CN1748680A - Medendazole new form for treating nasal polyp and nasal polyp disease - Google Patents
Medendazole new form for treating nasal polyp and nasal polyp disease Download PDFInfo
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- CN1748680A CN1748680A CN 200410078454 CN200410078454A CN1748680A CN 1748680 A CN1748680 A CN 1748680A CN 200410078454 CN200410078454 CN 200410078454 CN 200410078454 A CN200410078454 A CN 200410078454A CN 1748680 A CN1748680 A CN 1748680A
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Abstract
The present invention relates to the preparation process of nebula, aerosol, powder spraying agent and nose drop of mebendazole and their application in treating nasal polyp and nasal polyp disease and in preventing recurrence of polyp after surgical operation treatment, laser treatment and other treatment.
Description
The present invention relates to use mebendazole to prepare spray, aerosol, powder spray and nasal drop, these spray, aerosol, powder spray and nasal drop that contain mebendazole are being treated nasal polyp and nasal polyp, and prevent the application in the nasal polyp recurrence behind means such as operative treatment, laser therapy treatment nasal polyp.
One, polypous pathogenic factor:
Nasal polyp is a kind of commonly encountered diseases, and adult sickness rate is about 1%-2%.According to clinical observation, it is 30% that the polypous sickness rate of patient of endogenous bronchial asthma is arranged, and patient's polyp sickness rate that aspirin do not tolerate (bronchus type) is arranged up to 50%.The polypous cause of disease is not clear so far, in respect of theories such as infection, allergy, wound, chemical stimulation, metabolic disease, Nervous and Mental Factors.
Polypous treatment is difficulty relatively, and operative treatment easily recurs, and relapse rate is up to 15%-20%.Its Drug therapy adopts various steroid medicines usually, but after adopting steroid medicine, can cause the dependency to steroid medicine.These reasons make polypous research and treatment come into one's own day by day, find the new polypous medicine of treatment, are effective, and do not produce dependency simultaneously, become the focus that people pay close attention to.
From histopathology, nasal polyp is canescence, an obstructive massive texture in nasal cavity or the nasal sinuses, contains the liquid of edema, originates from the complete top layer epithelium of nasal cavity, mostly is both sides and multiple.Histologic classification 80%-90% is the acidophil polyp, is to be the inflammatory cell infiltration of feature with the eosinophilia, and other inflammatory cell has mastocyte, hugely has a liking for cell, plasma cell and lymphocyte etc.The nasal polyp that merges bronchial asthma and aspirin sensitive belongs to acidophil.Merging fiber cystis degeneration, Kartagener ' s syndrome (ciliary dyskinesia) and antro-choanal polyp is that to increase with neutrophil cell be feature.
According to clinical and pathological manifestations analysis, allergy may be the polypous cause of disease.Polypous formation is that the stimulation owing to multiple reason or unknown cause causes the damage of nasal mucosa top layer, exuviation, make fibroblast proliferation justacrine cytokine, promote mastocyte differentiation and growth, mastocyte takes off the granule reflection under non-specific factor stimulates, the release and the acidophil that cause inflammatory mediator soak into, media such as histamine, LTC4, LTB4 increase, and cause and ooze out and edema; MBP, the ECP that acidophil discharges etc. destroy the nerve of nasal mucosa vessels, and vascular permeability is increased, and have further increased the weight of inflammatory reaction.Because the inflammatory reaction that continues forms polyp.
On the other hand, owing to nasal membrane inflammatory cell infiltration, edema, pressure increases, cause epithelium to break, lamina propria is from damaged outstanding, and mucosa continuity is on every side grown, the top layer epithelial cellization of organizing of deviating from is given birth to, and forms polyp the base of a fruit, and blood vessel is grown into, and set up vessel pedicle, body of gland is elongated, in the polyp of growing into, and shape elongated tubular body of gland, under the effect of inflammatory reaction and gravity, polyp constantly increases.
Two, polypous treatment present situation:
Polypous modern treatment is advocated the method that the employing glucocorticoid combines with operative treatment.
(1) operative treatment principle
Extract comparatively simply for little single-shot polyp, should adopt operation more widely for the polyp with recurrence of pilosity, the functional endoscopic sinus surgery (FES) that adopts is comparatively measured at present, the sieve room of each exposure can be removed totally.For the polyp that repeatedly recurs, advocate to sieve widely hole and part sphenoidectomy.Also optionally adopt YAG laser ablation nasal polyp, go out insufficiency of blood, patient is painful light, but inapplicable and serious intractable nasal polyp patient.
Patient with bronchial asthma and aspirin sensitive is also advocated row nasal polypectomy completely, operation not only can not cause and increase the weight of asthma, and, recovered normal BITONG airway dysfunction and the asthma state of an illness is clearly better because the focus of nasal cavity and nasal sinuses has been removed in operation.But the patient's recurrence after operation rate that merges asthma is higher, and operation can not change patient to the sensitivity of aspirin and the high response of air flue, therefore should carry out glucocorticoid treatment after the operation.
(2) glucocorticoid treatment
In recent years, a large amount of data proof glucocorticoids have significant curative effect in polypous treatment.Because nasal polyp is the persistence diseases associated with inflammation of nasal cavity, any operation completely all can not be removed the polypous cause of disease, has only the glucocorticoid of employing and operation therapeutic alliance, just can delay and prevent the recurrence of polyp.
The Therapeutic Principle who takes at present is, the less polyp for just sending out adopts intranasal to spray into glucocorticoid treatment merely, polyp is dwindled or disappears; For bigger polyp, can add with oral, intramuscular injection or concha nasalis inferior mucosa systemic administration such as injection down, adopt the local medicine that sprays of intranasal to keep treatment, can make the part patient exempt operative treatment; To cases with severe, should after accepting glucocorticoid treatment, perform the operation, and adhere to that after operation the nose part more than a year sucks treatment, though can not stop recurrence fully, can avoid recurrence in a long time.Nasal spray commonly used has beclometasone (BDP, beclomethason dipropionate, trade name Beconase), budesonide (budesonide, trade name Rhinocort), fluticasone propionate (fluticasone propionate, trade name Flonase), third scorching pine (the triamcinolone acetonide, trade name Nasacort), 9-removes fluorine fluocinonide (flunisolide, trade name Rhinalar), Triamcinolone acetonide acetate etc., local application does not influence the function of nasal cavity cilium system, but all need long-term prescription, though send out even there is the report observation also to have no side effect to 5 years; But a lot of bibliographical informations are also arranged, continue the local glucocorticoid that uses and to cause pharyngeal fungal infection.For there being steroid to use contraindication person,, can not use the corticosteroid treatment nasal polyp as osteoporosis, peptic ulcer, serious hypertension, diabetes, psychiatric department disease, epilepsy, glaucoma, cataract etc.
Also there is report to adopt plug for sending (thiotepa) in the polypous report of operation back auxiliary treatment.Plug is an antineoplastic agent for group, participates in the immunoreation of body, suppresses the induction period and the propagation phase of immunologic process, suppresses cell proliferation and allergy, the hyperemia of alleviating is arranged, stop regenerated effect (new drug and clinical, 1996; 15 (5): 318).
Two, mebendazole brief introduction
Mebendazole, english common name are Mebendazole; Generic name is: 5-benzoyl Carbendazim, benzoyl miaow amine methyl ester, benzophenone guanidine methyl ester, benzophenone rice amine ester, mebendazole, Methylimidazole. etc.Be broad-spectrum de-worming medicine.Can influence the multiple biochemical metabolism approach of polypide.This medicine can suppress the picked-up of Enterozoa to glucose, causes the intravital glycogen depletion of worm; Also can combine and suppress micropipe aggregation with the polypide tubulin, thus transhipment of secretion inhibitor granule and the motion of other subcellular organelle; Also can suppress polypide mitochondrion fumaric reductase system, reduce ATP and generate, thereby disturb polypide existence and breeding and cause its death.This medicine has and kills the effect that hookworm ovum and whipworm ovum and part are killed roundworm egg fully.In vitro tests proof 5mg/L can suppress the growth of ancylostome larva.In addition, use this medicine heavy dose of, the long course of treatment, treats the effect of trichonematosis and echinococcosis in addition.The human oral mebendazole absorbs few (5%-10%).The 2-5 hour blood drug level peaking in oral back, but less than 0.3% of dosage.Take 200mg every day, blood drug level is no more than 0.3mg/L after 3 days.Medicine is distributed in positions such as blood plasma, liver, lung in vivo, mainly at intrahepatic metabolism.Half-life is 2.5-5.5 hour, and hepatic disfunction (cholestasis) Shi Zeke reaches 35 hours.This medicine is drained through digestive tract with original shape or the amino metabolite of 2-in oral back 24 hours, and 5%-10% is with homaluria.
Three, so far, all do not see any report or document record that mebendazole is used for the treatment of nasal polyp or prevents nasal polyp recurrence both at home and abroad as yet.
The present invention is made into compound recipe with mebendazole as independent effective ingredient or with other medicines, makes the dosage form of nasal-cavity administration, and these dosage forms include, but are not limited to: nasal drop, spray, aerosol and powder spray.
Indication with mebendazole or the nasal drop made from the compound recipe that contains mebendazole, spray, aerosol and powder spray of the present invention, include, but are not limited to following disease: nasal polyp and nasal polyp, chronic sinusitis, nasal polyp or nasal polyp, rhinitis, pharyngitis, tracheitis and bronchitis.
Use of the present invention with mebendazole or the nasal drop made from the compound recipe that contains mebendazole, spray, aerosol and powder spray, for nasal polyp or nasal polyp patient, directly nasal-cavity administration can make big nasal polyp dwindle effectively, and little nasal polyp is disappeared; Or administration behind nasal polypectomy, can stop polypous recurrence; For rhinitis, pharyngitis, tracheitis and bronchitis, can the amelioration of inflammation symptom.
Nasal drop of the present invention, spray and aerosol all meet the definition of the Pharmacopoeia of the People's Republic of China (version was two ones in 2000) about nasal drop, spray and aerosol.
Nasal polyp of the present invention is that those skilled in the art is known, has it to define accurately in the modern medical book, refers to canescence, the Fructus Litchi shape neoplasm of nasal cavity.Its pathological change as previously mentioned.Rhinitis of the present invention, pharyngitis, tracheitis and bronchitis also are that the ordinary artisan of this area is known, have it to define accurately in the modern medical book.
By following examples mebendazole nasal drop of the present invention, spray, aerosol and powder spray treatment nasal polyp or nasal polyp, rhinitis, pharyngitis, tracheitis and bronchitic application are described.It should be noted that, following embodiment just is used for explanation and unrestricted the present invention, well-known to those skilled in the artly by other administration route mebendazole is used for the treatment of nasal polyp or nasal polyp, rhinitis, pharyngitis, tracheitis and bronchitic technology all within the scope of the invention.
The preparation of embodiment 1 mebendazole nasal mist
In ten thousand grades of environment, mebendazole is dissolved in normal saline, be prepared into the solution of 1mg/ml, add geramine, the concentration that makes geramine is 0.02%.In the nasal mist bottle, the spray valve of screwing on promptly gets the mebendazole nasal mist with this liquid medicine filling.
The preparation of embodiment 2 mebendazole nasal aerosol
In ten thousand grades of environment, mebendazole is dissolved in normal saline, be prepared into the solution of 1mg/ml, add geramine, the concentration that makes geramine is 0.02%.This liquid medicine filling in the nasal aerosol bottle, is added propellant, load onto aerosol valve, promptly get the mebendazole nasal aerosol.
The preparation of embodiment 3 mebendazole nasal cavity powder sprays
In ten thousand grades of environment, with mebendazole 20mg, hydroxypropyl cellulose (HPC) 980mg, Benasept 0.1mg co-blended, the mebendazole that obtains homogeneous is the powder body of 1 μ g/mg, and diameter of particle should be 30～150 μ m, be filled in the hard capsule, get nasal-cavity administration mebendazole powder spray.Per nasal sprays into administration with the dust cloud device during use.
The preparation of embodiment 4 mebendazole nasal drop
In ten thousand grades of environment, mebendazole is dissolved in normal saline, be prepared into the solution of 1mg/ml, add geramine, the concentration that makes geramine is 0.02%.This liquid medicine filling in the nasal drop bottle, is promptly got the mebendazole nasal drop.
Embodiment 5 mebendazole sprays treatment nasal polyp
(1) case and method:
Not underwent operative and corticosteroid treatment nasal polyp first visit case, totally 22 examples.
The judgement of nasal polyp size: with reference to method [Johansen LV, et al.Clin Otolaryngol, 1993 of Johansen etc.; 18:524], through the prenasal sem observation, be that object of reference is kept the score with concha nasalis.Nasal polyp surpasses middle nasal concha edge person and remembers 0.5 fen, does not reach concha nasalis inferior upper limb person above the middle nasal concha edge and remembers 1 fen, and the person remembers 2 fens not reach at the lower edge above the concha nasalis inferior upper limb, and the person remembers 3 fens to reach the lower edge.Reduce 1.5 and be divided into produce effects, 1 is divided into effectively.
The nasal obstruction degree by light, in, severe 3 point-score records, reduce 2 and be divided into produce effects, 1 is divided into effectively.
Male 12 examples among the 22 routine nasal polyp patients, women 10 examples.45 years old mean age (25～57 years old).Asthma history person's 4 examples (women 2 examples, male 2 examples) are wherein arranged, and to aspirin (tablet for alleviating pain) allergy sufferers 3 examples (male), nasal polyp reaches 3 fens person's 5 examples, 2 fens person's 9 examples, 1 fen person's 8 example.Severe 8 examples of having a stuffy nose, moderate 12 examples of having a stuffy nose, 2 examples of slightly having a stuffy nose.
The patient is divided into treatment group (12 example) and matched group (10 example) at random, and the treatment group contains 3 fens person's 3 examples of nasal polyp, 2 fens person's 5 examples, 1 fen person's 4 example, severe 5 examples of having a stuffy nose, moderate 5 examples of having a stuffy nose, 2 examples of slightly having a stuffy nose; Matched group contains 3 fens person's 2 examples of nasal polyp, 2 fens person's 4 examples, 1 fen person's 4 example, severe 3 examples of having a stuffy nose, moderate 7 examples of having a stuffy nose.Matched group adopts the treatment of beclometasone spray, and every day, the nasal-cavity administration spray was three times, continued for two weeks after, changed in the 3rd week and spray secondary every day, change spray every day into once around the, be one month the course of treatment; The treatment group adopts the mebendazole spray to treat, and sprays the nasal-cavity administration spray every day once, continues spray after 5 days, does not spray medicine in 2 days at interval, and then sprays once a day 5 days, and the interval is 2 days again, and so medication is one month.
In the beclometasone spray, the dosage of beclometasone is the every spray of 50ug/0.14ml; In the mebendazole spray, the dosage of mebendazole is the every spray of 70ug/0.14ml.
Check after one month in two weeks of medication and medication, observation nasal polyp size, the variation of keeping the score, nasal obstruction alleviate degree and have no side effect generation etc.
(2) result:
The change that the nasal polyp size is kept the score: matched group is after treating January, and nasal polyp is all seen obvious retraction, and nasal polyp had been crossed the intranasal hole after wherein 3 fens persons treated and finish, and the person had 1 routine nasal polyp to disappear in 1 minute.Treatment group nasal polyp also all obviously bounces back, and person's 3 examples all bounced back to the concha nasalis inferior upper limb when treatment finishes in 3 minutes, and the person had 3 examples, 1 fen person to have 2 routine nasal polyps to disappear in 2 minutes.
The improvement of nasal obstruction symptom: patient's nasal obstruction symptom all has improvement in various degree in treatment group and the matched group.In the 5 routine severes nasal obstruction of treatment group, have 4 routine medications after 1 month olfactory sensation recover to some extent; Have in the 3 routine severes nasal obstruction of matched group 1 routine medication after 1 month olfactory sensation recover to some extent.Nasal obstruction is improved not obvious person's 2 examples in the treatment group, and nasal obstruction is improved not obvious person's 1 example in the matched group.
Conclusion: for polypous Drug therapy, external nasal spray or the aerosol treatments of adopting corticosteroid more.Adopt the mebendazole spray, its curative effect is similar to the beclometasone spray or be better than the beclometasone spray slightly.
Embodiment 2 mebendazole treatment by aerosol nasal polyps
Repeat " embodiment 5 " described experiment, what adopt except that curative is that patient's state of an illness of the toluene rice azoles aerosol of " embodiment 2 " preparation and observation is with quantity is different, patient goes into group standard, therapeutic scheme, curative effect judging standard all with " embodiment 5 ", experimental result is similar with " embodiment 5 ", promptly adopt mebendazole treatment by aerosol nasal polyp, its curative effect is similar to the beclometasone spray or be better than the beclometasone spray slightly.
Embodiment 3 mebendazole nasal drop treatment nasal polyp
Repeat " embodiment 5 " described experiment, what adopt except that curative is the toluene rice azoles nasal drop of " embodiment 4 " preparation, administrated method changes each collunarium and observation into for the every spray with spray patient's state of an illness and quantity is different, patient goes into group standard, therapeutic scheme, curative effect judging standard all with " embodiment 5 ", experimental result is similar with " embodiment 5 ", promptly adopt mebendazole nasal drop treatment nasal polyp, its curative effect is similar to the beclometasone spray or be better than the beclometasone spray slightly.
Embodiment 4 mebendazole powder sprays treatment nasal polyp
Repeat " embodiment 1 " described experiment, what adopt except that curative is that patient's state of an illness of toluene rice azoles powder spray, observation of " embodiment 3 " preparation is with quantity is different, patient goes into group standard, therapeutic scheme, curative effect judging standard all with " embodiment 1 ", experimental result is similar with " embodiment 1 ", promptly adopt mebendazole powder spray treatment nasal polyp, its curative effect is similar to the beclometasone spray or be better than the beclometasone spray slightly.
Embodiment 5 mebendazole sprays treatment nasal polyp recurrence
60 years old women is diagnosed as multiple nasal polyp, adopts the sieve room polypectomy of functional endoscopic sinus surgery with each exposure, postoperative 30 days, nasal polyp recurrence is with " embodiment 1 " described mebendazole spray treatment, once a day, after 30 days, check, the nasal polyp of recurrence diminishes.Continuation is used the mebendazole spray with method, check after 20 days, and nasal polyp disappears.
Embodiment 6 mebendazole treatment by aerosol nasal polyp recurrences
An adult male, the nasal polyp recurrence after operation is treated with local suction of the capable nose of " embodiment 2 " described mebendazole aerosol, whenever greatly once, continues 30 days, check, the nasal polyp of recurrence diminishes.Continuation is used the mebendazole spray with method, 20 big back checks, and nasal polyp disappears substantially.
Embodiment 7 mebendazole powder sprays treatment nasal polyp recurrence
An adult female, the nasal polyp recurrence after operation is treated with local suction of the capable nose of " embodiment 3 " described mebendazole powder spray, once a day, held 30 days, check, nasal polyp disappears substantially.
Embodiment 8 mebendazole nasal drop treatment nasal polyp recurrence
An adult male, the nasal polyp recurrence after operation with the capable nose dropping treatment of " embodiment 4 " described mebendazole nasal drop, once a day, continues 30 days, check, the nasal polyp of recurrence diminishes.
Claims (3)
1. the dosage form of the nasal-cavity administration that mebendazole is made as effective ingredient, these dosage forms comprise:
1. nasal drop;
2. spray;
3. aerosol;
4. powder spray.
2. the application of mebendazole in the production of the nasal drop that is used as treatment nasal polyp and nasal polyp, spray, aerosol, powder spray.
3. mebendazole is as the application in the production of the nasal drop, the spray that prevent nasal polyp recurrence after surgical interventions such as nasal polyp operative treatment, laser therapy, aerosol, powder spray.
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| CN 200410078454 CN1748680A (en) | 2004-09-14 | 2004-09-14 | Medendazole new form for treating nasal polyp and nasal polyp disease |
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| Application Number | Priority Date | Filing Date | Title |
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| CN 200410078454 CN1748680A (en) | 2004-09-14 | 2004-09-14 | Medendazole new form for treating nasal polyp and nasal polyp disease |
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