CN101073552B - Double hydrochloride vertebral gel spray for purifying nose and its use - Google Patents

Abstract

The invention discloses a trypanazine hydrochloride nasal gel spray, which contains a therapeutically effective dose of trypanazine hydrochloride and a gel matrix, and the trypanazine hydrochloride nasal gel spray is used in the preparation of anti-trypanosomiasis application in medicines. The hydrochloric acid trioshuangjing nasal gel spray is in a liquid state in vitro, the dosage is easy to accurately control, and it is convenient to use. When it is sprayed into the nasal cavity, it can be evenly dispersed on the surface of the nasal mucosa and diffuses with the nasal mucus to form a gel. The nasal cavity stays for a long time and is not easy to be lost. The drug can be directly injected into the brain, so that the trypsin hydrochloride has brain selectivity, and the bioavailability of the cerebrospinal fluid is 2 to 5 times that of intravenous administration, and it has small local irritation and low toxicity. , Good biocompatibility and so on.

Description

Trioshuangjing Hydrochloride Nasal Gel Spray and Its Application in the Preparation of Drugs

technical field

The invention relates to a nasal gel spray, in particular to a triabiquinone hydrochloride nasal gel spray and an application thereof. the

Background technique

Trybizine hydrochloride (T-46) is a triazine compound derivative with antimalarial and antitrypanosomal effects, chemical name: O, O'-bis-(4,6-diamino-1 , 2-dihydro-2,2-tetramethylene-1,3,5-triazin-1-yl)-1,6-hexanediol dihydrochloride, or O, O'-bis-( 7,9-diamino-6,8,10-triazaspiro[4.5]dec-7,9-dien-6-yl)-1,6-hexanediol dihydrochloride, now named hydrochloric acid Trybizine hydrochloride, chemical name 10,10'-[1,6-Hexanediylbis(oxy)]bis(6,8,10-triazaspiro[4.5]deca-6,8-diene-7,9- diamine)dihydrochloride, the structural formula is as follows:

The trypanosin hydrochloride is a new type of anti-trypanosomal drug firstly developed by the applicant. The Chinese patent CN93112460.3 discloses its preparation method and application. Literature (Zhou Weicheng, Zhang Xiuping. The research and development of anti-trypanosome innovative drug trypanosin hydrochloride, China Pharmaceutical Industry Journal, 2000, 31 (1): 22-25.) reported the pharmacodynamics and toxicology of trypanosin hydrochloride , pharmacokinetics, insecticidal mechanism, clinical efficacy and development prospects for cattle. And it has been proved that trybisquine hydrochloride has a good curative effect on trypanosomiasis cattle, and its biggest feature is that it can be effective after one injection without repeated administration. Moreover, the pharmacodynamics in vivo and in vitro prove that the trypanosin hydrochloride has a good curative effect on trypanosoma Rhodesia and trypanosoma gambiae that cause human trypanosomiasis. But at present there is only trypanozoic hydrochloride veterinary injection. After this veterinary injection is used in mice, monkeys and camels, the concentration of the drug in the animal brain is low, and the effect of completely curing systemic trypanosomiasis cannot be achieved. And the in vivo pharmacodynamics also showed that trypanazepam hydrochloride could not cure the central nervous system (CNS) infected mice. This may be due to the fact that the drug is highly hydrophilic and difficult to penetrate the blood-brain barrier (BBB). In the late stages of human trypanosomiasis, trypanosomes invade brain tissue and cause diffuse brain damage. Therefore, the inability of trypsin hydrochloride to pass through the blood-brain barrier has become a huge obstacle in the development of human medicines. the

However, there is no preparation for human use of trypanazepam hydrochloride. Therefore, there is an urgent need to develop a human preparation of trypanazepam hydrochloride, which can pass through the blood-brain barrier to achieve the purpose of systemic treatment of trypanosomiasis; and it can be used conveniently and improve the compliance of patients with medication. How to make trypansin hydrochloride nasal administration can be truly applicable to organisms, and the problem of making the dosage form suitable for nasal administration has not been solved, such as the combination and proportioning of trypansin hydrochloride and various auxiliary materials, and the preparation contains Penetration enhancers such as laurocaprazine, dimethyl-β-cyclodextrin, menthol, borneol, etc., have relatively high toxicity to nasal mucosa and cilia. Really suitable for practical use. the

Contents of the invention

Therefore, one of the objects of the present invention is to provide a trypanzacin hydrochloride nasal gel spray, which comprises a therapeutically effective amount of trypanazepam hydrochloride and a gel matrix. the

In the nasal gel spray of the present invention, the content of said trypanazine hydrochloride is preferably 0.05-3%, more preferably 0.05-2%, most preferably 0.2-1%; The gel base comprises a gelling agent and water, the content of the gelling agent is preferably 0.1 to 30%, more preferably 1 to 20%, and water is the remainder, and the above contents all refer to the entire The weight percentage of nasal gel spray. the

The nasal gel spray of the present invention may also comprise: an antiseptic in an amount of no more than 1% (preferably no more than 0.2%), an isotonic regulator and/or an amount of no more than 10% (preferably no more than 5%) In order to adjust the pH regulator of the nasal gel spray with a pH of 4-9, the pH of the gel spray is preferably adjusted to 5-8, more preferably 6-7, so as to reduce acid-base irritation to the nasal cavity. the

Described preservative can use various preservatives in the prior art, is preferably selected from glycerin, benzalkonium chloride, benzalkonium bromide, domiphen, benzethonium, cetylpyridinium chloride, Alkane ammonium bromide, chlorobutanol, benzyl alcohol, phenylethyl alcohol, phenoxyethanol, cinnamaldehyde, eucalyptus oil, perilla oil, chlorhexidine, chlorhexidine iodine, polyvinylpyrrolidone iodine, phenol, o-phenyl Phenol, Benzocresol, Chlorocresol, Chloroxylenol, Thymol, Benzoic Acid, Sodium Benzoate, O-Hydroxybenzoic Acid, Sorbic Acid, Potassium Sorbate, Thimerosal, Methylparaben, Bparaben One or more of esters, propylparaben and butylparaben. the

The isotonicity regulator can be selected from NaCl, KCl, glucose and/or mannitol. the

Described pH adjusting agent can use various inorganic acid and/or base, organic acid and/or base, is preferably selected from sodium hydroxide, hydrochloric acid, sulfuric acid, sodium carbonate, sodium bicarbonate, ammoniacal liquor, citric acid, Sodium citrate, acetic acid, sodium acetate, phosphoric acid, trisodium phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, maleic acid, lactic acid, tartaric acid, boric acid, sodium borate, ethanolamine, triethanolamine, ethylenediamine, glutamine One or more of sodium bicarbonate and trishydroxymethylaminomethane. the

Described gelling agent can use various gelling agents, preferably gellan gum (gellang gum) is Gelrite, carbomer (Carbopol) and/or poloxamer (poloxamer); Carbomer is selected from Carbomer 1342, Carbomer 910, Carbomer 934, Carbomer 940 and/or Carbomer 974P, preferably Carbomer 934, Carbomer 940 and/or Carbomer 974P; Poloxamer selection Poloxamer 407 and/or Poloxamer 188, preferably Poloxamer 407. the

Of course, the nasal gel spray of the present invention may also contain other commonly used additives, such as flavoring agents, pigments or lubricants. the

The second object of the present invention is to provide the application of the trypanosine hydrochloride nasal gel spray of the present invention in the preparation of anti-trypanosomiasis medicaments. The trypanosomes include Rhodesian trypanosoma, Trypanosoma gambiae and/or Trypanosoma evanii, preferably Rhodesian trypanosoma and Trypanosoma gambiae. the

The gel spray for the nose of the present invention is a bisquinone hydrochloride with a bisquinone hydrochloride as an active ingredient, and a gelling agent, a preservative, and an isotonic regulator are dissolved in water, and the pH is adjusted to be 4 to 9 with a pH regulator. The hydrochloric acid cone double net nasal gel spray of the present invention made by adding water to constant volume can also be filled with it industrially, and a spray pump is installed. The trypanocitine hydrochloride nasal gel spray of the present invention is suitable for the prevention and treatment of trypanosomiasis, especially the prevention and/or treatment of Trypanosoma Rhodesia and Trypanosoma gambiae that cause human trypanosomiasis. the

The hydrochloric acid cone double cleaning nasal gel spray of the present invention is in a liquid state in vitro, sprayed into the nasal cavity, can be evenly dispersed on the surface of the nasal mucosa, and interdiffused with the nasal mucus in the nasal cavity to form a gel on the olfactory mucosa. The residence time is longer, it is not easy to lose, and it can maintain the effective drug concentration. It can be administered to the brain through the olfactory mucosa, and the drug can be directly injected into the brain, so that trybosin hydrochloride has brain selectivity, and the bioavailability of cerebrospinal fluid is 2 times that of intravenous administration. ~5 times. Because of its high concentration in the cerebrospinal fluid, it can treat/prevent human or animal systemic trypanosomiasis, especially brain trypanosomiasis infection. The trioshuangjing hydrochloride nasal gel spray of the present invention is easy to accurately control the dose, convenient to use, and has the characteristics of small local irritation, low toxicity, good biocompatibility, good therapeutic effect and the like. the

Detailed ways

The present invention will be further described below in conjunction with examples, but these examples do not constitute any limitation to the present invention. the

Embodiment 1～10

Table 1 The composition of the triamcinol hydrochloride nasal gel spray of the present invention

T-46(g): trypanazin hydrochloride; PEG: polyethylene glycol; the components of Examples 1-18 were made up to 1000 mL with water for injection. The commercial name of the junction angle of the present invention is Gelrite, which is purchased from Shanghai Zhongwei Biochemical Co., Ltd. the

Examples 1-4, 18 preparation method: ① take the prescribed amount of isotonicity regulator, gelling agent and preservative in 850mL of water for injection, heat in a water bath at 90°C to dissolve completely. 2. Tribenzidine hydrochloride is used respectively [30ml 0.1mol/L (embodiment 1), 50mL 0.1mol/L (embodiment 2), 100mL 0.1mol/L (embodiment 3), 100mL 0.2mol/L (embodiment 3) 4), 30ml 0.1mol/L (embodiment 18)] hydrochloric acid dissolving, add in the above-mentioned solution under stirring, fully mix. ③Examples 1 and 18 use 30% ethanolamine, and examples 2-4 use 30% trishydroxymethylaminomethane to adjust the pH to the required pH in Table 1, add water for injection to a total of 1000mL, and pack in white medical plastic bottles In the process, the nasal cavity spray pump is loaded on to obtain the triosine hydrochloride nasal gel spray of the present invention. the

The preparation method of embodiment 5～16: 1. get water for injection 680ml (but embodiment 11～16 uses 900ml, 850ml, 900ml, 900ml, 850ml, 850ml respectively), adds preservative and isotonic regulator (with other components) Example, at this time and add other components), stirring to dissolve. ②Take the gelling agent, sprinkle it into the aforementioned solution, and refrigerate overnight at 4°C (however, Examples 11-16 are not refrigerated at 4°C overnight), so that the gelling agent is fully swollen and dispersed evenly to obtain a clear solution. ③Tyrabisquine hydrochloride uses 100ml0.1mol/L (but embodiment 7～11, 13～16 use 100ml 0.2mol/L, 100ml 0.5mol/L, 100ml 1mol respectively. Put the gel into 680mL of water for injection, and refrigerate overnight at 4°C to make the gel-forming agent fully swell and disperse evenly to obtain a clear solution.② Dissolve the hydrochloric acid tribenzidine with water for injection, add it to the above solution under stirring, and mix well. 3. Add water for injection to a total amount of 1000mL, pack in white medical plastic bottles, and install a nasal cavity spray pump to obtain the hydrochloric acid cone double-clean nasal gel spray 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) dissolved in hydrochloric acid, add to the above solution under stirring, and mix well . 4. adjust the pH to the required pH in Table 1 with boric acid, add water for injection to a total amount of 1000mL, pack in white medical plastic bottles, and install a nasal cavity spray pump to obtain the hydrochloric acid cone double-clean nasal gel of the present invention spray. the

Preparation method of Example 17: ① Take the prescribed amount of gelling agent in 680 mL of water for injection, and refrigerate overnight at 4°C to make the gelling agent fully swell and disperse evenly to obtain a clear solution. ②Tyrabiquinone hydrochloride was dissolved with water for injection, added into the above solution under stirring, and mixed well. 3. Add water for injection to a total amount of 1000mL, pack in white medical plastic bottles, and install a nasal cavity spray pump to obtain the hydrochloric acid cone double-clean nasal gel spray of the present invention. the

Effect Example 1

12 SD rats, body weight 250-300 grams, half male and half male, are randomly divided into 2 groups (nasal administration test group and intravenous administration control group), 6 in every group, administered once a day, test group (n=6 ) nasal cavity gives the nasal gel spray of 0.75mg/mouse embodiment 5, and the matched group (n=6) intravenously gives 0.75mg/mouse hydrochloride trishuangjing injection, after administration respectively 15,30,45,60 , 90, 120, 180, 240, and 360 min were used to measure the concentration of trypsinazine hydrochloride in the cerebrospinal fluid of SD rats by high performance liquid chromatography. the

As can be seen from the data in Table 2, the bioavailability of the rat cerebrospinal fluid of the nasal gel spray is 2.2 times that of the rat administered intravenously. the

Table 2 Cerebrospinal fluid drug concentration

Claims (8)

1. a hydrochloride trisquinone nasal gel spray, which comprises a therapeutically effective amount of triscinene hydrochloride, a gel matrix and an amount of a pH regulator for regulating the pH of the nasal gel spray to 6 to 7; wherein , the content of the said trypamethylene hydrochloride is 0.05～3%, the described gel matrix contains gelling agent and water, the content of the described gelling agent is 0.1～30%, water is the remainder, the above content All refer to the percentage by weight of the whole described nasal gel spray, and the gel forming agent is selected from gellan gum Gelrite, Carbomer 1342, Carbomer 910, Carbomer 934, Carbomer 940, Carbomer 974P, Poloxamer 407 and/or Poloxamer 188. 2. The nasal gel spray according to claim 1, characterized in that it further comprises: a preservative in an amount not exceeding 1% and/or an isotonic regulator in an amount not exceeding 10%. 3. nasal gel spray according to claim 2, is characterized in that, described antiseptic is selected from glycerin, benzalkonium chloride, benzalkonium bromide, domiphen, benzethonium, decachloride Hexaalkylpyridine, Alkane Ammonium Bromide, Chlorobutanol, Benzyl Alcohol, Phenyl Alcohol, Phenoxyethanol, Cinnamaldehyde, Eucalyptus Oil, Perilla Oil, Chlorhexidine, Chlorhexidine Iodine, Polyvinylpyrrolidone Iodine, Phenol, o-Phenylphenol, Benzocresol, Chlorocresol, Chloroxylenol, Thymol, Benzoic Acid, Sodium Benzoate, O-Hydroxybenzoic Acid, Sorbic Acid, Potassium Sorbate, Thimerosal, Methylparaben One or more in , ethylparaben, propylparaben and butylparaben; Described isotonic regulator is selected from NaCl, KCl, glucose and/or mannitol; Described pH The regulator is selected from sodium hydroxide, hydrochloric acid, sulfuric acid, sodium carbonate, sodium bicarbonate, ammonia water, citric acid, sodium citrate, acetic acid, sodium acetate, phosphoric acid, trisodium phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate , maleic acid, lactic acid, tartaric acid, boric acid, sodium borate, ethanolamine, triethanolamine, ethylenediamine, sodium glutamate, and trishydroxymethylaminomethane. 4. The nasal gel spray according to any one of claims 1-3, characterized in that: the content of said trypanazine hydrochloride is 0.05-2%. 5. The nasal gel spray according to any one of claims 1-3, characterized in that: the content of the gel-forming agent is 1-20%. 6. The nasal gel spray according to claim 1, characterized in that: every 1000ml of Trishuangjing hydrochloride nasal gel spray is made up of the following components: Trishuangjing hydrochloride 1g, poloxamer 407200g , benzalkonium chloride 0.1g, NaCl 8g, hydrochloric acid and boric acid to adjust the pH to 6, and water for injection to make up to 1000ml. 7. the application of the trypanosine hydrochloride nasal gel spray as claimed in claim 1 in the preparation of anti-trypanosomiasis medicaments. 8. The application according to claim 7, wherein the trypanosome is Trypanosoma rhodesia, Trypanosoma gambiae and/or Trypanosoma evanii.