JPH01283225A - Aerosol preparation for treating infectious disease of bovine respiratory organ and treating method using the same - Google Patents

Abstract

PURPOSE:To obtain the title preparation capable of directly and aseptically spraying a medicine into a focus part in simple operation by enclosing an aqueous solution of water soluble antibiotic and inert gas such as carbon dioxide into an aerosol vessel in a specific concentration, inner pressure and volume ratio. CONSTITUTION:An aseptic aqueous solution containing a water soluble antibiotic (e.g., aminoglucoside-based antibiotic such as kanamycin sulfate or gentamicin sulfate) as a main ingredient and aseptic inert gas selected from carbon dioxide, air and nitrogen gas are enclosed in an aerosol vessel so that amount of the antibiotic is 50mg-10g, especially 200mg-5g and liquid amount of the aqueous solution is 5-100ml, especially 10-20ml and volume ratio thereof is 20-45% and inner pressure of the inert gas is 5-8kg/cm<2> and volume ratio thereof is 55-80%. A catheter having length attaining a bovine bronchial tube branched part is connected to the opening of the preparation and a medicine is administered through the catheter to the bovine bronchial tube. Local concentration of the medicine in the focus part is enhanced by administration of a small amount of the medicine and high-level effect for remedy can be exhibited.

Description

Detailed Description of the Invention [Field of Industrial Application] The present invention relates to an aerosol preparation having an effective therapeutic effect on respiratory diseases in cattle, particularly pneumonia, a treatment method using the aerosol preparation, and the treatment method. Regarding the therapeutic Kira used].

[Conventional technology] In recent years, the scale of dairy farming and beef cattle fattening operations has expanded year by year.
Group rearing methods are rapidly becoming popular for labor saving and rationalization. However, with this type of breeding, pneumonia, diarrhea, mastitis, metabolic diseases, etc. occur frequently, and pneumonia in particular has a high mortality rate during the chewing and fattening stages, so the damage it inflicts on livestock farmers is extremely large. It has become.

Conventionally, aminoglycoside antibiotics such as kanamycin sulfate and gentamicin sulfate have been used to treat pneumonia in cattle, but when administered systemically through oral administration or injection, the target concentration is 11 degrees lower than expected. Therefore, the therapeutic effect is low, and there are many problems with long-term drug residue in organs other than the lungs or at the injection site.Furthermore, oral administration is usually not possible due to the problem of lumen size.

Therefore, methods of increasing the local concentration of drugs by directly administering the drug to the diseased part of the lung have been developed, such as inhalation therapy ([Livestock Treatment
191 (5) 39-42 (1979)), Intraorgan injection therapy ([Livestock Treatment J 68 (11) 34-38 (19
68), ), intraparenchymal lung injection therapy ([Livestock practice J 25
5 (9) 30-34 (1984)) was considered.

However, with inhalation therapy, the equipment is large and operations such as adjusting the spray particles are complicated, and the actual application technique is difficult, such as the need to inhale deeply into the lungs at the moment of spraying. There is a problem that the drug concentration in the lesion is not much different from that in the muscle because the amount of drug reaching the lesion is not sufficient.

Furthermore, in recent years, there have been many negative reports regarding the effectiveness of intratracheal injection therapy, such as the uneven distribution of drug solutions in the lungs and large individual differences. Intraparenchymal lung injection therapy is not usually available because it inevitably causes pleural adhesions.

Therefore, as a further improvement of these methods, intratracheal spray therapy ([Livestock Clinic J 262 (4) 17-24
(1985) ) was proposed. This involves using a compressor device, inserting a catheter through the cow's nostril, and spraying a medicinal solution into the bronchial bifurcation.

In this therapy, the drug is distributed almost uniformly in the bronchioles and alveoli of each lobe of the lung, and the presence of the drug is observed at extremely high concentrations in the focal areas, making it highly effective as a local therapy. Of course, since lungs are generally not edible, drug residue poses no public health problem.

However, this therapy uses a compressor device, which requires extensive handling on site and makes it impossible to inject aseptically. Additionally, there are safety issues such as guaranteed service life.

[Problems to be Solved by the Invention] The present invention further improves the above-mentioned intratracheal spray therapy, and enables the local administration of a drug at a high concentration only to the lesion, in a simple and sterile manner. The purpose of this invention is to provide a preparation for treating bovine respiratory tract infections that can be manipulated in a similar manner, and a method for using the same.

[Means and effects for solving the problem] The present inventors have created an aerosol-type preparation for injection for bovine respiratory infections so that each livestock farmer who uses it can easily and hygienically use it. Focusing on the fact that it can be handled, we investigated various conditions that would allow the drug to reach the lesion most effectively and exert the best therapeutic effect, and as a result, we arrived at the present invention.

That is, the present invention is characterized in that a sterile aqueous solution containing a water-soluble antibiotic as a main component and a sterile inert gas selected from carbon dioxide, air, and nitrogen gas are sealed in an aerosol container. The amount of antibiotic is 50#1g~10=j
The liquid volume of the aqueous solution is in the range of 5 to 100 m and is in the range of 20 to 45% of the volume of the aerosol container, and the internal pressure of the inert gas in the aerosol container is about 5 to 8 kg. /cm'', and the volume ratio to the volume of the aerosol container must be in the range of about 55 to 80%. A method for treating bovine respiratory tract infections, which comprises connecting a catheter with a length that reaches the live bronchus, opening the opening, and administering a drug to the bovine bronchus in the form of a spray via the catheter, and the aerosol described above. The present invention relates to a kit for treating bovine respiratory tract infections, which is a combination of a preparation and the catheter described above.

As mentioned above, according to the preparation and treatment method of the present invention, the drug is administered only to the lesion area, so the therapeutic effect is high, the dose and frequency of administration can be reduced compared to conventional injection administration, and the drug is edible. There is no problem of chemical residue in the body.

Furthermore, since the present invention uses an aerosol method, it is much easier to handle than conventional intratracheal spray methods, and sterile conditions can be maintained.

To explain in detail, the aerosol preparation of the present invention uses a sterile inert gas selected from carbon dioxide, air, and nitrogen gas as the compressed gas for injection, so it is not commonly used for aerosol injection in the past. Fluoro7, L
Unlike liquefied gases such as PG and dimedyl ether, it is neither anesthetic nor irritating, and does not have any adverse effects on the living tissues of cows. It is also stable against drugs, and its main components will not be degraded.

The internal pressure of these gases in the container should be 5 to 8 kg/c.
The reason for setting ut is that if the pressure is less than 5 kg/cm, the atomization of the drug will be poor, while if it is more than 8 kg/cm, the pressure will be too high and will not be good for the cow's alveoli, and also from the viewpoint of container safety. This is because there is a problem.

As the water-soluble antibiotic as a medicinal ingredient, In kanamycin or gentamicin sulfate is preferred. These are easy to prepare as an aqueous solution, are odorless, have little mucosal irritation, have little bitterness, and have stable potency as a solution.
This is because it has a wide range of antibacterial properties and is effective against many pneumonia-causing bacteria. Additionally, these antibiotics have mucolytic properties when administered in aerosol form, further increasing their clinical effectiveness.

The content of water-soluble antibiotic is 50 mg to 1 og, preferably 200 mq to 5 q. If the amount is less than this, the effect will be reduced, and if it is more than this, not only will the economic efficiency become bad, but also the persistence in other edible organs will become a problem.

Note that this is a single dose and may be administered once a day.

As described above, since the aerosol preparation of the present invention is a single dose, there is no possibility of making a mistake in the dosage, and there is no need to adjust the dosage as required in the past.

Comparing this dosage with that of conventional injections, the injections are administered three times a day at 10-20mg/k (), and the weight of the cow is 50-100kg as a larva and 6.5kg at the end of fattening.
00 to 700 kg, this daily dose is 1.5 kg.
~? 1g/head. In the present invention, the amount of antibiotic used is much smaller than this, and the concentration in the lesion is higher.

The amount of liquid in the container is 5~ioom! , preferably 10-2
It has 0 power. If the amount of fluid is too low, the drug will not be distributed to all of the anterior, middle, and posterior lobes; if it is too high, the alveoli will infiltrate, resulting in a temporary increase in respiratory rate and loss of energy. The ratio of this liquid amount to the container volume is in the range of 20 to 45%. If the amount is more than this, the medium spray pressure (J) will be lowered and the mist will not be ejected until the end.On the other hand, if it is less than this, the economy will be poor.

The catheter should be long enough to reach the bronchial bifurcation from the nasal cavity of the cow, but if it is too long, it will be difficult to handle, so the length of the catheter is usually 1.2 to 2 m, preferably 1.0 to 2 m, depending on the age of the cow.
It is about 8■1. General (preferably made of plastic or rubber, with a spray nozzle attached to the tip.The nozzle should have a mechanism that can spray the chemical solution, but since the particle size of the mist is determined by the nozzle, use a suitable one. It is necessary to choose the particle size of the mist. If the particle size of the mist is too large, the medicinal solution to the lungs will be localized, and on the other hand, if it is a little trickled, it will be re-expelled. preferable.

The aerosol container may be made of metal, glass, resin, etc., but aluminum is particularly preferred from the viewpoint of economy, safety, and ease of handling.

In addition to the water-soluble antibiotic, the aerosol preparation of the present invention contains a bronchodilator such as ephedrine, an anti-plusamine agent such as cranmin, and an adrenocortical hormone.

Agents with auxiliary effects may be added, such as enzyme preparations such as lysodeme chloride, and also parabens.

Preservatives such as propionate and benzyl alcohol.

Buffers such as sodium citrate and sodium phosphate, stabilizers such as sodium thiosulfate and sodium bisulfite, solvents such as ethyl alcohol and propylene glycol,
Surfactants such as sucrose fatty acid ester and propylene glycol fatty acid ester, and other drugs necessary for formulation may be added.

[Example code] The present invention will be explained in detail below.

Example 1 Aqueous solution 1 Namycin sulfate 25m3 Potency, sodium citrate (buffer) 16mg, sodium bisulfite (antioxidant) 3.5mtj, methylparaben (preservative) 0.8mfI, propylparaben (preservative)
Prepare a sterile drug solution containing 0.08 mg and order 35 in diameter.

A cylindrical aluminum container with a height of 67# and a volume of 55d (
The above drug solution 21rd and carbon dioxide gas 0.65'j as a propellant were aseptically filled into the epoxy resin inner surface coating using a Pamasol gas filling machine (manufactured by Pamasol, Switzerland) to obtain an aerosol product. Product pressure is 6.6~6.8'
j/cm2 (25°C).

-11= A catheter was connected to the injection port of this aerosol product, and the catheter was inserted to the bronchial bifurcation site of the cow and sprayed.

Spray time was 15-20 seconds.

Example 2 Gentamicin sulfate 25 mg titer in aqueous solution lIn1, 8 mg disodium hydrogen phosphate, 3.51 nl sodium bisulfite, 0.8 m3 methylparaben. A sterile drug solution containing 0.08 mg of propylparaben was prepared, and 21 g of the drug solution and 0.30 g of nitrogen as a propellant were placed in a cylindrical aluminum container with a diameter of 35 mm, a height of 67 m, and a volume of 55 d using a Pamasol gas filling TIX machine. The aerosol product was obtained by aseptic filling. Product pressure is 6.2~6.5Kg/c
m2 (25°C).

A catheter was connected and sprayed in the same manner as in Example 1. The spray time was 16-21 seconds.

Example 3 Dihydrostreptomycin sulfate 25 in aqueous solution 1rn1
0I11! j titer, sodium citrate 204. A sterile drug solution containing 0.65 mg of methylparaben and 0.06 mg of propylparaben was prepared in 1 mL of Rongalit, and placed in a cylindrical aluminum container with a diameter of 35 #, a height of 67 m, and a volume of 55 m. 31
g was aseptically filled using a Pamasol gas filling machine to obtain an aerosol product.

The pressure of the product is 6.7~7. OK! j/cm2 (25℃)
and the nebulization time through the catheter was 13-18 seconds.

Form-A Fradiomycin sulfate in aqueous solution 1d 12. Sff1g titer.

Citric acid 1~Thulium 611g, Sodium bisulfite 3,! 4. Prepare a sterile drug solution containing 8 mg of medylparaben O and 0.08 mg of propylparaben.
5 shoes.

15.75 rnl of drug solution and 0.35 g of nitrogen as propellant in a cylindrical aluminum container with a height of 67 # and a volume of 55 d.
was aseptically filled using a Pamanlu gas filling machine to obtain an aerosol product.

Product pressure is 6.5-6.7 KI/cm2 (25°C)
and the nebulization time through the catheter was 11-15 seconds.

Example 5 Namycin sulfate 5Qmg titer in 1ml aqueous solution, sodium citrate 16#lJ, sodium bisulfite 3.
85～. A sterile drug solution containing benzyl alcohol 111nfI was prepared, and the diameter was 40s, the height was 118m, and the volume was 1.
52.5 ml of drug solution in a 28 d cylindrical aluminum container
ml and 1.45 g of carbon dioxide gas as a propellant were aseptically filled using a Pamasol gas filling machine to obtain a product. The product pressure was 6.5-6.8 Kg/cm2 (25°C) and the spray time through the catheter was 37-48 seconds.

The therapeutic effects of the intratracheal spray of Example 1 and the kanamycin sulfate injection on calf pneumonia were compared and studied.

■, Test method 1) Test cow 6 Holstein calves diagnosed with pneumonia based on clinical findings
The test was divided into 30 animals in the spray group and 30 animals in the injection group. Table 1 shows the age and weight of the test cows.

Table 1 Table 2) Test drugs and administration method The spray group contained the spray prepared in Example 1 (1 container, 20
Kanamycin sulfate (containing a titer of 500 my) was sprayed once per head using an intratracheal spray catheter. The endotracheal spray catheter was inserted through the nose to the endotracheal bifurcation.

In the injection area, kanamycin sulfate injection 1'l (KM 25
0m3 titer/m1) at 20mg/kg body weight
Titers were administered intramuscularly once daily for 3 consecutive days.

3) Clinical examination and diagnostic criteria for pneumonia Before and after treatment, clinical findings not shown in Table 2 will be examined, including the five main causes of pneumonia: fever, respiratory status, enucleation, nasal discharge, and Russell. Based on the severity, the diagnostic criteria in Table 3 were set and pneumonia was diagnosed. Heart rate and respiratory rate were excluded because they abnormally increase during retention in cows with foot rods, and were used as reference for diagnosis like other items. In addition, according to Table 4, severe, severe,
The disease was classified as mild.

Table 2 Table 3 Table 4 Table 4) Evaluation of efficacy Usually, antibiotics are injected continuously for 3 days to treat bovine pneumonia, and the effectiveness can often be determined within 5 days. Since relapse often occurs between the 5th and 7th day of treatment, the first administration was on day 0, the 7th day was used as the day for evaluating efficacy, and the efficacy was evaluated in four stages according to the efficacy evaluation criteria in Table 5. In addition, the cure rate was calculated according to the following formula, and the target area and the test area were statistically compared (×2 test).

Table 5 ■, Test results The number of dogs by diagnostic rank before treatment and at the time of effect evaluation in the above test is as shown in Table 6 below. Table 7 shows the number of animals and cure rate by disease category.

Looking at Table 6 and Table 7 (Table 6), which shows the clinical symptoms before and after treatment (discussion of test results), in the spray group, 96.6% of those with fever were found to have developed a fever, which ranged from 13% to 13%.
4%, and 93.3% had abnormalities in breathing status.
From 10.0% to 43.4%, those with nucleation from 10.0% to 26.6%, those with nasal discharge from 96.7% to 26.6%, and those with Russell's 36.7%
This decreased from 33% to 33%. On the other hand, in the injection area,
The percentage of those with fever increased from 100% to 58.6%, and the percentage of those with abnormalities in breathing status increased from 90.0% to 65.0%.
5%, those with nuclei from 100% to 58.6%, those with nasal discharge from 93.3% to 48.2%, and those with Russell from 50.5%. 13.7
%. Therefore, although therapeutic effects were observed in both groups, the spray group showed a better effect.

In addition, one dog in the injection group died before the effectiveness evaluation date.

In addition, looking at the effectiveness evaluation results by disease category (Table 7), the treatment rates for the spray group and injection group were 86.7% and 56.7%, respectively, with a significant difference at a 5% risk rate. Admitted. The treatment rate for each disease category was 77% for severe disease in the spray group.
In the injection group, 45.5% were severe, 46.2% severe, and 100% mild. Therefore, in severe cases and severe cases, the spray group showed a higher cure rate, with a significant difference at a 5% risk rate.

The dosage of the spray is 50 kanamycin sulfate per animal.
The titer was 0mff, while that of the injection was 210.
6 mg (potency) (average value), which was more than 4 times the dosage.

Test Example 2 The therapeutic effects of the intratracheal spray of Example 2 and the kanamycin sulfate injection on calf pneumonia were compared.

■, Test method 1) Holstein calf diagnosed with pneumonia based on clinical findings during the test 6
The test was divided into 30 animals in the spray group and 30 animals in the injection group. Table 8 shows the ages and weights during the test.

Table 8 2) Test drug and administration method In the spray group, the spray prepared in Example 2 (1 container, 20
(containing 500 mg titer of gentamicin sulfate in d),
Kabutil for intratracheal spraying was administered 01 times per animal. The endotracheal spray catheter was inserted through the nose to the endotracheal bifurcation.

In the injection area, kanamycin sulfate injection (containing KM 250 mg titer/weight) was administered at a titer of 20 m3 per I Ks of body weight.
It was administered intramuscularly once a day for 3 consecutive days.

3) Clinical examination and diagnostic criteria for pneumonia Same as Test Example 1 4) Efficacy Judgment Same as Test Example 1 ■, Test results The number of dogs by diagnostic rank before treatment and at the time of effect evaluation in the above test is as shown in Table 9 below. It is. The number of animals and cure rate by disease category are shown in Table 10.

(See margin below) Table 9 () indicates percentage Table 10 □J口■ □ ■, Discussion on test resultsClinical symptoms Looking at the clinical symptoms before and after treatment (Table 9), in the propellant group , those with fever ranged from 100% to 20.0%.
%, 93.4% to 36.6% had abnormal respiratory status, and 93.3% to 2% had nuclear outbreaks.
3.3%, 90.0% to 2.0% had nasal discharge.
6.6%, and Russell's admission decreased from 46.7% to 0%, respectively. In addition, in the Chuken drug area, the number of cases where fever was observed increased from 96.7% to 39.2%.
24 90.0% to 64 cases where abnormality was observed in breathing condition
．． 3%, and 90.0% had nuclear eO,7
90.0% to 39.3% had nasal discharge.
%, those recognized by Russell ranged from 50.0% to 14
．． It decreased to 0%. Therefore, the therapeutic effect was observed in both groups, or the spray group showed a better effect.

In addition, two dogs in the injection group died before the effectiveness evaluation date.

In addition, looking at the effectiveness evaluation results by disease category (Table 10), the cure rate for the spray group and injection group was 90.0, respectively.
% and 60.0%, and a significant difference was observed at a 5% risk rate.

The cure rate for each disease category was 91.7% for severe disease in the spray group;
The rate of severe cases was 85.7%, and the rate of mild cases was 100%; in the injection group, the rate was 45.5% for severe cases, 46.2% for severe cases, and 100% for mild cases.

Therefore, in severe case 1, the spray group showed a higher cure rate, with a significant difference at a 5% risk rate.

[Effects of the Invention] As explained above, according to the present invention, it is possible to spray a drug into a lesion in a sterile manner with a much simpler operation than the conventional methods of directly injecting the drug into the lesion. can.

Therefore, according to the present invention, it is possible to increase the local concentration of the drug in the diseased area with a small amount of drug, and to achieve a high therapeutic effect on respiratory infections in cattle. Can be used hygienically.

(8733) Agent Patent Attorney Yoshiaki Inomata (Baka
1 person) Volunteered to write procedural amendments) Showa 63°h 7th

Claims (7)

[Claims] (1) A sterile aqueous solution containing a water-soluble antibiotic as a main component and a sterile inert gas selected from carbon dioxide, air, and nitrogen gas are sealed in an aerosol container, and the water-soluble antibiotic is The amount of the aqueous solution is in the range of 50 mg to 10 g, the amount of the aqueous solution is in the range of 5 to 100 ml, and is in the range of 20 to 45% of the volume of the aerosol container, and the internal pressure of the inert gas in the aerosol container is is about 5-8
An aerosol preparation for treating bovine respiratory infections, characterized in that the volume ratio to the volume of the aerosol container is approximately 55 to 80%. (2) The aerosol preparation for treating bovine respiratory infections according to claim 1, wherein the water-soluble antibiotic is an aminoglycoside antibiotic such as kanamycin sulfate or gentamicin sulfate. (3) The aerosol preparation for treating bovine respiratory infections according to claim 1, wherein the total amount of the aerosol preparation is for one dose. (4) A catheter with a length that reaches the bovine bronchus is connected to the opening of the aerosol preparation for treating bovine respiratory tract infection according to claim 1, and the drug is sprayed into the bovine bronchus through the catheter by opening the opening. A method for treating bovine respiratory tract infection, the method comprising administering the following: (5) The method for treating bovine respiratory infections according to claim 4, wherein the water-soluble antibiotic is an aminoglycoside antibiotic such as kanamycin sulfate or gentamicin sulfate. (6) For the treatment of bovine respiratory tract infections, which is a combination of the aerosol preparation for treating bovine respiratory tract infections according to claim 1 and a catheter having a length that can reach the bovine bronchus from the opening of the aerosol preparation. kit. (7) The kit for treating bovine respiratory infections according to claim 6, wherein the water-soluble antibiotic is an aminoglycoside antibiotic such as kanamycin sulfate or gentamicin sulfate.