Background technology
Scopolamine hydrobromide, the chemistry of its active component is by name: 6 β, 7 beta epoxides-1 α H-tropane-3 α-alcohol (-) tropate hydrobromate trihydrate, English by name: ScopolamineHydrobromide Nasal Dry Powder Inhalation, chemical structural formula is:
Molecular formula: C
17H
21NO
4HBr3H
2O
Molecular weight: 438.32.
The scopolamine hydrobromide raw material has been that version Chinese Pharmacopoeia in 2000 two ones (P488) records, English Scopolamine Hydrobromide by name.The scopolamine that extracts the dried floral (Flos Daturae) of China's one datura metel in nineteen sixty from plant of Solanaceae is made hydrobromate then.Nineteen sixty-five formally puts into production.Chinese Pharmacopoeia version in 2000 is recorded its raw material, and dosage form is tablet and injection, belongs to anticholinergic agent.
Scopolamine hydrobromide is the stronger M cholinoceptor medicine capable of blocking of a kind of peripheral action, its peripheral action is the strong and weak point of holding time than atropine, has central inhibitory action, can suppress glandular secretion, remove blood capillary spasm, microcirculation improvement, expansion bronchus, remove smooth muscle spasm, brain is had calmness, syngignoscism.Can be used as tranquilizer clinically, be used for the preceding administration of general anesthesia, Parkinsonism, motion sickness, manic property psychosis, organophosphate poisoning etc.
Carsickness, seasick, the disease of air sickness medically is being collectively referred to as motion sickness.In people's the internal ear, have a cover to manage the sensation health at the organ-vestibular apparatus of locus and motion, the maintenance of total balance of the body mainly is under neural domination, and the adjusting by vestibular apparatus realizes.If vestibular apparatus is relatively poor to the adaptive capacity that irregular positions such as rotation change, can form strong impulse and cause and be overexcited, produce a series of symptoms, as pale complexion, discomfort dizzy, uncomfortable in chest, perspiration, feel sick, vomiting etc., Here it is motion sickness.Scopolamine hydrobromide can pass through to reduce the irritability of lost receptor, and suppresses the conduction of vestibulocerebellum path, plays anti-corona antiemetic effect, and is reliable as preventing and treating the motion sickness curative effect clinically.The preparation of antimotion sickness drug, the domestic scopolamine hydrobromide plaster (every subsides contain hydrobromic acid scopolamine 2.5mg) that has Minsheng Pharmaceutical Factory, Hangzhou City. to produce; Also having the cinetosis sheet is compound preparation, and every contains hydrobromic acid scopolamine 0.2mg, sodium phenobarbital 30mg, atropine 0.15mg.There is Baoding slow-release patch (Scopoderm TTS) that makes of Switzerland " Ciba-Geigy " to include scopolamine 1.5mg abroad, entered domestic market (import licence X920286).This preparation is a skin patch, can keep active 72 hours, but Jia Ge Ang is expensive.
The control motion sickness need a kind of fast, convenient, safe medicine-feeding way to be alleviating various symptoms, oral and Transdermal absorption is because their hysteresis, relief of symptoms needs certain hour, and that drug administration by injection uses is inconvenient.The nasal cavity administration is paid attention to by vast pharmacy work person advancing year, the research and development nasal cavity preparation.Nasal-cavity administration has following advantage: 1) numerous trickle fine hair arranged on the nasal membrane, can increase the effective surface area of drug absorption greatly, upward subcutaneous have abundant blood capillary, so drug absorption is rapid; 2) directly enter body circulation, no liver first-pass effect after the drug absorption; 3) gastrointestinal tract is difficult to absorb the big polar medicine of water solublity, then has good absorption by nasal mucosa.
Summary of the invention
First purpose of the present invention is the problems referred to above at existing various scopolamine hydrobromide preparations existence, provides a kind of drug absorption rapid, convenient, safe scopolamine hydrobromide dry powder inhalant for nose.
Second purpose of the present invention is to provide a kind of preparation method of above-mentioned scopolamine hydrobromide dry powder inhalant for nose.
First purpose of the present invention is achieved in that scopolamine hydrobromide dry powder inhalant for nose of the present invention, the part by weight of its principal agent scopolamine hydrobromide and adjuvant is 1:100-150, the parts by weight of each component are in the adjuvant, bioadhesive polymer 3-10, carrier 10-30, filling diluent 100, binding agent 0.1-0.15.
The optimum weight umber of each component is in the scopolamine hydrobromide dry powder inhalant for nose of the present invention: scopolamine hydrobromide 1, bioadhesive polymer 5, carrier 20, filling diluent 100, binding agent 0.125.
Preparation of the present invention is a nasal formulations, requires the pastille powder can be longer in the nasal cavity holdup time, so principal agent is mixed with an amount of bioadhesive polymer, prolongs its holdup time at nasal cavity.Bioadhesive polymer is suitable selects hypromellose or sodium carboxymethyl cellulose or their mixture for use, preferably selects hypromellose for use; Binding agent is suitable selects hypromellose or sodium carboxymethyl cellulose for use, preferably selects hypromellose for use; And suitable lactose or mannitol or their mixture selected for use of filling diluent.The above-mentioned suitable adjuvant of selecting for use is less to the toxicity of nose cilium.
The inventor adopts the toad palate mucosa to carry out the screening of adjuvant, with propranolol as the infringement positive control, the negative contrast of normal saline, the nasal mucosa toxicity of some adjuvant the results are shown in Table 1.
|
Adjuvant concentration duration of oscillation (min) recovery situation |
Bioadhesive polymer |
HPMC 0.5% 60~70 recovers CMC-Na 1% 90~100 immediately and recovers immediately to recover behind Carbopol 940 (carbomer) 2%~15 irrecoverable sodium alginate 0.5% 35~40 30min |
Disperse diluent |
Lactose 5% 60~70 recover immediately microcrystalline Cellulose 5% 5/ |
Positive control |
Propranolol 1% 15 is irrecoverable |
Negative control |
Normal saline 0.9% 3~4 hour/ |
Table 1
Annotate: microcrystalline Cellulose is the water-insoluble adjuvant.
Above-mentioned nasal ciliary toxicity research method is toad palate mucosa vitro method, and is specific as follows:
Bufo siccus lain on the back be fixed on the frog board, separate palatine mucosa on it with operating scissors, get 3 * 3mm mucosa approximately, clean clot and foreign body with normal saline, be divided into two after, upwards be tiled in mucosal surface on the microscope slide, be subjected to test solution (another piece mucosa is contrast with the normal saline) in right amount in the mucomembranous surface dropping, covered gently, in the motion conditions that 40 times of optical microscopes are observed mucomembranous cilium down, the persistent period of record ciliary movement.After motion stops,, continue to observe ciliary movement and whether recover, and record recovers the back exercise duration with being subjected to test solution on the normal saline edulcoration mucosa.
The above results shows that in three kinds of bioadhesive material, to nasal cavity toxicity minimum, hydroxypropyl emthylcellulose (also claim hypromellose, english abbreviation is HPMC) takes second place with carmethose (CMC-Na), and both restorabilitys are very nearly the same; Two kinds are disperseed in the diluent preferable with lactose.
Carrier selects for use microcrystalline Cellulose preferable among the present invention, and the effect of carrier is compound with principal agent, and disintegration rate is accelerated, and also has an effect of aid adhesion.
The present invention is a nasal formulations, require the pastille powder can have the treatment meaning nasal cavity turbinates area deposition, so diameter of aspirin particle is had certain requirement.All diameter of particle all should be less than 200 μ m (i.e. 80 orders), and possesses good flowability, the particle diameter that is fit to is 5~200 μ m, particle less than 5 μ m might enter pulmonary, then be difficult to adhere on the nasal mucosa greater than the particle of 200 μ m and easily be eliminated, diameter of aspirin particle is more suitable at 30~150 μ m.
The suitable vesicle type dry powder inhalant for nose that adopts of scopolamine hydrobromide dry powder inhalant for nose of the present invention.The optimum content of every interior scopolamine hydrobromide of vesicle is 200 μ g.Suction apparatus can adopt the dose double vesicle type nose powder inhalation device of German Pfeiffer company, and this suction apparatus volume is little, uses easy to carry.
Second purpose of the present invention is achieved in that the method for preparation scopolamine hydrobromide dry powder inhalant for nose of the present invention comprises the step of following order,
(1) behind scopolamine hydrobromide and bioadhesive polymer, carrier, binding agent, the filling diluent pulverize separately, cross 200 mesh sieves, standby, the consumption of above-mentioned each component in (3) and (4) step thereafter be, the part by weight of principal agent scopolamine hydrobromide and adjuvant is 1:100-150, and the parts by weight of each component are in the adjuvant, bioadhesive polymer 3-10, carrier 10-30, filling diluent 100, binding agent 0.1-0.15;
(2) preparation binding agent ethanol-water solution, standby, the content of binding agent is 0.5% (w/v) in the binding agent ethanol-water solution, concentration of ethanol is 25-75% (v/v);
(3) take by weighing scopolamine hydrobromide, it is dissolved in the binding agent ethanol-water solution of respective amount, standby.
(4) took by weighing bioadhesive polymer, carrier, the filling diluent of 200 mesh sieves, behind the mix homogeneously, with the binding agent ethanol-water solution system soft material of pastille made in (3) step, crossing 30 mesh sieves granulates, put 60 ℃ of about 30min of baking oven, take out, cross 60 mesh sieve granulate, put 60 ℃ of oven for drying, cross 100 orders and 400 mesh sieves, choose 100~400 order powder body, survey the content of principal agent, qualified back fill, promptly.
Above-mentioned preparation method of the present invention has adopted principal agent to add the binding agent granulation, compares with direct mixing method, compares the mixing homogeneity of principal agent in granule, in particulate different parts sampling and measuring, the results are shown in following table 2:
Table 2
In the table 2, method 1 is a direct mixing method, and promptly the method for principal agent after pulverizing and the direct mix homogeneously granulation of each adjuvant, method 2 is that principal agent of the present invention adds the binding agent granulation.By The above results as seen, the suitable employing method 2 of the adding of principal agent is about to principal agent and is dissolved in earlier in the binding agent ethanol-water solution, granulates again.This preparation method helps the mix homogeneously of trace drug.
By The above results as seen, the suitable employing method 2 of the adding of principal agent is about to principal agent and is dissolved in the binding agent, granulates.This preparation method helps the mix homogeneously of trace drug.
The dosage of scopolamine hydrobromide dry powder inhalant for nose of the present invention is that the scopolamine hydrobromide raw material that records with reference to Chinese Pharmacopoeia and preparation and Ministry of Health of the People's Republic of China's ministry standard salbutamol sulfate powder spray [standard laid down by the ministries or commissions of the Central Government WS-240 (X-198)-94-(2)] are worked out.
For determine scopolamine hydrobromide dry powder inhalant for nose of the present invention safety, the applicant has carried out the local irritation test:
1. rabbit maximum dosage-feeding test:
Scopolamine hydrobromide dry powder inhalant for nose sprays into administration with the dosage of 400 a μ g/ rabbit continuously to the rabbit nasal cavity, and maximum tolerated dose is equivalent to 76 times of people's dose for being equivalent to 140 times of clinical people's dose with weighing machine in body surface area.
2. rabbit nasal mucosa local excitation test:
Scopolamine hydrobromide dry powder inhalant for nose is with clinical dosage (200 μ g/ time), respectively two nasal cavity singles of rabbit are reached repeatedly (continuous 7 days, total dosage is the 1.4mg/ rabbit) spray into administration, be equivalent to 35 times of clinical people's dose with weighing machine, be equivalent to 12 times of people's dose in body surface area.Observe the irritant reaction of medicine to nasal mucosa, the result shows that rabbit nasal mucosa form and pathology there is no significantly irritant reaction and the symptom relevant with medicine, and rarely seen pupil has slight amplification phenomenon.
The above results shows: scopolamine hydrobromide dry powder inhalant for nose toxicity is low, zest is little, and is safe and convenient to use.
Scopolamine dry powder inhalant for nose of the present invention exists with the pressed powder form, and stability obviously improves than liquid preparation; Scopolamine dry powder inhalant for nose convenient drug administration of the present invention, medicine can be alleviated the symptom of motion sickness rapidly by Nasal Mucosa Absorption, and sustainable effect 3-5 hour, and pay act on little.
Adopt three kinds of route of administration of scopolamine, i.e. intravenous injection (IV), oral (PO), nasal cavity administration (IN) are carried out bioavailability relatively to 12 healthy male volunteers.Dosage is the 0.4mg scopolamine hydrobromide.Drug absorption was rapid after the result showed IN and PO, and administration promptly reached peak concentration in 1 hour, was respectively 0.37h and 0.78h, and Cmax (Cmax) is respectively 1680 and 164pg/ml.The absolute bioavailability of nasal cavity administration and oral administration is respectively 83% and 3.7%, and both have significant difference (p<0.05).Show that the administration of scopolamine nasal cavity is reliable, a rapidly and effective route of administration.
The specific embodiment
Embodiment one:
Present embodiment is a most preferred embodiment.
The scopolamine hydrobromide dry powder inhalant for nose of present embodiment is a vesicle type dry powder inhalant for nose.In 1000 vesicles, principal agent and adjuvant weight as follows:
Scopolamine hydrobromide 0.2g
Hypromellose (as bioadhesive polymer) 1.0g
Microcrystalline Cellulose (as carrier) 4.0g
Lactose (as filling diluent) 20.0g
Hypromellose (as binding agent) 0.025g
To prepare 1000 is example, and the preparation method of above-mentioned scopolamine hydrobromide dry powder inhalant for nose comprises the step of following order:
(1) behind principal agent scopolamine hydrobromide and adjuvant hypromellose, microcrystalline Cellulose, the lactose pulverize separately, cross 200 mesh sieves, standby;
(2) ethanol-water solution of getting hypromellose and 75% (v/v) is prepared the binding agent ethanol-water solution, is mixed with the hypromellose ethanol-water solution of 0.5% (w/v), and is standby;
(3) take by weighing the 0.2g scopolamine hydrobromide, it is dissolved in the hypromellose ethanol-water solution of 5ml, standby.
(4) take by weighing hypromellose 1.0g, microcrystalline Cellulose 4.0g, the lactose 20.0g mix homogeneously of above-mentioned mistake 200 mesh sieves after, with the made hypromellose ethanol-water solution system soft material that contains the hydrobromic acid scopolamine in (3) step, crossing 30 mesh sieves granulates, put 60 ℃ of baking oven 30min, take out, cross 60 mesh sieve granulate, put 60 ℃ of oven for drying, cross 100 orders and 400 mesh sieves, choose 100~400 order powder body, survey drug content, qualified back fill promptly gets vesicle type scopolamine hydrobromide dry powder inhalant for nose to vesicle.
The applicant studies the purity test of the vesicle type scopolamine hydrobromide dry powder inhalant for nose of present embodiment gained, assay, Emptying Rate, related substance etc. respectively, and the result is as follows:
1, this product is a capsule type inhalant, need carry out Emptying Rate and measure.The Emptying Rate assay method carries out with reference to two appendix powder sprays of version Chinese Pharmacopoeia in 2000 Emptying Rate algoscopy, and pumping velocity changes 20 ± 5L/min into by 60 ± 5L/min, to be fit to the handling characteristics of this preparation.The Emptying Rate of 10 vesicles is all greater than 90%.
2, related substance: Chinese Pharmacopoeia two ones of versions in 2000 have been recorded scopolamine hydrobromide raw material, tablet, injection, the three checks that item does not all carry out the related substance inspection down, all adopts high performance liquid chromatography (being called for short the HPLC method) to carry out the inspection of related substance under Dante bromine scopolamine raw material, injection, the capsule inspection item.By literature search, adopt following chromatographic condition to carry out the mensuration and the research of this product related substance.
Chromatographic condition:
Chromatographic column: ODS C
18(DiamonsilTM)
Mobile phase: 50mM potassium dihydrogen phosphate/1% triethylamine (phosphoric acid is transferred pH to 3.5): acetonitrile=9:1
Flow velocity: 1.0mL/min
Ultraviolet detection wavelength: 210nm
Sampling volume: 100 μ L
Measurement result shows that used adjuvant does not have influence to measuring in the preparation, related substance does not have obvious increase in preparation process, but for being controlled at the amount of related substance in preparation and the storage process, in quality standard, still list the related substance inspection in, adopt Self-control method, carried out this product raw material, blank adjuvant and powder spray three's related substance inspection.
3, assay: assay adopts HPLC to carry out, the same related substance of chromatographic condition, carry out assay with external standard method, method is simple, repeatability and precision are all good, the assay limits is according to formulation characteristic, and the content limit with reference to homemade salbutamol sulfate powder spray is decided to be 90.0~115.0%.
With scopolamine hydrobromide peak area (A) is vertical coordinate, and concentration C (μ g/mL) gets regression equation for abscissa carries out linear regression:
A=38329.2601C+15293.8825,r=1.0000(n=7)
Method recovery test result: 99.96 ± 0.83% (c.v. is 0.83%)
Day interpolation: 99.76 ± 0.56%
In the daytime poor: 99.48 ± 0.26%
It is as follows that the applicant has carried out stability study to the vesicle type scopolamine hydrobromide dry powder inhalant for nose of embodiment gained:
1, accelerated test: this product vesicle (plastic-aluminum, three batches), simulation listing packing is put 40 ℃, under the condition of relative humidity 75%, placed six months, respectively at 1,2,3, take a sample once June, carries out the investigation of projects such as appearance character, Emptying Rate, content, related substance, and with contrast in 0 month, every index has no significant change, and assay all meets the clinical research quality standard.
2, exposure experiments to light: get this product vesicle (plastic-aluminum, three batches), simulation listing packing, vesicle upwards is tiled in the surface plate, puts illumination and is in the light cupboard of 4500Lux and placed 10 days, respectively at 5,10 days the sampling, carry out every mensuration, and with 0 day the contrast, every index has no significant change, and assay all meets the clinical research quality standard.
3, long term test: this product vesicle (plastic-aluminum, three batches), simulation listing packing, put under 25 ℃, relative humidity 60% condition and place, respectively at 3,6,9,12 months the sampling once, carry out every mensuration, and with 0 month the contrast, every index has no significant change, and the result meets the clinical research quality standard.
4, influence factor's test:
(1) hot test: get this product, put in 40,60 ℃ of baking ovens and place, carry out every mensuration respectively at sampling in 5,10 days, measurement result shows: 40 ℃ of tests of this product 10 days, and every index was compared with 0 day and is had no significant change; 60 ℃ tested 5,10 days, and vesicle all is out of shape, and Emptying Rate can't be measured, and other every indexs were compared with 0 day and had no significant change.
(2) high wet test: get this product (vesicle) and put in 25 ℃, RH75% and the RH92.5% exsiccator, respectively at sampling in 5,10 days, carry out the investigation of appearance character, content, related substance, Emptying Rate, the result shows: every index was compared with 0 day and is had no significant change.
(3) exposure experiments to light: get this product (vesicle) and put in the 4500Lux light cupboard, vesicle is towards last, in sampling in 5,10 days, carry out the investigation of appearance character, content, related substance, Emptying Rate, the result shows that related substance slightly increases, but still up to specification, other no significant changes.
Influence factor's result of the test shows: this product principal agent is to warm, wet and high light is all comparatively stable, is heated, behind the wet and strong illumination, and content and related substance have no significant change, and related substance slightly increases after the illumination, but still up to specification.
The vesicle type scopolamine dry powder inhalant for nose of present embodiment adopts the dose double packing, cooperates the dose double vesicle type nose powder inhalation device of German Pfeiffer company, and drug powder is initiatively sucked by the patient.During use, push rod presses down, and punctures the aluminium foil on vesicle surface, and the push rod front end is put in the nostril, and is air-breathing, and medicated powder can enter nasal cavity in the vesicle, adheres on the nasal mucosa, and medicine is brought into play curative effect through Nasal Mucosa Absorption.
Embodiment two:
In per 1000 scopolamine hydrobromide vesicles principal agent and each adjuvant weight as follows:
Scopolamine hydrobromide 0.2g,
Hypromellose (as bioadhesive polymer) 0.6g,
Microcrystalline Cellulose 6.0g,
Lactose 20.0g,
Hypromellose (as binding agent) 0.03g.
The preparation method of above-mentioned vesicle only is that with embodiment one difference the consumption of each component is different, and as mentioned above, the consumption of hypromellose ethanol-water solution is 6ml in (3) step.
Embodiment three:
In per 1000 scopolamine hydrobromide vesicles principal agent and each adjuvant weight as follows:
Scopolamine hydrobromide 0.2g,
Hypromellose (as bioadhesive polymer) 2.0g,
Microcrystalline Cellulose 6.0g,
Lactose 20.0g,
Hypromellose (as binding agent) 0.02g.
The consumption that the preparation method of above-mentioned vesicle and embodiment one difference only are each component as mentioned above, the consumption of hypromellose ethanol-water solution is 4ml in (3) step.
Embodiment four:
In per 1000 scopolamine hydrobromide vesicles principal agent and each adjuvant weight as follows:
Scopolamine hydrobromide 0.2g,
Hypromellose (as bioadhesive polymer) 2.0g,
Microcrystalline Cellulose 2.0g,
Lactose 2 0.0g,
Hypromellose (as binding agent) 0.03g.
The consumption that the preparation method of above-mentioned vesicle and embodiment one difference only are each component as mentioned above, the consumption of hypromellose ethanol-water solution is 6ml in (3) step.
Embodiment five:
In per 1000 scopolamine hydrobromide vesicles principal agent and each adjuvant weight as follows:
Scopolamine hydrobromide 0.2g,
Hypromellose (as bioadhesive polymer) 1.5g,
Microcrystalline Cellulose 5.0g,
Lactose 2 0.0g,
Hypromellose (as binding agent) 0.025g.
The consumption that the preparation method of above-mentioned vesicle and embodiment one difference only are each component as mentioned above.
Embodiment six:
In per 1000 scopolamine hydrobromide vesicles principal agent and each adjuvant weight as follows:
Scopolamine hydrobromide 0.2g,
Hypromellose (as bioadhesive polymer) 1.0g,
Microcrystalline Cellulose 4.0g,
Lactose 25.0g,
Hypromellose (as binding agent) 0.025g.
The consumption that the preparation method of above-mentioned vesicle and embodiment one difference only are each component as mentioned above, and the concentration of alcohol of ethanol-water solution is 50% (v/v) in (2) step.
Embodiment seven:
In per 1000 scopolamine hydrobromide vesicles principal agent and each adjuvant weight as follows:
Scopolamine hydrobromide 0.2g,
Hypromellose (as bioadhesive polymer) 1.2g,
Microcrystalline Cellulose 3.8g,
Lactose 15.0g,
Hypromellose (as binding agent) 0.025g.
The consumption that the preparation method of above-mentioned vesicle and embodiment one difference only are each component as mentioned above, the concentration of alcohol of ethanol-water solution is 25% (v/v) in (2) step.
As replaceable one-tenth sodium carboxymethyl cellulose of the hypromellose of bioadhesive polymer or their mixture, replaceable as the hypromellose of binding agent is sodium carboxymethyl cellulose among above-mentioned each embodiment.After measured, adopt the quality of the product of hypromellose gained to compare with the product that adopts sodium carboxymethyl cellulose, the former is better.The index of investigating is: angle of repose, degree of tightness density contrast, adhesiveness, Emptying Rate and sieve are got rate.
After lactose in the various embodiments described above substituted with mannitol, measurement result showed that the quality of the product of gained is similar.