CN103932985B - zinc gluconate oral spray and preparation method thereof - Google Patents
zinc gluconate oral spray and preparation method thereof Download PDFInfo
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Abstract
The present invention relates to a kind of Zinc gluconate oral spray and preparation method thereof.This oral spray component by quality proportioning is: A: zinc gluconate: 28 ~ 164 parts; B: pharmaceutic adjuvant: glycerol 10 ~ 60 parts, sucralose 1 ~ 6 part, glycine 9 ~ 53 parts, fruit flavor agent 10 ~ 60 parts, purified water 1000 ~ 6000 parts; C: antibacterial: sodium benzoate 0.05 ~ 0.29 part, benzalkonium chloride 0.05 ~ 0.29 part.Made by rising temperature for dissolving, stirring, filtration sterilization, subpackage, products obtained therefrom dosage form is spray, through mouthspray administration, enable zinc ion infiltrate in nose, pharynx and sensitive organization of nasal sinuses portion with cold virus receptors bind, make the zinc ion in nose, pharynx, nasal sinuses portion mucosa define one barrier, stop cold virus spread further at iuntercellular and reach the object for the treatment of flu, alleviating the symptom of flu.
Description
Technical field
The present invention relates to and a kind ofly treat flu, the Zinc gluconate oral spray alleviating cold symptoms and preparation method thereof, belong to medical art.
Background technology
Flu is one of modal disease in the world, the cause of disease of flu mostly is suffers from cold and viral infection causes, there is the virus of kind more than 200 can cause flu morbidity, comprise rhinovirus (most commonly encountered diseases because of), coronavirus, adenovirus, the thin virus of respiratory syncystial and parainfluenza virus.Flu is a kind of disease that can not be ignored, and is one of major public health problem of facing mankind.Annual sickness rate of catching a cold according to statistics is 10 ~ 30%, and all parts of the world has thousands of people to infect every year.Almost everybody has personal experience, life all one's life almost nobody do not suffer from flu, symptom is: nasal obstruction, rhinorrhea, sneeze, cough, heating, systemic pain etc.The course of disease is usually at 1 ~ 2 week, if treatment can bring out the diseases such as pharyngitis, otitis media, bronchitis, pneumonia, acute nephritis, rheumatism and myocarditis not in time.This sick sickness rate is high, and infectiousness is strong, produces cause high risks to people's health and human labour.Crowd is by infect or inoculation can produce immunity in recent years, but to new variant viral strain unprotect effect.Because the variation of cold virus is very fast, and people often lack immunity to the cold virus new germline produced that makes a variation, so the outburst of flu and to be very popular may be catastrophic.
At home, gluconic acid zinc preparation is in a large number as zinc supplement, the product being used for the treatment of flu aspect is little, the zinc gluconate nasal spray that existing Nanjing Xingyin Pharmaceutical Industry Co., Ltd., Deng Jijia manufacturing enterprise of Shandong Tianshun Pharmaceutical Co., Ltd. produce, specification 15g:0.3g, every bottle 120 spray, often spray is containing zinc gluconate 2.5mg.Nasal spray is strong to nasal mucosa zest, and patient accepts difficulty.And interrelated data is reported, use zinc gluconate nasal spray to cause and permanently lose olfactory sensation, patient accepts difficulty clinically.
Chinese patent document CN1408358A discloses the prescription composition of a kind of zinc gluconate (colloid) nasal spray, and principal agent is zinc gluconate, and because nasal spray is strong to nasal mucosa zest, patient accepts difficulty.
Chinese patent document CN1100306A discloses a kind of compound zinc gluconate capsules, tablet, buccal tablet and preparation method thereof, principal agent is zinc gluconate, ibuprofen, chlorphenamine, be processed into capsule, tablet, buccal tablet, this buccal tablet mouthfeel is pained, because zinc gluconate discharges zinc ion rapidly in oral cavity, there is a kind of peculiar taste, poor containing sense of taste when changing, be not suitable with the use of patient.Relevant report zinc gluconate both at home and abroad direct gastrointestinal tract oral medication flu curative effect is undesirable.
Above invention technology is compound preparation, containing chlorphenamine, and has drowsiness side effect of Denging; Therefore driver, to operate machine or work high above the ground personnel need be cautious use of.Due to above various deficiency, existing zinc gluconate cold-treating preparation product is very limited in clinical practice.
Chinese patent document CN101961321B discloses zinc gluconate sugar-tablet preparation and preparation method thereof, principal agent is zinc gluconate, by with suitable pharmaceutic adjuvant, made by steps such as high temperatureization sugar, vacuum sugar boilings, its dosage form is translucent hard sugar sheet, through buccal administration, sugar-tablet, by buccal, reaches treatment flu, alleviates the object of the symptom of flu.This sugar-tablet overcomes the defect of above-mentioned preparation to a certain extent, but following points are not enough:
1, this invention sugar-tablet volume is comparatively large, and sugar-tablet is about 4.5g heavily about, and within less than 7 years old, child's buccal easily causes danger;
2, this invention is because this sugar-tablet is containing white sugar amount higher (be about sugar-tablet sheet heavy 32.28%), and having diabetes patient cannot normally take;
3, this invented technology is comparatively complicated, and in particularly sugar cook process, temperature is higher, easily causes the decomposition under zinc gluconate and pharmaceutic adjuvant hot conditions, and the change of chemical constitution essence occurs.
Summary of the invention
The present invention is directed to the deficiencies in the prior art, provide a kind of and treat flu, the Zinc gluconate oral spray alleviating cold symptoms and preparation method thereof.
Technical scheme of the present invention is as follows:
A kind of Zinc gluconate oral spray, be made up by mass parts of following raw material:
A: zinc gluconate: 28 ~ 164 parts;
B: pharmaceutic adjuvant: glycerol 10 ~ 60 parts, sucralose 1 ~ 6 part, glycine 9 ~ 53 parts, fruit flavor agent 10 ~ 60 parts, purified water 1000 ~ 6000 parts;
C: antibacterial: sodium benzoate 0.05 ~ 0.29 part, benzalkonium chloride 0.05 ~ 0.29 part.
Preferably, a kind of Zinc gluconate oral spray, be made up by mass parts of following raw material:
A: zinc gluconate 28 ~ 120 parts;
B: pharmaceutic adjuvant: glycerol 10 ~ 44 parts, sucralose 1 ~ 4 part, glycine 9 ~ 39 parts, fruit flavor agent 10 ~ 44 parts, purified water 1000 ~ 4390 parts;
C: antibacterial: sodium benzoate 0.05 ~ 0.21 part, benzalkonium chloride 0.05 ~ 0.21 part.
Preferred further, a kind of Zinc gluconate oral spray, be made up by mass parts of following raw material:
A: zinc gluconate 28 parts;
B: pharmaceutic adjuvant: glycerol 10 parts, sucralose 1 part, glycine 9 parts, fruit flavor agent 10 parts, purified water 1000 parts
C: antibacterial: sodium benzoate 0.05 part, benzalkonium chloride 0.05 part;
Or
A: zinc gluconate 120 parts;
B: pharmaceutic adjuvant: glycerol 44 parts, sucralose 4 parts, glycine 39 parts, fruit flavor agent 44 parts, purified water 4390 parts;
C: antibacterial: sodium benzoate 0.21 part, benzalkonium chloride 0.21 part;
Or
A: zinc gluconate 74 parts;
B: pharmaceutic adjuvant: glycerol 27 parts, sucralose 2.5 parts, glycine 24 parts, fruit flavor agent 27 parts, purified water 2695 parts;
C: antibacterial: sodium benzoate 0.13 part, benzalkonium chloride 0.13 part.
What the raw material that the invention described above uses was not specified is conventional commercial products.
The preparation method of the Zinc gluconate oral spray of the invention described above, step is as follows:
(1) by recipe quantity take zinc gluconate, glycine, glycerol, sodium benzoate, benzalkonium chloride, sucralose, purified water and seasoning fruit flavor agent for subsequent use;
(2) in dissolving tank, add zinc gluconate, glycine, glycerol, sucralose and purified water, open and stir, be heated to 60 ~ 80 DEG C, make it dissolve completely, room temperature is for subsequent use;
(3) step (2) gained solution, after degerming with 0.22 μm of membrane filtration, be delivered in sterilized tank, room temperature is for subsequent use;
(4) in dissolving tank, add sodium benzoate, the fruit flavor agent of benzalkonium chloride and seasoning and purified water, open and stir, be heated to 50 ~ 70 DEG C, make it dissolve completely, room temperature is for subsequent use;
(5) feed liquid obtained with step (4) for feed liquid obtained for step (3) is mixed, stir, obtain supernatant liquid;
(6) solution of above-mentioned steps (5) gained is sub-packed in spray bottle; Quan Jian, packaging, warehouse-in.
According to the present invention, preferably, above-mentioned steps (1), (2), (4), (5), (6) are all implemented under 100,000 grades of clean internal conditions.
According to the present invention, further preferably, a kind of preparation method of Zinc gluconate oral spray, step is as follows:
(1) by recipe quantity take zinc gluconate, glycine, glycerol, sodium benzoate, benzalkonium chloride, sucralose, purified water and seasoning fruit flavor agent for subsequent use;
(2) in dissolving tank, add zinc gluconate, glycine, glycerol, sucralose and purified water, open and stir, be heated to 80 DEG C, make it dissolve completely, room temperature is for subsequent use;
(3) step (2) gained solution, after degerming with 0.22 μm of membrane filtration, be delivered in sterilized tank, room temperature is for subsequent use;
(4) in dissolving tank, add sodium benzoate, the fruit flavor agent of benzalkonium chloride and seasoning and purified water, open and stir, be heated to 50 DEG C, make it dissolve completely, room temperature is for subsequent use;
(5) feed liquid obtained with step (4) for feed liquid obtained for step (3) is mixed, stir, obtain supernatant liquid;
(6) solution of above-mentioned steps (5) gained is sub-packed in spray bottle; Quan Jian, packaging, warehouse-in.
Above-mentioned steps (1), (2), (4), (5), (6) are all implemented under 100,000 grades of clean internal conditions.
Zinc gluconate oral medicine spray preparation of the present invention, employing zinc gluconate is effective ingredient, with pharmaceutic adjuvant Gan You ﹑ Gan An Suan ﹑ tri-chlorine Zhe Tang ﹑ fruit flavor agent and purified water, and antibacterial sodium benzoate and benzalkonium chloride etc., pass through rising temperature for dissolving, stir, filtration sterilization, subpackage is made, products obtained therefrom dosage form is spray, wherein in the present invention, add correctives glycine, zinc ion complexation in glycine and zinc gluconate, slow releasing zinc ion in oral cavity, avoid the metal sense of taste of zinc ion on the one hand, clinical effect continues slow releasing zinc ion and extends drug effect object to reach on the other hand, so mouthfeel is good, people are made more to be happy to take.Through mouthspray administration, enable zinc ion infiltrate in nose, pharynx and sensitive organization of nasal sinuses portion with cold virus receptors bind, make the zinc ion in nose, pharynx, nasal sinuses portion mucosa define one barrier, stop cold virus spread further at iuntercellular and reach the object for the treatment of flu, alleviating the symptom of flu.
In preparation method described in invention, Zinc gluconate oral spray is quality controllable.
In preparation method of the present invention, Zinc gluconate oral spray quality standard is following but do not limit the following stated Zinc gluconate oral spray standard.
Zinc gluconate oral spray quality standard
This product is containing zinc gluconate (C
12h
22o
14zn) should be 93.0% ~ 107.0% of labelled amount.
[character] this product character is colourless or micro-yellow liquid, and taste is sweet.
[discriminating] (1) is got this product 1ml(and is about equivalent to zinc gluconate 0.1g), the 50ml that adds water adds ferric chloride test solution 1, should show buff after diluting.
(2) aqueous solution of this product shows the identification of zinc salt, according to " Chinese Pharmacopoeia version two (annex III) in 2010 "
Every regulation relevant under [inspection] should meet " Chinese Pharmacopoeia version two (annex IF) in 2010 " spray item.
[assay] precision measures this product appropriate (being about equivalent to zinc gluconate 0.35g), add water 10ml, ammonification-ammonium chloride buffer (pH10.0) 5ml, add ammonium fluoride 1g again and chromium black T indicator a little, be titrated to solution with Calcium Disodium Versenate volumetric solution (0.05mol/L) and change aeruginous into from aubergine, and lasting 30 seconds do not fade.Every 1ml Calcium Disodium Versenate volumetric solution (0.05mol/L) is equivalent to the C of 22.78mg
12h
22o
14zn.
Zinc gluconate oral spray formu of the present invention safety, efficient, quality controllable, easy to use, though this spray be formula compared with existing zinc gluconate cold medicine, dosage form or have significant distinctive feature in preparation method.
Be specially:
1, do not contain chlorphenamine in Zinc gluconate oral spray formu formula of the present invention, patient takes rear without drowsiness property, and the people being applicable to various working environment use.
2, correctives glycine is added in the present invention, zinc ion complexation in glycine and zinc gluconate, slow releasing zinc ion in oral cavity, avoids the metal sense of taste of zinc ion on the one hand, and clinical effect continues slow releasing zinc ion and extends drug effect object to reach on the other hand; The dosage form of Zinc gluconate oral spray formu is supernatant liquid, and mouthfeel is good, compliance is strong, patient gladly accepts, and is particularly suitable for old man and child's use.
3, Zinc gluconate oral spray of the present invention passes through mouthspray, zinc ion is enable to infiltrate nose, pharynx and sensitive organization of nasal sinuses portion and be combined with ICAM-1 virus receptor, zinc ion in such nose, pharynx, nasal sinuses portion mucosa defines one barrier, stops cold virus spread further at iuntercellular and reach the object for the treatment of flu, alleviating the symptom of flu.
4, Zinc gluconate oral spray is multiple agent type, adds sodium benzoate, benzalkonium chloride antibacterial, to prevent spray in use microbiological contamination.
In conjunction with the prescription of Zinc gluconate oral spray, determine adjuvant, and its consumption is screened.Make oral spray quality controllable, be easy to suitability for industrialized production.
Zinc gluconate oral spray should be delicious good to eat, and easily accepted by patient, therefore mouthfeel is an important inspection target.The present invention makes correctives with fruit flavor agent, glycine, screens its consumption; With taste, outward appearance, be shaped to standard.The results are shown in Table 1.
Table 1 correctives consumption the selection result (unit: g)
| Prescription component | 1 | 2 | 3 | 4 | 5 | 6 |
| Zinc gluconate | 28 | 28 | 28 | 28 | 28 | 28 |
| Sucralose | 1 | 1 | 1 | 1 | 1 | 1 |
| Sodium benzoate | 0.05 | 0.05 | 0.05 | 0.05 | 0.05 | 0.05 |
| Benzalkonium chloride | 0.05 | 0.05 | 0.05 | 0.05 | 0.05 | 0.05 |
| Glycerol | 10 | 10 | 10 | 10 | 10 | 10 |
| Glycine | 0 | 3 | 6 | 9 | 12 | 15 |
| Fruit flavor agent | 10 | 10 | 10 | 10 | 10 | 10 |
| Purified water | 1000 | 1000 | 1000 | 1000 | 1000 | 1000 |
Prescription evaluation and result:
Prescription 1; Appearance luster is even, and taste is obviously puckery;
Prescription 2; Appearance luster is even, and taste is more puckery;
Prescription 3; Appearance luster is even, and taste is micro-puckery;
Prescription 4; Appearance luster is even, and taste is suitable for;
Prescription 5; Appearance luster is even, and taste is suitable for;
Prescription 6; Appearance luster is even, and taste is suitable for;
Comprehensive above prescription, result is visible, and differences in appearance is not obvious.Prescription 1,2,3, middle mouthfeel astringent taste is obvious, mouthfeel is not good, and the not obvious taste of prescription 4,5,6 astringent sense is suitable for, and is applicable to the requirement of prescription, consider supplementary product consumption in preparation, determine the most preferred quantities selecting the consumption of fruit flavor agent and glycine in prescription 4 as the correctives of this preparation.
Because Zinc gluconate oral spray is multiple agent type, therefore antibacterial must be added.As the antibacterial of Zinc gluconate oral spray, not only require effectively, also require rapidly, namely within the interval time of patient's repeatedly medication, reach antibacterial.According to the requirement of Zinc gluconate oral spray, because single antibacterial Chang Buneng reaches quick-acting object, therefore adopt compound preservative to play synergism, improve bactericidal potency.Sodium benzoate is added to embodiment 1, the Zinc gluconate oral spray of benzalkonium chloride opens bottle cap and carry out microbial limit Analysis of test results; The results are shown in Table 2.
Table 2 Zinc gluconate oral spray microbial limit is analyzed
Have in table and analyze known, after adding antibacterial, Zinc gluconate oral spray opens bottle cap 8 days; The equal conformance with standard of microbial limit.
Accompanying drawing explanation
Fig. 1 is that Zinc gluconate oral spray of the present invention contrasts with the clinical efficacy of ribavirin aerosol, and Zinc gluconate oral spray is the product of embodiment 1, see embodiment 7.
Detailed description of the invention
Below in conjunction with embodiment, the present invention is described further, but be not limited thereto.
In embodiment, supplementary material source is described as follows:
| Supplementary material title | Manufacturing enterprise | Operative norm |
| Zinc gluconate | Desheng, Shanghai science and technology group (Anqing) pharmaceutical Co. Ltd | Chinese Pharmacopoeia 2010 editions two |
| Sucralose | JK Sucralose Inc | National standard (GB25531) |
| Sodium benzoate | Zhenjiang advance Chemical Co., Ltd. | Chinese Pharmacopoeia 2010 editions two |
| Glycerol | Hu'nan Erkang Pharmaceutical Co., Ltd. | Chinese Pharmacopoeia 2010 editions two |
| Glycine | Jinzhou Ji Rong aminoacid company limited | Chinese Pharmacopoeia 2010 editions two |
| Benzalkonium chloride | Shanghai Jinshan longitude and latitude Chemical Co., Ltd. | Chinese Pharmacopoeia 2010 editions two |
| Fruit flavor agent | Beijing Powdery Food Co., Ltd. | National standard (GB2760-2007) |
| Purified water | Shandong Sibangde Pharmaceutical Co., Ltd. | Chinese Pharmacopoeia 2010 editions two |
Device involved in embodiment and equipment are oral spray and produce common apparatus, and market can be purchased.Be described as follows:
Dissolving tank 200L: Shandong Medical Devices Co., Ltd. of Xinhua.
Micro semi-auto double end filling machine (model QGBW): Yangzhou Mei Da filling machine company limited.
The preparation of embodiment 1, Zinc gluconate oral spray
A: zinc gluconate 28 parts;
B: pharmaceutic adjuvant: glycerol 10 parts, sucralose 1 part, glycine 9 parts, fruit flavor agent 10 parts, purified water 1000 parts;
C: antibacterial: sodium benzoate 0.05 part, benzalkonium chloride 0.05 part;
Be prepared as follows and form:
(1) in 100,000 grades of clean areas, by recipe quantity take zinc gluconate, glycine, glycerol, sodium benzoate, benzalkonium chloride, sucralose, purified water and seasoning fruit flavor agent for subsequent use.
(2) in 100,000 grades of clean areas, add zinc gluconate, glycine, glycerol, sucralose and purified water in dissolving tank, open and stir, be heated to 80 DEG C, make it dissolve completely, room temperature is for subsequent use;
(3) step (2) gained solution, after degerming with 0.22 μm of membrane filtration, be delivered in sterilized tank, room temperature is for subsequent use;
(4) in 100,000 grades of clean areas, in dissolving tank, add sodium benzoate, the fruit flavor agent of benzalkonium chloride and seasoning and purified water, open and stir, be heated to 50 DEG C, make it dissolve completely, room temperature is for subsequent use;
(5) in 100,000 grades of clean areas, feed liquid obtained with step (4) for feed liquid obtained for step (3) is mixed, stirs, obtain supernatant liquid;
(6) in 100,000 grades of clean areas, above-mentioned solution is sub-packed in spray bottle, every bottle of 22ml.Finally, Quan Jian, packaging, warehouse-in.20100301。
The preparation of embodiment 2, Zinc gluconate oral spray
A: zinc gluconate 120 parts;
B: pharmaceutic adjuvant: glycerol 44 parts, sucralose 4 parts, glycine 39 parts, fruit flavor agent 44 parts, purified water 4390 parts;
C: antibacterial: sodium benzoate 0.21 part, benzalkonium chloride 0.21 part;
Be prepared as follows and form:
(1) in 100,000 grades of clean areas, by recipe quantity take zinc gluconate, glycine, glycerol, sucralose, purified water and seasoning fruit flavor agent for subsequent use.
(2) in 100,000 grades of clean areas, add zinc gluconate, glycine, glycerol, sodium benzoate, benzalkonium chloride, sucralose and purified water in dissolving tank, open and stir, be heated to 60 DEG C, make it dissolve completely, room temperature is for subsequent use;
(3) step (2) gained solution, after degerming with 0.22 μm of membrane filtration, be delivered in sterilized tank, room temperature is for subsequent use;
(4) in 100,000 grades of clean areas, in dissolving tank, add sodium benzoate, the fruit flavor agent of benzalkonium chloride and seasoning and purified water, open and stir, be heated to 70 DEG C, make it dissolve completely, room temperature is for subsequent use;
(5) in 100,000 grades of clean areas, feed liquid obtained with step (4) for feed liquid obtained for step (3) is mixed, stirs, obtain supernatant liquid;
(6) in 100,000 grades of clean areas, above-mentioned solution is sub-packed in spray bottle, every bottle of 22ml.Finally, Quan Jian, packaging, warehouse-in.Batch number: 20100302.
The preparation of embodiment 3, Zinc gluconate oral spray
Zinc gluconate oral spray, supplementary material is composed as follows:
A: zinc gluconate 74 parts;
B: pharmaceutic adjuvant: glycerol 27 parts, sucralose 2.5 parts, glycine 24 parts, fruit flavor agent 27 parts, purified water 2695 parts;
C: antibacterial: sodium benzoate 0.13 part, benzalkonium chloride 0.13 part;
Be prepared as follows and form:
(1) in 100,000 grades of clean areas, by recipe quantity take zinc gluconate, glycine, glycerol, sodium benzoate, benzalkonium chloride, sucralose, purified water and seasoning fruit flavor agent for subsequent use.
(2) in 100,000 grades of clean areas, add zinc gluconate, glycine, glycerol, sucralose and purified water in dissolving tank, open and stir, be heated to 70 ~ 80 DEG C, make it dissolve completely, room temperature is for subsequent use;
(3) step (2) gained solution, after degerming with 0.22 μm of membrane filtration, be delivered in sterilized tank, room temperature is for subsequent use;
(4) in 100,000 grades of clean areas, in dissolving tank, add sodium benzoate, the fruit flavor agent of benzalkonium chloride and seasoning and purified water, open and stir, be heated to 60 ~ 70 DEG C, make it dissolve completely, room temperature is for subsequent use;
(5) in 100,000 grades of clean areas, feed liquid obtained with step (4) for feed liquid obtained for step (3) is mixed, stirs, obtain supernatant liquid;
(6) in 100,000 grades of clean areas, above-mentioned solution is sub-packed in spray bottle, every bottle of 22ml.Finally, Quan Jian, packaging, warehouse-in.Batch number: 20100303.
The preparation of embodiment 4, Zinc gluconate oral spray
Zinc gluconate oral spray, supplementary material is composed as follows:
A: zinc gluconate 28 parts;
B: pharmaceutic adjuvant: glycerol 10 parts, sucralose 1 part, glycine 9 parts, fruit flavor agent 10 parts, purified water 1000 parts
C: antibacterial: sodium benzoate 0.05 part, benzalkonium chloride 0.05 part;
Be prepared as follows and form:
(1) in 100,000 grades of clean areas, by recipe quantity take zinc gluconate, glycine, glycerol, sodium benzoate, benzalkonium chloride, sucralose, purified water and seasoning fruit flavor agent for subsequent use.
(2) in 100,000 grades of clean areas, add zinc gluconate, glycine, glycerol, sodium benzoate, benzalkonium chloride, sucralose and purified water in dissolving tank, open and stir, be heated to 60 ~ 70 DEG C, make it dissolve completely, room temperature is for subsequent use;
(3) step (2) gained solution, after degerming with 0.22 μm of membrane filtration, be delivered in sterilized tank, room temperature is for subsequent use;
(4) in 100,000 grades of clean areas, in dissolving tank, add sodium benzoate, the fruit flavor agent of benzalkonium chloride and seasoning and purified water, open and stir, be heated to 50 ~ 60 DEG C, make it dissolve completely, room temperature is for subsequent use;
(5) in 100,000 grades of clean areas, feed liquid obtained with step (4) for feed liquid obtained for step (3) is mixed, stirs, obtain supernatant liquid;
(6) above-mentioned solution is sub-packed in spray bottle, every bottle of 22ml.Finally, Quan Jian, packaging, warehouse-in.Batch number: 20100304.
Embodiment 5, Zinc gluconate oral spray oral mucosa irritation test
1, test material
(1) medicine: Zinc gluconate oral spray, Zinc gluconate oral spray (lot number 20100301) prepared by embodiment 1, every bottle of 22ml(is containing zinc gluconate 27.2mg/ml), stand-by, Shandong Sibangde Pharmaceutical Co., Ltd. of manufacturing enterprise.
Excipient (blank spray): with the adjuvant of embodiment 1, by the preparation method of embodiment 1, do not add zinc gluconate, obtained liquid, stand-by.
(2) animal: animal Wistar rat 24, male and female half and half, body weight 220 ~ 280g, is provided by Shandong University's Experimental Animal Center.
2, experimental technique
2.1 groupings: 30 rat are divided into A, B two groups at random, often organize 6.A group is medication group, and B group is excipient (blank spray).
2.2 dosage medicine group consumptions are equivalent to 45 times of human dose.
First number before 2.3 medication administrations and weigh in afterwards, and survey respiratory frequency.Medication is with reference to new drug preclinical study guideline compilation, specific as follows.A, B two groups rat to spray Zinc gluconate oral spray solution every day respectively, to excipient (blank spray) solution 3 times, each 3 sprays, are equivalent to 45 times of human dose.Conventional raising after administration.Successive administration 7 days.After last spray medicine, 24h puts to death rat, takes out bottleneck throat mucosal tissue, checks.
2.4 observed contents observe the death condition after rat medication, the change (with or without hyperemia, redness, color dot, festering) of animal overall health of patients (body weight, breathing, the mental status, quadruped locomotion situation etc.) and bottleneck throat mucosa local.
3, experimental result
3.1 overall health of patients are at viewing duration, and compare before and after the medication of medication group rat self, compare with solvent control group and blank group, overall health of patients shows no obvious abnormalities, and partial data sees the following form 3,4.
Table 3 oral stimulation reaction scoring
Result: gross examination of skeletal muscle display Zinc gluconate oral spray is to the oral cavity intact mucosa of Golden Hamster and the equal nonirritant of damaged mucosa; Histopathologic examination's display Zinc gluconate oral spray does not all produce the pathological changes such as inflammation to intact mucosa and damaged mucosa; Histopathology scoring display Zinc gluconate oral spray is to intact mucosa and the equal nonirritant of damaged mucosa.
The scoring of table 4 oral cavity tissue reaction microscope
| Grouping | Number of animals | Accumulative stimulation index | Irritant reaction |
| Zinc gluconate oral spray intact mucosa group | 6 | 0 | Nonirritant |
| The damaged mucosa group of Zinc gluconate oral spray | 6 | 0 | Nonirritant |
| Excipient (blank) intact mucosa group | 6 | 0 | Nonirritant |
| The damaged mucosa group of excipient (blank) | 6 | 0 | Nonirritant |
Conclusion: Zinc gluconate oral spray is to the oral mucosa nonirritant of Golden Hamster, and therefore, Zinc gluconate oral spray is treated flu in treatment, alleviated in the symptom of flu is safe.
4, experiment conclusion
Experimental result shows, and high dose Zinc gluconate oral spray (being equivalent to 4 times of human dose) is after bottleneck throat topical, and overall health of patients and the bottleneck throat local mucous membrane of tested rat are showed no exception.Visible, Zinc gluconate oral spray local application to laboratory animal bottleneck throat mucosa without obvious irritation.Can think that the medication of Zinc gluconate oral spray bottleneck throat is safe.
Embodiment 6, Zinc gluconate oral spray are to acute toxicity test in mice
1, test material
(1) medicine: the Zinc gluconate oral spray (lot number 20100301) prepared by embodiment 1, every bottle of 22ml(is containing zinc gluconate 27.2mg/ml), stand-by, Shandong Sibangde Pharmaceutical Co., Ltd. of manufacturing enterprise.
(2) animal: Kun Ming mice, body weight 18 ~ 22g, 50.Male and female half and half, grade is regular grade; Thered is provided by Shandong University's Experimental Animal Center.
2, test method
By 50 white mice, be divided into 5 groups at random, often organize 10, male and female half and half, after fasting 8 hours (can't help water), press medicine 250g/kg, 300g/kg, 360g/kg, 432g/kg, 518g/kg respectively, gastric infusion, 1 dosage≤0.8ml, low dose group single administration, high dose group can administration at twice in 24 hours, observes the situation such as spirit, behavior, diet of white mice after administration.Record mice dying T/A, cuts open the dead white mice of inspection, observes the pathological change of each organs and tissues, experiment totally 7 days, add up mice dying number after off-test, with SPSS13.0 computed in software Zinc gluconate oral spray to the LD50 of white mice and 95% fiducial limit thereof, the results are shown in Table 5
Table 5 Zinc gluconate oral spray acute toxicity test in mice
| Dosage (g/kg) | Number of animals/only | Death toll/only | Mortality rate % | Survival rate % |
| 250 | 10 | 0 | 0 | 100 |
| 300 | 10 | 0 | 0 | 100 |
| 360 | 10 | 2 | 20% | 80 |
| 432 | 10 | 3 | 30% | 70 |
| 518 | 10 | 4 | 40% | 60 |
Conclusion: Zinc gluconate oral spray is to the LD50 of mice and 95% fiducial limit thereof, and LD50 is 419g/kg, 95% is crediblely limited to 370 ~ 459g/kg, proves that Zinc gluconate oral spray toxicity is very low; Clinical drug safety.
Embodiment 7, Zinc gluconate oral spray Preliminay clinical trials
1, test material
(1) medicine: the Zinc gluconate oral spray (lot number 20100301) prepared by embodiment 1, every bottle of 22ml(is containing zinc gluconate 27.2mg/ml), manufacturing enterprise: Shandong Sibangde Pharmaceutical Co., Ltd..
Ribavirin spray: Penglai, shandong Province Nuo Kang pharmaceutcal corporation, Ltd, specification is every bottle and includes ribavirin 400mg, often presses containing the accurate word H20043189 of ribavirin 3mg(traditional Chinese medicines);
(2) study subject: this test comprises 100 study subjects altogether, 1.5 ~ 11 years old age (average 3.2 years old), random packet; To the summary of these study subjects in table 6.Result of the test is: the experimenter of (N=100) 100% completes test.
The experimenter personnel that table 6. is tested
2, test method
(1) inclusion criteria: meet flu diagnostic criteria: patient occur in the cold symptoms such as nasal obstruction, sneeze, watery nasal discharge, throat pain, cough, hoarseness 2 and more than, can with symptoms such as heating, headache, systemic pain, weak discomforts; Get rid of the above-mentioned symptom that other diseases causes; Patient need meet above 3 conditions simultaneously; Occur in above-mentioned symptom 24 ~ 48h.
(2) requirement is taken: all Eligible subjects accept every day 4 times during this period, each two sprays, every minor tick 2 hours treatment; Cold patients, must not in the half an hour before or after spray clothes at clinical period Zinc gluconate oral spray, edible citrus fruit or fruit juice.
(3) clinical indexes
All selected objects, by experienced clinicist's detailed medical history-taking, make physical examination, and are recorded in time " in clinical trial patient chart (CRF) ".
Observe every day and record experimenter's symptom, sign situation of change.Duration of test itemized record diet situation, does not change dietary habit without special circumstances, and close observation also has no adverse reaction in recording medicine process.In table 7;
Table 7. observes the symptoms scoring
Result: pass through controlled clinical trial, add up according to table 7 pair cold symptoms total mark, calculate according to total mark and throw off a cold the time, always have 100 cold patients and finally reach evaluation criteria (all cold symptoms disappearances), its average cold symptoms course of disease of Zinc gluconate oral spray group is 3 ± 1.1 days, the average cold symptoms course of disease of ribavirin spray group is 3 ± 1.2 days, 2 groups of comparing difference not statistically significants (P ﹥ 0.05), show that 2 kinds of clinical drug curative effects are consistent, be treatment flu, alleviate the active drug of cold symptoms.See the curative effect comparision of Fig. 1 Zinc gluconate oral spray and ribavirin spray.
Claims (7)
1. a Zinc gluconate oral spray, is characterized in that, is made up by mass parts of following raw material:
A: zinc gluconate 28 ~ 120 parts;
B: pharmaceutic adjuvant: glycerol 10 ~ 44 parts, sucralose 1 ~ 4 part, glycine 9 ~ 39 parts, fruit flavor agent 10 ~ 44 parts, purified water 1000 ~ 4390 parts;
C: antibacterial: sodium benzoate 0.05 ~ 0.21 part, benzalkonium chloride 0.05 ~ 0.21 part.
2. Zinc gluconate oral spray as claimed in claim 1, is characterized in that, be made up of following raw material by mass parts:
A: zinc gluconate 28 parts;
B: pharmaceutic adjuvant: glycerol 10 parts, sucralose 1 part, glycine 9 parts, fruit flavor agent 10 parts, purified water 1000 parts;
C: antibacterial: sodium benzoate 0.05 part, benzalkonium chloride 0.05 part.
3. Zinc gluconate oral spray as claimed in claim 1, is characterized in that, be made up of following raw material by mass parts:
A: zinc gluconate 120 parts;
B: pharmaceutic adjuvant: glycerol 44 parts, sucralose 4 parts, glycine 39 parts, fruit flavor agent 44 parts, purified water 4390 parts;
C: antibacterial: sodium benzoate 0.21 part, benzalkonium chloride 0.21 part.
4. Zinc gluconate oral spray as claimed in claim 1, is characterized in that, be made up of following raw material by mass parts:
A: zinc gluconate 74 parts;
B: pharmaceutic adjuvant: glycerol 27 parts, sucralose 2.5 parts, glycine 24 parts, fruit flavor agent 27 parts, purified water 2695 parts;
C: antibacterial: sodium benzoate 0.13 part, benzalkonium chloride 0.13 part.
5. the preparation method of the Zinc gluconate oral spray as described in as arbitrary in Claims 1 to 4, it is characterized in that, step is as follows:
(1) by recipe quantity take zinc gluconate, glycine, glycerol, sodium benzoate, benzalkonium chloride, sucralose, purified water and seasoning fruit flavor agent for subsequent use;
(2) in dissolving tank, add zinc gluconate, glycine, glycerol, sucralose and purified water, open and stir, be heated to 60 ~ 80 DEG C, make it dissolve completely, room temperature is for subsequent use;
(3) step (2) gained solution, after degerming with 0.22 μm of membrane filtration, be delivered in sterilized tank, room temperature is for subsequent use;
(4) in dissolving tank, add sodium benzoate, the fruit flavor agent of benzalkonium chloride and seasoning and purified water, open and stir, be heated to 50 ~ 70 DEG C, make it dissolve completely, room temperature is for subsequent use;
(5) feed liquid obtained with step (4) for feed liquid obtained for step (3) is mixed, stir, obtain supernatant liquid;
(6) solution of above-mentioned steps (5) gained is sub-packed in spray bottle; Quan Jian, packaging, warehouse-in.
6. the preparation method of Zinc gluconate oral spray as claimed in claim 5, it is characterized in that, step (1), (2), (4), (5), (6) are all implemented under 100,000 grades of clean internal conditions.
7. the preparation method of Zinc gluconate oral spray as claimed in claim 5, it is characterized in that, step is as follows:
(1) by recipe quantity take zinc gluconate, glycine, glycerol, sodium benzoate, benzalkonium chloride, sucralose, purified water and seasoning fruit flavor agent for subsequent use;
(2) in dissolving tank, add zinc gluconate, glycine, glycerol, sucralose and purified water, open and stir, be heated to 80 DEG C, make it dissolve completely, room temperature is for subsequent use;
(3) step (2) gained solution, after degerming with 0.22 μm of membrane filtration, be delivered in sterilized tank, room temperature is for subsequent use;
(4) in dissolving tank, add sodium benzoate, the fruit flavor agent of benzalkonium chloride and seasoning and purified water, open and stir, be heated to 50 DEG C, make it dissolve completely, room temperature is for subsequent use;
(5) feed liquid obtained with step (4) for feed liquid obtained for step (3) is mixed, stir, obtain supernatant liquid;
(6) solution of above-mentioned steps (5) gained is sub-packed in spray bottle; Quan Jian, packaging, warehouse-in;
Above-mentioned steps (1), (2), (4), (5), (6) are all implemented under 100,000 grades of clean internal conditions.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101780038A (en) * | 2010-03-30 | 2010-07-21 | 上海现代药物制剂工程研究中心有限公司 | Zolpidem tartrate oral spraying agent and preparation method thereof |
| CN101961321A (en) * | 2010-09-17 | 2011-02-02 | 山东居仁生物医药技术研究所 | Zinc gluconate sugar tablet preparation and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101780038A (en) * | 2010-03-30 | 2010-07-21 | 上海现代药物制剂工程研究中心有限公司 | Zolpidem tartrate oral spraying agent and preparation method thereof |
| CN101961321A (en) * | 2010-09-17 | 2011-02-02 | 山东居仁生物医药技术研究所 | Zinc gluconate sugar tablet preparation and preparation method thereof |
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