CN101549149B - New nasal spray formulation of calcitonin aqueous solution - Google Patents
New nasal spray formulation of calcitonin aqueous solution Download PDFInfo
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- CN101549149B CN101549149B CN2008102223193A CN200810222319A CN101549149B CN 101549149 B CN101549149 B CN 101549149B CN 2008102223193 A CN2008102223193 A CN 2008102223193A CN 200810222319 A CN200810222319 A CN 200810222319A CN 101549149 B CN101549149 B CN 101549149B
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Abstract
The invention relates to a new nasal spray formulation of a calcitonin aqueous solution, belonging to the technical field of formulations. By the screening of various auxiliary materials, the invention obtains a composition different from that reported in any literature documents from a plurality of prescriptions and applications thereof in preparing medicaments for treating osteoporosis, Paget disease, malignant hypercalcemia and the like. The main composition ingredients of the new formulation comprise 0.05-1mg/ml of calcitonin, 10-50mmol/L of phosphate buffer, 0.5-50mmol/L of disodium ethylene diamine tetraacetate, 0.06-2ug/ml of trasylol, 0.5-2 % (w/v) of sodium chloride or 0.5-10% (w/v) of mannite, 0.01-5% (w/v) of brij and 0.01-0.2 percent of benzalkonium bromide, thus preparing the formulation with unit volume of 0.1-10ml.
Description
Technical field
The invention belongs to the preparation technique field, relate to a kind of aqueous solution nasal spray formulation of new calcitonin particularly.
Background technology
Calcitonin belongs to the polypeptide hormone class, is used for the treatment of osteoporosis, Paget disease and malignant hypercalcemia.Calcitonin can extract from multiple source, comprises salmon, eel, pig and people.Wherein the calcitonin that aminoacid sequence is identical with native form is to make by chemosynthesis and recombinant technique.
The domestic existing commercially available dosage form of calcitonin has three kinds of injection, lyophilized injectable powder, nasal liquid spray, and route of administration has three kinds of subcutaneous injection, intramuscular injection and nasal spray administrations.Wherein, nasal cavity medicine is because of characteristics such as its medication are convenient, compliance is good, and application is stronger, has occupied the increasing market share on market.Yet the nasal liquid spray has only three tame list marketings on the domestic market, and wherein also having one family of Novartis is imported product, and its product far can not satisfy the needs of domestic market, and product price is also high.The present invention is intended to provide for domestic patient a kind of liquid preparation of new nasal-cavity administration, thereby selects for the more medication of domestic consumer, reduces the drug cost of extensive patients.Because the calcitonin product has been the market approval add that nasal-cavity administration has great advantage than other administering mode tools, thereby the present invention to have a good application prospect in good curative effects in aspect such as treatment osteoporosis, Paget disease and malignant hypercalcemias.
According to the patent of nasal-cavity administration calcitonin spray, adopt citrate as stabilizing agent and penetration enhancer, the bioavailability of its report is also lower, is 13.36 ± 3.38% (Chinese patent CN 01807605.X).The present invention is according to the characteristics of calcitonin and the requirement of nasal liquid spray, in numerous adjuvant selections and proportioning, screen, final kind and the ratio of determining various adjuvants among the present invention, by selecting suitable technology, the liquid nasal spray formulation of the salmon calcitonin that prepare the bioavailability height, has good stability.
Summary of the invention
The invention provides a kind of new calcitonin aqueous solution nasal spray formulation.
The evaluation index of estimating the nasal liquid spray mainly is bioavailability of medicament and stability.Because many medicines and adjuvant have harmful effect to the nasal cavity ciliary movement, cause that than strong stimulation untoward reaction such as nasal mucosa damage, nasal obstruction, allergy appear in life-time service.Therefore the adjuvant of selecting not have cilium toxicity, the patient respiratory defencive function not being had an influence is to estimate whether another important indicator of actual application value of preparation.
The nasal liquid spray is mainly by the passive absorption of nasal mucosa, molecular weight less than 1000, fat-soluble medicine is absorbed easily.The salmon calcitonin molecular weight is 3431.9, and hydrophilic is stronger, and it absorbs the slow transport through intercellular substance, and bioavailability is low, needs to add penetration enhancer, to satisfy the requirement of preparation.
PH value is another index of quality of the pharmaceutical preparations control.Low ph environment helps the stability of salmon calcitonin and the absorption of medicine, yet low pH value also can cause the atrophy of epidermis cell simultaneously, causes the discomfort of nasal cavity.
Osmotic pressure also is the index that preparation need be considered, for reducing zest, avoids untoward reaction such as haemolysis, and preparation should be kept and ooze with the grade of Cell sap or height oozes, and is concrete, should be equal to or higher than 250mOsm/L.
Because this product is designed to multiple dosing, for preventing microbial contamination, also needs to add suitable preservatives.
Penetration enhancer:
Nasal mucosa penetration enhancer commonly used at present has cholate, surfactant, intercalating agent, fatty acid, protease inhibitor etc.The transdermal enhancing effect of known cholate, fatty acid is directly proportional with its damage to body.In surfactant, anion surfactants such as sodium lauryl sulphate, sodium lauryl sulphate have obvious irritation to nasal cavity, therefore consider to select in non-ionic surface active agent suitable penetration enhancer and consumption.To polysorbas20 commonly used, Tween 80, Brij (Brij-78) with 0.1%
(w/v)Concentration carry out study on the stability.
The intercalating agent that is usually used in penetration enhancer has disodiumedetate (EDTA-Na
2), sodium ethylene diamine tetracetate calcium, cyclodextrin and derivant thereof.Owing to use human bioavailability can not reach requirement separately, therefore consider to select disodiumedetate (EDTA-Na
2) or DM-(MD-β-CD) use with nonionic surfactant combinations.EDTA-Na wherein
2Usually as antioxidant stabilizer and antibacterial, typical concentrations is 1-50mmol/L in liquid preparation.Simultaneously, EDTA-Na
2Be used for nasal formulations, can also promote the absorption of medicine at nasal mucosa, its mechanism of action may be to combine with some active ions such as calcium ion etc. on the mucosa, causes membrane permeability to increase and promotes the absorption of medicine.Sodium ethylene diamine tetracetate calcium also often is employed as chelating agen, but because this preparation may be used to treat hypercalcemia, the adding of sodium ethylene diamine tetracetate calcium may cause the increase of local blood calcium, therefore, does not carry out the test of sodium ethylene diamine tetracetate calcium.
Because the nasal cavity endoenzyme has very strong degraded destruction to protein and the polypeptide drug that enters nasal cavity, so the aprotinin existence can improve the absorption of polypeptide drug at nasal cavity.
The pH value stabilizing agent:
Salmon calcitonin stability under low ph environment is better, and pH value is low more in the 3.0-5.0 scope, and stability is good more.Cross low pH value and can cause uncomfortable sensation, when pH value 2.9, can cause the atrophy of epidermis cell.Take all factors into consideration, select the 3.5-4.5pH value to help the stability of this product, reduce stimulation simultaneously as far as possible nasal cavity.According to Chinese patent CN01807605.X, the control pH value is 3.7.According to the commonly used buffer salt system of two regulations of Chinese Pharmacopoeia version in 2005, buffering range has pH value 3.5-4.5's: phosphoric acid-triethylamine buffer system, phosphoric acid-phosphate buffer, acetic acid-sodium acetate buffer system, citric acid-citrate buffer system, citric acid-sodium hydrogen phosphate buffer solution system, ethanol-triethylamine buffer solution system, sodium formate buffer etc.Because formic acid, acetic acid have penetrating odor, nasal membrane is had zest, therefore phosphoric acid-phosphate buffer, phosphoric acid-triethylamine buffer system, citric acid-citrate buffer system, the citric acid-sodium hydrogen phosphate buffer solution system pH value buffer capacity of variable concentrations are investigated.In this pH value scope, citric acid-citrate buffer system, citric acid-sodium hydrogen phosphate buffer solution system, phosphoric acid-phosphate buffer all have stronger pH buffer capacity, therefore adopt phosphoric acid-phosphate buffer, contrast citric acid-citrate buffer system is as investigating object.
Osmotic pressure regulator:
Nose needs suitable osmotic pressure with solution, and osmotic pressure regulator commonly used has sodium chloride, mannitol, lactic acid etc.Through overtesting, 0.75%
(w/v)Sodium chloride or 5%
(w/v)Mannitol concentration all can give the osmotic pressure suitable with preparation.
Antiseptic:
Because this product is designed to multiple dosing,, need to add suitable preservatives for preventing microbial contamination.In antibacterial commonly used, selected phenethanol, benzyl alcohol, methyl hydroxybenzoate, ethyl hydroxybenzoate, propylparaben, benzalkonium bromide to carry out the test of this product.With parabens antiseptic consumption commonly used, be used for the solution of this preparation, can not dissolve fully.And adopting phenethanol, benzyl alcohol as antiseptic, preparation contains the response rate tangible reduction.Adopt 0.01%
(w/v)Benzalkonium bromide is less to cilium toxicity as antiseptic, and is good through testing its fungistatic effect, can suppress about 10 in 40 days
-6The growth of the staphylococcus aureus of cfu, escherichia coli, bacillus subtilis, Candida albicans, aspergillus niger.
According to result of study, determined a kind of new calcitonin aqueous solution nasal spray formulation, it is mainly formed and is: the disodiumedetate of the calcitonin of 0.222mg/ml, the phosphate buffer of 20mmol/L, 20mmol/L, 1ug/ml aprotinin, 0.75%
(w/v)Sodium chloride or 5%
(w/v)Mannitol, 0.1%
(w/v)Brij, 0.01%
(w/v)Benzalkonium bromide, be prepared into the preparation that specification is 0.222mg/ml.According to the clinical application amount, be suitable for making the preparation of each packing 0.1-5ml.
In preparation research, the stability of target product is the key point of preparation success or not, and the determiner of this index is except the character of principal agent, and most important is exactly the composition kind and the proportioning of adjuvant.Therefore, to make up according to a certain percentage be the difficult point and the focus of all preparation researches to various adjuvants.Investigate through a large amount of prescriptions, we comform and have obtained a kind of prescription that is different from present any bibliographical information in the side of many places and form (a kind of pharmaceutical composition), have good stability, the another optional practical plan for calcitonin aqueous solution preparation field has good industrialization prospect.
Detailed Description Of The Invention:
By required component of this product and trial test situation, the design orthogonal design, test the main evaluation index of the variation of (40 ℃ of high temperature, high light 4000 ± 500lxx placed respectively 10 days) back salmon calcitonin nasal spray agent content and related substance with the influence factor, carry out prescription screening as preparation stability.The prescription design is as table 1.
The screening (mg/ml) of table 1 salmon calcitonin nasal spray prescription
Study on the stability result to above prescription shows, increases EDTA-Na2 or MD-β-CD, and sample stability increases, but adds two kinds of adjuvant sample stability no significant differences.Simultaneously, add tween 20, tween 80 or Brij-78 sample stability no significant difference.
Prescription R2, R3, R5, R6, R8, R9 are measured its bioavailability, and the result shows that bioavailability R8＞R9 writes out a prescription greater than all the other, shows under test dose, uses the preparation bioavailability height of Brij, and is short effective thoroughly; The short saturating effect of EDTA-Na2 is stronger than tested number MD-β-CD, because EDTA-Na2 also has the effect of antioxidant and antibacterial simultaneously, therefore selects the penetration enhancer of EDTA-Na2 as preparation for use.
Design prescription once more according to result of the test, the results are shown in Table 2.
The screening once more (mg/ml) of table 2 salmon calcitonin nasal spray prescription
Influence factor's result of the test of his-and-hers watches 2 prescriptions shows, adopts 5%
(w/v)Mannitol is than adopting 0.75%
(w/v)Sodium chloride makes preparation have better stability; Increase EDTA-Na
2Consumption can improve stability of sample to 20mmol/L, can not cause tangible influence to stability but continue to increase its consumption.Therefore in preparation, select EDTA-Na for use
2Concentration be 20mmol/L.Use aprotinin can strengthen stability of sample simultaneously.
According to claim 1-4, this product prescription consists of: as the calcitonin of principal agent, as the Brij of penetration enhancer and disodiumedetate, as the mannitol of osmotic pressure regulator or sodium chloride, as the sodium hydrogen phosphate of pH value stabilizing agent and phosphoric acid, as the benzalkonium bromide of antiseptic, can also contain the aprotinin as penetration enhancer.Determine that according to every month consumption of 28 times the goods specification is every 3.5ml.Preparation prescription is:
Salmon calcitonin nasal spray preparation technology:
The cleaning of interior packaging material and sterilization: the used inner packing of preparation is 5ml U-save vial and quantitative nasal spray pump.Wherein quantitatively the nasal spray pump is be up to the standards packing, directly use after the assay was approved of microbial limit.The U-save vial uses purified water, water for injection washing respectively, and the sterilization pressure-air dries up, and is through 350 ℃ of oven dry of tunnel baking oven 15 minutes, standby.Check clarity and visible foreign matters before inner packing is used.
The preparation of salmon calcitonin nasal spray: measure Brij, disodiumedetate, sodium chloride, sodium hydrogen phosphate, 5% benzalkonium bromide solution, join in the 80% prescription water gaging by prescription, regulate pH value to 3.7 with phosphoric acid; Measure salmon calcitonin by prescription, with 10% recipe quantity water dissolution.Mix,, add water to recipe quantity with the degerming of 0.45um membrane filtration.Wherein used process water is water for injection.
The inspection of semifinished product: solution preparation back pick test, control project: pH value, content, related substance.
Fill: adjust the fill loading amount according to indicating loading amount with water for injection, the liquid of changing dressings begins fill.The fill loading amount of taking a sample to check.At any time check loading amount stability in the pouring process.Filling machine fill, gland carry out synchronously with machine.Fill finishes and clears out a gathering place.
Initial survey: after fill finished, product carried out initial survey, the clarity of lamp inspection solution and visible foreign matters.
Warehouse-in: initial survey qualified products counting, warehouse-in.
Check: sampling, press the quality standard check.
Outer package: after the examination and test of products is qualified, label, carry out outer package.
Stability of sample is investigated
According to the sample of each prescription of prescription design preparation, placed 40 ℃, intensity of illumination 4000 ± 500lxx condition respectively following 10 days, investigate its stability.The results are shown in Table 3.
Table 3 prescription is investigated its study on the stability
The bioavailability of medicine and the mensuration of plasma concentration
With reference to two calcitonin bioassary methods of Chinese Pharmacopoeia version in 2005, by the degree that working sample nasal-cavity administration and intravenously administrable cause blood calcium to reduce, measure calcitonin and tire, determine the bioavailability of medicine by nasal-cavity administration.
Preparing solvent: take by weighing bovine serum albumin 0.2g, add water 20ml, mixing is put 56 ℃ of water-bath kind insulations 1 hour, takes out and puts to room temperature, and is frozen down in-10 ℃～-20 ℃.Take out before the experiment, in 36 ℃ ± 0.5 ℃ water-bath, melt.Add in the aqueous solution that contains the 2g sodium acetate, add the about 3.5ml of concentrated hydrochloric acid, add water to the nearly 200ml of total amount again, regulate pH value to 3.5～4.5, add water to 200ml at last with hydrochloric acid or sodium hydroxide.
The above-mentioned solvent of the preparation of need testing solution combines the solution of 2 kinds of concentration by high low dosage, and highly concentrated solution concentration is controlled at 10ug/25ul.The ratio of high-concentration and low-concentration (r) is 2: 1.
Get healthy qualified, same source, body weight 220～250g, body weight difference and be no more than the female Wistar rats of 20g, fasting is 16 hours before the test, freely drinks distilled water, divides into groups immediately by body weight, and every group is no less than 5.Be used in combination ketamine and Sai La piperazine anesthetized rat, in carotid artery, insert conduit then.Fixing three-way valve on this conduit can be taken a sample to blood by this valve, and the available normal saline that comprises heparin is replaced blood.8mm in the rat nasal cavity is inserted in the tip of micropipette, thus the salmon calcitonin (sCT) of administration in the rat nasal cavity through preparing.The salmon calcitonin (sCT) of matched group tail vein injection same dose.For single dose research, the sCT of high low dosage group difference administration 10ug and 5ug.In multiple dose research, at 0,30,60 and 90 minute time-division, four administration sCT, each administration volume is 25ul, and the high low dosage group of accumulated dose is respectively 40ug and 20ug.
In single dose research, collect blood sample before administration and after the administration 5,15,30,60 and 120 minutes the time.In multiple dose research, collect blood sample during before administration and after the first administration 30,60,90,120 and 150 minutes.Before any other administration, always carry out the collection of blood sample.
Each blood sample (0.5ml) is collected in 1ml in the syringe of heparinization, is transferred to then in the refrigerated 1.5ml polypropylene tube, this polypropylene tube comprises the heparin (500U/ml) of 10ul.About 3000rpm, 2-8 ℃ of centrifugal down should the pipe 20 minutes, then the blood plasma supernatant is transferred in-20 ℃ of micro-centrifuge tubes that store down.Measure the blood calcium value with o-cresolphthalein complexone.Tire and experimental error according to quantitative response parallel assay method calculating in the bioassay statistic law (two appendix XIV of Chinese Pharmacopoeia version in 2005).Calculate the value (being equivalent to intravenous injection) of bioavailability by tire area under curve among the figure that the time is done of blood plasma sCT.
Bioavailability and plasma concentration when table 4 difference is write out a prescription the sCT rat intranasal administration of forming
| Prescription | Bioavailability (% ± sdev) | Maximal plasma concentration (% ± sdev) |
| R8 | 25.73±0.47 | 25.84±0.82 |
| R9 | 24.46±0.38 | 24.43±0.76 |
| R1-2 (containing aprotinin) | 28.54±2.79 | 28.62±3.03 |
| R1-6 (containing aprotinin, citrate) | 24.13±3.14 | 24.45±3.45 |
The specific embodiment
Embodiment 1
Prescription one is got salmon calcitonin 777mg and is made the solution that contains salmon calcitonin 2.22mg/ml with the water for injection dissolving; Brij 3.5g, disodium EDTA 3.5g, sodium hydrogen phosphate 25.07g, sodium chloride 31.5g, 5% benzalkonium bromide solution 7ml are dissolved in 80% amount water for injection, reconcile pH value to 3.7 with phosphoric acid, mix, with 0.45 μ m membrane filtration degerming, add water for injection to 3500ml, promptly.
Embodiment 2
Prescription two is got salmon calcitonin 777mg and is made the solution that contains salmon calcitonin 2.22mg/ml with the water for injection dissolving; Brij 3.5g, disodium EDTA 3.5g, sodium hydrogen phosphate 25.07g, 3.5mg aprotinin, sodium chloride 31.5g, 5% benzalkonium bromide solution 7ml are dissolved in 80% amount water for injection, reconcile pH value to 3.7 with phosphoric acid, mix, with 0.45 μ m membrane filtration degerming, add water for injection to 3500ml, promptly.
Claims (5)
1. the aqueous solution nasal spray formulation of a calcitonin, it is mainly formed: the Brij of the sodium chloride of the disodiumedetate of 0.05-1mg/ml calcitonin, 10-50mmol/L phosphate buffer, 0.5-50mmol/L, 0.5-2% (w/v) or the mannitol of 0.5-10% (w/v), 0.01-5% (w/v), the benzalkonium bromide of 0.01-0.2% (w/v) are prepared into the preparation that unit volume is 0.1-10ml.
2. preparation as claimed in claim 1, it is mainly formed: the Brij of the mannitol, 0.1% (w/v) of the sodium chloride or 5% (w/v) of the disodiumedetate, 0.75% (w/v) of 0.222mg/ml calcitonin, 20mmol/L phosphate buffer, 20mmol/L, 0.01-0.2% (w/v) benzalkonium bromide, being prepared into specification is 0.222mg/ml, the preparation of every 0.1-5ml.
3. preparation as claimed in claim 1, its another feature is: can also contain the 0.06-2ug/ml aprotinin.
4. preparation as claimed in claim 3, it is mainly formed: the disodiumedetate of 0.222mg/ml calcitonin, 20mmol/L phosphate buffer, 20mmol/L, 1ug/ml aprotinin, the benzalkonium bromide of the Brij, 0.01% (w/v) of the mannitol, 0.1% (w/v) of the sodium chloride of 0.75% (w/v) or 5% (w/v), being prepared into specification is 0.222mg/ml, the preparation of every 0.1-5ml.
5. any described preparation of claim 1-4 is used for the treatment of application in the medicine of osteoporosis, Paget disease and malignant hypercalcemia etc. in preparation.
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|---|---|---|---|
| CN2008102223193A CN101549149B (en) | 2008-09-17 | 2008-09-17 | New nasal spray formulation of calcitonin aqueous solution |
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| CN107753426A (en) * | 2017-10-19 | 2018-03-06 | 山东京卫制药有限公司 | A kind of sterile nasal spray of Ketotifen Fumarate and preparation method 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 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1422160A (en) * | 2000-02-04 | 2003-06-04 | 尤尼金实验室公司 | Nasal calcitonin formulations |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1422160A (en) * | 2000-02-04 | 2003-06-04 | 尤尼金实验室公司 | Nasal calcitonin formulations |
Non-Patent Citations (1)
| Title |
|---|
| 沈志红等.<鲑降钙素鼻喷雾剂的研制>.<中国医药工业杂志>.2002,第33卷(第8期),全文. * |
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