine of astringing to arrest bleeding effect are Rhizoma Cimicifugae, Rhizoma Chuanxiong, Rhizoma Ligustici, Gypsum Fibrosum, the Radix Angelicae Dahuricae, Herba Asari, Fructus Piperis Longi, Olibanum, Spina Gleditsiae, Rhizoma Alpiniae Officinarum; Have heat clearing and damp drying as the genitals with agent, the Chinese medicine of anti-inflammatory anti-itch effect is Radix Sophorae Flavescentis, Galla Chinensis, Bud of hairyvein agrimony; Has heat-clearing and toxic substances removing, the Chinese medicine of clearing throat effect is walnut oil, Oleum menthae, Fel Sus domestica unguentum, Camphora, Flos Caryophylli, Herba Patriniae, Radix Arnebiae (Radix Lithospermi), Aloe, Oleum Curcumae, catechu, Concha Meretricis Seu Cyclinae, Myrrha, and above-mentioned flavour of a drug also can use other Chinese medicine that is applicable to that body cavity is used and the warp compound recipe of compatibility composition rationally through the compound recipe of compatibility composition.
The example of the Chinese medicine that is applied to application on human skin that the aqueous drug composition having property of reversible thermosetting gelation of Chinese medicine of the present invention and compound recipe thereof contains is as follows.Have removing heat from blood and promoting blood circulation, the Chinese medicine of the effect of moisturizing of dispeling the wind is Radix Cynanchi Paniculati, Radix Angelicae Sinensis, Radix Arnebiae (Radix Lithospermi), Radix Saposhnikoviae, the Radix Angelicae Dahuricae; Have heat-clearing and toxic substances removing, cooling blood and relieving pain, the Chinese medicine that can be used for herpes zoster is Radix Sophorae Flavescentis, propolis, Cortex Moutan, Herba Erigerontis, Rhizoma Paridis, Rhizoma Acori Graminei, Borneolum Syntheticum, Herba Violae, Flos Chrysanthemi Indici, Radix Scutellariae, Fructus Forsythiae; Have heat clearing and damp drying, the Chinese medicine of dispelling wind itching-relieving action is Rhizoma Coptidis, Flos Carthami, Rhizoma Chuanxiong, Fructus Mume, Radix Ginseng, Fructus Schisandrae Chinensis, the Flos Sophorae Immaturus, the Radix Paeoniae Alba, Rhizoma Belamcandae, Galla Chinensis, Alumen; Have diffusing wind damp eliminating, the disappear Chinese medicine of Cuo effect of invigorating blood circulation is Rhizoma Curcumae Longae, Herba Chenopodii, Herba Solidaginis, Herb Gynostemmae Pentaphylli, Herba Senecionis Scandentis; Has blood circulation promoting and blood stasis dispelling, the Chinese medicine of dispelling wind for relieving itching effect is Fructus Cnidii, Folium Eucalypti Robustae, bark of Melia azedarach L., the Fructus Kochiae, Cortex Phellodendri, Radix Sangusorbae, Herba Artemisiae Scopariae, Pollen Tyjphae, Periostracum Cicadae, the bright Radix Stemonae, the Fructus Ligustri Lucidi leaf, Herba Schizonepetae, Herba Menthae, Folium Mori, Rhizoma Polygoni Cuspidati, Flos Lonicerae, Pseudobulbus Bletillae (Rhizoma Bletillae), Radix Et Rhizoma Rhei, Aloe, Radix Glycyrrhizae, Radix Aristolochiae, Radix Asparagi, Rhizoma Cyperi, Herba Equiseti Hiemalis, Folium Perillae, Semen Raphani, Semen Sinapis Albae, Radix Isatidis, Herba Artemisiae Annuae, Rhizoma Dioscoreae Bulbiferae, Herba Orostachyos, Semen Sinapis, fresh Folium Aloe, Herba Polygoni cymosi, Mentholum, thymol, Radix Polygoni Multiflori, Cortex Dictamni, and above-mentioned flavour of a drug also can use other Chinese medicine that is applicable to that skin is used and the warp compound recipe of compatibility composition rationally through the compound recipe of compatibility composition.
The example of the Western medicine in the Chinese medicine and western medicine compound recipe that is applied to people's eye that contains in the aqueous drug composition having property of reversible thermosetting gelation of Chinese medicine of the present invention and compound recipe thereof is as follows.As antibiotic be erythromycin, chloromycetin, methanesulfonic sodium, gentamycin, tetracycline, lincomycin, clindamycin, amphotericin B, norfloxacin, micatin, the husky star in fluorine Lip river, clotrimazole, terbinafine, rifampicin, acyclovir, idoxuridine and trifluorothymidine; As antiallergic agent be 3-(1H-tetrazolium-5-yl) phenyloxamic acid (hereinafter to be referred as MTOC), ketotifen fumarate, sodium cromoglicate, a promise nitrile acid, Ao Patading, pheniramine, levocabastine; As the betamethasone of antibiotic medicine, dexamethasone, fluorometholone, enoxolone dipotassium, lysozyme, difluoroaniline sodium acetate, Niflan, indometacin, Cortisone, allantoin, 6-ACA 6-aminocaproic acid, diclofenac sodium, ketorolac; As miotic be pilocarpine, carbachol; As the flavin adenine dinucleotide (FAD) of vitamins, pyridoxal 5-phosphate, vitamin B12; As vasoconstrictor be naphazoline, phenylephrine, oxymetazoline, tetrahydrozoline, thiophene Lip river azoles quinoline; Quick as antihistaminic Piao Er, diphenhydramine; As the N-ethyl-N-(.gamma.-picolyl)tropamide of mydriatic, oxamphetamine, atropine, scopolamine, Propantheline, acetyl ring penta benzene, phenylephrine; As the timolol of glaucoma treatment medicine, block to such an extent that feel at ease, brimonidine, A Luoniding, metoprolol, carteolol, betaxolol, guanethidine, dorzolamide, cloth Yin helps amine, latanoprost, Unoprostone; As the cataract therapy medicine be glutathion, catalin, phacolin, sorbinil; As the lignocaine of local anesthetic, benoxinate, bupivacaine; As immunosuppressant be cyclosporin, azathioprine, mitomycin; As metabolic antagonist be fluorouracil, fluorofur, methotrexate; As congested remover is epinephrine; (5-(3-thienyl)-tetrazolium-1-yl) acetic acid (hereinafter to be referred as TAT) as diabetes nethike embrane therapeutic agent; As the sodium chondroitin sulfate of amino acids, the sulfonic acid glycine; As the autonomic nerve agent be neostigmine methylsulfate, and above-mentioned mixture, that also can use other is applicable to medicament of ophthalmic and composition thereof.
The example of the Western medicine in the Chinese medicine and western medicine compound recipe that is applicable to people's nasal cavity that contains in the aqueous drug composition having property of reversible thermosetting gelation of Chinese medicine of the present invention and compound recipe thereof is as follows.As antibiotic be neomycin, streptomycin, chloromycetin, gentamycin, kanamycin, nitrofural, norfloxacin, sulfamethoxazole, mupirocin; As antihistaminic be acrivastine, mizolastine, azelastine, levocabastine, clemastine, ebastine, loratadine, cetirizine, terfenadine, chlorphenamine, dimenhydrinate, Cyproheptadine, phenindamine, tripelennamine, triprolidine, astemizole; As the antiallergic antiinflammatory be sodium cromoglicate, ketotifen fumarate, zaprinast, triamcinolone acetonide, mometasone, fluticasone, budesonide, cortisone acetate, prednisolone acetate, dexamethasone, meticortelone, betamethasone, flunisolide; As local anesthetic be tetracaine, procaine; As vasoconstrictor and Decongestant be ephedrine, naphazoline, oxymetazoline, tetrahydrozoline, indanazoline, thiophene Lip river azoles quinoline, xylometazoline; As amino acids is chondroitin sulfate; Absorb the dipyrone that is of bringing down a fever as nasal system; Absorbing antiviral as nasal system is acyclovir; The vitamin drug that absorbs as nasal system is a vitamin B12; As the medicine that works by the nasal absorption maincenter, and above-mentioned mixture, that also can use other is applicable to medicament that nasal cavity is used and composition thereof.
The body cavity that is applied to that contains in the aqueous drug composition having property of reversible thermosetting gelation of Chinese medicine of the present invention and compound recipe thereof is an auditory meatus, oral cavity or oral pit, and rectum, urethra, the example of the Western medicine in the Chinese medicine and western medicine compound recipe of vagina is as follows.Is ofloxacin as auditory meatus with the anti-inflammation agent of agent, erythromycin, chloromycetin, lincomycin, neomycin, albomycin, lomefloxacin, sulphacetamide etc.; As oral cavity or oral pit with agent be Dequavet, lysozyme, ribavirin, Anethol Trithione, thymus protein, nystatin, cyclosporin etc.; As the clotrimazole of genitals with agent, metronidazole, chlorhexidine etc.; As bronchodilator is aminophylline; As metabolic antagonist is fluorouracil; Ataractic as hypnosis for stable; As the antipyretic-antalgic antiinflammatory be aspirin, indometacin, the indenes acid of relaxing, Phenylbutazone, ibuprofen etc.; As the adrenal hormone agent be dexamethasone, omcilon, hydrocortisone; Lignocaine as local anesthetic; As the bacteresulf of suppuration illness medication, kanamycin, tobramycin and erythromycin; As the norfloxacin and the nalidixan of synthetic antibacterial, and above-mentioned mixture, that also can use other is applicable to medicament that body cavity is used and composition thereof.
The example of the Western medicine in the Chinese medicine and western medicine compound recipe that is applied to application on human skin that contains in the aqueous drug composition having property of reversible thermosetting gelation of Chinese medicine of the present invention and compound recipe thereof is as follows.As parasitic dermatosis with agent be Antazoline, fluconazol, ciclopiroxolamin, siccanin, acetic acid quinoline in pair last of the ten Heavenly stems, clotrimazole, salicylic acid, neomycin, sulfadiazine; As suppurative illness with agent be sulfamethoxazole sodium, erythromycin, gentamycin sulfate; As analgesic agent be indometacin, ketoprofen, betamethasone valerate, fluocinonide, hydrocortisone, prednisone, mometasone, prednicarbate, allantoin, dexamethasone; As pruritus is diphenhydramine; As local anesthetic be procaine, lignocaine; As local anesthetic be oxygen benzyl alkanamine, hibitane, benzoyl peroxide, tribromocresol, resorcinol, Noxythiolin, anaflex, cresol sulfonic acid, Ta Zhaluote; As the vitamins derivant be tretinoin, isotretinoin, etretinate; As strong oxidizer is dithranol; As metabolic poison is podophyllotoxin.And above-mentioned mixture, that also can use other is applicable to medicament that department of dermatologry is used and composition thereof.
The aqueous drug composition having property of reversible thermosetting gelation of Chinese medicine of the present invention and compound recipe thereof contains the pharmaceutically permissible buffer agent that adds as required, salt, antiseptic and solubilizing agent etc.As the pH regulator agent hydrochloric acid, sulphuric acid, citric acid, tartaric acid, phosphoric acid, boric acid, acids such as acetic acid, sodium hydroxide, ethanolamine, diethanolamine, bases such as triethanolamine arranged.This aqueous pharmaceutical compositions should regulate pH value and application site physiology pH value adapts.As antiseptic chlorination benzylamine, positive soap classes such as Septin arranged; Nipagin, p-hydroxybenzoic acid acetic acid, p-hydroxybenzoic acid esters such as propyl parabene and Butyl Chemosept; Methaform, phenethanol, benzylalcohol, chlorobutanol, alcohols such as phenoxyethanol; Benzalkonium bromide, Benzalkonii Chloridum etc.; Sodium dehydroacetate, organic acid and its esters such as sorbic acid and sodium sorbate.
Suitably add surfactant or chelating agen in addition, the general scope of using of these compositions is about 0.002～1% for about 0.001～2% preferably.Solubilizing agent can be enumerated soil temperature 80, the polycondensation sorbitol, and hardened castor oil and cyclodextrin can the employing scope be 0～15%.
The method for making of the aqueous drug composition having property of reversible thermosetting gelation of Chinese medicine of the present invention and compound recipe thereof does not have specific restriction, according to what of contained prescriptions of Chinese medicine amount, following two kinds of method for makings are generally arranged, for example the prescriptions of Chinese medicine amount is less, then citrate can be dissolved in sterile purified water, regulate the pH value of this solution with the pH regulator agent, after adding Chinese medicine extraction medicinal liquid and suitable antiseptic, add the methocel solution that is dissolved in sterile purified water in advance, regulate pH value once more, use the sterile purified water polishing, water-cooled limit, limit stirs the mixture.If the prescriptions of Chinese medicine amount is bigger, then citrate can be dissolved in Chinese medicine extraction liquid, regulate the pH value of this solution with the pH regulator agent, after adding suitable antiseptic, add the methocel solution that is dissolved in sterile purified water in advance, regulate pH value once more, use the sterile purified water polishing, water-cooled limit, limit stirs the mixture.If desired, can add various additives after this, for example buffer agent, salt and antiseptic.In addition, the Chinese medicine extraction composition is a slightly solubility or when insoluble, can make its suspension or dissolve it with solubilizing agent.
The aqueous drug composition having property of reversible thermosetting gelation of this Chinese medicine and compound recipe thereof in the concentration range of above-mentioned requirements, have by solution this specific character to gel conversion, be not only applicable to human body and be applicable to other all mammals yet, can be in other mammal eyes, position local applications such as nasal cavity and other body cavitys and skin.
Following examples illustrate the various forms of the present invention, and non-limiting scope of the present invention.
Embodiment 1
Prescription content (making total amount is 200g) recipe quantity gelling temperature (℃)
Flos Buddlejae 50g
Flos Chrysanthemi 15g
Radix Cynanchi Paniculati 15g
Semen Cassiae 10g
Borneolum Syntheticum 0.2g
MC100 8.0g 27
Sodium citrate 7.6g
Methaform 1.0g
Citric acid pH 7.0
Embodiment 2
Prescription content (making total amount is 200g) recipe quantity gelling temperature (℃)
Semen Cassiae 30g
Rhizoma Et Radix Notopterygii 15g
Flos Buddlejae 15g
Concha Haliotidis 25g
Radix Clematidis 15g
Radix Angelicae Sinensis 10g
MC400 7g 25
Sodium triphosphate 10g
Hydroxyethyl Ammonium Chloride 0.01g
Citric acid pH 5.5
Embodiment 3
Prescription content (making total amount is 200g) recipe quantity gelling temperature (℃)
Flos Chrysanthemi Indici 30g
Semen Cassiae 15g
Flos Carthami 10g
Radix Ginseng 10g
MC400 6g 30
Sodium tartrate 6g
Benzalkonii Chloridum 0.02g
Ethanolamine pH7.4
Embodiment 4
Prescription content (making total amount is 200g) recipe quantity gelling temperature (℃)
Flos Lonicerae 30g
Radix Scutellariae 20g
Herba Lophatheri 15g
Margarita hydrolyzed solution 10ml
Borneolum Syntheticum 0.2g
MC50 7g 35
Sodium triphosphate 3.0g
Methyl parahydroxybenzoate 0.01g
Sodium hydroxide pH 6.8
Embodiment 5
Prescription content (making total amount is 200g) recipe quantity gelling temperature (℃)
Cortex Phellodendri 20g
Galla Chinensis 15g
Peppermint 0.5ml
Borneolum Syntheticum 0.1g
Ciprofloxacin 0.6g
MC50 3.5g 30
Sodium triphosphate 7.2g
Methyl parahydroxybenzoate 0.026g
Propyl p-hydroxybenzoate 0.014g
Tartaric acid or sodium hydroxide pH 6.8
Embodiment 6
Prescription content (making total amount is 200g) recipe quantity gelling temperature (℃)
Radix Genkwa 30g
Cortex Lycii 20g
Rhizoma Chuanxiong 20g
Herba Asari 5g
Spina Gleditsiae 10g
Rhizoma Alpiniae Officinarum 10g
Borax 5g
Borneolum Syntheticum 0.1g
MC15 5.5g 30
Sodium tetraborate 6.0g
Ethylparaben 0.02g
Triethanolamine pH 6.5
Embodiment 7
Prescription content (making total amount is 200g) recipe quantity gelling temperature (℃)
Fructus Xanthii 30g
Radix Angelicae Dahuricae 20g
Flos Magnoliae 15g
Borneolum Syntheticum 1.5g
Oleum menthae 2ml
Chlorphenamine 0.2g
MC100 4.5g 29
Sodium citrate 7g
Sodium dihydrogen phosphate or sodium hydrogen phosphate pH 7.4
Embodiment 8
Prescription content (making total amount is 200g) recipe quantity gelling temperature (℃)
Herba Centipedae 30g
Flos Magnoliae 20g
Flos Lonicerae 30g
Radix Scutellariae 15g
Borneolum Syntheticum 1g
Diphenhydramine 1g
MC50 3.0g 34
Dipotassium tetraborate 6.2g
Chlorobutanol 0.5g
Sodium hydroxide pH 8.4
Embodiment 9
Prescription content (making total amount is 200g) recipe quantity gelling temperature (℃)
Fructus Piperis Longi 10g
Rhizoma Alpiniae Officinarum 20g
Flos Caryophylli 15g
Radix Angelicae Dahuricae 10g
Olibanum 5g
Gypsum Fibrosum 5g
Borneolum Syntheticum 1.5g
MC100 4.2g 27
Sodium triphosphate 7.2g
Chlorination benzylamine 0.005g
Citric acid pH 6.0
Embodiment 10
Prescription content (making total amount is 200g) recipe quantity gelling temperature (℃)
Herba Andrographis 20g
Flos Genkwa 15g
Rhizoma Imperatae 10g
Herba Ephedrae 5g
Borneolum Syntheticum 1g
Gentamycin 600,000 units
MC400 3.0g 33
Sodium tartrate 6.6g
Ethylparaben 0.02g
Citric acid pH 6.0
Embodiment 11
Prescription content (making total amount is 200g) recipe quantity gelling temperature (℃)
Rhizoma Curcumae Longae 20g
Herba Polygoni cymosi 10g
Radix Sophorae Flavescentis 10g
Aloe 20g
Herba Solidaginis 15g
Herb Gynostemmae Pentaphylli 10g
Radix Angelicae Dahuricae 5g
Radix Trichosanthis 5g
MC400 3.0g 35
Sodium citrate 3.5g
Benzalkonium bromide 0.01g
Citric acid pH 5.0
Embodiment 12
Prescription content (making total amount is 200g) recipe quantity gelling temperature (℃)
Rhizoma Coptidis 20g
Flos Carthami 10g
Rhizoma Chuanxiong 10g
Fructus Schisandrae Chinensis 15g
Radix Paeoniae Alba 10g
Ofloxacin 0.6g
MC400 3.0g 37
Potassium citrate 3.5g
Chlorobutanol 0.5g
Citric acid pH 5.0
Embodiment 13
Prescription content (making total amount is 200g) recipe quantity gelling temperature (℃)
Fel Ursi powder 0.5g
Moschus 0.5g
Catechu 1g
Borneolum Syntheticum 2g
Camphora 2g
MC100 3.5g 35
Sodium tetraborate 7.0g
Benzalkonii Chloridum 0.01g
Citric acid pH 5.0
Embodiment 14
Prescription content (making total amount is 200g) recipe quantity gelling temperature (℃)
Radix Sophorae Flavescentis 30g
Cortex Moutan 15g
Rhizoma Paridis 10g
Rhizoma Acori Graminei 10g
Rhizoma Chuanxiong 15g
Rhizoma Belamcandae 10g
Galla Chinensis 10g
Butenafine 1g
MC15 7.0g 26
Sodium citrate 9g
Hydroxyethyl Ammonium Chloride 0.01g
Citric acid pH5.0
Embodiment 15
Prescription content (making total amount is 200g) recipe quantity gelling temperature (℃)
Radix Et Rhizoma Rhei 10g
Aloe 15g
Folium Perillae 20g
Cortex Moutan 10g
Radix Angelicae Sinensis 20g
Cortex Dictamni 10g
MC15 9.0g 25
Soluble tartar. 8g
Ethylparaben 0.2g
Tartaric acid pH4.5
Embodiment 16
Prescription content (making total amount is 200g) recipe quantity gelling temperature (℃)
Fructus Cnidii 20g
Fructus Kochiae 10g
Herba Violae 15g
Herba Equiseti Hiemalis 10g
Clotrimazole 1g
MC400 7g 33
Sodium tetraborate 8g
Citric acid pH5.5
Embodiment 17
Prescription content (making total amount is 200g) recipe quantity gelling temperature (℃)
Radix Arnebiae (Radix Lithospermi) 20g
Herba Artemisiae Scopariae 15g
Periostracum Cicadae 10g
Radix Angelicae Dahuricae 10g
Borneolum Syntheticum 1g
Sulfadiazine 3g
MC15 7.0g 29
Sodium citrate 7.6g
Hydroxyethyl Ammonium Chloride 0.02g
Citric acid pH5.5
Embodiment 18
Prescription content (making total amount is 200g) recipe quantity gelling temperature (℃)
Flos Carthami 30g
Rhizoma Chuanxiong 15g
Bright Radix Stemonae 20g
Radix Sangusorbae 15g
Fructus Forsythiae 10g
Indomethacin 2g
MC5 10g 32
Sodium tetraborate 6g
Hydroxyethyl Ammonium Chloride 0.01g
Citric acid or sodium hydroxide pH7.0
The specific embodiment:
Embodiment 1
Get Flos Buddlejae 50g, Flos Chrysanthemi 15g, Radix Cynanchi Paniculati 15g extracts volatile oil, medicinal residues and Semen Cassiae 10g decoct with water 2 times, and each 2 hours, collecting decoction filtered, filtrate concentrates, and adds ethanol in the concentrated solution and makes and contain the alcohol amount and reach 75%, precipitate with ethanol, cold preservation (2～2 ℃) 24 hours filters, and filtrate recycling ethanol is to there not being the alcohol flavor, add Borneolum Syntheticum 0.2g, add the 50ml distilled water, water precipitating (2～2 ℃) 24 hours, filter, add above-mentioned volatile ingredient, be Chinese medicine extraction liquid of the present invention.Other gets sodium citrate 7.6g, and methaform 1.0g is dissolved in the above-mentioned Chinese medicine extraction liquid, dissolving, toward wherein adding the MC100 8.0g that is dissolved in the 25ml sterile purified water, thoroughly stir and regulate pH7.0 with citric acid, mend to 200g with sterile purified water, the thorough stirring and dissolving in water-cooled limit, limit gets eye drop.
Embodiment 2
Depend on pine torch 30g, Rhizoma Et Radix Notopterygii 15g, Flos Buddlejae 15g, Concha Haliotidis 25g, Radix Clematidis 15g, Radix Angelicae Sinensis 10g, decoct with water three times, each 1 hour, collecting decoction, filter, get filtrate and be concentrated into concentrated solution, add 3～5 times of ethanol, make precipitation, reclaim ethanol and be concentrated into concentrated solution, add water 50ml, water precipitating (2～2 ℃) 24 hours filters, and is Chinese medicine extraction liquid of the present invention.Other gets Sodium triphosphate 10g and is dissolved among the sterile purified water 50ml, regulates pH5.0 with citric acid, adds Hydroxyethyl Ammonium Chloride 0.01g, add the MC 4007.0g that is dissolved in the 25ml sterile purified water again, regulate pH5.5, mend to 200g with sterile purified water with citric acid, the thorough stirring and dissolving in water-cooled limit, limit gets eye drop.
Embodiment 3
Get Flos Chrysanthemi Indici 30g, Semen Cassiae 15g, Flos Carthami 10g, Radix Ginseng 10g decocts with water secondary, each 1 hour, collecting decoction filters, and gets filtrate and is concentrated into concentrated solution, add 3 times of ethanol, make precipitation, reclaim ethanol and be concentrated into concentrated solution, add water 50ml, water precipitating (2～2 ℃) 24 hours filters, and is Chinese medicine extraction liquid of the present invention.Other gets sodium tartrate 6g, add in the 50ml sterile purified water and thoroughly stir, regulate pH6.5 with ethanolamine, merge above-mentioned two kinds of solution, add Benzalkonii Chloridum 0.02g, add the MC4006g that is dissolved in the 50ml sterile purified water again, regulate pH7.4 with ethanolamine, mend to 200g with sterile purified water, the thorough stirring and dissolving in water-cooled limit, limit gets eye drop.
Embodiment 4
Extracting honeysuckle 30g, Radix Scutellariae 20g, Herba Lophatheri 15g, decoct with water secondary, each 1 hour, collecting decoction, filter, get filtrate and be concentrated into concentrated solution, add 3 times of ethanol, make precipitation, reclaim ethanol and be concentrated into concentrated solution, add Margarita hydrolyzed solution 10ml, Borneolum Syntheticum fine powder 0.2g stirs evenly, and adds water 50ml, water precipitating (2～2 ℃) 24 hours filters, and is Chinese medicine extraction liquid of the present invention.Be heated to about 60 ℃, to wherein adding methyl parahydroxybenzoate 0.01g, after the cooling, add the Sodium triphosphate dissolving, add the MC557.0g that is dissolved in the 50ml sterile purified water again, regulate pH6.8, mend to 200g with sterile purified water with tartaric acid or sodium hydroxide, the thorough stirring and dissolving in water-cooled limit, limit gets eye drop.
Claims (11)
1. the aqueous drug composition having property of reversible thermosetting gelation that contains Chinese medicine and compound recipe thereof of tool clinical treatment effect is characterized in that its component is that Chinese medicine and compound recipe thereof and the substrate be made up of certain density methylcellulose and multivalence hydrochlorate constitute; Wherein, Chinese medicine and compound recipe thereof are selected from Chinese medicine compound and the Chinese medicine and western medicine compound recipe that ophthalmology, nasal cavity, auditory meatus, oral cavity, rectum, urethra, vagina and department of dermatologry are formed with single medicinal material or compatibility; The concentration range of methylcellulose is 1.0%～5.0%; The multivalence hydrochlorate is selected from tartrate, phosphate, citrate and borate, to consider in the position of osmotic pressure at eye and nasal cavity, tartrate, phosphate, citrate and boratory concentration range are decided to be 2.0～4.0% respectively, 1.0～6.0%, 2.0～4.0%, in 1.0～3.0% the scope; At the position that is not subjected to osmotic pressure influence, with tartrate, phosphate, citrate and boratory concentration range are decided to be 2.0%～15.0%, 1.0%～10.0%, 2.0%～15.0%, 1.0%～4.0% respectively; Wherein said percentage ratio is meant w/v; This pharmaceutical composition has near human temperature by the characteristic of solution to gel conversion, at eye, and nasal cavity, auditory meatus, oral cavity, rectum, urethra, vagina and skin part local application.
2. the aqueous drug composition having property of reversible thermosetting gelation of Chinese medicine as claimed in claim 1 and compound recipe thereof, wherein methylcellulose has following characteristics: 2% methylated cellulose aqueous solution is 3～4000mPas at 20 ℃ of range of viscosities, and methoxyl group containing ratio scope is 27%～32%.
3. the aqueous drug composition having property of reversible thermosetting gelation of Chinese medicine as claimed in claim 1 and compound recipe thereof, wherein 2% methylated cellulose aqueous solution is 5～400mPas at 20 ℃ of range of viscosities.
4. the aqueous drug composition having property of reversible thermosetting gelation of Chinese medicine as claimed in claim 1 and compound recipe thereof, wherein 2% methylated cellulose aqueous solution is 10～50mPas at 20 ℃ of range of viscosities,
5. the aqueous drug composition having property of reversible thermosetting gelation of Chinese medicine as claimed in claim 1 and compound recipe thereof, wherein the concentration range of methylcellulose is 2.0%～4.0%.
6. the aqueous drug composition having property of reversible thermosetting gelation of Chinese medicine as claimed in claim 1 and compound recipe thereof, wherein the concentration range of methylcellulose is 3.0%～3.5%.
7. the aqueous drug composition having property of reversible thermosetting gelation of Chinese medicine as claimed in claim 1 and compound recipe thereof, wherein the multivalence hydrochlorate is selected from tartrate, phosphate, citrate and borate, to consider in the position of osmotic pressure at eye and nasal cavity, tartrate, phosphate, citrate and boratory concentration range are decided to be 2.5%～4.0% respectively, 2.0%～5.0%, 2.5%～4.0%, 1.2%～2.8%; At the position that is not subjected to osmotic pressure influence, tartrate, phosphate, citrate and boratory concentration range are decided to be 3.0%～12.0%, 2.0%～8.0%, 3.0%～12.0%, 1.5%～3.5% respectively.
8. the aqueous drug composition having property of reversible thermosetting gelation of Chinese medicine as claimed in claim 1 and compound recipe thereof, wherein the multivalence hydrochlorate is selected from tartrate, phosphate, citrate and borate, to consider in the position of osmotic pressure at eye and nasal cavity, tartrate, phosphate, citrate and boratory concentration range are decided to be 3.2%～3.8% respectively, 3.0%～4.0%, 3.2%～3.8%, 1.8%～2.5%; At the position that is not subjected to osmotic pressure influence, tartrate, phosphate, citrate and boratory concentration range are decided to be 4.0%～10.0%, 3.0%～6.0%, 4.0%～10.0%, 2.0%～3.0% respectively.
9. the aqueous drug composition having property of reversible thermosetting gelation of Chinese medicine as claimed in claim 1 and compound recipe thereof, wherein the multivalence hydrochlorate is selected from citrate and tartrate.
10. the aqueous drug composition having property of reversible thermosetting gelation of Chinese medicine as claimed in claim 1 and compound recipe thereof, wherein the multivalence hydrochlorate is selected from citrate.
11. the aqueous drug composition having property of reversible thermosetting gelation of Chinese medicine as claimed in claim 1 and compound recipe thereof, wherein also the requirement of the different preparation types of foundation adds pharmaceutically permissible pH regulator agent, osmotic pressure regulator, antiseptic, solubilizing agent, surfactant, chelating agen or its combination.
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