CN100349611C - Redfish calcitonin inhalation powder-atomizing agent and preparing method - Google Patents
Redfish calcitonin inhalation powder-atomizing agent and preparing method Download PDFInfo
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- CN100349611C CN100349611C CNB2005100956459A CN200510095645A CN100349611C CN 100349611 C CN100349611 C CN 100349611C CN B2005100956459 A CNB2005100956459 A CN B2005100956459A CN 200510095645 A CN200510095645 A CN 200510095645A CN 100349611 C CN100349611 C CN 100349611C
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Abstract
The present invention relates to the field of medicinal preparation, particularly to a redfish calcitonin powder-atomizing agent and a preparation method of the agent. The redfish calcitonin powder-atomizing agent can be absorbed at the lung part after being inhaled from oral cavity to exert therapeutic effect. The redfish calcitonin powder-atomizing agent of the present invention is composed of three portions of redfish calcitonin, 500 to 2000 portions of mannitol and 500 to 2000 portions of amino acid. The redfish calcitonin powder-atomizing agent has the advantages of favorable solubility, bulk density, rest angle and atomizing performance, and difficult moisture absorption.
Description
Technical field
The present invention relates to field of pharmaceutical preparations, be specifically related to a kind of salmon calcitonin powder spray and preparation method thereof, especially can after the oral cavity sucks, bring into play salmon calcitonin powder spray of drug effect and preparation method thereof in pulmonary's absorption.
Background technology
Calcitonin is the excretory a kind of polypeptide hormone of regulating alcium and phosphor metabolization of thyroid follicular cells, is made up of 32 aminoacid, is found by people such as Copp in 1961, and people such as Kumar in 1963 and Foster further prove.The amino acid residue of the excretory calcitonin of different animals has certain difference, secretion from biological activity ratio's secretion of the calcitonins of Fish surplus the biological activity strong 50 of mammiferous calcitonin times.Human calcitonin (HCT), calcitonin (PCT), salmon calcitonin (sCT) and 4 kinds of calcitonins of Anguillar japonica calcitonin (ECT) are arranged at present.Wherein the biological activity of sCT is the strongest.Mainly calcitonin is used for diseases such as hypercalcemia, morphotropism osteodynia (PagetShi pain) and osteoporosis clinically, vast amount of clinical confirms that calcitonin is evident in efficacy to prevention and treatment women's osteosporosis after menopause.
Postmenopausal osteoporosis (PMOP) is postmenopausal women's commonly encountered diseases, causes skeleton pain, and fracture risk increases, and has a strong impact on patient's Health and Living quality.Treating osteoporotic main path is to reduce bone loss, keeps and bone density improving, and calcitonin is one of main medicine, and it can reduce blood calcium by skeleton, kidney and gastrointestinal are regulated.Can suppress the absorption and the bone self-dissolving of bone to skeleton, the calcium that skeleton is discharged reduces, and skeleton constantly absorbs the calcium in the blood plasma again simultaneously, and calcium is descended, and also can suppress the dissolving and the transfer of bone mineral, suppresses bone matrix and decomposes, and increases calcium in the urine, phosphorus is drained.To kidney, suppress the heavily absorption of renal tubules to calcium, phosphorus, sodium, be increased in the drainage in the urine.
The main route of administration of calcitonin is a drug administration by injection at present, because patient needs long-term prescription, secular injection meeting brings inconvenience and misery to patient.CN1370523A discloses the nose powder inhalation of salmon calcitonin, form by methylcellulose, surfactant, diluent etc., reach therapeutic effect by Nasal Mucosa Absorption, but the life-time service surfactant can damage the nasal mucosa cell, and nasal-cavity administration has quantitative inaccuracy, drug powder at the nasal cavity skewness, easily from shortcomings such as nasal cavity losses.
Pulmonary's inhalation is the acute attack that is used for trachea diastole treatment asthma the earliest,, this application method more and more in the transmission of polypeptide protein class medicine, shows very big superiority because possessing following characteristics: at first, pulmonary has huge surface area, can send the bigger albumen of molecular weight, polypeptide drug efficiently; Secondly, alveolar is by the simple epithelium cellularity, and medicine is very short by the distance of air-blood exchange, and speed is also very fast; Once more, the pulmonary administration approach can be avoided the first pass effect of medicine, improves the bioavailability of human body.
The drug loading of powder spray is big, but because the particularity of pulmonary administration, must be little with good water solubility, zest, the adjuvant of good biocompatibility.In order to promote the absorption of salmon calcitonin, there is document to be disclosed in and adds surfactant or penetration enhancers in the powder spray, as Capric acid sodium salt, bile salts etc. in pulmonary.But the life-time service surfactant can produce infringement to pulmonary.
As everyone knows, medicated powder will pass through the human organ passage that trachea, bronchus etc. are quite grown one section humidity from the oral cavity to the pulmonary, and too easily moisture absorption will be adsorbed in airway walls, to not alveolar go, and too light, again easily with breathing effusion.So the most important condition that pulmonary's induction type powder spray salmon calcitonin will be brought into play drug effect is particle diameter little, opaque light (density is little), the good fluidity (angle of repose is little) of medicated powder, medicated powder could arrive alveolar and the mistake of less exhalation ease by the oral cavity.Particle diameter is little just easily to be absorbed in pulmonary.But, just because of the little surface area of medicated powder particle diameter is big, so generally speaking very easily moisture absorption of powder spray itself.No matter how little particle diameter is, must affect the treatment in case form piece after the moisture absorption.This is the big technological difficulties that pulmonary sucks powder spray.This seminar finds in the research in early stage, when salmon calcitonin being prepared into pulmonary and sucking powder spray, selects for use mannitol, L-leucine relatively good as adjuvant, shows that particle is more even than rounding, particle size distribution.But also exist particle very easily to stick together and assemble, make the body system problems such as instability that become, therefore, still can not form the technical scheme (preparation of Redfish calcitonin inhalation powder-atomizing agents such as Xiong Lianjie and the pharmaceutics property research thereof that are fit to suitability for industrialized production, " Acta Pharmaceutica Sinica " 2003,38 (3): 218-222).
Summary of the invention
The invention discloses a kind of salmon calcitonin powder spray, select carrier and suitable proportioning thereof with the salmon calcitonin compatibility, make that the salmon calcitonin powder diameter that obtains is little, opaque is light, not only the dissolubility of medicated powder, bulk density, angle of repose, atomization are all better, and are difficult for moisture absorption.Prepared salmon calcitonin powder spray steady quality is fit to industrialized great production.
Technical scheme of the present invention is as follows:
Salmon calcitonin powder spray of the present invention is characterized in that being made up of following component and weight ratio:
3 parts of salmon calcitonins
Mannitol 500-2000 part
Aminoacid 500-2000 part
Wherein aminoacid is threonine, aspartic acid, glutamic acid, isoleucine, arginine and/or leucine, and described aminoacid all is L type aminoacid.Preferred leucine and threonine.
Above-mentioned salmon calcitonin powder spray, the preferred weight ratio of each component is:
3 parts of salmon calcitonins
Mannitol 800-1200 part
Amino acid/11 000-1600 part.
Above-mentioned salmon calcitonin powder spray, preferred threonine of aminoacid wherein and leucine.
When the preferred threonine of aminoacid, preferably each components by weight is:
3 parts of salmon calcitonins
1200 parts in mannitol
1300 parts of threonine.
The also preferred leucine of above-mentioned salmon calcitonin powder spray, aminoacid wherein.
When the preferred leucine of aminoacid, preferably each components by weight is:
3 parts of salmon calcitonins
1000 parts in mannitol
1500 parts of leucines.
Generally in the preparation powder spray, the threonine of use and leucine all are the L type aminoacid of native configurations.
The preparation method of the salmon calcitonin powder spray of the invention described above comprises: mannitol, aminoacid, salmon calcitonin are added in the entry dissolve, principal agent and adjuvant concentration in mixed liquor is 0.1～5%, spray drying.
Above-mentioned preparation method, wherein preferred inlet temperature is 105-115 ℃ during spray drying, outlet temperature is 70-80 ℃.
In preparation, the preferred 800ml/min of nozzle air current amount during spray drying.
The above-mentioned method for preparing the salmon calcitonin powder spray, not only salmon calcitonin structure in preparation process is not destroyed, its powder diameter of the salmon calcitonin powder spray that makes is little, opaque is light, not only the dissolubility of medicated powder, bulk density, angle of repose, atomization are all better, and are difficult for moisture absorption in processing, storage, use.
During the dried powder that method for preparing goes out further incapsulates, promptly can be used for clinical.
Because the dosage of salmon calcitonin is extremely low, the amount of adjuvant is moderate when being used to suck, if drug level is too high, then under the bio-occlusion pharmaceutical quantities, the total amount of administration just reduces, and causes the administration error to increase, and is difficult for dosed administration accurately; And if principal agent concentration is low excessively, under minimum dosage, need the total amount of administration just to increase, exceed the safety range that the human lung sucks amount of powder, life-time service very easily causes damage to pulmonary.The inventor studies the back and finds, and is when 3 parts of principal agents, proper during adjuvant 1000-4000 part.So accurately administration can not increase pulmonary's infringement again.
Find (see Table 1 and table 2) in the research of the pharmaceutics of Redfish calcitonin inhalation powder-atomizing agent, use mannitol to make diluent separately, the water solublity of product is relatively poor, and the spray test effect is undesirable, capsule residual quantity more (prescription 1); Spray drying behind independent use mannitol and the medicine dissolution, the hygroscopicity of product is defective, and atomizing effect is undesirable; After adding aminoacid, opaque improves, and density reduces, and powder can form smog and uniform deposition during spray test, does not see graininess aggregation (prescription 3,4,5), can prepare qualified products.And use spray drying behind propylhomoserin acid and the medicine dissolution separately, and the water solublity of product is relatively poor, and electrostatic interaction is very strong, and powder is easily assembled, and atomizing effect is undesirable.
Table 1 is grouped at early-stage Study middle part and the physical and chemical parameter of prepared product
| Prescription 1 | Prescription 2 | Prescription 3 | Prescription 4 | Prescription 5 | Prescription 6 | ||
| Salmon calcitonin | 0.03g | 0.03g | 0.03g | 0.03g | 0.03g | 0.03g | |
| Mannitol | 25.0g | 25.0g | 17.0g | 10.0g | 8.0g | 0 | |
| Leucine | 0 | 0 | 8.0g | 15.0g | 17.0g | 25.0g | |
| Quality evaluation | Dissolubility | Defective | Qualified | Qualified | Qualified | Qualified | Defective |
| Bulk density | 0.26 | 0.24 | 0.18 | 0.10 | 0.09 | 0.25 | |
| Angle of repose | 42.5° | 42.2° | 38.8° | 35.1° | 39.2 | 39.9° | |
| Hygroscopicity | Defective | Defective | Qualified | Qualified | Qualified | Qualified | |
| Electrostatic interaction | Qualified | Qualified | Qualified | Qualified | Qualified | Defective | |
| Atomizing effect | Medium | Difference | Qualified | Excellent | Qualified | Difference | |
| Softgel shell powder residual quantity | 9.1％ | 4.2％ | 3.7％ | 2.9％ | 18％ | 25.2％ | |
*The preparation technology of prescription 1 mixes the back with two components directly to pulverize
The situation of change of capsule under 75% relative humidity that each prescription of table 2. is made
| Prescription 1 * | Prescription 2 | Prescription 3 | Prescription 4 | Prescription 5 | Prescription 6 | |
| Weightening finish | 1.0％ | 1.4％ | 1.5％ | 1.5％ | 2.1％ | 5.0％ |
| Atomizing effect | Deposit has more granule | Deposit has granule, and capsule has block residual | Deposit has a small amount of fine particle | Atomizing effect is good, to be the powdery uniform deposition | Deposit has a small amount of fine particle | Deposit has granule, and capsule has large stretch of residual |
| Residual quantity | 11.2％ | 10.3％ | 5.9％ | 3.7％ | 4.8％ | 38.1％ |
Further finding in the research, when prescription consists of 3 parts of salmon calcitonins and 1000-4000 part adjuvant, and adjuvant is when using mannitol and aminoacid simultaneously, when mannitol: can be when amino acid whose amount ratio is 1: 4～4: 1 to dissolubility, bulk density, angle of repose, the atomizing effect of product and the residual quantity after using produce good synergism, especially can reduce the hygroscopicity of salmon calcitonin powder spray.Particularly select for use threonine or leucine to cooperate with mannitol, when mannitol: when threonine or leucine are 1: 2～6: 5, the overall merit better effects if.Therefore formed technical scheme of the present invention: 3 parts of salmon calcitonins, mannitol 500-2000 part, aminoacid 500-2000 part, the anti-moisture sorption effect of the salmon calcitonin for preparing in this scope is good, and the comprehensive quality evaluation is more excellent, and dosage is suitable, is fit to clinical use.And not in this scope some index of prepared spray differ greatly, can not prepare qualified product.Preferred on this basis scheme is: 3 parts of salmon calcitonins, mannitol 800-1200 part, amino acid/11 000-1600 part, the dissolubility of the product for preparing like this, angle of repose, bulk density, character such as resistance to water soak are all in very ideal scope, the materialization effect is very good, at different aminoacid, with the ratio of mannitol difference to some extent, optimum as salmon calcitonin: mannitol: leucine is 3 parts: 1000 parts: during 1500 parts of ratios, and salmon calcitonin: mannitol: leucine is 3 parts: 1200 parts: during 1300 parts of ratios, atomizing effect the best of powder spray, this is an optimized prescription.
The test method and the evaluation criterion of listed each index of salmon calcitonin powder spray are as follows in table 1, the table 2:
Dissolubility: get 2 of the Redfish calcitonin inhalation powder-atomizing agents of trial-production, open softgel shell, content is put into the test tube with ground stopper that 2ml water is housed, its dissolving situation is observed in jolting 1 minute.If powder can dissolve and the solution clarification, dissolubility is qualified; If show muddy, then dissolubility is defective.
Bulk density: after with analytical balance spray-dried powders being weighed, put in the little graduated cylinder, measure the volume of powder behind the jog, with weight (g) compare with volume (ml) get final product the bulk density of powder, bulk density with little be good.
Angle of repose: body ends the measurement at angle and adopts the fixed funnel method, get the about 6cm of bore, one in the little funnel of the about 0.4cm of caliber (internal diameter) is fixed on the iron stand, shop, funnel below a blank sheet of paper, the about 4-5cm of the height of funnel exit and paper, slowly pour the medicated powder end into funnel from funnel top, make under its spontaneous current in heaps, till the top of cone rigidly connects when contacting hopper outlet, measure the radius r and the height H of the bottom surface of this medicated powder cone, calculate angle of repose: angle of repose=arctg (H/r).
Powder residual quantity and atomization: with the Redfish calcitonin inhalation powder-atomizing agent precision weigh (W1) of trial-production, put into special-purpose inhaler (production of Shanghai balance pharmaceutical factory), capsule is punched, again inhaler is linked to each other with the 5000ml vial, junction deploy switch knob, this knob is initially located in the closed position.With 60L/min throughput evacuation, open above-mentioned knob, the medicated powder in the capsule promptly sprays from inhaler, and continuous three times, each 1.5 seconds.If powder forms even smog, the no big granule in deposition back exists, and illustrates that atomization is good; If most of powder is atomized,, only there is small quantities of particles at the bottle end, and atomization is medium; If most of powder is not atomized, form bulk at the bottle bottom sediments, illustrate that atomization is poor.Exhausted capsule shells is taken out from suction apparatus, and precision is weighed (W2), with small brushes the residual powder of inside capsule wall is wiped away only, claims capsulae vacuus weight (W3) again.The computational methods of capsule 's content powder residual quantity are:
[(W2-W3)/(W1-W3)]×100％
Humidity effect and capsule wall attach test: get Redfish calcitonin inhalation powder-atomizing agent, the accurate title, decide, and in 25 ℃ of room temperature underlying RH75% environment, takes out after 24 hours, once more the weighing capsules weight.Then powder is poured out, observed the variation of characters powder, and attach situation to understand capsule wall by the residual quantity of powder in the last method mensuration capsule.
Salmon calcitonin powder spray of the present invention can capsule form use.The size of used capsule can be any model, and preferred model is less than No. 0, selects usually 1-4 number.The capsule of salmon calcitonin dust cloud can not only carry out suitability for industrialized production easily, and is easy to carry.The amount of salmon calcitonin powder is certain in the capsule, and inhalation dose is accurate when guaranteeing to use, and inhales or few the suction but the effectively preventing patient.
The content of capsule provided by the present invention is by the powder constituent of average diameter less than 100 μ m.The average diameter of preferred powder is less than 10 μ m, and the average diameter of most preferred powder is less than 5 μ m, usually between 0.5-5 μ m.
In the research of Redfish calcitonin inhalation powder-atomizing agent, find, except preparation form quality influence to product big, many influence factors are also arranged among the preparation technology:
Spray drying is one of common method of preparation powder spray, because the powder of spray drying gained is thinner, can reach the requirement of inhalation, or can reach this requirement through comminution by gas stream slightly; Spray-dired process is very fast, and drug solution can be converted into dry powder by liquid state in the several seconds, can reduce the chance of microbial contamination on the one hand, and salmon calcitonin is difficult for being destroyed by high temperature in the so short time on the other hand.In process of the test, also once attempted relevant reported method, salmon calcitonin solution is put 40 ℃ of oven dry, this process need 24 hours or longer time, increased the chance of microbial contamination greatly, also attempted freeze-drying method in addition, cycle is also more than 24 hours, in view of above comparison, selected the spray drying method that the production cycle shortens greatly for use.
Find in the experiment that the throughput of nozzle is when 800ml/min reduces to 650ml/min, the deposition ratio in the effective position fall is little; But when the throughput of nozzle when 650ml/min reduces to 500ml/min, deposition ratio in the effective position significantly descends.When throughput was described less than certain threshold value, the diameter of particle of formation enlarged markedly, so the drug deposition amount of effective site is significantly reduced.The throughput of nozzle is bigger, heal height and granularity of the yield of product is littler, when throughput is increased to 800ml/min by 400ml/min, yield can be increased to about 60% by about 30%, particle diameter is reduced to below the 3 μ m by 12.5 μ m, consider above-mentioned factor, throughput is transferred to maximum horizontal (800ml/min).
Experiment shows that the relation of the response rate of product and nozzle flow velocity (P) is the closest, has only moderate nozzle flow velocity just to have the higher response rate.P is too little or P is all unfavorable to yield too greatly.May be hour at P, spray velocity is slow, and the time is long, and loss is many; Spray velocity is too fast, and droplet has little time dry solidification, and part sticks on the chamber wall and causes damage.Second factor that influences the response rate is inlet temperature, and yield was higher when inlet temperature was higher; Quantity of solvent more also has higher recovery in addition, may be because quantity of solvent when big the granularity of powder less, be difficult for deposition.
Particulate rounding property is main relevant with P and quantity of solvent.P is littler, and the granule rounding property may be because nozzle flow velocity when less better, and it is less relatively that particle collides inter-adhesive probability mutually; Quantity of solvent is littler, and the concentration of solute is higher, molding easily in the dry run, and particulate rounding property is better.
Influence is not very big to process conditions to bulk density.
From experimental result, P and A are bigger to influence angle of repose of micropowder, and angle of repose was less when P and A were big.
Hygroscopicity and P relation are bigger, and P is bigger, and hygroscopicity is littler.Lower in addition inlet temperature and less quantity of solvent all can reduce the moisture absorption weightening finish of micropowder.Grain diameter is main relevant with quantity of solvent, and quantity of solvent is bigger, and particle diameter is littler.
Because the atomizing effect by the salmon calcitonin powder spray of the technical program preparation is good, so can utilize the commercially available treatment asthma and the suction powder unit of chronic bronchitis.The inhaler of Shanghai balance pharmaceutical factory for example.What in fact this device play a part is capsule to be squeezed break, and the medicated powder of general treatment asthma and chronic bronchitis is drawn into air flue can produce predetermined curative effect than the center, and the salmon calcitonin powder spray is must suck alveolar region definite curative effect is just arranged.Salmon calcitonin powder spray of the present invention can use by means of the suction powder unit of commercially available treatment asthma and chronic bronchitis, this physicochemical property that salmon calcitonin powder spray of the present invention also is described is good, especially atomizing effect excellence, so that can use the former device of medicated powder that only can spray, salmon calcitonin powder spray spray of the present invention is drawn to pulmonary to the air flue place.And salmon calcitonin capsule of the present invention promptly uses hands to pinch brokenly, and content wherein can the air-flow effect when breathing enters alveolar and plays a role.This is very easily for patient's self-administration under the outdoor situations.
In addition, described crowded broken capsular device can use repeatedly.Ghost can be abandoned behind the capsule 's content extinction, to this device in insert a capsule when using next time again.This device can use repeatedly.
Redfish calcitonin inhalation powder-atomizing agent of the present invention proves that through pharmacology test it is than commercially available salmon calcitonin nasal spray curative effect height, and is approaching with the intraperitoneal injection curative effect with dosage.
Redfish calcitonin inhalation powder-atomizing agent is tested the blood calcium that falls of rat
1. experiment purpose
With intraperitoneal injection, commercially available nasal spray intranasal administration with suck blank adjuvant and contrast, observe the blood calcium effect of falling after rat is used Redfish calcitonin inhalation powder-atomizing agent.And calculate the absorption fraction of salmon calcitonin in the inhalant according to the percent that blood calcium reduces.
2. experiment material
(1) animal: 70 of cleaning level SD rats, female, Chinese-foreign joint Shanghai Hippel-Bi Ke Experimental Animal Center provides, and body weight 180-200g uses after 2 days at this laboratory rearing at least.
(2) medicine:
1) Redfish calcitonin inhalation powder-atomizing agent of the present invention.During use capsule 's content is poured out, with precision be 100,000/ analytical balance claim calmly by dosage requirements of experiment is accurate, in another capsulae vacuus of carefully packing into.
2) salmon calcitonin injection.Novartis Pharma Schweiz AG produces, and specification: 50IU/ml is diluted to 5IU/ml with deionized water during use.
3) salmon calcitonin nasal spray.The Beijing ShiQiao Biology Pharmacy Co., Ltd produces, specification: 28 sprays, every spray 20 μ g.
4) blank adjuvant.All the components in the Redfish calcitonin inhalation powder-atomizing agent except that the principal agent salmon calcitonin becomes by identical prepared.
5) the manual test kit of measuring of blood calcium.Build up bio-engineering research by Nanjing and produced, lot number 20050531.
3. experimental technique
(1) the animal grouping is divided into 7 groups with 70 rats by body weight, 10 every group at random.Redfish calcitonin inhalation powder-atomizing agent 30IU/kg of the present invention, 60IU/kg, 75IU/kg, a 120IU/kg4 dosage group are established in experiment respectively; The lumbar injection matched group, the intranasal administration group, dosage is 60IU/kg; Blank adjuvant matched group.
(2) medication is by the heavy medicated powder that accurately takes by weighing of animal body, after the fasting 12 hours (freely drinking water), uses the ether deep anaesthesia before the rat test, be fixed on the Mus plate, will make doser then by oneself and insert trachea, up to pulmonary by the oral cavity, by the rat autonomous respiration, drug powder is sucked pulmonary, with rubber pipette bulb the residual drug powder is blown into the rat trachea, the record administration time is in 0.25,0.5,0.75,1,1.5,2,2.5, blood was got on the rat optical fundus in 3,4,6 hours, with the centrifugal 3-4min of 2500r/min, separation of serum, with the accurate upper serum 20ul that takes out of micro-sampling pin, to be measured.
(3) the blood calcium pH-value determination pH is with the blood calcium concentration of methylthymol blue colorimetric method for determining rat.
4. result of the test
After the rat medication calcium percentage rate falls
From table 4 to table 9 as seen, 4 dosage groups of Redfish calcitonin inhalation powder-atomizing agent suck back 30min through pulmonary, and the rat serum calcium concentration begins to have tangible reduction, after the administration about 2-4 hour drug effect reach maximum, after 4 hours, blood calcium progressively recovers.T check (α=0.05) shows that pulmonary sucks the drug effect there was no significant difference of 75IU/kg dosage and lumbar injection 60IU/kg dosage, the drug effect there was no significant difference of pulmonary administration 30IU/kg dosage and collunarium 60IU/kg dosage.
The full name of last string AAC is in each table: Area Above The Curve, area on the calcium curve falls in representative.Its implication is: fall after the medication calcium percentage rate to the curve of time mapping and medication before area between the calcium level (100%).
Behind the table 3. rat pulmonary administration salmon calcitonin 30IU/kg calcium percentage rate (%) falls
| Time (h) | AAC | |||||||||||
| 0.0 | 0.3 | 0.5 | 0.8 | 1.0 | 1.5 | 2.0 | 2.5 | 3.0 | 4.0 | 6.0 | ||
| On average | 100.0 | 97.9 | 95.2 | 96.5 | 91.6 | 88.8 | 83.4 | 80.6 | 82.2 | 87.7 | 97.7 | 63.4 |
| SD | 0.0 | 3.3 | 3.9 | 8.7 | 4.4 | 6.1 | 4.4 | 3.6 | 5.9 | 8.5 | 5.2 | 26.0 |
Behind the table 4. rat pulmonary administration salmon calcitonin 60IU/kg calcium percentage rate (%) falls
| Time (h) | AAC | |||||||||||
| 0.0 | 0.25 | 0.5 | 0.75 | 1.0 | 1.5 | 2.0 | 2.5 | 3.0 | 4.0 | 6.0 | ||
| On average | 100.0 | 96.5 | 91.6 | 89.4 | 83.3 | 78.8 | 72.1 | 71.0 | 70.1 | 69.9 | 78.8 | 139.7 |
| SD | 0.0 | 1.6 | 2.7 | 2.5 | 2.9 | 7.8 | 7.2 | 4.6 | 4.7 | 9.6 | 10.6 | 37.3 |
Behind the table 5. rat pulmonary administration salmon calcitonin 75IU/kg calcium percentage rate (%) falls
| Time (h) | AAC | |||||||||||
| 0.0 | 0.25 | 0.5 | 0.75 | 1.0 | 1.5 | 2.0 | 2.5 | 3.0 | 4.0 | 6.0 | ||
| On average | 100.0 | 89.9 | 85.7 | 84.6 | 74.9 | 72.3 | 69.9 | 71.2 | 65.2 | 62.5 | 77.5 | 167.6 |
| SD | 0.0 | 6.4 | 6.8 | 6.0 | 4.0 | 5.3 | 4.8 | 10.1 | 8.6 | 7.4 | 11.5 | 20.1 |
Behind the table 6. rat pulmonary administration salmon calcitonin 120IU/kg calcium percentage rate (%) falls
| Time (h) | AAC |
| 0.0 | 0.25 | 0.5 | 0.75 | 1.0 | 1.5 | 2.0 | 2.5 | 3.0 | 4.0 | 6.0 | ||
| On average | 100.0 | 93.0 | 91.3 | 86.7 | 89.9 | 74.5 | 77.1 | 65.9 | 55.3 | 56.6 | 65.7 | 185.1 |
| SD | 0.0 | 7.4 | 12.2 | 6.7 | 9.4 | 13.2 | 23.7 | 23.5 | 13.0 | 6.5 | 22.6 | 61.1 |
Behind the table 7. rats by intraperitoneal injection salmon calcitonin 60IU/kg calcium percentage rate (%) falls
| Time (h) | AAC | |||||||||||
| 0.0 | 0.25 | 0.5 | 0.75 | 1.0 | 1.5 | 2.0 | 2.5 | 3.0 | 4.0 | 6.0 | ||
| On average | 100.0 | 91.4 | 88.1 | 79.9 | 82.2 | 75.6 | 74.4 | 72.6 | 64.9 | 63.9 | 79.0 | 157.0 |
| SD | 0.0 | 1.6 | 2.7 | 2.5 | 2.9 | 7.8 | 7.2 | 4.6 | 4.7 | 9.6 | 10.6 | 50.4 |
Table 8. rat collunarium gives to fall calcium percentage rate (%) behind the salmon calcitonin 60IU/kg
| Time (h) | AAC | |||||||||||
| 0.0 | 0.25 | 0.5 | 0.75 | 1.0 | 1.5 | 2.0 | 2.5 | 3.0 | 4.0 | 6.0 | ||
| On average | 100.0 | 91.1 | 85.3 | 85.4 | 83.3 | 81.1 | 82.2 | 83.7 | 88.7 | 90.1 | 102.8 | 62.9 |
| SD | 0.0 | 4.2 | 5.8 | 5.6 | 4.7 | 5.3 | 8.4 | 10.7 | 10.1 | 7.6 | 6.6 | 32.8 |
Behind the blank adjuvant of table 9. rat pulmonary administration calcium percentage rate (%) falls
| Time (h) | AAC | |||||||||||
| 0.0 | 0.25 | 0.5 | 0.75 | 1.0 | 1.5 | 2.0 | 2.5 | 3.0 | 4.0 | 6.0 | ||
| On average | 100.0 | 97.0 | 98.1 | 99.2 | 98.1 | 95.9 | 92.8 | 94.5 | 95.0 | 94.7 | 94.5 | 27.7 |
| ?SD | 0.0 | 4.4 | 10.0 | 8.2 | 6.6 | 8.0 | 5.3 | 3.5 | 4.0 | 2.1 | 1.7 | 22.6 |
The specific embodiment
Supplementary material source and quality standard:
00 edition second Xiaohuoban Medicine Biological Technology Co., Ltd., Beijing of the medicinal Chinese Pharmacopoeia of salmon calcitonin
00 edition second Shanghai chemical reagents corporation of Chinese Medicine group of the medicinal Chinese Pharmacopoeia of mannitol
The medicinal the Sanitation Ministry medicine standard of L-leucine Tianjin aminoacid company
The medicinal the Sanitation Ministry medicine standard of L-threonine Tianjin aminoacid company
Embodiment 1
With dissolving in the about 200ml water of mannitol 17.0g, leucine 8.0g adding, add salmon calcitonin 0.03g, add water to 1600ml then, with 0.2 μ m filtering with microporous membrane, spray drying.Condition is, 110 ℃ of inlet temperatures, outlet temperature are controlled between 70～75 ℃, and whirlwind speed is 90%, and the nozzle air current amount is 800ml/min.White salmon calcitonin powder, measure salmon calcitonin content, be sub-packed in the hard capsule promptly.The powder spray bulk density 0.18 that makes, 38.8 ° of angle of reposes, softgel shell powder residual quantity is 3.7%, and deposit has a small amount of fine particle during spray test, and atomizing effect is qualified.
Embodiment 2
With dissolving in the about 200ml water of mannitol 12.0g, leucine 13.0g adding, add salmon calcitonin 0.03g, add water to 1600ml then, with 0.2 μ m filtering with microporous membrane, spray drying.Condition is, 110 ℃ of inlet temperatures, outlet temperature are controlled between 70～75 ℃, and whirlwind speed is 90%, and the nozzle air current amount is 800ml/min.White salmon calcitonin powder, measure salmon calcitonin content, be sub-packed in the hard capsule promptly.The powder spray bulk density 0.12 that makes, 36.2 ° of angle of reposes, softgel shell powder residual quantity is 3.5%, and deposit has few fine particle during spray test, and atomizing effect is more excellent.
Embodiment 3
With dissolving in the about 200ml water of mannitol 10.0g, leucine 15.0g adding, add salmon calcitonin 0.03g, add water to 1600ml then, with 0.2 μ m filtering with microporous membrane, spray drying.Condition is, 110 ℃ of inlet temperatures, outlet temperature are controlled between 70～75 ℃, and whirlwind speed is 90%, and the nozzle air current amount is 800ml/min.White salmon calcitonin powder, measure salmon calcitonin content, be sub-packed in the hard capsule promptly.The powder spray bulk density 0.10 that makes, 35.1 ° of angle of reposes, softgel shell powder residual quantity is 2.9%, powder can form smog and uniform deposition during spray test, does not see the graininess aggregation, the atomizing effect optimum.
Embodiment 4
With dissolving in the about 200ml water of mannitol 9.0g, leucine 16.0g adding, add salmon calcitonin 0.03g, add water to 1600ml then, with 0.2 μ m filtering with microporous membrane, spray drying.Condition is, 110 ℃ of inlet temperatures, outlet temperature are controlled between 70～75 ℃, and whirlwind speed is 90%, and the nozzle air current amount is 800ml/min.White salmon calcitonin powder, measure salmon calcitonin content, be sub-packed in the hard capsule promptly.The powder spray bulk density 0.10 that makes, 37.1 ° of angle of reposes, softgel shell powder residual quantity is 3.6%, and deposit has few fine particle during spray test, and atomizing effect is more excellent.
Embodiment 5
With dissolving in the about 200ml water of mannitol 8.0g, leucine 17.0g adding, add salmon calcitonin 0.03g, add water to 1600ml then, with 0.2 μ m filtering with microporous membrane, spray drying.Condition is, 110 ℃ of inlet temperatures, outlet temperature are controlled between 70～75 ℃, and whirlwind speed is 90%, and the nozzle air current amount is 800ml/min.White salmon calcitonin powder, measure salmon calcitonin content, be sub-packed in the hard capsule promptly.The powder spray bulk density 0.09 that makes, 39.2 ° of angle of reposes, softgel shell powder residual quantity is 18%, and deposit has a small amount of fine particle during spray test, and atomizing effect is qualified.
Embodiment 6
With dissolving in the about 200ml water of mannitol 12.0g, threonine 13.0g adding, add salmon calcitonin 0.03g, add water to 1600ml then, with 0.2 μ m filtering with microporous membrane, spray drying.Condition is, 110 ℃ of inlet temperatures, outlet temperature are controlled between 70～75 ℃, and whirlwind speed is 90%, and the nozzle air current amount is 800ml/min.White salmon calcitonin powder, measure salmon calcitonin content, be sub-packed in the hard capsule promptly.The powder spray bulk density 0.11 that makes, 34.8 ° of angle of reposes, softgel shell powder residual quantity is 2.7%, powder can form smog and uniform deposition during spray test, does not see the graininess aggregation, the atomizing effect optimum.
Embodiment 7
With dissolving in the about 200ml water of mannitol 12.0g, L-arginine 13.0g adding, add salmon calcitonin 0.03g, add water to 1600ml then, with 0.2 μ m filtering with microporous membrane, spray drying.Condition is, 110 ℃ of inlet temperatures, outlet temperature are controlled between 70～75 ℃, and whirlwind speed is 90%, and the nozzle air current amount is 800ml/min.White salmon calcitonin powder, measure salmon calcitonin content, be sub-packed in the hard capsule promptly.The powder spray bulk density 0.11 that makes, spend angle of reposes 35.9, and softgel shell powder residual quantity is 2.8%, and powder can form smog and uniform deposition during spray test, does not see the graininess aggregation, and atomizing effect is excellent.
Spray-dried powders morphologic observation result: with optical microscope and Electronic Speculum the capsule 's content powder is observed respectively, visible this powder is one fine particle under 1000 times optical microscope, no adhesion, no agglomerate, good dispersion is a kind of spheroidal structure.
Spray-dried powders laser particle size measurement result: Britain Malvern Instruments Ltd. laser granulometry has carried out granulometry to the capsule 's content powder of different lot numbers, as a result the various embodiments described above sample granularity less than the shared percentage ratio of the part of 5 μ m all greater than 70%.
The atomizing effect of salmon calcitonin powder spray of preparation is good, moistly all meets the requirements dissolubility, bulk density, angle of repose and drawing.
Claims (10)
1, a kind of salmon calcitonin powder spray is characterized in that being made up of following component and weight ratio:
3 parts of salmon calcitonins
Mannitol 800-1200 part
Amino acid/11 000-1600 part
Wherein aminoacid is threonine, aspartic acid, glutamic acid, isoleucine, arginine and/or leucine, and described aminoacid all is L type aminoacid.
2, the salmon calcitonin powder spray of claim 1, aminoacid wherein is threonine or leucine.
3, claim 1 or 2 salmon calcitonin powder spray, aminoacid wherein is threonine.
4, the salmon calcitonin powder spray of claim 3, form by following component and weight ratio:
3 parts of salmon calcitonins
1200 parts in mannitol
1300 parts of threonine.
5, claim 1 or 2 salmon calcitonin powder spray, aminoacid wherein is leucine.
6, the salmon calcitonin powder spray of claim 5, form by following component and weight ratio:
3 parts of salmon calcitonins
1000 parts in mannitol
1500 parts of leucines.
7, the preparation method of each salmon calcitonin powder spray in the claim 1 to 6 comprises: mannitol, aminoacid, salmon calcitonin are added in the entry dissolve, principal agent and the adjuvant concentration in mixed liquor is 0.1～5%, spray drying.
8, the preparation method of claim 7, wherein the spray drying inlet temperature is 105-115 ℃, outlet temperature is 70-80 ℃.
9, the preparation method of claim 7, the wherein preferred 800ml/min of nozzle air current amount during spray drying.
10, the preparation method of claim 7 further comprises dried powder is incapsulated.
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| Application Number | Priority Date | Filing Date | Title |
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| CNB2005100956459A CN100349611C (en) | 2005-11-25 | 2005-11-25 | Redfish calcitonin inhalation powder-atomizing agent and preparing method |
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| CNB2005100956459A CN100349611C (en) | 2005-11-25 | 2005-11-25 | Redfish calcitonin inhalation powder-atomizing agent and preparing method |
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| CN100349611C true CN100349611C (en) | 2007-11-21 |
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| CN102225058A (en) * | 2011-06-22 | 2011-10-26 | 中国药科大学 | Oseltamivir phosphate dry powder inhalations and preparation method thereof |
| CN102743339B (en) * | 2012-07-20 | 2015-01-14 | 苏州大学 | Alkaline phosphatase micro-/nano-particle and preparation method thereof |
| CN106727348B (en) * | 2016-12-20 | 2020-10-13 | 广州中大南沙科技创新产业园有限公司 | Moisture-proof and moisture-proof low-density carrier particles, and preparation method and application thereof |
| CN108969754B (en) * | 2018-09-04 | 2019-06-21 | 深圳大佛药业股份有限公司 | A kind of Salmon Calcitonin Nasal Spray and preparation method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0809654B1 (en) * | 1995-02-08 | 2000-04-12 | Therapicon Srl | Calcitonin salmon analogues, their preparation, medicinal use and use as analytical agents |
| CN1193745C (en) * | 2001-02-27 | 2005-03-23 | 国家医药管理局上海医药工业研究院 | Salmon calcitonin snuff and its prepn |
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2005
- 2005-11-25 CN CNB2005100956459A patent/CN100349611C/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0809654B1 (en) * | 1995-02-08 | 2000-04-12 | Therapicon Srl | Calcitonin salmon analogues, their preparation, medicinal use and use as analytical agents |
| CN1193745C (en) * | 2001-02-27 | 2005-03-23 | 国家医药管理局上海医药工业研究院 | Salmon calcitonin snuff and its prepn |
Non-Patent Citations (1)
| Title |
|---|
| 鲑降钙素吸入粉雾剂的制备及其药剂学性质研究 熊莲洁，等.药学学报，第38卷第3期 2003 * |
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