CN103877008A - Gastrodin in-situ gel for treating inner ear diseases - Google Patents

Abstract

The invention relates to gastrodin in-situ gel for treating inner ear diseases, wherein the inner ear diseases include meniere disease, sudden deafness and vestibular neuronitis. The gastrodin in-situ gel is characterized by being composed of the components in parts by weight: 10-20 parts of gastrodin, 0.3-0.8 part of ion-activated gel material, 0.5-2 parts of transfer accelerant, 0.02-0.05 part of preservative and 100 parts of purified water. The in-situ gel provided by the invention is suitable for intranasal administration and capable of remarkably increasing the efficiency for transferring gastrodin from the auditory tube to the inner ear and greatly increasing the local bioavailability of gastrodin to the inner ear.

Description

A kind of gastrodine in-situ gel for the treatment of disease of inner ear

Technical field

The present invention relates to medicinal preparation, be specifically related to a kind of pharmaceutical product containing organic effective ingredient.

Background technology

The symptoms such as disease of inner ear is as dizzy in Meniere, idiopathic sudden deafness and vestibular neuronitis etc. can produce, tinnitus, hearing loss, bring great misery to patient.Estimate according to World Health Organization (WHO), approximately there are 2.5 hundred million hearing loss people in the whole world, and old people's prevalence is higher than 30%.Internal ear blood barrier (the blood labyrinth barrier that gets lost, BLB) be to guarantee the necessary important system of internal ear specific function, the factor of the lost barrier of any destruction blood, as free radical, pressure hormone, noise exposure, aminoglycoside antibiotics etc., all may cause the variation of environment in cochlea, affect inner ear function.Along with the increasing of environmental noise pollution effect and the appearance of aged tendency of population, this type of disease worldwide sickness rate has the trend of rising.Because internal ear (comprising cochlea and vestibular system) is responsive organ, inconvenience operation, therefore disease of inner ear is generally selected conservative treatment, i.e. Drug therapy.But owing to being similar to the existence of the lost barrier of internal ear blood of blood brain barrier, after whole body administration, medicine is difficult to arrive diseased region---internal ear and bring into play curative effect, often need to use larger therapeutic dose, easily cause whole body toxic and side effects.

In order to avoid the lost barrier of internal ear blood, the disease of inner ear of the interior route of administration treatment of normal employing tympanum at present clinically, by medicine, in auripuncture is injected to tympanum, medicine infiltrates through internal ear by round window membrane again; Or by implantation, microtubular head end is fixed on to REN, tail end is placed in external and connects micro pump, realizes the sustainable supply of medicine.Although this invasive administration approach can be walked around the lost barrier of blood, there is location targeting, there is the problem such as safety, compliance simultaneously.According to the literature, in tympanum, administration exists infection in the perforation of ear drum, tympanum, round window membrane damage, of short duration vertigo and tinnitus and audition further to descend degradation complication.Therefore, be necessary to continue to explore safety, effectively, noinvasive, internal ear route of administration easily.

Have clinically much Chinese medicine to can be used for the treatment of the disease of inner ear such as Meniere, wherein most widely used is gastrodia elata, in many treatments, in the Chinese medicinal formulae of Ménière, has all used Rhizoma Gastrodiae.Gastrodia rare Chinese medicine, is the dry tuber of orchid Rhizoma Gastrodiae (Gastrodia elata Blume), and property is flat, sweet in the mouth, effect of suppressing the hyperactive liver to relieve the wind syndrome relieving convulsion for tool.The main active of Rhizoma Gastrodiae is gastrodine, and research shows, gastrodine has the multiple pharmacological effect such as calmness, analgesia, convulsion, blood vessel dilating, and toxicity is low, and untoward reaction is little, clinically for the treatment of the disease of inner ear such as Meniere, evident in efficacy.At present gastrodine mainly adopts oral or quiet note administration, and the medicine whole body that distributes in vivo, is difficult to arrive inner ear labyrinth region, and the dose of lesions position is very little, directly affects the performance of its curative effect.How to break through the lost barrier of internal ear blood and be still a thorny difficult problem.

Summary of the invention

The technical problem to be solved in the present invention is to provide a kind of gastrodine in-situ gel for the treatment of disease of inner ear, this in-situ gel is applicable to nasal-cavity administration, and can significantly improve the efficiency that gastrodine is transported to internal ear through pharyngotympanic tube, can increase substantially the local bioavailability of internal ear of gastrodine.

The technical scheme that the present invention addresses the above problem is as follows:

A kind of gastrodine in-situ gel for the treatment of disease of inner ear, wherein said disease of inner ear is Meniere, sudden deafness and vestibular neuronitis, it is characterized in that, this in-situ gel is made up of gastrodine 10～20 weight portions, ion-sensitive type gel rubber material 0.3～0.8 weight portion, transhipment promoter 0.5～2 weight portion, antiseptic 0.02～0.05 weight portion and purified water 100 weight portions, wherein

Described ion-sensitive type gel rubber material is deacetylated gellan gum or sodium alginate;

Described transhipment promoter is Borneolum Syntheticum or Oleum menthae;

Described antiseptic is ethyl hydroxybenzoate or benzene gadolinium oronain.

The preparation method of above-mentioned gastrodine in-situ gel is made up of following steps:

Take in proportion ion-sensitive type gel rubber material and antiseptic, add the purified water of total amount 80%, dissolve and let cool to room temperature in 90 ℃, add gastrodine, after dissolving, solution is filtered through sintered glass funnel after 4 ℃ of cold preservation 24h, add transhipment promoter, then add remaining purified water, stir evenly, subpackage.

Gastrodine in-situ gel of the present invention is liquid preparation, splash into or spray into after nasal cavity, can with nose mucus in ionization, form gel, attach on nasal mucosa, prolong drug is in the holdup time of nasal cavity, and the gastrodine discharging can be transported to internal ear performance drug effect through pharyngotympanic tube.Transhipment promoter in in-situ gel of the present invention has significant facilitation through pharyngotympanic tube to the efficiency of internal ear transhipment to gastrodine, can increase substantially the local bioavailability of internal ear of gastrodine.

The effect of gastrodine in-situ gel of the present invention is confirmed by following experiment.

1, quiet note and via intranasal application give the guinea pig inner ear pharmacokinetic studies of gastrodine

Get healthy male guinea pig, be divided into two groups.First group: through tail vein injection gastrodine, dosage is 30mg/kg, after administration 5,15,30,45,60,90 and 120min get blood through eye socket; Second group: after the anesthesia of the shallow degree of ether, give gastrodine in-situ gel (containing gastrodine 100mg/mL, do not add and transport promoter) by microsyringe via intranasal application, dosage is all 30mg/kg, after administration 5,15,30,45,60,90 and 120min, extract perilympha with the broken oeil de boeuf of microsyringe diagonal stabbing, each time point is got 4 ears, sample dilutes with appropriate methanol, centrifugal rear direct injected, adopts UPLC method to measure drug level, and result is as shown in Fig. 1 and table 1.From Fig. 1 and table 1, compared with quiet note, after the administration of gastrodine via intranasal application, the local bioavailability of internal ear Chinese medicine improves approximately 1 times.

The quiet note of table 1 or via intranasal application give internal ear pharmacokinetic parameters (n=4) after gastrodine

* p<0.05, with the comparison of Bolos intravenous administration group

2, the impact of Borneolum Syntheticum on the pleasant transhipment of gastrodine via intranasal application

Preparation is containing the gastrodine nasal in-situ gel (containing gastrodine 100mg/mL) of Borneolum Syntheticum 0,10,20mg/mL respectively.After Cavia porcellus is anaesthetized with the shallow degree of ether, with microsyringe respectively via intranasal application give above-mentioned three kinds of test samples, dosage is 30mg/kg in gastrodine, after administration 5,15,30,45,60,90 and 120min, extract perilympha with the broken Cavia porcellus of microsyringe diagonal stabbing ear oeil de boeuf, each time point is got 4 ears, sample dilutes with appropriate methanol, centrifugal rear direct injected, adopts UPLC method to measure drug level, and result is as shown in Fig. 2 and table 2.From Fig. 2 and table 2, Borneolum Syntheticum has an obvious facilitation to gastrodine via intranasal application is pleasant, and the AUC of high and low dose group increases respectively 2.91 and 2.05 times.

The impact (n=4) of table 2 Borneolum Syntheticum on the pleasant pharmacokinetic parameters of gastrodine via intranasal application

* p<0.05, and does not add the comparison of Borneolum Syntheticum group

3, the impact of Oleum menthae on the pleasant transhipment of gastrodine via intranasal application

Preparation is containing the gastrodine nasal in situ gel (containing gastrodine 100mg/mL) of Oleum menthae 0,10,20mg/mL respectively.After Cavia porcellus is anaesthetized with the shallow degree of ether, with microsyringe respectively via intranasal application give above-mentioned three kinds of test samples, dosage is 30mg/kg in gastrodine, after administration 5,15,30,45,60,90 and 120min, extract perilympha with the broken Cavia porcellus of microsyringe diagonal stabbing ear oeil de boeuf, each time point is got 4 ears, sample dilutes with appropriate methanol, centrifugal rear direct injected, adopts UPLC method to measure drug level, and result is as shown in Fig. 3 and table 3.From Fig. 3 and table 3, Oleum menthae is stronger compared with Borneolum Syntheticum to the pleasant facilitation of gastrodine via intranasal application, and the AUC of high and low dose group increases respectively 3.84 and 3.24 times.

The impact (n=4) of table 3 Oleum menthae on the pleasant pharmacokinetic parameters of gastrodine via intranasal application

* p<0.05, and does not add the comparison of Herba Menthae line of oils

Accompanying drawing explanation

Curve chart when the quiet note of Fig. 1 and via intranasal application give the medicine of gastrodine effect comparison.

Curve chart when Fig. 2 Borneolum Syntheticum promotes the medicine of gastrodine via intranasal application pleasant effect.

Curve chart when Fig. 3 Oleum menthae promotes the medicine of gastrodine via intranasal application pleasant effect.

The specific embodiment

Embodiment 1

1, prescription: gastrodine 10g, deacetylated gellan gum 0.5g, peppermint 1g, ethyl hydroxybenzoate 0.03g, purified water 100g.

2, method for making: take deacetylated gellan gum and ethyl hydroxybenzoate, add 80g purified water, dissolve and let cool to room temperature in 90 ℃, add gastrodine, the solution after dissolving filters through sintered glass funnel after 4 ℃ of cold preservation 24h, adds Oleum menthae and remaining purified water, stir evenly, subpackage, to obtain final product.

Embodiment 2

1, prescription: gastrodine 20g, sodium alginate 0.8g, Borneolum Syntheticum 2g, benzalkonium chloride 0.02g, purified water 100g.

2, method for making: take sodium alginate and benzene gadolinium oronain, add 80g purified water, dissolve and let cool to room temperature in 90 ℃, add gastrodine, the solution after dissolving filters through sintered glass funnel after 4 ℃ of cold preservation 24h, adds Borneolum Syntheticum fine powder again, add again remaining purified water to enough, stir evenly, subpackage, to obtain final product.

Embodiment 3

1, prescription: gastrodine 10g, deacetylated gellan gum 0.3g, Oleum menthae 0.5g, ethyl hydroxybenzoate 0.05g, purified water 100g.

2, method for making: take deacetylated gellan gum and ethyl hydroxybenzoate, add 80g purified water, dissolve and let cool to room temperature in 90 ℃, add gastrodine, the solution after dissolving filters through sintered glass funnel after 4 ℃ of cold preservation 24h, adds Oleum menthae again, add again remaining purified water to enough, stir evenly, subpackage, to obtain final product.

Claims (2)

1. treat the gastrodine in-situ gel of disease of inner ear for one kind, wherein said disease of inner ear is Meniere, sudden deafness and vestibular neuronitis, it is characterized in that, this in-situ gel is made up of gastrodine 10～20 weight portions, ion-sensitive type gel rubber material 0.3～0.8 weight portion, transhipment promoter 0.5～2 weight portion, antiseptic 0.02～0.05 weight portion and purified water 100 weight portions, wherein

Described ion-sensitive type gel rubber material is deacetylated gellan gum or sodium alginate;

Described transhipment promoter is Borneolum Syntheticum or Oleum menthae;

Described antiseptic is ethyl hydroxybenzoate or benzene gadolinium oronain.

2. a preparation method for the treatment of the gastrodine in-situ gel of disease of inner ear described in claim 1, the method is made up of following steps:

Take in proportion ion-sensitive type gel rubber material and antiseptic, add the purified water of total amount 80%, dissolve and let cool to room temperature in 90 ℃, add gastrodine, after dissolving, solution is filtered through sintered glass funnel after 4 ℃ of cold preservation 24h, add transhipment promoter, then add remaining purified water, stir evenly, subpackage.

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