CN112717123A - Cat nose drops and application thereof - Google Patents
Cat nose drops and application thereof Download PDFInfo
- Publication number
- CN112717123A CN112717123A CN202011598820.7A CN202011598820A CN112717123A CN 112717123 A CN112717123 A CN 112717123A CN 202011598820 A CN202011598820 A CN 202011598820A CN 112717123 A CN112717123 A CN 112717123A
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- China
- Prior art keywords
- cat
- sodium
- solution
- interferon
- omega
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- 239000000243 solution Substances 0.000 claims description 19
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- 241000588724 Escherichia coli Species 0.000 claims description 14
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Abstract
The invention discloses cat nose drops, which comprise the following components in percentage by weight: the invention also discloses a preparation method and specific application of the cat nose and bronchitis eye drops, wherein the eye drops have the characteristics of small dosage and good curative effect, and are applied to preparation of medicaments widely used in clinical pet.
Description
Technical Field
The invention relates to the technical field of molecular biology, in particular to cat nose drops and application thereof, and application of a reagent in pet health care.
Background
The Feline nasal branch is also called Feline viral rhinotracheitis, Feline rhinotracheitis or Feline infectious rhinotracheitis, and is a Feline upper respiratory disease with stronger infectivity, acute infectivity and high contact caused by Feline herpesvirus type I (FHV-1). Cats that are not immunized, immunocompromised or immunosuppressed, especially kittens and kittens, are susceptible. Patients and recessive carriers can infect cats directly with body fluids and contaminants, and can also transmit pathogens through tools, bedding, people, fleas, flies and the like as vectors.
FHV-1 belongs in classification to the family of herpesviridae, the subfamily herpesviridae A, and has the general characteristics of herpesviruses. FHV-1 has only one serotype; FHV-1 is less resistant to the external environment and sensitive to acids, heat and lipid solvents; formaldehyde and phenol kill it easily. The inactivated vaccine can survive for 180 days at the temperature of minus 60 ℃ and is inactivated for 4-5 minutes at the temperature of 50 ℃. Under the dry condition, the inactivation can be carried out within 12 hours. FHV-1 can adsorb and agglutinate cat red blood cells, and can detect virus antigen and antibody by hemagglutination test and hemagglutination inhibition test. FHV-1 is mainly infected by contact, the secretion of virus through nose, eye and pharynx is discharged, the susceptible cat is infected by respiratory tract by the direct contact between nose and the inhalation of flying powder containing virus, and the naturally recovered or artificially inoculated resistant cat can carry poison and expel toxin for a long time and becomes a dangerous infection source. Meanwhile, FHV-1 has high species specificity, is only seen in cats, can cause infection of other animals in the family of felidae sometimes, and does not cause diseases to other animals except the family of felidae.
The virus mainly attacks the young cats, when the symptoms of the infected cats are serious, the body temperature is raised, the upper respiratory tract infection is obvious, the morbidity can reach 100 percent, and the mortality can reach 50 percent. The disease cat is the main infection source and can be transmitted by direct contact or placenta. The disease was first discovered from the united states and subsequently discovered and prevalent in canada, uk, netherlands, switzerland, hungary, vietnam, etc., and suspected cases were discovered many times in our country and viruses were isolated.
The virus is infected under stress and in places with high population density, such as housing houses, breeding farms, cat houses and multi-cat breeding areas. Can produce a toxic state, intermittently expel toxin, and cats recovered by herpes virus can remain latent in the nervous tissues and have recurrent infection for life. Detoxification can be activated in the presence of stress, hypoimmunity, or immunosuppressive therapy. Parturition and lactation can reactivate the latently infected virus, which can subsequently infect kittens and unvaccinated adult cats.
The disease has short latent period and high propagation speed, and is suddenly attacked. Kittens have severe clinical symptoms and higher mortality rates than adult cats. The body temperature of the sick cat is high fever, and the disease is manifested as ocular and nasal catarrhal inflammation, and mucopurulent secretion can occur during secondary bacterial infection. The hair around the affected cat's eye and nose may be shed or form a scab due to secretion stimulation, and inflammatory exudation of the skin under the scab may be observed when artificially removed. Severe cases can develop extreme depression or lethargy, loss of appetite, and are associated with significant upper respiratory symptoms, such as: sneezing, dyspnea, coughing, and the like, in individual affected cats may develop mouth ulcers or hard palate ulcers. Some cats with chronic infection may turn into chronic infection with symptoms of long-term cough and sinusitis, and most cats turning into chronic infection are adult cats.
Clinical manifestations of nasal branches in cats are mostly upper respiratory symptoms and ocular inflammation. The diseased cats often first show eye diseases, which are also the most harmful to the diseased cats, such as: keratitis, conjunctivitis, stromal keratitis, anterior uveitis, eosinophilic keratitis, etc. At present, the clinical diagnosis research on the disease characteristics, molecular characteristics, pathological changes and clinical diagnosis of the feline herpesvirus is more, but the clinical treatment of the feline herpesvirus, particularly the treatment of ocular inflammation, is not reported. Moreover, the feline infectious rhinotracheitis is a disease with very low cure rate, the cure rate is only 12.5 percent, and no specific medicine is available at present. At present, generally, broad-spectrum antibiotics are mostly used in a treatment method to prevent bacterial secondary infection of sick cats so as to prevent sequelae from occurring, but the cure rate is still low and the diseases cannot be cured radically.
Therefore, the market urgently needs the eye drops for treating the cat nasal bronchitis, which are used for intervening in eye symptoms, effectively reducing eye secretion, relieving conjunctivitis and keratitis and further reducing the death rate of cat nasal bronchitis infection.
Disclosure of Invention
In order to overcome the defects, the invention provides cat snuff eye drops which comprise the following components in percentage by weight: omega-interferon filtrate (10-100 ten thousand IU/ml) fermented by escherichia coli, 1-7% of sodium hyaluronate, 0.1-3% of preservative, 0.5-5% of isoosmotic adjusting agent and the balance of water for injection.
Further preferably, the isotonic regulator in the invention is one or more selected from glycerol, sodium chloride, glucose, sodium carbonate, sodium bicarbonate, disodium hydrogen phosphate, sodium dihydrogen phosphate, boric acid, borax, mannitol and propylene glycol, and the preservative is one or more selected from parabens, sodium benzoate and salts thereof, sorbic acid and salts thereof, chlorobutanol, benzyl alcohol, phenethyl alcohol, chlorhexidine acetate or quaternary ammonium compound cationic surfactant and benzalkonium bromide.
More preferably, the cat nose and branch eye drops have p H value of 6.4-7.4, good solubility and no irritation to eyes.
The invention also provides a preparation method of the cat nose drops, which comprises the following steps:
1) accurately weighing isoosmotic adjusting agent, dissolving with 1/10-1/5 total volume of water for injection, and stirring to obtain clear and transparent solution.
2) Transferring the solution to a solution preparation tank, adding water for injection to dilute the solution to 1/4-4/5 total volume, then sequentially adding omega-interferon filtrate fermented by escherichia coli, preservative and sodium hyaluronate, stirring the mixture until the mixture is completely dissolved, and adjusting the pH value of the solution to 6.4-7.4 by utilizing p H regulator.
3) Adding water for injection to the total volume, and stirring for 10-20 minutes.
4) Sterilizing the medicinal liquid with 0.22um microporous filter, filtering, packaging, and preserving.
Taking 30000ml of cat nose drops as an example, the method comprises the following steps:
1) accurately weighing isoosmotic adjusting agent, dissolving with 5000ml water for injection, and stirring to obtain clear and transparent solution.
2) Transferring the solution to a solution preparation tank, adding water for injection to dilute to 20000ml, sequentially adding omega-interferon filtrate fermented by Escherichia coli, antiseptic and sodium hyaluronate, stirring to dissolve completely, and adjusting pH of the solution to 6.4-7.4 with p H regulator.
3) Adding water for injection to 30000ml, and stirring for 10-20 minutes.
4) Sterilizing the medicinal liquid with 0.22um microporous filter, filtering, packaging, and preserving.
Wherein, further preferably, the pH regulator is one or more of citric acid and sodium citrate, acetic acid and sodium acetate, citric acid and sodium citrate, hydrochloric acid or sodium hydroxide.
Further preferably, the preparation method of the omega-interferon filtrate fermented by escherichia coli comprises the following steps: the omega-interferon filtrate obtained by fermenting the escherichia coli is an escherichia coli strain with high expression, and is prepared by freezing and vacuum drying after fermentation, separation and purification.
The omega-interferon has the main effect of treating upper respiratory tract inflammation, oral ulcer, keratoconjunctivitis and chronic nasosinusitis caused by early infection of the feline herpes virus.
The preservative in the method is selected from benzalkonium bromide, and the method has the special advantage that the preservative has an inhibition effect on fungi, gram-positive bacteria and gram-negative bacteria and is a broad-spectrum efficient bacteriostatic agent. The invention unexpectedly discovers that the anti-feline herpesvirus cytokine and the benzalkonium bromide are combined, the bacteriostatic action of the obtained eye drops is greatly improved, the bacteriostatic effect of the eye drops can be effectively ensured, and the use safety of patients is improved.
Further, the invention provides application of the cat snuff eye drops, which is application in preparing a medicine for treating or preventing cat infectious rhinotracheitis.
Advantageous effects
The eye drops have simple components and reliable effect, can be prepared into a multi-dose packaging form, realize repeated use, and avoid the defect of high production cost of single-dose eye drops.
According to the invention, through the mutual matching of the ph regulator and the isotonic regulator, the p H of the product is adjusted to be 6.4-7.4, which is close to tear p H, so that the safety and comfort of use are improved, and the irritation is small. The obtained eye drops are isotonic, the osmotic pressure ratio is about 0.9-1.1, the product and tears have similar osmotic pressure, the irritation of clinical use is reduced, the curative effect is improved, and the irritation of the product to eyes due to low osmosis is avoided.
The sodium hyaluronate used in the present invention can promote the regeneration of skin at the injured part by promoting the proliferation and differentiation of epidermal cells and scavenging oxygen radicals, and has a certain preventive effect even when used in advance.
The eye drops obtained by the invention can be enduringly stable, clear and transparent within 6 months, and no new impurities are generated, thus being safe and effective and having controllable quality.
The eye drops obtained by the invention can produce symptom relief or cure to different degrees within 1-7 days of treating cat eye symptoms, and the clinical manifestations are as follows: effectively reduces the secretion of the eyes, effectively eliminates the swelling of the eyes, relieves the symptoms of conjunctivitis, keratitis and the like.
Drawings
FIG. 1 is a schematic diagram of protein SDS of omega-interferon expressed by Escherichia coli under different induction time conditions, wherein M is protein marker, and 0, 1, 2, and 3 are protein expression detections with induction times of 0, 1, 2, and 3h, respectively.
Fig. 2 is clinical pictures of cat nose drops before and after treatment, wherein A is before treatment and B is after treatment.
Detailed Description
The following examples further illustrate the present invention but are not to be construed as limiting the invention. Modifications or substitutions to methods, procedures, or conditions of the invention may be made without departing from the spirit and scope of the invention.
Unless otherwise specified, the technical means used in the examples are conventional means well known to those skilled in the art.
Example 1 preparation of omega-interferon filtrate from E.coli fermentation
1.1 preparation of seeds for omega-Interferon production
1.1.1 first-order seed propagation and identification of bacterial species BL-21 (see: Wang hong Bin, Jia Xiao Juan, Yan Li Min, Sui Lei, Wang hong Ning, Liu Wen et al expression and antiviral activity comparison of novel cat-derived interferon FeIFN-omega and interferon FeIFN-alpha [ J ]. Bioengineering, 2008(09): 1556-. Storing at 2-8 ℃ for no more than 14 days; passage in culture medium should not exceed 4 generations.
1.1.2 second-stage seed propagation the first-stage seeds were inoculated into LB liquid medium containing 100. mu.g/mL Kan and cultured at 32 ℃ for 12 hours. Storing at 2-8 ℃ for no more than 14 days.
1.2 culture Medium for production
1.2.1 LB medium each 1000mL medium contains tryptone 10g, yeast powder 5g, sodium chloride 10 g.
1.2.2 fermentation Medium A commercially available fermentation medium was used and prepared as required.
1.2.3 supplemented materials every 1000mL of culture medium contain tryptone 20g, yeast powder 10g, glucose 20 g.
1.3 fermentation
Ventilating and culturing in a fermentation tank, adding 40-50% (V/V) fermentation medium and 0.06% defoaming agent, and high pressure sterilizing. Sterilizing, cooling to 32 deg.C, inoculating secondary seed bacterial liquid 2% of the culture medium, culturing at 32 deg.C, maintaining dissolved oxygen value above 20% and pH value 7.4-7.6, sampling and detecting bacterial liquid every hour, and measuring OD with enzyme-labeling instrument600The value is obtained. OD of bacterial liquid600Feeding is started according to 10% of the culture medium amount when the value reaches 1.5-3.0, and feeding is performed until the fermentation is completed. OD of bacterial liquid600When the value reaches 4.0-5.0, adding IPTG until the final concentration is 1mM, starting induction, and performing induced expression for 3-4 h to obtain a bacterial liquid.
After fermentation, the cells were collected by centrifugation, the wet cells were weighed and frozen at-20 ℃ or below. And (4) sterilizing the fermentation liquor and then discarding.
1.4 analysis of expression level
A small amount of the bacterial cells were analyzed by SDS-PAGE, and the target protein was found to have a molecular weight of 19.3 kD. + -. 1.93kD and an expression level of 20% or higher (see FIG. 1).
1.5 Inclusion body preparation
1.5.1 disruption of cells
Weighing a certain amount of thallus, re-suspending the thallus in PBS (0.01M, pH7.0) according to the wet weight ratio of 20-40 mL/g, and crushing the thallus by using a high-pressure homogenizer, wherein the specific parameters are as follows: 700-800bar, 20-50 HZ, 3 cycles of crushing, and microscopic examination of the crushed condition of the thalli; after microscopic examination, the inclusion bodies are collected after centrifugation for 10min at 8000r/min at 2-8 ℃.
1.5.2 Inclusion body washes
The collected inclusion body precipitate is resuspended in PBS (0.01M, pH7.0) buffer solution according to the proportion of 3-5 mL/g (wet weight) of the initial bacteria weight, and washed 1 time by 5% Triton X-100, 1 time by 1mol/L urea, 1 time by 5% Triton X-100 and 1 time by PBS in sequence. Centrifuging at 8000r/min for 10min at 2-8 ℃, and collecting precipitate by centrifugation.
1.5.3 Inclusion body cleavage
Resuspending the washed inclusion body in an inclusion body lysis solution (10mmol/L Tris-HCl, 8mol/L urea, 0.1mmol/L EDTA, 1mmol/L DTT, 0.5% Triton X-100) with the dosage of 3 mL/g; stirring until the precipitate is dissolved, centrifuging at 2-8 ℃ at 10000r/min for 10min, and collecting and purifying the supernatant.
1.6 protein purification
1.6.1 protein isolation the collected supernatant was chromatographed using Sephacryl S-200 medium.
1.6.2 protein renaturation
The protein separated by chromatography is replaced into renaturation buffer solution (20mmol/L Tris-HCl, 0.1mol/L L-Arg, 1mmol/L GSSG, 1mmol/L ME and 0.2mmol/L EDTA) by G-25 packing, and renaturation is carried out for 12h under slow stirring at the temperature of 2-8 ℃.
1.6.3 preparation of protein stock
Desalting renatured protein by using G-25 filler, collecting target protein, filtering with 0.22 μm filter membrane, and temporarily storing at-20 deg.C for use.
EXAMPLE 2 optimization of preparation method of Cat nose drops
Preparing the cat nose drops according to the final concentration by weight: omega-interferon filtrate (10-100 ten thousand IU/ml) fermented by escherichia coli, 1-7% of sodium hyaluronate, 0.1-3% of preservative, 0.5-5% of isoosmotic adjusting agent and the balance of water for injection, and the method specifically comprises the following steps:
1) accurately weighing isoosmotic adjusting agent, dissolving with 500ml water for injection, and stirring to obtain clear and transparent solution.
2) Transferring the solution to a solution preparation tank, adding water for injection to dilute to 3000ml, then sequentially adding omega-interferon filtrate fermented by escherichia coli, preservative and sodium hyaluronate, stirring until the omega-interferon filtrate, the preservative and the sodium hyaluronate are completely dissolved, and adjusting the pH value of the solution to 6.4-7.4 by using p H regulator.
3) Adding water for injection to 5000ml, and stirring for 10-20 minutes.
4) Sterilizing the medicinal liquid with 0.22um microporous filter, filtering, packaging, and preserving.
Wherein the specific formula is shown in table 1:
TABLE 1 detailed component proportion of cat nose drops
And (3) testing the pet: test 56 cats were diagnosed with nasal infections by PCR and these samples were collected in pet hospitals 2015 to 2020 (divided into 8 groups with water for injection as a negative control).
The application scheme is as follows: the above compositions are applied directly to the surface of the affected eye or eyes, preferably between the corneal surface and the lower eyelid. The composition can be administered once a day, 4-6 drops each time, for four days as one treatment course, rest for one day, and repeat for three treatment courses.
The therapeutic effect judgment standard is as follows: according to the therapeutic effect standard of the literature, (1) curing: symptoms and signs disappear completely; (2) the effect is shown: disappearance of all symptoms or disappearance of major symptoms and signs; (3) the method has the following advantages: the main symptoms and signs basically disappear; (4) and (4) invalidation: symptoms and signs were not improved. The scores were scored 8, 6, 4 and 2, respectively, according to the above criteria, and the total score was calculated after summarization, see table 2.
TABLE 2 record of the scoring status and situation of the experimental groups
| Group of | Cure of disease | Show effect | Is effective | Invalidation | |
| 1 | 4 | 2 | 1 | - | 48 |
| 2 | 5 | 1 | 1 | - | 50 |
| 3 | 5 | 1 | 1 | - | 50 |
| 4 | 4 | 1 | 2 | - | 46 |
| 5 | 3 | 3 | 1 | - | 46 |
| 6 | 2 | 3 | 1 | 1 | 40 |
| 7 | 3 | 2 | 2 | - | 44 |
| 8 (negative control) | - | - | 2 | 5 | 18 |
And (3) analyzing clinical results: after three courses of treatment, the experimental group is obviously better than the negative control group, which shows that the eye drop for treating nasal obstruction of cats can effectively treat nasal obstruction of cats, and has remarkable curative effect and high cure rate, wherein the 2 nd group and the 3 rd group have the best effect, 5 cases (71.4%) are cured, 1 case (7.3%) is remarkably effective, 1 case (7.3%) is effective, 0 case (0%) is ineffective, and the total effective rate is 100%. Five days after treatment, peripheral limbal infiltrates began to decrease in density. There were no signs of breakthrough epithelial keratitis. After ten days, the infiltrate continued to decrease and conjunctivitis had resolved. The infection was completely cured within two weeks as confirmed by normal eye examination and color, and the pet cat resumed normal behavior and activity (see figure 2). However, the second group is considered to have the best effect by comprehensively considering the dosage, cost and the comprehensive influence of the medicine on the pet cat, and the best effect can be realized under the condition of considering both the cost and the curative effect. Other drops of isotonic adjusting agents and preservatives also produce varying degrees of symptomatic relief or healing within 1-7 days of treatment for the condition of the cat's eye, and similar therapeutic effects can be achieved despite fluctuations in specific dosage.
Although the present invention and its embodiments have been described in detail, it should be understood that various changes, modifications, substitutions, combinations, and simplifications which may be made by those skilled in the art without departing from the technical principles of the present invention should be considered as equivalent substitutions, and these modifications should also be construed as the protection scope of the present invention.
Claims (7)
1. The cat-nosebleed eye drop is characterized by comprising the following components in percentage by weight: omega-interferon filtrate (10-100 ten thousand IU/ml) fermented by escherichia coli, 1-7% of sodium hyaluronate, 0.1-3% of preservative, 0.5-5% of isoosmotic adjusting agent and the balance of water for injection.
2. The feline nasal drop of claim 1, wherein the isotonicity adjusting agent is selected from one or more of glycerol, sodium chloride, dextrose, sodium carbonate, sodium bicarbonate, disodium hydrogen phosphate, sodium dihydrogen phosphate, boric acid, borax, mannitol, and propylene glycol, and the preservative is selected from one or more of parabens, sodium benzoate and salts thereof, sorbic acid and salts thereof, chlorobutanol, benzyl alcohol, phenethyl alcohol, chlorhexidine acetate or quaternary ammonium compound cationic surfactants, and benzalkonium bromide.
3. The ophthalmic solution for cat nose branches as claimed in claim 1, which has p H value of 6.4-7.4, good solubility and no irritation to eyes.
4. A preparation method of cat nose drops comprises the following steps:
1) accurately weighing isoosmotic adjusting agent, dissolving with 1/10-1/5 total volume of water for injection, and stirring to obtain clear and transparent solution;
2) transferring the solution to a solution preparation tank, adding water for injection to dilute the solution to 1/4-4/5 total volume, then sequentially adding omega-interferon filtrate fermented by escherichia coli, preservative and sodium hyaluronate, stirring the mixture until the mixture is completely dissolved, and adjusting the pH value of the solution to 6.4-7.4 by utilizing p H regulator;
3) adding water for injection to the total volume, and stirring for 10-20 minutes;
4) sterilizing the medicinal liquid with 0.22um microporous filter, filtering, packaging, and preserving.
5. The process for preparing an ophthalmic solution for nasal cavity of cat as claimed in claim 4, wherein the p H regulator is one or more of citric acid and sodium citrate, acetic acid and sodium acetate, citric acid and sodium citrate, hydrochloric acid or sodium hydroxide.
6. The method for preparing feline rhinotracheitis ophthalmic solution as claimed in claim 4, wherein the method for preparing the omega-interferon filtrate fermented by Escherichia coli comprises: the method is characterized in that escherichia coli strains capable of efficiently expressing omega-interferon are utilized, and fermentation, separation and purification are carried out to obtain the omega-interferon.
7. The use of the cat snuff eye drops as claimed in claim 1, which is used for preparing a medicament for treating or preventing cat infectious rhinotracheitis.
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| 刘院斌等: "《眼科基础及诊疗实践》", 31 July 2015, 西安交通大学出版社 * |
| 唐星编: "《全国高等医药院校药学类专业第五轮规划教材 药剂学 供生物制药生物技术生物工程和海洋药学专业使用 第4版》", 31 December 2019, 中国医药科技出版社 * |
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