CN1706365A - Reversible thermal gelation aqueous pharmaceutical composition - Google Patents
Reversible thermal gelation aqueous pharmaceutical composition Download PDFInfo
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- CN1706365A CN1706365A CN 200510043412 CN200510043412A CN1706365A CN 1706365 A CN1706365 A CN 1706365A CN 200510043412 CN200510043412 CN 200510043412 CN 200510043412 A CN200510043412 A CN 200510043412A CN 1706365 A CN1706365 A CN 1706365A
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Abstract
The reversibly hot gelified water soluble medicine composition may be used in pharmacological treatment and diagnosis of diseases of eyes, nasal cavity, other body cavity and skin. The composition consists of medicine in effective amount, methyl cellulose in certain concentration, salt, pH regulator, etc, and has the features of being well flowable liquid before being applied and fast gelification by the local body temperature after being applied.
Description
Technical field:
The present invention relates to contain a kind of efficacy component, with the aqueous drug composition having property of reversible thermosetting gelation that is combined as substrate of methylcellulose and multivalence hydrochlorate.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 characteristics 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 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.
Summary of the invention:
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 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.
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 reversibly hot gelified water soluble Pharmaceutical composition of the present invention, 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.
Concentration range according to above-mentioned each component, select a prescription that is applicable to Timolol maleate eye drops, as follows: methylcellulose concentration 3.5%, sodium citrate concentration 3.5%, with about citron acid for adjusting pH value to 6.8, prepare 0.5% Timoptic-XE type eye drop, with 93121431.9 patented products, the 0.5% Timoptic-XE type eye drop (RYSMON of the import Japan that buys
TG) both one-tenth gel characteristics of comparison.
In 30 ℃ of waters bath with thermostatic control, insulation 20min, both all do not become gel, but the viscosity of our product is obviously big than imported product viscosity, and gelation tendencies is arranged, and the imported product flowability is still the same with liquid.In 33 ℃ of waters bath with thermostatic control, insulation 20min, we can realize gelling by product, reversing gently after the taking-up, gel is to gliding and distortion; And the viscosity of imported product increases than before, opalescence also occurs, but reversing gently after taking out gets final product landing in the 1min.Thereby think to become gel characteristic, comprise into the patented product RYSMON that gelling temp and gel hardness all are better than Japan with our substrate and 0.5% Timoptic-XE type eye drop of method preparation on the throne
TG
At people's eye, the temperature of nasal cavity all between 32～34 ℃, therefore leaves standstill the ideal situation that 20min is application in 33 ℃ of waters bath with thermostatic control, and it also is optimal becoming the gel test result.Therefore, think that our substrate can form gel quickly when the people uses near body temperature but uncomfortable sensation can not arranged because gel hardness is too big.Therefore think more superior than patent 93121431.9 of our medium characteristics.
Aqueous pharmaceutical compositions of the present invention can be used for for example eye, the treatment and the diagnosis of nasal cavity and other body cavitys and dermatosis.
The medicament of the be applied to people eye that contains in the present composition or the example of diagnostic agent are as follows.As antibiotic for example 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 for example 3-(1H-tetrazolium-5-yl) phenyloxamic acid (hereinafter to be referred as MTOC) of antiallergic agent, 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 for example pilocarpine of miotic, carbachol; As the flavin adenine dinucleotide (FAD) of vitamins, pyridoxal 5-phosphate, vitamin B12; As for example naphazoline of vasoconstrictor, phenylephrine, oxymetazoline, tetrahydrozoline, thiophene Lip river azoles quinoline; Quick as antihistaminic Piao Er, diphenhydramine; As for example N-ethyl-N-(.gamma.-picolyl)tropamide of mydriatic, oxamphetamine, atropine, scopolamine, Propantheline, acetyl ring penta benzene, phenylephrine; For example timolol as the glaucoma treatment medicine blocks to such an extent that feel at ease, brimonidine, and A Luoniding, metoprolol, carteolol, betaxolol, guanethidine, dorzolamide, cloth Yin helps amine, latanoprost, Unoprostone; As for example glutathion of cataract therapy medicine, catalin, phacolin, sorbinil; As for example lignocaine of local anesthetic, benoxinate, bupivacaine; For example fluorescein sodium as the ophthalmic diagnostic agent; As for example cyclosporin of immunosuppressant, azathioprine, mitomycin; As for example fluorouracil of metabolic antagonist, fluorofur, methotrexate; The for example epinephrine of congested remover for example; For example (5-(3-thienyl)-tetrazolium-1-yl) acetic acid (hereinafter to be referred as TAT) of diabetes nethike embrane therapeutic agent for example; As the sodium chondroitin sulfate of amino acids, the sulfonic acid glycine; For example neostigmine methylsulfate as the autonomic nerve agent.And above-mentioned mixture, also can use the medicament of other treatment eye disorders nuclear focus.
The example of the medicament of the be applied to people nasal cavity that contains in the present composition is as follows.As antibiotic for example neomycin, streptomycin, chloromycetin, gentamycin, kanamycin, nitrofural, norfloxacin, sulfamethoxazole, mupirocin; As antihistaminic for example acrivastine, mizolastine, azelastine, levocabastine, clemastine, ebastine, loratadine, cetirizine, terfenadine, chlorphenamine, dimenhydrinate, Cyproheptadine, phenindamine, tripelennamine, triprolidine, astemizole; As for example sodium cromoglicate of antiallergic antiinflammatory, ketotifen fumarate, zaprinast, triamcinolone acetonide, mometasone, fluticasone, budesonide, cortisone acetate, prednisolone acetate, dexamethasone, meticortelone, betamethasone, flunisolide; As for example tetracaine of local anesthetic, procaine; As for example ephedrine of vasoconstrictor and Decongestant, naphazoline, oxymetazoline, tetrahydrozoline, indanazoline, thiophene Lip river azoles quinoline, xylometazoline; For example chondroitin sulfate as amino acids; Absorb for example dipyrone of bringing down a fever as nasal system; Absorb antiviral for example acyclovir as nasal system; The vitamin drug that absorbs as nasal system is vitamin B12 for example; As a lot of medicines that work by the nasal absorption maincenter.And above-mentioned mixture, also can use other the treatment nasal cavity disease and the medicament of focus.
The be applied to body cavity that contains in the present composition is an auditory meatus, oral cavity or oral pit, and rectum, urethra, the example of the medicament of vagina is as follows.As auditory meatus with the anti-inflammation agent of agent ofloxacin for example, erythromycin, chloromycetin, lincomycin, neomycin, albomycin, lomefloxacin, sulphacetamide etc.; As for example Dequavet of oral cavity or the agent of oral pit usefulness, lysozyme, ribavirin, Anethol Trithione, thymus protein, nystatin, cyclosporin etc.; As the clotrimazole of genitals with agent, metronidazole, chlorhexidine etc.; For example aminophylline as bronchodilator; For example fluorouracil as metabolic antagonist; Ataractic for example stable as hypnosis; As for example aspirin of antipyretic-antalgic antiinflammatory, indometacin, the indenes acid of relaxing, Phenylbutazone, ibuprofen etc.; As for example dexamethasone of adrenal hormone agent, omcilon, hydrocortisone; For example lignocaine as local anesthetic; As for example bacteresulf of suppuration illness medication, kanamycin, tobramycin and erythromycin; For example norfloxacin and nalidixan as synthetic antibacterial.And above-mentioned mixture, also can use other the treatment body cavity disease and the medicament of focus.
The example of the medicament of the be applied to application on human skin that contains in the present composition is as follows.As for example Antazoline of parasitic dermatosis with agent, fluconazol, ciclopiroxolamin, siccanin, acetic acid quinoline in two last of the ten Heavenly stems, clotrimazole, salicylic acid, neomycin, sulfadiazine; As for example sulfamethoxazole sodium of suppurative illness with agent, erythromycin, gentamycin sulfate; As for example indometacin of analgesic agent, ketoprofen, betamethasone valerate, fluocinonide, hydrocortisone, prednisone, mometasone, prednicarbate, allantoin, dexamethasone; For example diphenhydramine as pruritus; As for example procaine of local anesthetic, lignocaine; As for example oxygen benzyl alkanamine of local anesthetic, hibitane, benzoyl peroxide, tribromocresol, resorcinol, Noxythiolin, anaflex, cresol sulfonic acid, Ta Zhaluote; As for example tretinoin of vitamins derivant, isotretinoin, etretinate; For example dithranol as strong oxidizer; For example podophyllotoxin as metabolic poison.And above-mentioned mixture, also can use other the treatment skin disorder and the medicament of focus.
The content of effective agent is different variant because of the kind of medicament.Generally preferably in about 0.001%～10% scope.Aqueous pharmaceutical compositions of the present invention can contain the pharmaceutically permissible buffer agent that adds as required, salt, antiseptic and solubilizing agent etc.The hydrochloric acid that has that can be used as the pH regulator agent, sulphuric acid, citric acid, tartaric acid, phosphoric acid, boric acid, acids such as acetic acid, sodium hydroxide, ethanolamine, diethanolamine, bases such as triethanolamine.This aqueous pharmaceutical compositions should regulate pH value and application site physiology pH value adapts.Can make has chlorination benzylamine, positive soap classes such as Septin as antiseptic; 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.
Can suitably add surfactant or chelating agen in addition, the general spendable scope of these compositions is about 0.001～2%, is about 0.002～1% 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 aqueous pharmaceutical compositions of the present invention does not have specific restriction, for example citrate is dissolved in sterile purified water, regulate the pH value of this solution with the pH regulator agent, after adding medicament 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 desired, can add various additives after this, for example buffer agent, salt and antiseptic.In addition, medicament is a slightly solubility or when insoluble, can make its suspension or dissolve it with solubilizing agent.
Said composition 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.
The specific embodiment:
Embodiment 1
Erythromycin 0.1g, sodium citrate 3.8g, methaform 0.5g are dissolved among the sterile purified water 50ml and dissolve, toward wherein adding the MC1004.5g that is dissolved in the 25ml sterile purified water, thoroughly stir with citric acid or sodium hydroxide and regulate pH7.0, mend to 100ml with sterile purified water, the thorough stirring and dissolving in water-cooled limit, limit gets eye drop.
Embodiment 2
Levofloxacin hydrochloride 0.3g, sodium citrate 3.5g, benzalkonium chloride 0.01g are dissolved among the sterile purified water 50ml and dissolve, toward wherein adding the MC153.5g that is dissolved in the 25ml sterile purified water, thoroughly stir with citric acid or sodium hydroxide and regulate pH7.0, mend to 100ml with sterile purified water, the thorough stirring and dissolving in water-cooled limit, limit gets eye drop.
Embodiment 3
Sodium triphosphate 6.0g is dissolved among the sterile purified water 50ml, regulates pH5.0 with citric acid.Toward wherein adding norfloxacin 0.3g, Hydroxyethyl Ammonium Chloride 0.005g, add the MC40003.5g that is dissolved in the 25ml sterile purified water again.Regulate pH5.5 with citric acid, mend to 100ml with sterile purified water, the thorough stirring and dissolving in water-cooled limit, limit gets eye drop.
Embodiment 4
Sodium triphosphate 5.0g, Benzalkonii Chloridum 0.01g are dissolved among the sterile purified water 50ml, toward wherein adding idoxuridine 0.1g that is dissolved among the 3N sodium hydroxide 10ml and the MC1003.5g that is dissolved in the 25ml sterile purified water.Regulate pH 6.0 with the 3N sodium hydroxide, mend to 100ml with sterile purified water, the thorough stirring and dissolving in water-cooled limit, limit gets eye drop.
Embodiment 5
Niflan 0.1g, sodium tartrate 3.0g are added thoroughly stirring in the 50ml sterile purified water, regulate pH6.5 with ethanolamine.Toward wherein adding Benzalkonii Chloridum 0.01g, add the MC4003.0g that is dissolved in the 25ml sterile purified water again.Regulate pH7.4 with ethanolamine, mend to 100ml with sterile purified water, the thorough stirring and dissolving in water-cooled limit, limit gets eye drop.
Embodiment 6
Methyl parahydroxybenzoate 0.026g, propyl p-hydroxybenzoate 0.014g are added among the about 60 ℃ sterile purified water 50ml of preheating, fully stirring and dissolving.After this liquid at room temperature cools off, add sodium tetraborate 3g dissolving.Toward wherein adding timolol 0.3g, add the MC553.5g that is dissolved in the 25ml sterile purified water again.Regulate pH6.8 with sodium hydroxide, mend to 100ml with sterile purified water, the thorough stirring and dissolving in water-cooled limit, limit gets eye drop.
Embodiment 7
According to embodiment 6, use the same method the eye drop of forming shown in showing.
Embodiment 8
According to embodiment 5, use the same method the eye drop of forming shown in showing.
Embodiment 9 uses the same method according to embodiment 6, the eye drop of forming shown in must showing.
Embodiment 10
According to embodiment 3, use the same method the nasal drop of forming shown in showing.
Embodiment 11
According to embodiment 6, use the same method the nasal drop of forming shown in showing.
Embodiment 12～13
According to embodiment 1, use the same method the nasal drop of forming shown in showing.
Embodiment 14 uses the same method according to embodiment 6, the nasal drop of forming shown in must showing
Embodiment 15
According to embodiment 5, use the same method the nasal drop of forming shown in showing.
Embodiment 16
According to embodiment 1, use the same method the body cavity agent of forming shown in showing
Embodiment 17～20
According to embodiment 6, use the same method the body cavity agent of forming shown in showing
Embodiment 21
According to embodiment 6, use the same method the skin agent of forming shown in showing
Embodiment 22-23
According to embodiment 1, use the same method the skin agent of forming shown in showing.
Embodiment 24
According to embodiment 5, use the same method the skin agent of forming shown in showing.
Embodiment 25～26
According to embodiment 1, use the same method the skin agent of forming shown in showing.
Table
| Embodiment | The prescription content | ????W/V％? | Gelling temperature |
| ??1? ? ? ? ? ? | Erythromycin MC100 sodium citrate methaform citric acid or sodium hydroxide | ????0.1? ????4.5? ????3.8? ????0.5? ????pH7.0? | ? ????25? ? ? ? |
| ??2? ? ? ? ? | Levofloxacin hydrochloride MC15 sodium citrate benzalkonium chloride citric acid or sodium hydroxide | ????0.3? ????3.5? ????3.5? ????0.01? ????pH5.5? | ? ????32? ? ? ? |
| ??3? ? ? ? ? | Norfloxacin MC4000 Sodium triphosphate Hydroxyethyl Ammonium Chloride citric acid | ????0.3? ????3.5? ????6.0? ????0.005? ????pH5.5? | ? ????27? ? ? ? |
| ??4? ? ? ? ? | Idoxuridine MC100 Sodium triphosphate Benzalkonii Chloridum sodium hydroxide | ????0.1? ????3.5? ????5.0? ????0.01? ????pH6.0? | ? ????29? ? ? ? |
| ??5? ? ? ? ? | Niflan MC400 sodium tartrate Benzalkonii Chloridum ethanolamine | ????0.1? ????3.0? ????3.0? ????0.01? ????pH7.4? | ? ????35? ? ? ? |
| ??6? ? ? ? ? ? | Timolol MC55 sodium tetraborate methyl parahydroxybenzoate propyl p-hydroxybenzoate sodium hydroxide | ????0.3? ????3.5? ????3? ????0.026? ????0.014? ????pH6.8? | ? ????32? ? ? ? ? |
| ????7? ? ? ? ? | Lidocaine hydrochloride MC15 sodium tetraborate ethylparaben triethanolamine | ????0.5? ????3.5? ????3.0? ????0.02? ????pH6.5? | ? ????33? ? ? ? |
| ????8? ? ? ? | Fluorescein sodium MC100 Sodium triphosphate sodium dihydrogen phosphate or sodium hydrogen phosphate | ????1.0? ????3.5? ????6.0? ????pH7.4? | ? ????30? ? ? |
| ????9? ? ? ? ? | Fluorouracil MC55 dipotassium tetraborate chlorobutanol sodium hydroxide | ????1.0? ????3.0? ????2.5? ????0.5? ????pH8.4? | ? ????36? ? ? ? |
| ????10? ? ? ? ? | Kanamycin MC100 tri-potassium phosphate chlorination benzylamine citric acid | ????0.5? ????3.2? ????5.2? ????0.005? ????pH6.0? | ? ????33? ? ? ? |
| ????11? ? ? ? ? | Levocabastine MC400 sodium tetraborate ethylparaben citric acid | ????0.05? ????3.0? ????2.8? ????0.02? ????pH6.0? | ? ????33? ? ? ? |
| ????12? ? ? ? ? | Ketotifen fumarate MC400 sodium citrate benzalkonium bromide citric acid | ????0.2063? ????3.0? ????3.5? ????0.01? ????pH5.0? | ? ????33? ? ? ? |
| ????13? ? ? ? ? | Momestasone furoate MC100 potassium citrate chlorobutanol citric acid | ????0.1? ????3.0? ????3.5? ????0.5? ????pH5.0? | ????34? ? ? ? ? |
| ????14? ? ? ? ? | Naphcon MC55 sodium tetraborate Benzalkonii Chloridum citric acid | ????0.1? ????3.5? ????3.0? ????0.01? ????pH5.0? | ????32? ? ? ? ? |
| ????15? ? ? ? ? | Vitamin B12 MC55 Soluble tartar. ethylparaben citric acid | ????3.5? ????3.2? ????3.5? ????0.02? ????pH5.0? | ????33? ? ? ? ? |
| ????16? ? ? ? ? | Dequavet MC15 sodium citrate chlorobutanol citric acid | ????0.25? ????3.2? ????3.0? ????0.5? ????pH5.0? | ????35? ? ? ? ? |
| ????17? ? ? ? ? | Metronidazole MC5 sodium tetraborate Hydroxyethyl Ammonium Chloride sodium hydroxide | ????0.1? ????5.0? ????4? ????0.005? ????pH6.0? | ????33? ? ? ? ? |
| ????18? ? ? ? ? | Aminophylline MC400 sodium tartrate Hydroxyethyl Ammonium Chloride sodium hydroxide | ????2.5? ? ????3.2? ????3.5? ????0.005? ????pH9.0? | ????33? ? ? ? ? |
| ????19? ? ? ? ? | Stable MC400 sodium tetraborate Hydroxyethyl Ammonium Chloride citric acid | ????0.5? ????3.8? ????2.0? ????0.005? ????pH5.5? | ????36? ? ? ? ? |
| ????20? ? ? | Dexamethasone MC100 sodium tetraborate | ????0.1? ????3.5? ????2.5? | ????33? ? ? |
| The Hydroxyethyl Ammonium Chloride citric acid | ????0.005? ????pH5.5? | |||
| ????21? ? ? ? | Antazoline MC400 sodium tetraborate citric acid | ????1.0? ????3.5? ????3.5? ????pH5.5? | ????33? ? ? ? | |
| ????22? ? ? ? ? | Sulfadiazine MC15 sodium citrate Hydroxyethyl Ammonium Chloride citric acid | ????5? ????3.5? ????4.5? ????0.005? ????pH5.0? | ????28? ? ? ? ? | |
| ????23? ? ? ? ? | Indometacin MC400 sodium citrate ethylparaben citric acid | ????1.0? ????4.5? ????4.0? ????0.1? ????pH4.5? | ????32? ? ? ? ? | |
| ????24? ? ? ? ? | Diphhydramine hydrochloride MC4000 sodium citrate Hydroxyethyl Ammonium Chloride citric acid | ????1.0? ????3.5? ????5.8? ????0.01? ????pH5.5? | ????29? ? ? ? ? | |
| ????25? ? ? ? ? | Hibitane MC100 sodium citrate Hydroxyethyl Ammonium Chloride citric acid or sodium hydroxide | ????0.5? ????3.5? ????4? ????0.01? ????pH5.0? | ????33? ? ? ? ? | |
| ????26? ? ? ? ? | Tretinoin MC400 sodium citrate Hydroxyethyl Ammonium Chloride citric acid | 500,000 units/g 3 5.5 0.005 pH5.0 | ????33? ? ? ? ? | |
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