JPS6034905A - Pharmaceutical preparation of active substance on surface of lung - Google Patents

Abstract

PURPOSE:The titled pharmaceutical preparation suspensible in physiologic salt solution in a short time without causing deterioration of active substance on the surface of the lung in ability to reduce surface tension in air cells, having low toxicity and improved solidification state, obtained by adding sugar alcohol or lactose to the active substance on the surface of the lung. CONSTITUTION:The titled pharmaceutical preparation containing an active substance on the surface of the lung and a sugaralcohol (e.g., mannitol, xylitol, or sorbitol) or lactose in a weight ratio of 1:(0.4-2.0) (preferably 0.8-1.5). The pharmaceutical preparation is obtained by suspending and dissolving uniformly given amounts of the active substance on the surface of the lung and the sugaralcohol of lactose in water or an ethanol-water mixed solution (blending volume ratio of 1:4-9) at <=40 deg.C, weighting and packing the prepared suspension into sealed containers such as vials or ampuls, and after drying and solidifying the solution by lyophilization, sealing the containers.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to pulmonary surfactant formulations that are briefly suspended in saline or water.

Pulmonary surfactant was recently developed as a treatment for respiratory distress syndrome. It is what was done. This substance consists mainly of lipids, especially phospholipids, and is a drug that is injected into collapsed alveoli through the airway. Therefore, since the main ingredient is insoluble in water, a sterile suspension is adopted as the dosage form for lung surfactant R-Furi, and furthermore, in order to maintain quality stability during long-term storage. It is usually a sterile powder preparation that is suspended in physiological saline or water before use. However, if a single powder preparation of a pulmonary surfactant is simply added with physiological saline or water and shaken, it is impossible to prepare a homogeneous cloudy solution over several hours. In addition, in the method of irradiating ultrasonic waves from the outside of the preparation container, the preparation time is 30%
It takes a long time, up to 40 minutes, and cannot be used in an emergency. Therefore, when using a single powder preparation in an emergency.

It was necessary to open the formulation container and prepare the suspension using an immersion ultrasound generator. However, this method has the limitation that it cannot be carried out except in a special facility such as a sterile room in order to maintain the sterility of the preparation.

On the other hand, as a formulation means for suspending crude drugs that are insoluble or sparingly soluble in water, suspending agents 9 such as celluloses such as sodium carboxymethyl cellulose can be used.

A method of adding a surfactant such as IJ Solvay 80 or polyethylene glycol 1500, or a synthetic polymer compound such as polyvinylpyrrolidone or polyvinyl alcohol is frequently used.

However, it has been found that these suspending agents have no suspending effect in pulmonary surfactant formulations.

Other suspending agents used include white sugar. However, although pulmonary surfactant preparations containing sucrose are suspended in a relatively short time compared to those using the above-mentioned suspending agents, the sucrose itself is highly hygroscopic and the resulting preparation dries out. However, it is difficult to obtain a good solidification state, and therefore there is a problem in terms of the stability of the preparation during long-term storage.

The present inventors conducted extensive research in view of the above circumstances, and found that by adding sugar alcohol or lactose, pulmonary surfactants deteriorate in their ability to lower alveolar surface tension, which is their original main effect. The present invention was completed after discovering that the preparation can be suspended in physiological saline in a short time without any problems, has low toxicity to lung cells, and has a good solidification state.

According to the present invention, there is provided a pulmonary surfactant preparation comprising a pulmonary surfactant and a sugar alcohol or lactose.

The lung surface active substance which is the main drug of the present invention is the well-known lung surface active substance TA-546 (Japanese Patent Application Laid-Open No. 55-16072
No. 1 Publication), Pulmonary Surfactant Composition (Japanese Unexamined Patent Publication No. 57-995)
No. 24) and surface-active substances (JP-A-58-4529)
Publication No. 9) and surfactant (%
No. 189) and other pulmonary surfactants containing dipalmitoylphosphatidylcholine as a main component. Examples of sugar alcohols include mannitol, xylitol, and nrubitol, with mannitol being preferred. Commercially available products can be used for both sugar alcohol and lactose. The weight mixing ratio is 0.4 to 2.0 parts of sugar alcohol or lactose to 1 part of lung surfactant. It is preferably set to 0.8 to 1.5.

Although the weight ratio of sugar alcohol or lactose may be 20 or more, it has been found that if too much is used, toxicity to lung cells tends to occur.

The preparation of the present invention consists of homogeneously suspending and dissolving the above-described predetermined amount of the pulmonary surfactant and sugar alcohol or lactose in water or an ethanol-water mixture (mixing volume ratio 1:4-9) at 40°C or below; Weigh and dispense the resulting suspension into a sealed container such as a vial or ampoule.

It can be produced by drying and solidifying the contents using a freeze-drying method and then sealing the container. Alternatively, a predetermined amount of the lung surfactant and sugar alcohol or lactose powder is uniformly mixed or kneaded, dried thoroughly, and then weighed and dispensed into a sealed container using the powder filling method. It can also be manufactured by sealing. In the freeze-drying method.

This is done by freezing the contents at -20° to -80°C and drying this under vacuum for 12-96 hours. Note 9
Since the preparation of the present invention needs to be prepared as a sterile preparation, the pulmonary surfactant, alcohol and lactose used are sterilized, and a series of operations in the manufacturing process are performed under sterile conditions.

The suspension properties of the formulation of the present invention produced as described above will be explained below using specific examples.

Are suspension tests conducted in 10 containers each of test preparations of the same composition? (Inject 2 m/i of physiological saline individually without opening the package, then attach the preparation container to an Iwaki K M Shaker V-8 type shaker (manufactured by Iwaki ■) and shake at 300 strokes per minute. The suspension state of the drug in each container was then visually observed through a magnifying glass every minute.The shaking at 300 strokes per minute was equivalent to the number of strokes per minute when shaking by hand. Suspensionability was judged by five people, and the judgment on whether or not it was suspended was made by noticing any small lumps in the container, and the preparation being uniformly dispersed in the physiological saline and becoming a white, slightly viscous liquid. The results were shown in Table 1. Suspension property was determined by each person calculating the percentage of the number of suspensions in each union to the total number of suspensions. The percentages are expressed as the average value of five people.The weight ratio of sugar alcohol or lactose per bottle is expressed as a weight ratio to the pulmonary surfactant substance 120"', where V is 1. For comparison, the suspension properties of a formulation consisting of a pulmonary surfactant and a commonly used suspending agent and a formulation of a pulmonary surfactant alone are listed for comparison. The product was manufactured in almost the same manner as the above-mentioned method for manufacturing the preparation of the present invention, except that the suspending agent was changed to the above-mentioned suspension agent.The mixing ratio of the suspending agent was as follows: The mixing ratio of sugar alcohol or lactose in the formulation of the present invention was set to be the same as that of the formulation of the present invention.
The one described in Publication No. 9 was used.

(Margins below) As is clear from Table 1, preparations containing commonly used suspending agents do not suspend in physiological saline even when shaken for 20 minutes or more, except in the case of white sugar.

The formulation of the invention is found to become suspended within about 3 minutes.

Therefore, with the preparation of the present invention, a suspension of physiological saline can be prepared in a short time by simply shaking it by hand, and the preparation is not subject to the constraints that are imposed on single preparations, so it can be said that it is a preparation that meets the needs of medical practice. can.

The present invention will be further explained below with reference to Examples.

Example 1 Pulmonary surfactant 120"P and mannitol 48 Akebono 2
The sample was accurately weighed and collected under aseptic conditions into a 0 ml vial, and 8+++ liters of sterile water was added thereto to form a uniform suspension using an ultrasonic generator. This suspension was frozen at -40C and solidified under vacuum for 36 hours. After solidification, the vial was sealed by pressure sealing under aseptic conditions. The same operation was repeated to produce 10 preparations. In addition, by the same operation, mannitol was added at 120my and 180rn.
! and 10 preparations each containing 240 mg were manufactured. The gastric turbidity of the resulting preparation was as shown in Table 1 above.

Example 2 120 ml of pulmonary surfactant and 60 ml of xylitol were accurately weighed and collected in a 20 ml 1% vial under aseptic conditions, and 7 ml of an ethanol-water mixture (volume ratio: 1
, 9) was added and stirred using a stirrer under heating until a uniform suspension was obtained. The resulting suspension -, 40tZ"
The mixture was frozen and consolidated under vacuum for 30 hours, and then the vial was sealed by rolling/kneeling under aseptic conditions.

Repeat the same operation.

Ten formulations were manufactured. Also, xylitol 60n+1
10 each of formulations in which 144〃・1 and 180ml− were changed.
Books were manufactured as described above. The suspension properties of the obtained preparations were as shown in Table 1 above.

Example 3: 8 omy of nlubitol and 120 μm of pulmonary surfactant
The sample was accurately weighed and collected under aseptic conditions into a 0 ml vial, and the following procedure was performed in the same manner as in Example 2 to produce 10 preparations. Also, nlubitol 80m: if144mP and 240
Ten bottles each of the formulations changed to m1 were also produced in the same manner. The suspension properties of the obtained preparations were as shown in Table 1 above.

Example 4 Lung surfactant 120rnf and lactose 60Tn! 20
Accurately weigh and collect the sample under sterile conditions into a ml-capacity vial.
Add to this 8 ml of ethanol-water mixture (volume ratio 1 near)
was added and stirred using a stirrer while heating until a homogeneous suspension was obtained. The suspension was frozen at -50C and solidified under vacuum for 24 hours. After solidification, the vial was sealed under aseptic conditions by pressure sealing. Repeat the same operation.

Ten formulations were manufactured. Also, 60ml of lactose is 96mP.

10 bottles of each of the formulations changed to 144q and 18ON were produced in the same manner. The suspension properties of the obtained formulation were as described above.
It was as shown in the head.

Example 5 Accurately weighed lung surfactant 6.75 ? Add ethanol-water mixture (volume ratio 1:9) 35 (11) and stir.
was added and stirred at 40C for about 45 minutes until a homogeneous suspension formed. After this suspension was allowed to cool to room temperature, water was added to bring the total volume to 450 m6.

The mixture was stirred gently for an additional 5 minutes. Accurately measure 4 me of the obtained solution using a pipette and place it in 10 vials with a capacity of 10 ml.
The solution was dispensed into 0 tubes, frozen at -40C, and the contents were dried and solidified under vacuum for 36 hours. After solidification, the vial was sealed by pressure sealing method. All of the above operations were performed under sterile conditions. The contents of pulmonary surfactant and mannitol in the preparation thus obtained were 60±3rIvJ and 60±2rnf, respectively. Five bottles were randomly selected from the 100 bottles obtained and a suspension test was conducted, and all five bottles were found to be physiological saline fi.
l ml.

It was suspended within 3 minutes.

Example 6 Accurately weighed 15.80 f of lactose was dissolved in 700 ml of an ethanol-water mixture (volume ratio 1:8), and to this solution was added an accurately weighed amount of lung surfactant 12.802,
4 (1:) After stirring for 30 minutes, it was allowed to cool to room temperature. Water was added to the resulting liquid to make exactly 800 ml, and after gently stirring this for 5 minutes, the mixture was poured into exactly 75 ml portions. It was dispensed into 100 vials with a weighed capacity of 20 ml.The contents of the vial were frozen in Ti, F-45C, solidified under vacuum for 48 hours, and then sealed.All operations were performed under aseptic conditions. The content of pulmonary surfactant in each bottle of the resulting preparation was 120±5.
rrg, lactose content was 14816 rng. When 5 bottles of the preparation were randomly selected from 100 bottles and a suspension test was conducted, all 5 bottles were suspended in 2 ml of physiological saline within 3 minutes.

As the pulmonary surfactant in Examples 1 to 6, those described in JP-A-58-45299 were used.

Example 7 1.109 ml of pulmonary surfactant TA-546 described in JP-A-55-160721 and 1.107 ml of lactose were each accurately weighed, and the amount was 59 ml! of water and made into a uniform suspension using an ultrasonic generator. 6 in this liquid
After adding ml of water and stirring for 5 minutes, 6 ml each was accurately dispensed into ten 20 ml vials using a pipette. The contents were then frozen at -200, dried and solidified under vacuum for 12 hours, and then sealed. TA-546(7) content per bottle is 100±3y
g, the lactose content was 100 ± 2 mJ. Three of the 10 preparations obtained were randomly selected for a suspension test, and all three were suspended in 2 ml of physiological saline within 3 minutes.The operation was carried out under aseptic conditions. went.

Example 8 Pulmonary surfactant composition 110% and mannitol 130ηt as described in JP-A-57-99524 were accurately weighed and collected into a 20ml vial.

To this was added 8 ml of an ethanol-water mixture (volume ratio 1:5), and a homogeneous suspension was obtained using an ultrasonic generator. The contents were then frozen at 1-60C and dried and solidified over 60 hours. The same operation was repeated twice to produce three preparations. When the suspension properties of the obtained preparation were tested, it was suspended in 2.5 ml of physiological saline within 3 minutes.

Example 9 (blank below) Example 9 Surf Actan (1.44 F) and lactose (0.62 Si') described in Japanese Patent Application No. 58-38189 were each accurately weighed, and this was added to an ethanol-water mixture ( 1:9)
80ml (!) and stirred at 20tl' for 30 minutes to make a homogeneous suspension. Added 5ml of water to this solution and stirred for another 5 minutes, then added 20ml of 7me each using a pipette.
The liquid was accurately dispensed into 10 liter vials. The contents were then frozen at -35C and solidified by vacuum drying for 72 hours, after which the vial was sealed. All operations were performed under sterile conditions. The surfactant content per bottle of the obtained preparation was 119±3 tons, and the lactose content was 51±2 tons. When three bottles were randomly selected and a suspension test was conducted, all three bottles were suspended in physiological saline solution 2.
ml within 3 minutes.

Example 10 Surface active substance 12 described in JP-A-58-45299
Accurately place 0'7', 7 and 200 Akebono mannitol in a mortar, and add ethanol-water mixture (volume ratio 1:4) to this mortar.
) 5 ml was added dropwise in several portions and kneaded for 30 minutes. This was then treated with OC for 24 hours in the presence of a dehydrating agent.
It was vacuum dried for 4 hours. 2 ml of physiological saline was added to the obtained dry powder 310 mL and shaken at 300 strokes, resulting in a homogeneous suspension after 3 minutes.

Patent applicant Tokyo Tanabe Pharmaceutical Co., Ltd. Agent Masanobu Hisataka (and 1 other person) Procedure Amendment (method) % formula % 1. Indication of incident % Application No. 142,520/1982 2 Name of the invention Lung surface activity Substance and Preparation 3, Relationship with the case of the person making the amendment Patent Applicant Tokyo 10be Pharmaceutical Co., Ltd. 4 Attorney 7 Contents of the Amendment We will submit a clean copy of the application and specification (with no changes to the content) as shown in the attached sheet.

Claims (1)

[Scope of Claims] 1. A pulmonary surfactant preparation characterized by blending a pulmonary surfactant with sugar alcohol or lactose. 2. The pulmonary surfactant preparation according to claim 1, wherein the weight ratio of the pulmonary surfactant to the sugar alcohol or lactose is 1:0.4 to 20. 3. The pulmonary surfactant preparation according to claim 2, wherein the sugar alcohol is mannitol. 4. The pulmonary surfactant preparation according to claim 2, wherein the sugar alcohol is xylitol. 5. The pulmonary surfactant preparation according to claim 2, wherein the sugar alcohol is sorbitol.