CN101073552B - Double hydrochloride vertebral gel spray for purifying nose and its use - Google Patents
Double hydrochloride vertebral gel spray for purifying nose and its use Download PDFInfo
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- CN101073552B CN101073552B CN2006100267427A CN200610026742A CN101073552B CN 101073552 B CN101073552 B CN 101073552B CN 2006100267427 A CN2006100267427 A CN 2006100267427A CN 200610026742 A CN200610026742 A CN 200610026742A CN 101073552 B CN101073552 B CN 101073552B
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Abstract
The invention is concerned with the Vertebral double net hydrochloride clean gelatin nebula pressurized spray for nose, which consists of Vertebral double net hydrochloride and gel substrate. It is uses for anti-trypanosomiasis. It is: stays in liquid form, in order to control to spray into nasal cavity easily and separates on the surface of Nasal evenly and forms gelatin by interdiffusing with nose grume. With its long lasting inside the nasal cavity, it can direct input the medicine to the brain that is 2-5 times over injection through vein.
Description
Technical field
The present invention relates to a kind of nasal gel spray, relate in particular to two gel spray for purifying nose of a kind of hydrochloric acid awl and application thereof.
Background technology
The hydrochloric acid awl is two only, and (trybizine hydrochloride T-46) is a kind of triaizine compounds derivant with malaria and anti-trypanosomicide effect, and chemistry is by name: O, O '-two-(4,6-diaminostilbene, 2-dihydro-2,2-tetramethylene-1,3,5-triazine-1-yl)-1,6-hexanediol dihydrochloride, or O, O '-two-(7,9-diaminourea-6,8,10-thriazaspiro [4.5] last of the ten Heavenly stems-7,9-diene-6-yl)-1,6-hexanediol dihydrochloride, existing called after hydrochloric acid awl two clean (trybizine hydroch loride), chemical name 10,10 '-[1,6-Hexanediylbis (oxy)] bis (6,8,10-triazaspiro[4.5] deca-6,8-diene-7,9-diamine) dihydrochloride, structural formula is as follows:
This hydrochloric acid awl is two to be the novel anti trypanocides that the applicant takes the lead in succeeding in developing only, and Chinese patent CN93112460.3 discloses its preparation method and application.Document (Zhou Weicheng, Zhang Xiuping. the two clean research and development of anti-trypanosomicide new medicine hydrochloric acid awl, Chinese Journal of Pharmaceuticals, 2000,31 (1): 22-25.) reported the two clean pharmacodynamicss of hydrochloric acid awl, toxicology, pharmacokinetics, insecticidal mechanism, to clinical efficacy and the development prospect of cattle.And people have proved that hydrochloric acid awl is two and only the dehab cattle have been had good curative effect that its maximum characteristics are that a shot can take effect, and do not need repeat administration.And the inside and outside pharmacodynamics proves that this hydrochloric acid awl is two and only trypanosoma rhodesiense and the castellanella gambiense who causes people's african trypanosomiasis is had good curative effect.But the two clean veterinary injections of hydrochloric acid awl are only arranged at present, and after this veterinary injection was used for mice, monkey and camel, drug level was on the low side in the animal brain, does not reach the effect of curing the whole body african trypanosomiasis fully.And pharmacodynamics also shows two central nervous system (CNS) mice infected of can not curing only of hydrochloric acid awl in the body.This may be that this medicine hydrophilic is strong, difficult blood brain barrier (blood-brain barrier, cause BBB) of seeing through.And the later stage of people's african trypanosomiasis, cerebral tissue is invaded in the trypanosomicide meeting, causes diffuse brain injuries.Therefore, the hydrochloric acid awl is two can not see through the huge obstacle that blood brain barrier becomes the exploit person medication only.
And also do not have hydrochloric acid to bore two clean human preparations at present.Therefore, press for the two clean human preparations of a kind of hydrochloric acid awl of exploitation, make it pass through blood brain barrier, reach the purpose of whole body therapeutic african trypanosomiasis; And it can conveniently use, and improves the compliance of patient's medication.How to make the two clean nose administrations of hydrochloric acid awl can really be applicable to organism, the problem that makes dosage form can be fit to nasal-cavity administration is not resolved, for example the two clean and various adjuvants of hydrochloric acid awl share and the proportioning problem, and preparation contains penetration enhancers such as laurocapram, DM-, Mentholum, Borneolum Syntheticum, itself has big toxicity etc. to nasal mucosa and cilium, and these problems make the two clean nose administrations of hydrochloric acid awl can not really be suitable for practicality.
Summary of the invention
Therefore, one of purpose of the present invention provides the two gel spray for purifying nose of a kind of hydrochloric acid awl, and it comprises the two clean and gel-type vehicles of the hydrochloric acid awl for the treatment of effective dose.
In nasal gel spray of the present invention, the two clean content of described hydrochloric acid awl preferably are 0.05～3%, more preferably are 0.05～2%, are 0.2～1% best; Described gel-type vehicle comprises gelatinizing agent and water, and the content of described gelatinizing agent preferably is 0.1～30%, more preferably is 1～20%, and water is surplus, and above content all refers to account for the percentage by weight of whole described nasal gel spray.
Nasal gel spray of the present invention can also comprise: it is 4～9 pH regulator agent for regulating nasal gel spray pH that antiseptic, the consumption that consumption is no more than 1% (preferably being no more than 0.2%) is no more than the isoosmotic adjusting agent of 10% (preferably being no more than 5%) and/or consumption, preferably regulating gel spray pH is 5～8, more preferably 6～7, to reduce the stimulation of acid-base pair nasal cavity.
Described antiseptic can use various antiseptic of the prior art, preferably is selected from glycerol, benzalkonium chloride, benzalkonium bromide, degree rice phenol, Benzethonium, cetylpyridinium chloride, Cetrimide, chlorobutanol, benzyl alcohol, phenethanol, phenoxyethanol, cinnamic aldehyde, eucalyptus oil, perilla oil, chlorhexidine, chlorhexidine iodine, povidon iodine, phenol, o-phenyl phenol, phenyl methylcarbamate, chlorocresol, chlorinated dimethyl phenol, thymol, benzoic acid, sodium benzoate, oxybenzoic acid, sorbic acid, potassium sorbate, thimerosal, methyl hydroxybenzoate, ethyl hydroxybenzoate, in propylparaben and the butoben one or more.
Described isoosmotic adjusting agent can be selected from NaCl, KCl, glucose and/or mannitol.
Described pH regulator agent can be used various mineral acids and/or alkali, organic acid and/or alkali, preferably is selected from sodium hydroxide, hydrochloric acid, sulphuric acid, sodium carbonate, sodium bicarbonate, ammonia, citric acid, sodium citrate, acetic acid, sodium acetate, phosphoric acid, tertiary sodium phosphate, sodium hydrogen phosphate, sodium dihydrogen phosphate, maleic acid, lactic acid, tartaric acid, boric acid, sodium borate, ethanolamine, triethanolamine, ethylenediamine, sodium glutamate and the Tris one or more.
Described gelatinizing agent can use various gelatinizing agents, and being preferably gellan gum (gellan gum) is Gelrite, carbomer (Carbopol) and/or poloxamer (poloxamer); Carbomer is selected from carbomer 1342, carbomer 910, carbomer 934, Acritamer 940 and/or carbomer 974P, preferred carbomer 934, Acritamer 940 and/or carbomer 974P; Poloxamer is selected from poloxamer 407 and/or poloxamer 188, preferred poloxamer 407.
Certainly, nasal gel spray of the present invention can also comprise other additive commonly used, as: flavouring agent, pigment or lubricant etc.
Two of purpose of the present invention provides the application of the two gel spray for purifying nose of hydrochloric acid awl of the present invention in the medicine of preparation anti-trypanosomiasis.Described trypanosomicide comprises trypanosomicides such as trypanosoma rhodesiense, castellanella gambiense and/or Trypanosoma evansi, preferred trypanosoma rhodesiense and castellanella gambiense.
The two gel spray for purifying nose of hydrochloric acid awl of the present invention are that boring two with hydrochloric acid is active component only, and gelatinizing agent, antiseptic, isoosmotic adjusting agent be dissolved in water, regulating pH with the pH regulator agent is 4～9, add the two gel spray for purifying nose of hydrochloric acid awl of the present invention that the water standardize solution is made, industrial can also be with its fill, atomizing pump is installed.The two gel spray for purifying nose of hydrochloric acid of the present invention awl are applicable to and are used for prevention and treatment african trypanosomiasis, especially preventing and/or treating the trypanosoma rhodesiense that causes people's african trypanosomiasis and castellanella gambiense.
The two gel spray for purifying nose of hydrochloric acid awl of the present invention are in the external liquid condition that is, spray into nasal cavity, can be dispersed in the nasal mucosa surface, and be diffused in mutually and form gel on the olfactory mucosa with nose mucus in the nasal cavity, longer in the nasal cavity time of staying, be difficult for running off, can keep active drug concentration, to the brain administration, directly import medicine in the brain through olfactory mucosa, make that hydrochloric acid awl is two to have the brain selectivity only, the cerebrospinal fluid bioavailability is 2～5 times of intravenously administrable.Because its concentration in cerebrospinal fluid is higher, thereby can treat/prevent human or animal body general african trypanosomiasis, especially the brain trypanosomicide is infected sick.The accurately control easily of the two gel spray for purifying nose dosage of hydrochloric acid of the present invention awl, easy to use, and characteristics such as local irritation is little, and toxicity is low, and good biocompatibility and therapeutic effect are good.
The specific embodiment
The present invention is further elaborated below in conjunction with embodiment, but these embodiment do not constitute any restriction to the present invention.
Embodiment 1～10
The component of the two gel spray for purifying nose of table 1 hydrochloric acid awl of the present invention
T-46 (g): the hydrochloric acid awl is two clean; PEG: Polyethylene Glycol; The component of embodiment 1～18 complements to 1000mL with water for injection.The cold horner's product of knot of the present invention are called Gelrite, purchase in Zhongwei Bio-Chemical Co Ltd, Shanghai.
The method for making of embodiment 1～4,18: isoosmotic adjusting agent, gelatinizing agent and the antiseptic of 1. getting recipe quantity are in the water for injection of 850mL, and heating makes dissolving fully in 90 ℃ of water-baths.2. hydrochloric acid is bored two [30ml 0.1mol/L (embodiment 1), 50mL 0.1mol/L (embodiment 2), 100mL 0.1mol/L (embodiment 3), 100mL 0.2mol/L (embodiment 4), 30ml 0.1mol/L (embodiment 18)] dissolving with hydrochloric acid of using respectively only, under agitation add in the above-mentioned solution, fully mixing.3. embodiment 1 and 18 usefulness, 30% ethanolamine, embodiment 2～4 usefulness 30% Tris are regulated pH required pH to the table 1, add the injection water to total amount 1000mL, be sub-packed in medical the moulding in the bottle of white, load onto the nasal mist pump, promptly get the two gel spray for purifying nose of hydrochloric acid awl of the present invention.
The method for making of embodiment 5～16: 1. get water for injection 680ml (but embodiment 11～16 uses 900ml, 850ml, 900ml, 900ml, 850ml, 850ml respectively), add antiseptic and the isoosmotic adjusting agent (embodiment that other component is arranged, also add other component this moment), stirring and dissolving.2. get gelatinizing agent, be sprinkled in the aforementioned solution, 4 ℃ of refrigerator cold-storages spend the night (but embodiment 11～16 need not 4 ℃ of refrigerator cold-storages spend the night), the abundant swelling of gelatinizing agent is uniformly dispersed obtains clear and bright solution.3. two clean (but embodiment 7～11,13～16 uses the method for making of 100ml 0.2mol/L, 100ml 0.5mol/L, 100ml 1mol embodiment 17 respectively: 1. get the recipe quantity gelatinizing agent in the water for injection of 680mL with 100ml0.1mol/L for hydrochloric acid awl, 4 ℃ of refrigerator cold-storages spend the night, and the abundant swelling of gelatinizing agent is uniformly dispersed obtains clear and bright solution.2. the hydrochloric acid awl is two only with adding the injection water dissolving, under agitation adds in the above-mentioned solution, fully mixing.3. add the injection water to total amount 1000mL, be sub-packed in medical the moulding in the bottle of white, load onto the nasal mist pump, promptly get the two gel spray for purifying nose of hydrochloric acid awl of the present invention.
/ L, 100ml 1mol/L, 50ml 0.1mol/L, 50ml 0.3mol/L, 50ml 0.5mol/L, 100ml 1mol/L, 100ml 1mol/L) dissolving with hydrochloric acid, under agitation add in the above-mentioned solution, fully mixing.4. regulate pH required pH to the table 1 with boric acid, add the injection water, be sub-packed in medical the moulding in the bottle of white, load onto the nasal mist pump, promptly get hydrochloric acid awl pair gel spray for purifying nose of the present invention to total amount 1000mL.
The method for making of embodiment 17: 1. get the recipe quantity gelatinizing agent in the water for injection of 680mL, 4 ℃ of refrigerator cold-storages spend the night, and the abundant swelling of gelatinizing agent is uniformly dispersed obtains clear and bright solution.2. the hydrochloric acid awl is two only with adding the injection water dissolving, under agitation adds in the above-mentioned solution, fully mixing.3. add the injection water to total amount 1000mL, be sub-packed in medical the moulding in the bottle of white, load onto the nasal mist pump, promptly get the two gel spray for purifying nose of hydrochloric acid awl of the present invention.
Effect embodiment 1
12 SD rats, body weight 250-300 gram, male and female half and half, be divided into 2 groups (nasal-cavity administration test group and intravenously administrable matched groups) at random, every group 6, be administered once every day, test group (n=6) nasal cavity is given the nasal gel spray of 0.75mg/ Mus embodiment 5, matched group (n=6) vein gives 0.75mg/ Mus hydrochloric acid awl two clean injections, respectively after administration 15,30,45,60,90,120,180,240,360min adopts high-efficient liquid phase technique to measure to the two clean cerebrospinal fluid drug level of the hydrochloric acid awl of SD rat, and the two clean cerebrospinal fluid drug level of hydrochloric acid awl are as shown in table 2.
From the data of table 2 as seen, the rat brain spinal fluid bioavailability of nasal gel spray is 2.2 times of intravenously administrable rat.
Table 2 cerebrospinal fluid drug level
Claims (8)
1. two gel spray for purifying nose of hydrochloric acid awl, it comprises the pH regulator agent for adjusting nasal gel spray pH to 6～7 of two clean, the gel-type vehicles of the hydrochloric acid awl of treat effective dose and consumption; Wherein, the two clean content of described hydrochloric acid awl are 0.05～3%, described gel-type vehicle comprises gelatinizing agent and water, the content of described gelatinizing agent is 0.1～30%, water is surplus, above content all refers to account for the percentage by weight of whole described nasal gel spray, and described gelatinizing agent is selected from gellan gum Gelrite, carbomer 1342, carbomer 910, carbomer 934, Acritamer 940, carbomer 974P, poloxamer 407 and/or poloxamer 188.
2. nasal gel spray according to claim 1 is characterized in that it also comprises: consumption is no more than 1% antiseptic and/or consumption and is no more than 10% isoosmotic adjusting agent.
3. nasal gel spray according to claim 2, it is characterized in that described antiseptic is selected from glycerol, benzalkonium chloride, benzalkonium bromide, degree rice phenol, Benzethonium, cetylpyridinium chloride, Cetrimide, chlorobutanol, benzyl alcohol, phenethanol, phenoxyethanol, cinnamic aldehyde, eucalyptus oil, perilla oil, chlorhexidine, chlorhexidine iodine, povidon iodine, phenol, o-phenyl phenol, phenyl methylcarbamate, chlorocresol, chlorinated dimethyl phenol, thymol, benzoic acid, sodium benzoate, oxybenzoic acid, sorbic acid, potassium sorbate, thimerosal, methyl hydroxybenzoate, ethyl hydroxybenzoate, in propylparaben and the butoben one or more; Described isoosmotic adjusting agent is selected from NaCl, KCl, glucose and/or mannitol; Described pH regulator agent is selected from one or more in sodium hydroxide, hydrochloric acid, sulphuric acid, sodium carbonate, sodium bicarbonate, ammonia, citric acid, sodium citrate, acetic acid, sodium acetate, phosphoric acid, tertiary sodium phosphate, sodium hydrogen phosphate, sodium dihydrogen phosphate, maleic acid, lactic acid, tartaric acid, boric acid, sodium borate, ethanolamine, triethanolamine, ethylenediamine, sodium glutamate and the Tris.
4. according to each described nasal gel spray of claim 1～3, it is characterized in that: the two clean content of described hydrochloric acid awl are 0.05～2%.
5. according to each described nasal gel spray of claim 1～3, it is characterized in that: the content of described gelatinizing agent is 1～20%.
6. nasal gel spray according to claim 1, it is characterized in that: form by following component in the two gel spray for purifying nose of every 1000ml hydrochloric acid awl: the two clean 1g of hydrochloric acid awl, poloxamer 407200g, Benzalkonii Chloridum 0.1g, NaCl 8g, adjusting pH is 6 hydrochloric acid and boric acid, and water for injection complements to 1000ml.
7. the application of the claim 1 two gel spray for purifying nose of described hydrochloric acid awl in the medicine of preparation anti-trypanosomiasis.
8. application as claimed in claim 7 is characterized in that, described trypanosomicide is trypanosoma rhodesiense, castellanella gambiense and/or Trypanosoma evansi.
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| Application Number | Priority Date | Filing Date | Title |
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| CN2006100267427A CN101073552B (en) | 2006-05-19 | 2006-05-19 | Double hydrochloride vertebral gel spray for purifying nose and its use |
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| CN2006100267427A CN101073552B (en) | 2006-05-19 | 2006-05-19 | Double hydrochloride vertebral gel spray for purifying nose and its use |
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| CN101073552B true CN101073552B (en) | 2011-02-02 |
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| CN104083355B (en) * | 2014-07-07 | 2016-02-24 | 河北医科大学第二医院 | A kind of compositions for the preparation of anti-fungal keratitis eye drop |
| CN105754858A (en) * | 2016-03-04 | 2016-07-13 | 广西壮族自治区水产科学研究院 | Preservative for cryptocryon irritans cyst |
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| CN1189175C (en) * | 1998-10-08 | 2005-02-16 | 高新研究公司 | Novel compsns. and methods for prevention and treatment of protozoal disease |
| US20050227983A1 (en) * | 2004-03-24 | 2005-10-13 | Timmer Richard T | Triazine compounds and their analogs, compositions, and methods |
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2006
- 2006-05-19 CN CN2006100267427A patent/CN101073552B/en not_active Expired - Fee Related
Patent Citations (3)
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|---|---|---|---|---|
| CN1096514A (en) * | 1993-06-17 | 1994-12-21 | 国家医药管理局上海医药工业研究院 | triazine derivative and preparation method thereof |
| CN1189175C (en) * | 1998-10-08 | 2005-02-16 | 高新研究公司 | Novel compsns. and methods for prevention and treatment of protozoal disease |
| US20050227983A1 (en) * | 2004-03-24 | 2005-10-13 | Timmer Richard T | Triazine compounds and their analogs, compositions, and methods |
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