CN103655524B - Powder nose inhalant being used for the treatment of epilepsy and preparation method thereof - Google Patents
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Abstract
The invention discloses a kind of powder nose inhalant being used for the treatment of epilepsy and preparation method thereof.This powder nose inhalant is made up of the alpha-ararin micropowder meeting nasal-cavity administration, and the particle diameter of described micropowder is greater than 5 μm, and is no more than 200 μm, is preferably 10 ~ 100 μm; Its preparation method comprises: alpha-ararin raw material is formed the alpha-ararin micropowder meeting nasal-cavity administration through comminution by gas stream.The present invention is by making the micropowder meeting powder nose inhalant requirement by alpha-ararin, compared with oral formulations, while being used for the treatment of epilepsy, significantly improve its bioavailability, compared with injection, because this powder spray is not containing any adjuvant, decrease the misery that the anaphylaxis that causes and drug administration by injection bring to patient, and reduce its distribution in hepatic tissue, decrease the toxic and side effects of liver, decrease dosage simultaneously.
Description
Technical field
The present invention relates to a kind of medicine being used for the treatment of epilepsy, particularly relate to a kind of powder nose inhalant being used for the treatment of epilepsy and preparation method thereof.
Background technology
Epilepsy is the common chronic disease of nervous system, and treatment is complicated and the course for the treatment of is long, and antiepileptic mostly clinically is chemical drugs at present, but these medicines only can control symptom and be difficult to radical cure epilepsy, and long-term taking also may occur numerous side effect.According to ancient literature and modern medicine checking, much Chinese medicine has definite curative effect to epilepsy, and safety is good.
Alpha-ararin (α-asarone) is also known as α-asaricin, and be by extracting and developing in Chinese medicine Rhizoma Acori Graminei (Acorus gramineus), refiningly form, its chemical constitution is 2,4,5-trimethyl-1-propenylbenzene.Study and find, the antiepileptic mechanism of action of alpha-ararin mainly acts on GABA energy system, maintains the balance of excited in brain/suppression system; and by regulating the ion transport of intraor extracellular; reduce lipid peroxidation, play its neuroprotective, thus reduce the outbreak of epilepsy.
At present, the Aarin preparation of domestic listing mainly contains tablet, capsule and injection.Tablet and capsule are all less than 10% by its absolute bioavailability after oral administration.Due to the water solublity of alpha-ararin extreme difference, commercially available injection all with the addition of Tween-80 and propylene glycol, and Tween-80 and propylene glycol are the most direct reasons causing alpha-ararin injection to cause anaphylactic reaction and anaphylactic shock.In addition alpha-ararin is made Foradil Aerolizer formoterol fumarate (Zhongshan University at present, 201210093309.0) and atomized inhalation be used for the treatment of the research of disease by Pulmonary inhalation mode, this inhalation mode has rapid-action, easy to use, improve the advantages such as pulmonary deposition ratio, this is more conducive to the treatment of the pulmonary disease such as asthma, chronic obstructive pneumonia.(the Chen Wei such as Chen Wei, asarone submicron emulsion and nasal spray systematic research thereof, institute of materia medica of & China Concord Medical Science University of the Chinese Academy of Medical Sciences, Master's thesis, 2006) alpha-ararin is made oil-in-water (O/W) submicron emulsion to improve dissolubility and the drug loading of alpha-ararin, submicron emulsion nasal-cavity administration with pulmonary distribution the highest, liver and brain lower.Pan Yan etc. (Pan Yan, the feasibility study of release in asarone nasal-cavity administration brain, Traditional Chinese Medicine University Of Guangzhou, Master's thesis, 2010) have studied the feasibility of release in asarone nasal-cavity administration brain with HP-β-CD enclose asarone.But two kinds of preparation administrations all in liquid form, have solution (suspension) unstability and easily removed by nose cilium, medicine in shortcomings such as the nasal cavity holdup time are short, and then causes its bioavailability low, and there is the risk caused allergic reaction.
Summary of the invention
Technical problem to be solved by this invention is, overcomes the shortcoming of prior art, provides a kind of powder nose inhalant being used for the treatment of epilepsy and preparation method thereof.
In order to solve above technical problem, the invention provides a kind of powder nose inhalant being used for the treatment of epilepsy, it is made up of the alpha-ararin micropowder meeting nasal-cavity administration, and the particle diameter of described micropowder is greater than 5 μm, but is no more than 200 μm.
The technical scheme that the present invention limits further is: the particle diameter of described micropowder is mainly distributed in the scope of 10 ~ 100 μm.
Present invention also offers a kind of preparation method being used for the treatment of the powder nose inhalant of epilepsy, comprising: alpha-ararin raw material is formed through the comminution by gas stream of 0.8Mpa the alpha-ararin micropowder meeting nasal-cavity administration.
Further, the operation of aforementioned comminution by gas stream can utilize the equipment such as jet mill to realize.
The invention has the beneficial effects as follows: by alpha-ararin to be prepared into the micropowder meeting powder nose inhalant and require by the mode of comminution by gas stream, compared with oral formulations, while being used for the treatment of epilepsy, significantly improve its bioavailability, compared with injection, because this micropowder is not containing any adjuvant, decrease the misery that the anaphylaxis that causes and drug administration by injection bring to patient, and reduce its distribution in hepatic tissue, decrease the toxic and side effects of liver.Particularly because this micropowder is not containing the dry powder of any adjuvant, the probability because adjuvant reason causes nasal mucosa to stimulate can also be reduced, extend the holdup time of medicine at nasal cavity or olfactory bulb, add the content that medicine enters cerebral tissue, also reduce dosage, this has special meaning for epilepsy class brain diseases simultaneously.
Accompanying drawing explanation
Fig. 1 a-Fig. 1 b is the SEM figure of alpha-ararin after comminution by gas stream in one embodiment of the invention;
Fig. 2 is the grain size distribution of alpha-ararin after comminution by gas stream in one embodiment of the invention;
Fig. 3 is rat via intranasal application (i.n.) in one embodiment of the invention, gavage (i.g.) and quiet note (i.v.) alpha-ararin pharmacokinetic curve afterwards;
Fig. 4 a-4f be after rat via intranasal application (i.n.) in one embodiment of the invention, gavage (i.g.) and quiet note (i.v.) alpha-ararin 5,15,30,60,90,180min is in the distribution statistics figure of cerebral tissue different parts;
Fig. 5 be rat via intranasal application (i.n.) in one embodiment of the invention, gavage (i.g.) and quiet note (i.v.) afterwards alpha-ararin at the distribution statistics figure of hepatic tissue.
Detailed description of the invention
One aspect of the present invention provides a kind of powder nose inhalant being used for the treatment of epilepsy, and it is made up of the alpha-ararin micropowder meeting nasal-cavity administration.
Wherein, powder spray of the present invention is nasal formulations, its particle diameter is greater than 5 μm, but be no more than 200 μm, especially preferred at 10 ~ 100 μm, be preferably greater than 10 μm further, and be no more than 100 μm, it can have the nasal cavity turbinates district deposition of therapeutic potential, and has good fluidity, and is easy to as absorptions such as nasal mucosas.And if powder diameter too small (lower than 5 μm), be then easy to enter pulmonary, if excessive (being greater than 200 μm), then more difficultly again stable be adsorbed on the tissues such as nasal mucosa.
Another aspect of the present invention additionally provides a kind of preparation method being used for the treatment of the powder nose inhalant of epilepsy, comprising: alpha-ararin raw material is formed the alpha-ararin micropowder meeting nasal-cavity administration through comminution by gas stream.
For making the particle diameter of obtained alpha-ararin micropowder can be distributed in as much as possible within the scope of aforementioned preferable particle size, can by the Stress control of aforementioned comminution by gas stream in about 0.8Mpa.
The effective dose of powder nose inhalant of the present invention is 90 ~ 270mg/ days.
Below in conjunction with accompanying drawing and an embodiment, more specific detail is done to technical scheme of the present invention.
Embodiment 1 the present embodiment system is by alpha-ararin raw material and to pulverize pressure be that 0.8Mpa jet mill contacts and pulverizes, consult Fig. 1 a-1b and Fig. 2 can see, obtain the particle diameter major part of alpha-ararin micropowder at 10 ~ 100 μm, be suitable for being applied as powder nose inhalant (following be called for short " dry powder ").
Further, in the present embodiment, following experiment has also been carried out, to determine the bioavailability of this powder nose inhalant and the content etc. at brain and hepatic tissue thereof.
1. alpha-ararin pharmacokinetic studies:
Effective dose according to this powder nose inhalant converts, then the dosage of rat should be 1.6 ~ 4.8mg/ days.
The preparation of alpha-ararin gavage suspension: appropriate alpha-ararin is suspended in the solution of 0.5%CMC-Na, be prepared into the alpha-ararin suspension of 2mg/mL, alpha-ararin intravenous fluid is commercially available prod (producer: Hunan WZT Pharmaceutical Co., Ltd), and specification is 8mg/2mL.The powder spray of nasal-cavity administration is the dry powder that said flow is pulverized.18 rats are divided into three groups, often organize 6, award alpha-ararin respectively by gavage, quiet note and nasal cavity.Intravenous injection (being called for short " quiet note ") and the dosage of nasal-cavity administration are 10mg/kg, because oral administration biaavailability is lower, so the dosage of gavage selects 40mg/kg.After quiet note and nasal-cavity administration respectively at 1,3,5,10,15,30,45,60,90,120,180min eye socket gets blood 0.5mL to adding in the centrifuge tube of heparin sodium, after gastric infusion respectively at 5,10,15,30,45,60,90,120,180min eye socket gets blood 0.5mL to adding in the centrifuge tube of heparin sodium, the centrifugal 5min of 4000r/min, get blood plasma, HPLC detects.
Consulting Fig. 3 is rat via intranasal application (i.n.), gavage (i.g.) and quiet note (i.v.) alpha-ararin pharmacokinetic curve afterwards.
Referring to table 1 is again rat via intranasal application (i.n.), gavage (i.g.) and quiet note (i.v.) alpha-ararin pharmacokinetic parameter afterwards.
The bioavailability of Bolos intravenous administration is 100%, then the bioavailability of nasal-cavity administration and gastric infusion with the formula (1) calculate:
Table 1 rat via intranasal application (i.n.), gavage (i.g.) and quiet note (i.v.) alpha-ararin pharmacokinetic parameter and bioavailability afterwards
Can be seen by table 1, the bioavailability of gastric infusion is 18.89%, and the bioavailability of nasal-cavity administration is 81.37%, and obviously, powder nose inhalant of the present invention, compared with oral formulations, significantly improves alpha-ararin bioavailability.Wherein, the oral administration biaavailability in this experiment, also than the height of pertinent literature report, is inferred that reason is that CMC-Na adds alpha-ararin dispersion, thus is added the absorption of medicine.
2. alpha-ararin cerebral tissue and hepatic tissue distribution experiments:
72 rats are divided into three groups, and often organize 24, administering mode is the same, often group is respectively at 5,15,30,60,90,180min puts to death four rats, gets brain and liver, rat cerebral tissue is divided into olfactory bulb, cerebellum, hypothalamus, striatum, Hippocampus, antecedent and medullary substance 7 positions, HPLC detects the content of alpha-ararin at brain different parts, and its result can consult Fig. 4 a-4f and table 2.
According to Fig. 4 a-4f rat via intranasal application (i.n.), gavage (i.g.) and quiet note (i.v.) afterwards alpha-ararin medicine 5,15,30,60,90, the distribution statistics of 180min cerebral tissue different parts, can find: compared with injection, except 5min nasal-cavity administration cerebral tissue different parts alpha-ararin is lower than quiet note, all the other time points are all equal or higher; Special pathway due to nasal-cavity administration can increase the contact at medicine and olfactory bulb position and pressed powder adds the holdup time of medicine at nasal cavity, the content of nasal-cavity administration olfactory bulb position alpha-ararin is all higher than quiet note and gastric infusion, student t inspection is carried out to the concentration at the olfactory bulb position of three kinds of route of administration medicines, data statistic analysis result shows, nasal-cavity administration 15,30,60,90,180min and quiet note and gastric infusion have significant difference (p < 0.05).Medicine Brain targeting index calculates according to formula 2, can infer medicine olfactory bulb targeting exponential formula 3 by formula 2.Table 2 is rat via intranasal application (i.n.), gavage (i.g.) and quiet note (i.v.) pharmacokinetic parameter of alpha-ararin at olfactory bulb position and medicine olfactory bulb targeting index afterwards.
Can be seen by table 2, the AUC at nasal-cavity administration olfactory bulb position
(0 ~ 180)be 278.20 ± 62.67 μ g/g*min, be all greater than the AUC of quiet note (135.40 ± 9.00 μ g/g*min) and gavage (95.24 ± 12.86 μ g/g*min)
(0 ~ 180).The medicine olfactory bulb targeting index of quiet note, nasal cavity, gavage three kinds of route of administration is respectively 1.47,3.75 and 1.38, this shows, after nasal-cavity administration, cerebral tissue is entered by blood brain barrier after part medicine enters blood circulation by Nasal Mucosa Absorption, another part medicine is then direct to be avoided blood brain barrier by olfactory bulb path and enters cerebral tissue, so lower blood drug level also can make medicine reach higher concentration at cerebral tissue, and this treatment for brain diseases acquires a special sense.
Table 2 rat via intranasal application (i.n.), gavage (i.g.) and quiet note (i.v.) be the pharmacokinetic parameter of alpha-ararin at olfactory bulb position and medicine olfactory bulb targeting index afterwards
HPLC detects the content of alpha-ararin in liver after quiet note, gavage and nasal-cavity administration, and its result can consult Fig. 5.Can be found by Fig. 5, during 5min, the alpha-ararin concentration of the hepatic tissue of Bolos intravenous administration is greater than 4 μ g/g, and now the alpha-ararin concentration of nasal-cavity administration hepatic tissue is then less than 1 μ g/g, and has significant difference.After gastric infusion, the content of hepatic tissue Chinese medicine is then far above quiet note and nasal-cavity administration, and analyzing reason is following 2 points:
One, the difference of dosage, in preliminary experiment, alpha-ararin suspension oral gavage gives the amount of 10mg/kg and 20mg/kg respectively, due to the bioavailability that oral alpha-ararin is lower, only there are 1 or the time point that is less than 5 just can alpha-ararin be detected, so have finally chosen 40mg/kg as given low;
Two, the bioavailability that oral alpha-ararin is lower ascribes the first pass effect of liver to.
So powder nose inhalant can reduce the accumulation of medicine in liver and avoid the first pass effect of liver.
In addition, because this powder nose inhalant is not containing any adjuvant, compared with other nasal dosage form, decreases the probability caused allergic reaction, decrease dosage.
In addition to the implementation, the present invention can also have other embodiments.All employings are equal to the technical scheme of replacement or equivalent transformation formation, all drop on the protection domain of application claims.
Claims (2)
1. be used for the treatment of a powder nose inhalant for epilepsy, it is characterized in that, it is made up of the alpha-ararin micropowder meeting nasal-cavity administration, and the particle diameter of described micropowder is greater than 10 μm, but is no more than 100 μm.
2. one kind is used for the treatment of the preparation method of the powder nose inhalant of epilepsy as claimed in claim 1, it is characterized in that, comprise: alpha-ararin raw material is formed through the comminution by gas stream of 0.8MPa the alpha-ararin micropowder meeting nasal-cavity administration, the particle diameter of described micropowder is greater than 10 μm, but is no more than 100 μm.
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