CN108014099A - A kind of suction tobramycin solution and preparation method thereof - Google Patents
A kind of suction tobramycin solution and preparation method thereof Download PDFInfo
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- CN108014099A CN108014099A CN201711352292.5A CN201711352292A CN108014099A CN 108014099 A CN108014099 A CN 108014099A CN 201711352292 A CN201711352292 A CN 201711352292A CN 108014099 A CN108014099 A CN 108014099A
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- tobramycin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/702—Oligosaccharides, i.e. having three to five saccharide radicals attached to each other by glycosidic linkages
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/007—Pulmonary tract; Aromatherapy
- A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
- A61K9/0078—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
Abstract
The present invention provides a kind of suction tobramycin solution, including the tobramycin and pH adjusting agent being dissolved in 2.25~4.5mg/ml sodium-chloride water solutions, the concentration of tobramycin is 60~75mg/ml, and pH adjusting agent is sulfuric acid, and the pH value of suction tobramycin solution is 5.8~6.2.Invention suction is simple with tobramycin solution constituent, and by controlling sulfuric acid dosage to control solution ph weakly acidic pH, osmotic pressure is closely isotonic, reduces suction tobramycin solution because irritation causes bronchial spasm and cough；And after suction of the present invention stores 1 year at normal temperatures with tobramycin solution, tobramycin content is declined slightly, related material is less than 1.0%, meet the requirement to tobramycin inhalation solution in USP, solving existing suction tobramycin solution needs store for 2~8 DEG C the shortcomings that, to facilitate patient medication and reduce storage and cost of transportation.
Description
Technical field
The invention belongs to pharmaceutical technology field, and in particular to a kind of suction tobramycin solution and preparation method thereof.
Background technology
Cystic fibrosis (Cystic fibrosis) is a kind of common lethal autosomal recessive hereditary diseases, capsule
Fibrosis Europe and North America incidence about 1/ (2000~3000), in Asia, incidence is more European low with North America, U.S.
The incidence of state white man baby is about 1/3300, and Black people baby is about 1/15300, and Asian American is about 1/32000, diseased people
70% is child or adolescent in group.Learnt from the cystic fibrosis case analysis reported, cystic fibrosis has death
The characteristics of rate is high, median survival interval is short.Cystic fibrosis can cause water, the transhipment of bicarbonate plasma film to be affected, from
And produce sticky secretion.These secretion accumulate in different organs, block and form different cystic fibrosis symptoms,
As the chlorinity in sweat increases, indigestion, chronic pancreatitis, bronchial infection and air flue obstructive symptom, and fertility energy
Power decline etc., dysfunction are the most prominent with respiratory system damage.The respiratory secretions of cystic fibrosis patient is bacterium life
Long good culture medium, the baby with cystic fibrosis can continue that staphylococcus aureus or haemophilus influenzae or copper occurs
Bronchial infection caused by green pseudomonad, wherein it is most commonly seen with charrin disease, and incidence and case fatality rate are high.
The anti-infective therapy of pseudomonas aeruginosa can pass through the approach such as oral, vein and Neulized inhalation.Inhalation can
So that medicine directly acts on bronchial infection position, make treatment more efficient, while also reduce whole body application antibiotic not
Good reaction risk, has clinical advantage.And suction is the suitable nothing of a kind of apyrogeneity, preservative free, pH with tobramycin solution
Bacteria preparation, has listed in the international mainstream country such as the U.S., Japan, European Union, and wherein U.S.'s Time To Market is earliest, i.e., and 1997
PathoGenesis Corporation on December 22, (being now Novartis Pharmaceuticals Corp) are granted at first
300mg/5ml suction tobramycin solutions, trade name Tobi, on October 12nd, 2012, Chiesi USA Inc are granted
300mg/4mL suction tobramycin solutions, trade name Bethkis.Suction is tobamycin injection with tobramycin solution
Improved formulations, overcome tobramycin drug administration by injection and kill breathing because osmotic energy force difference causes infection site drug concentration low
The problem of pseudomonas aeruginosa effect in road sputum is poor.
Chinese patent CN1529589A discloses " optimal formulation for being used for aerosolized tobramycin ", and said preparation includes
75mg/ml is dissolved in the tobramycin in 045%w/V sodium-chloride water solutions, and wherein pH mole oozes between 4.0~5.5
Thoroughly pressure concentration in the range of 250~450mOsm/l, the patent invention improve be by the concentration of active ingredient tobramycin by
60mg/ml is improved to 75mg/ml, and in the case where dosage is constant, administered volume, which reduces, can shorten the atomized medicine introducing time, but
It is the place that the patent comes with some shortcomings：(1) for the pH of suction tobramycin solution between 4.0~5.5, pH value is relatively low,
Patients bronchial's spasm and cough can be caused, the serious compliance for reducing patient；(2) tobramycin bulk pharmaceutical chemicals are in alkalescent, when
Suction adds more pH adjusting agent sulfuric acid with the pH of tobramycin solution when between 4.0~5.5, it is necessary into preparation,
Sulfuric acid is easier to form tobramycin sulfate with tobramycin under acid condition, increases the content of tobramycin sulfate in liquid
Add, can also reduce the osmotic pressure of suction tobramycin solution；(3) suction is with the micro oxygen meeting dissolved in tobramycin solution
Degraded tobramycin, the stability of preparation reduce, and the storage temperature of the suction tobramycin solution of list marketing at present is 2
~8 degree, the term of validity is 2 years, and 25 degree of room temperature preserves the term of validity only 28 days.
In addition, Chinese patent CN105616345A disclose " a kind of tobramycin composition for inhalation and preparation method thereof and
Purposes ", said composition include：Tobramycin 4%~8% (w/v), sodium chloride 0.1%~0.9% (w/v), as stabilizer
Week reduction organic monoacid 0.1%~1.0% (w/v), for adjusting the strong acid of the composition pH, remaining is injection
Water；The pH value of wherein described composition is 5.6~7.5；The invention uses 0.1%~1.0% malic acid, tartaric acid, citric acid
Improve the stability of preparation as stabilizer, at the same by adjusting pH in particular range (preferably 5.6-7.5) to reduce branch gas
The generation of pipe spasm, but there is also clearly disadvantageous for the patent：(1) respiratory tissues can not bear the inhalation solution of alkalescence
(because alkaline inhalation solution can cause serious bronchial spasm), thus, alkaline inhalation solution is to be prohibited from using, beautiful to this
State's patent 5508269 has been disclosed when studying suction with tobramycin solution Tobi；(2) although malic acid, tartaric acid, citric acid
The stability of preparation can be improved, but since malic acid, tartaric acid, citric acid have different degrees of tart flavour, especially lemon
Tart flavour is extremely sour and has astringent taste, and undesirable taste can reduce the compliance of patient.
The content of the invention
The purpose of the present invention is overcoming stability existing for existing suction tobramycin solution poor, cause bronchial spasm
The problem of probability is big.
The technical scheme is that providing a kind of suction tobramycin solution, including it is dissolved in 2.25~4.5mg/
Tobramycin and pH adjusting agent in ml sodium-chloride water solutions, the concentration of tobramycin is 60~75mg/ml, and pH adjusting agent is sulphur
Acid, and the pH value of suction tobramycin solution is 5.8~6.2.
A kind of embodiment of optimization, the suction further include antioxidant with tobramycin solution.
Further, the antioxidant is carbonic acid or/and cysteine.
Further, the concentration of the cysteine is 0.005mg/ml~0.03mg/ml.
Further, the concentration of the cysteine is 0.015mg/ml~0.03mg/ml.
The design principle of above-mentioned suction tobramycin solution：Suction is developed by Novartis Co., Ltd earliest with tobramycin solution
Succeed and list, trade name Tobi, specification 300mg/5ml, the concentration of sodium chloride is 0.225%, i.e. 2.25mg/ml, the U.S.
Pharmacopeia (USP) 40 provides the pH value 4.5~6.5 of suction tobramycin solution, and osmotic pressure is between 165~190mOsm/l.Inhale
The adverse reaction such as bronchoconstriction and cough can not only be caused with the osmotic pressure of tobramycin solution is too high or too low by entering, while
Can influence the atomization of preparation, such as be atomized liquid particle diameter and particle diameter distribution, atomization speed, due in Tobi sodium chloride it is dense
Irritation can be also easy to produce because hypotonic, will be inhaled in the present invention for 2.25mg/ml, osmotic pressure between 165~190mOsm/l by spending
Enter and improved with tobramycin solution osmotic pressure near isotonic, the irritation because caused by hypotonic can be effectively improved.And the present invention is same
When by the control of the pH value of suction tobramycin solution 5.8~6.2, one side suction tobramycin solution is in weakly acidic pH bar
Oxidative degradation is very fast under part, although pH value reduce can to avoid the speed of oxidative degradation, such as pH at 3.0,4.5 oxidation drop
Solution, which can obtain, effectively to be overcome, but induction can be greatly increased under the conditions of pH 3.0,4.5 there is a phenomenon where bronchial spasm, thus
Suction directly affects the stability and drug safety of preparation with the pH of tobramycin solution, and pH to the stability of preparation and
The influence contrast of drug safety, i.e. stability improve, then security reduces；Otherwise security improves, stability
Reduce, it is not only with good stability by the control of its pH value 5.8~6.2 in the present invention, and also drug safety, Bu Huiyin
Play bronchial spasm；On the other hand, since tobramycin is in alkalescent, the pH of suction tobramycin solution and the dosage of sulfuric acid
Related, pH value is lower, and the dosage of required sulfuric acid is bigger, and since tobramycin can form tobramycin sulfate, sulphur with sulfuric acid
Acid forms after tobramycin sulfate the osmotic pressure that can lower suction tobramycin solution with tobramycin, and sulfuric acid dosage oozes more greatly
Saturating pressure drop is low more, and the dosage of sulfuric acid can influence the correlated performance and security of suction tobramycin solution；In short, suction is used
The dosage of tobramycin solution pH and sulfuric acid, the security of preparation, the performance of stability and preparation have the complexity of inherence
Association, thus only mono- index of pH and the inherent quality of preparation has close relationship.
For the embodiment of optimization, contain antioxidant in suction tobramycin solution, can effectively slow down appropriate cloth
The oxidative degradation of mycin, so as to improve the stability of suction tobramycin solution.As carbonic acid is that a kind of binary is weak in the present invention
Acid, dissociation constant all very littles, easily decompose release carbon dioxide, and the carbon dioxide discharged can reduce dissolved oxygen amount and residual oxygen in liquid
Amount, the oxidative degradation of tobramycin can be reduced by reducing oxygen content in suction tobramycin solution；And discharge two in carbonic acid
When oxidizing gas, the bubble of formation is avoided that dissolved oxygen is contacted with tobramycin, delays the oxidation of tobramycin, improves system
The stability of agent；The carbon dioxide of carbonic acid release at the same time can form carbonic acid again with water, can be in dynamic equilibrium in preparation, reach
Oxidation resistant effect for a long time；In addition suction with tobramycin solution in use, ultrasonic atomizer can make carbonic acid be decomposed into two
Carbonoxide and discharge, can be to avoid injury of the carbonic acid to human body.Cysteine is a kind of common amino acid, safe, can
For medicine, cosmetics, Biochemical Research etc., cysteine has reproducibility, can slow down the oxidative degradation of tobramycin；
And cysteine oxidation product is cystine, cystine belongs to amino acid together, and security is also high, i.e. reduzate cysteine and oxygen
Change product cystine security is high, and simultaneous oxidation product cystine can dissolve sputum, can strengthen tobramycin and kill verdigris vacation
Monad；In addition cysteine and Ag+, Hg+, Cu+Insoluble mercaptides, i.e. R-S-M ' can be formed Deng metal ion, R-S-
M "-S-R (M ', M " they are respectively 1 valency, divalent metal), thus influence of the metal ion to preparation can be reduced.
In addition, present invention also offers the preparation method of above-mentioned suction tobramycin solution, include the following steps：
1) sodium chloride is dissolved in cumulative volume 60~80%, temperature is in 25~30 DEG C of water for injection, stir to complete
Simultaneously inflated with nitrogen is dissolved, forms sodium-chloride water solution；
2) tobramycin is added into sodium-chloride water solution, stirs to being completely dissolved, adds 3~5mol/L sulfuric acid tune pH
It is worth to 5.8~6.2；
3) filling water for injection is settled to cumulative volume, stirs evenly, and is filtered with 0.22 μm of filter, and filling in low-density
In polyethylene material bottle, up to suction tobramycin solution.
Further, antioxidant has been additionally added in sodium-chloride water solution in the step 2).
Further, the antioxidant added in the step 2) in sodium-chloride water solution is that concentration is 0.005mg/ml
The cysteine of~0.03mg/ml.
Further, the antioxidant added in the step 2) in sodium-chloride water solution is carbonic acid, its Adding Way
It is 5.6~5.7 to be filled with the pH of carbon dioxide to solution into sodium-chloride water solution before tobramycin adds.The present invention
Middle suction derives from the carbon dioxide being filled with into sodium-chloride water solution and injection with the carbonic acid in tobramycin solution
Water is generated, and carbonic acid is a kind of weak diacid, and dissociation constant all very littles, under room temperature, normal pressure, carbon dioxide saturated solution pH is
5.6, pH is reached 3.7, (can really improve CO by cooling down, pressurizeing2Concentration) realize, the heat endurance of carbonic acid
Difference, can decompose in heating or vibration and release carbon dioxide, prepare in the water for injection used in suction tobramycin solution
It is oxygen-containing, carbon dioxide is few, be far from the saturated concentration for reaching normal temperature and pressure conditions carbon dioxide, and the present invention uses
Filling CO 2 gas terminal point control is carried out to suction tobramycin solution filling CO 2 gas, and with pH5.6~5.7,
Ensure that gas concentration lwevel reaches saturation or nearly saturation in each batch suction tobramycin solution.
Further, the antioxidant added in the step 2) in sodium-chloride water solution is carbonic acid and concentration is
The cysteine of 0.005mg/ml~0.03mg/ml, its Adding Way are first to sodium-chloride water solution before tobramycin addition
In to be filled with the pH of carbon dioxide to solution be 5.6~5.7, then sequentially add into sodium-chloride water solution cysteine and appropriate
Obramycin.
Compared with prior art, beneficial effects of the present invention：
(1) this suction provided by the invention is simple with tobramycin solution constituent, its pH value weakly acidic pH, oozes at the same time
Pressure is near isotonic thoroughly, it is possible to reduce suction tobramycin solution causes bronchial spasm and cough；And the present invention is sucked with appropriate
After Obramycin solution stores 1 year at normal temperatures, tobramycin content is declined slightly, and related material is less than 1.0%, meets USP
In requirement to tobramycin inhalation solution, solving existing suction tobramycin solution needs lacking in 2~8 DEG C of storages
Point, facilitates patient medication and reduces storage and cost of transportation.
(2) this suction tobramycin solution provided by the invention can be slowed down or be avoided by filling CO 2 gas
Oxidative degradation of the tobramycin under weakly acidic pH environment, improves the stability of the suction tobramycin solution；And dioxy
The carbonic acid and carbonic acid decomposition for changing carbon and water formation are in dynamic equilibrium, can realize antioxidation for a long time.
(3) this suction tobramycin solution provided by the invention, can by adding the cysteine with reproducibility
Effectively delay the oxidative degradation of tobramycin, while cysteine oxidation product is cystine, cystine belongs to amino acid together, safety
Property it is high, and cystine can dissolve sputum, can strengthen tobramycin and kill pseudomonas aeruginosa.
(4) this suction provided by the invention is remarkably improved disease with tobramycin solution compared with being injected intravenously administration
The drug concentration of affected part position, improves curative effect, reduces whole body toxic side effect.
Embodiment
The technical solution in the embodiment of the present invention is clearly and completely described below, it is clear that described embodiment
Only part of the embodiment of the present invention, instead of all the embodiments.Based on the embodiments of the present invention, the common skill in this area
All other embodiment that art personnel are obtained without making creative work, belongs to the model that the present invention protects
Enclose.
Embodiment 1：
0.9g sodium chloride is dissolved in 140ml temperature is in 30 DEG C of water for injection, and stirring is to being completely dissolved and inflated with nitrogen
20min, then adds 15g tobramycin, stirs to being completely dissolved, adds 5mol/L sulfuric acid tune pH value to 5.8, use if necessary
1mol/L sodium hydroxide solution tune pH value is to 5.8, then injects water to 200ml, stirs 15min, then with 0.22 μm of filtering
Device filters, and filling in low density polyethylene (LDPE) material bottle, up to suction tobramycin solution；Suction is used obtained by the present embodiment
Tobramycin solution osmolarity is 247mOsm/l.
Embodiment 2：
0.9g sodium chloride is dissolved in 120ml temperature is in 28 DEG C of water for injection, and stirring is to being completely dissolved and inflated with nitrogen
30min, then the pH of filling CO 2 gas to solution is 5.7, sequentially adds 1mg cysteines and 12g tobramycin, stirs
Mix to being completely dissolved, add 3mol/L sulfuric acid tune pH value to 5.9, if necessary with 1mol/L sodium hydroxide solution tune pH value extremely
5.9, then 200ml is injected water to, 20min is stirred, is then filtered with 0.22 μm of filter, and it is filling in low density polyethylene (LDPE)
In material bottle, up to suction tobramycin solution；Suction obtained by the present embodiment is with tobramycin solution osmolarity
232mOsm/l。
Embodiment 3：
0.9g sodium chloride is dissolved in 140ml temperature is in 30 DEG C of water for injection, and stirring is to being completely dissolved and inflated with nitrogen
20min, then the pH of filling CO 2 gas to solution is 5.7, then adds 15g tobramycin, stirring to being completely dissolved, then
4mol/L sulfuric acid tune pH value is added to 6.1, if necessary with 1mol/L sodium hydroxide solution tune pH value to 6.1, then adds water for injection
To 200ml, 30min is stirred, is then filtered with 0.22 μm of filter, and it is filling in low density polyethylene (LDPE) material bottle, up to inhaling
Enter to use tobramycin solution；Suction is 243mOsm/l with tobramycin solution osmolarity obtained by the present embodiment.
Embodiment 4：
0.9g sodium chloride is dissolved in 160ml temperature is in 25 DEG C of water for injection, and stirring is to being completely dissolved and inflated with nitrogen
40min, then the pH of filling CO 2 gas to solution is 5.6, then adds 15g tobramycin, stirring to being completely dissolved, then
5mol/L sulfuric acid tune pH value is added to 6.0, if necessary with 1mol/L sodium hydroxide solution tune pH value to 6.0, then adds water for injection
To 200ml, 15min is stirred, is then filtered with 0.22 μm of filter, and it is filling in low density polyethylene (LDPE) material bottle, up to inhaling
Enter to use tobramycin solution；Suction is 245mOsm/l with tobramycin solution osmolarity obtained by the present embodiment.
Embodiment 5：
0.9g sodium chloride is dissolved in 120ml temperature is in 30 DEG C of water for injection, and stirring is to being completely dissolved and inflated with nitrogen
20min, sequentially adds 3mg cysteines and 15g tobramycin, stirs to being completely dissolved, adds 5mol/L sulfuric acid tune pH
Value if necessary with 1mol/L sodium hydroxide solution tune pH value to 6.1, then injects water to 200ml to 6.1, stirs 30min,
Then filtered with 0.22 μm of filter, and it is filling in low density polyethylene (LDPE) material bottle, up to suction tobramycin solution；This
Suction is 252mOsm/l with tobramycin solution osmolarity obtained by embodiment.
Embodiment 6：
0.9g sodium chloride is dissolved in 140ml temperature is in 30 DEG C of water for injection, and stirring is to being completely dissolved and inflated with nitrogen
20min, then the pH of filling CO 2 gas to solution is 5.7, sequentially adds 6mg cysteines and 15g tobramycin, stirs
Mix to being completely dissolved, add 5mol/L sulfuric acid tune pH value to 6.2, if necessary with 1mol/L sodium hydroxide solution tune pH value extremely
6.2, then 200ml is injected water to, 15min is stirred, is then filtered with 0.22 μm of filter, and it is filling in low density polyethylene (LDPE)
In material bottle, up to suction tobramycin solution；Suction obtained by the present embodiment is with tobramycin solution osmolarity
249mOsm/l。
Embodiment 7：
0.45g sodium chloride is dissolved in 160ml temperature is in 30 DEG C of water for injection, and stirring is to being completely dissolved and inflated with nitrogen
30min, then the pH of filling CO 2 gas to solution is 5.7, sequentially adds 4mg cysteines and 15g tobramycin, stirs
Mix to being completely dissolved, add 5mol/L sulfuric acid tune pH value to 6.2, if necessary with 1mol/L sodium hydroxide solution tune pH value extremely
6.2, then 200ml is injected water to, 15min is stirred, is then filtered with 0.22 μm of filter, and it is filling in low density polyethylene (LDPE)
In material bottle, up to suction tobramycin solution；Suction obtained by the present embodiment is with tobramycin solution osmolarity
221mOsm/l。
Comparative example 1：
0.9g sodium chloride is dissolved in 140ml temperature is in 30 DEG C of water for injection, and stirring is to being completely dissolved and inflated with nitrogen
20min, then adds 15g tobramycin, stirs to being completely dissolved, and adds 5mol/L sulphur acid for adjusting pH value to 5.2, if necessary
With 1mol/L sodium hydroxide solution tune pH value to 5.2, then 200ml is injected water to, 15min is stirred, then with 0.22 μm of mistake
Filter filters, and filling in low density polyethylene (LDPE) material bottle, up to suction tobramycin solution；Gained suction is mould with appropriate cloth
Plain solution osmolarity is 236mOsm/l.
Comparative example 2：
Weigh tobramycin 15g, sodium chloride 0.9g and citric acid 1.6g to put with liquid filling, add 140ml waters for injection, control
Temperature is stirred to whole dissolvings at 30 DEG C, appropriate with the sulfuric acid solution of 5mol/L, adjusts pH to 6.0, benefit injects water to
200ml, stirs evenly, and is filtered through 0.22 μm of filter membrane, and filling in low density polyethylene (LDPE) material bottle, molten up to suction tobramycin
Liquid；Gained suction is 241mOsm/l with tobramycin solution osmolarity.
Comparative example 3：
0.45g sodium chloride is dissolved in 140ml temperature is in 30 DEG C of water for injection, and stirring is to being completely dissolved and inflated with nitrogen
20min, then adds 12g tobramycin, stirs to being completely dissolved, and adds 5mol/L sulphur acid for adjusting pH value to 6.0, if necessary
With 1mol/L sodium hydroxide solution tune pH value to 6.0, then 200ml is injected water to, 15min is stirred, then with 0.22 μm of mistake
Filter filters, and filling in low density polyethylene (LDPE) material bottle, up to suction tobramycin solution；Gained suction is mould with appropriate cloth
Plain solution osmolarity is 164mOsm/l.
Experimental example 1：
1~3 sample of 1~7 sample of the embodiment of the present invention and comparative example is taken, at 25 DEG C ± 2 DEG C, 60% ± 10% conditions of RH
Lower investigation stability, samples respectively at 0, December, observes sample appearance, measure content, related material, the result is shown in table 1.Content
And in relation to substance-measuring method with reference to American Pharmacopeia USP40 suction assay under tobramycin solution kind item and related
Substance-measuring method, the limit of assay is 90.0~110%, is 1.0% in relation to the total miscellaneous limit of material.
Table 1：
The result shows that color slightly deepens after 1~7 sample of the embodiment of the present invention is investigated 12 months at normal temperatures, tobramycin
Content is declined slightly, and related material meets the requirement to tobramycin inhalation solution in USP also below 1.0%, and comparative example
1st, 3 color samples significantly deepen, particularly the total miscellaneous limit 1.0% beyond USP40 of the related material of comparative example 3.
Experimental example 2：
Investigate and give the present invention suction tobramycin solution for preparing to animal schneiderian membrance, tracheal epithelium, lung tissue
Irritation test.Suction prepared by the present invention is 300mg/4ml with tobramycin solution specification, and usage and dosage is 2 times/day,
300mg/ times, i.e. Coming-of-Age Day is 10mg/kg (600mg/60kg) with dosage, then it is 60mg/kg to be converted into rat dose,equivalent.Tool
Body experimental program is as follows：
Animal pattern：SPF grades, SD rats, 6~8 week old, half male and half female, 80.
Experiment packet：It is randomly divided into 8 groups, i.e. 1 group of embodiment, 3 groups of embodiment, 5 groups of embodiment, 6 groups of embodiment, comparative example
1 group, 2 groups of comparative example, 3 groups of comparative example and negative control group, every group each 10.
Dosage：Test medicine group animal according to dosage gives suction tobramycin solution (300mg/4ml)；It is negative right
Sodium chloride injection is given according to group；Each group is administered twice a day, more than two minor tick 6h, gives rat 100mg/ within continuous 14 days
The suction tobramycin solution of kg/d (10 times) dosage.
Method of administration：Through snout inhalation.
Testing index：To observation post administration animal overall health of patients (such as breathing, circulation, central nervous system) and local excitation disease
Shape (such as asthma, cough, vomiting, asphyxia symptom).24h puts to death animal, observation respiratory tract local (nose, larynx, gas after the last administration
Pipe, bronchus) mucosal tissue whether there is phenomena such as congested, red and swollen, and carries out histopathologic examination.
Experimental result：The suction tobramycin solution of rat 100mg/kg/d (10 times) dosage is given within continuous 14 days, often
Animal overall health of patients is visually observed after secondary administration, observation animal larynx, glottis mucous membrane whether there is bleeding and oedema, and both sides lung surface has
Without bleeding, infection, pulmonary emphysema, trachea-bronchial epithelial cell and its branch's mucous membrane whether there is congested, bleeding and infection.1 group of embodiment, implement
3 groups of example, 5 groups of embodiment, 6 groups of embodiment are without obvious stimulation symptom, and larynx, glottis mucous membrane are without bleeding and oedema, both sides lung surface
Without bleeding, infection, lung without consolidation or pulmonary emphysema；Trachea-bronchial epithelial cell and its branch's mucous membrane have no bright without congested, bleeding and infection
Aobvious foam sample inflammatory exudate；Histopathological examination shows that lung tissue is showed no bleeding, inflammatory cell infiltration, fibroplasia etc.
Obvious pathological change；Tracheal epithelium, subcutaneous tissue have no obvious pathological change；Vestibule of nose portion squamous epithelium, respiratory region mucous membrane
Olfactory region epithelium has no the pathological changes such as bleeding, cell infiltration；It is similar with negative control group.And compared with negative control group, it is right
2 groups of ratio, 3 groups of comparative example have slight irritation, are become apparent with the performance of comparative example 2；1 group of glottis mucous membrane of comparative example, branch
Tunica mucosa tracheae has slight congested phenomenon.
Experiment conclusion：The appropriate cloth of suction prepared by the suction embodiment of the present invention 1, embodiment 3,5 groups of embodiment, embodiment 6
After mycin solution, animal schneiderian membrane, tracheae, lungs are showed no obvious abnormalities and pathological change, show suction prepared by the present invention
Enter small to respiratory system local irritation, safe with tobramycin solution.
Experimental example 3：
The suction tobramycin solution sample for taking the embodiment of the present invention 1,3,5,6 and comparative example 1,3 to prepare, to sample
Performance detection measure delivery rate, delivering total amount.Delivery rate with delivering total amount with reference to suction preparation (《Chinese Pharmacopoeia》(2015
Year version) general rule 0111 the 3rd method compressed for the liquid preparation delivery rate of atomizer with delivering total amount method, Pari Boy air
Machine, Parilc Plus types atomizer) measure；Its testing result is as shown in table 2.
Table 2：
| Sample source | Delivery rate (mg/min) | Deliver total amount (mg) |
| Embodiment 1 | 6.9 | 125.2 |
| Embodiment 3 | 6.7 | 131.7 |
| Embodiment 5 | 6.8 | 128.8 |
| Embodiment 6 | 6.8 | 127.1 |
| Comparative example 1 | 6.8 | 129.8 |
| Comparative example 3 | 6.7 | 125.6 |
Experimental example 4：
According to the preparation process of embodiment, the suction tobramycin solution that 200ml concentration is 75mg/ml, chlorination are prepared
The dosage of sodium is 0.9g, wherein prepare the suction tobramycin solution of different pH value with 5mol/L sulfuric acid, obtain pH for 4.0,
5.2nd, 6.0 suction tobramycin solution, investigates the osmotic pressure of suction tobramycin solution under the conditions of variant pH, delivering
Speed, delivering total amount, the results are shown in Table 3 for it.
Table 3：
Experimental example 5：
Investigation gives 1,3,5,6 sample of the embodiment of the present invention and physiological saline and pseudomonas aeruginosa killing effect is tested.
Specific experiment scheme is as follows：
Animal and packet：Clean (SPF) level, 6~8 week old male and healthy sprague dawley (SD) rats, by 100
Rat is randomly divided into 5 groups, every group 20.
Establish pulmonary inflammation model：After experimental rat is weighed, 10% chloraldurate (0.4mL/ is injected intraperitoneally by 3ml/kg dosage
G) anaesthetize, be fixed on special-purpose operating table, hit exactly and sterilize from neck, cut skin, blunt separation uses 1mL until exposure tracheae
Syringe is by 0.2mL P. aeruginosas bacteria suspension (about 6 × 108CFU/mL after) transtracheal is slowly injected into, rat is uprightly rocked
3min, makes bacterium be uniformly distributed in two lungs as far as possible.
Administration：After when inoculation 4 is small, it is administered when every 24 is small respectively.Suction prepared by the A group Neulized inhalations embodiment of the present invention 1
Enter and use tobramycin solution, suction tobramycin solution prepared by the B group Neulized inhalations embodiment of the present invention 3, C group Neulized inhalations
Suction tobramycin solution prepared by the embodiment of the present invention 5, the suction of the preparation of the D group Neulized inhalations embodiment of the present invention 6 is with appropriate
Obramycin solution, E groups are physiological saline Neulized inhalation.Abundant bloodletting after after treatment rat was put to death in 1,3,5,7 day, takes
Double lungs, left lung ice normal saline flushing 3 times, is placed in glass homogenizer and adds 2mL physiological saline grinding 15min, lung group is made
Homogenate is knitted, 10 doubling dilution lung homogenates, take each 100 μ l of concentration to be inoculated on MH agar mediums successively, 32 DEG C of incubations
24h, chooses tablet of the bacterium colony between 30~300 and carries out bacterium colony counting, the results are shown in Table 4 for count of bacteria.
Table 4：
As seen from Table 4, A groups, B groups, C groups, D groups kill the effect of pseudomonas aeruginosa and are superior to E groups, and C groups, D groups are killed
The effect of pseudomonas aeruginosa is better than A groups, B groups, so as to show, suction prepared by present invention tobramycin solution has preferable
Kill pseudomonas aeruginosa effect, and in tobramycin solution addition cysteine can strengthen tobramycin to kill verdigris false single
Born of the same parents bacterium.
The foregoing examples are only illustrative of the present invention, does not form the limitation to protection scope of the present invention, all
It is to be belonged to the same or similar design of the present invention within protection scope of the present invention.
Claims (10)
- A kind of 1. suction tobramycin solution, it is characterised in that：Including being dissolved in 2.25~4.5mg/ml sodium-chloride water solutions In tobramycin and pH adjusting agent, the concentration of tobramycin is 60~75mg/ml, and pH adjusting agent is sulfuric acid, and is sucked with appropriate The pH value of Obramycin solution is 5.8~6.2.
- 2. suction tobramycin solution as claimed in claim 1, it is characterised in that：Further include antioxidant.
- 3. suction tobramycin solution as claimed in claim 2, it is characterised in that：The antioxidant for carbonic acid or/and Cysteine.
- 4. suction tobramycin solution as claimed in claim 3, it is characterised in that：The concentration of the cysteine is 0.005mg/ml~0.03mg/ml.
- 5. suction tobramycin solution as claimed in claim 4, it is characterised in that：The concentration of the cysteine is 0.015mg/ml~0.03mg/ml.
- 6. the preparation method of suction tobramycin solution as claimed in claim 1, it is characterised in that：Include the following steps：1) sodium chloride is dissolved in cumulative volume 60~80%, temperature is in 25~30 DEG C of water for injection, stirring is to being completely dissolved And inflated with nitrogen, form sodium-chloride water solution；2) tobramycin is added into sodium-chloride water solution, stirs to being completely dissolved, adds 3~5mol/L sulfuric acid tune pH value extremely 5.8~6.2；3) plus water for injection is settled to cumulative volume, stirs evenly, and is filtered with 0.22 μm of filter, and filling in low density polyethylene (LDPE) In material bottle, up to suction tobramycin solution.
- 7. the preparation method of suction tobramycin solution as claimed in claim 6, it is characterised in that：In the step 2) Antioxidant has been additionally added in sodium-chloride water solution.
- 8. the preparation method of suction tobramycin solution as claimed in claim 7, it is characterised in that：In the step 2) The antioxidant added in sodium-chloride water solution is the cysteine that concentration is 0.005mg/ml~0.03mg/ml.
- 9. the preparation method of suction tobramycin solution as claimed in claim 7, it is characterised in that：In the step 2) The antioxidant added in sodium-chloride water solution is carbonic acid, its Adding Way is to sodium-chloride water solution before tobramycin adds In be filled with carbon dioxide to solution pH be 5.6~5.7.
- 10. the preparation method of suction tobramycin solution as claimed in claim 7, it is characterised in that：In the step 2) The cysteine that the antioxidant added in sodium-chloride water solution is carbonic acid and concentration is 0.005mg/ml~0.03mg/ml, Its Adding Way is 5.6 to be first filled with the pH of carbon dioxide to solution into sodium-chloride water solution before tobramycin addition ~5.7, then cysteine and tobramycin are sequentially added into sodium-chloride water solution.
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| CN111693622A (en) * | 2020-06-16 | 2020-09-22 | 上海市食品药品检验所 | Tobramycin raw material and related preparation impurity mass spectrum analysis method |
| CN113952320A (en) * | 2021-09-18 | 2022-01-21 | 健康元药业集团股份有限公司 | Drug assembly containing tobramycin inhalation solution and application thereof |
| CN115554280B (en) * | 2022-09-27 | 2023-08-18 | 东南大学 | Preparation method of tobramycin powder aerosol for inhalation |
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