JPS6089414A - Manufacture of ribosome composition - Google Patents

Abstract

(57) [Abstract] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention]

The present invention relates to a method for the production of aerosol compositions, in particular aerosol compositions containing active compounds for therapeutic or cosmetic use, and to apparatus used for their production. Certain therapeutically active compounds are administered to patients via inhalation therapy. That is, it is administered into the respiratory tract through the nose or mouth as a mist or gas, or together with a carrier in the form of a mist or gas. It is likewise suitable, for example, to administer the active compound by spraying as a gas or mist in the treatment of wounds, sprains or in the treatment of other skin diseases or in certain skin treatments, such as for salmon. It is desirable to administer the active compound so that it reaches the target site in as high a proportion as possible, sometimes remaining temporarily at the target site, and so that the active compound does not degrade during transport or immediately after contact with the patient. For example, when administering an anti-inflammatory bronchodilator known as bitolterol, penetration is highest in the bronchial tubes.
It is desirable to administer the compound in such a manner that the most potent amount of active compound is delivered to the site of action. In the past, it has been proposed to produce liposomal compositions containing bioactive compounds; for example, such compositions have been described in patent application Ser.
4 and 2,013,609A. However, in known compositions, the liposomal material has been pre-prepared, typically dried by lyophilization, and reconstituted by mixing with water. It has now been found that the efficacy of various active compounds is enhanced when they are administered as a suspension in a spray mixture with a carrier. In the present invention, a method for producing liposomes is provided. The method includes mixing at least two separate components (the first component containing water and the second component containing a lipid material) with an indenter and passing the mixture through a nozzle or similar device under pressure to contain the liposomes. It is characterized by producing an aerosol. Another aspect of the invention is a method of making a liposomal aerosol spray containing a compound for use in human or animal therapy. The method comprises mixing a first component comprising water under pressure with a second component comprising a lipid substance (at least one of the first or second component containing the compound as a solution or suspension).
The first method is characterized in that the mixture is passed through a nozzle or other similar device under pressure to produce the suzone.
and the second component are mixed in such a ratio as to provide a suitable measured amount of active compound. The active compound can be present as a solution both in the first component and in the second component, but is preferably present in the second component. Alternatively, the active ingredient can be present as a dry powder or suspension in the first or second component. However, by using a solution of the active compound, precipitation of suspended substances can be avoided,
Solutions of the active compound are preferred since dosage variations due to precipitation can be avoided. In the method of the present invention, a polymer can be produced by forming a mixture and/or by spraying, optionally in the form of an encapsulated active compound in an aqueous medium or sandwiched between lipid molecules or lipid layers. and contain it. By varying the mixing and/or spraying conditions of the two components, the size of the siliposomes and the ratio of active substance to lipid material to be loaded can be varied over a wide range. In this case, the ratio can be increased to about 100%. For example, by varying the degree of mixing obtained by the conditions carried out in the mixing chamber and/or in the spray nozzle (-, forming an aerosol mixture and/or spraying, spraying with a high concentration of free active compound). sprays containing low concentrations of the free active compound (with a sustained and controlled release of the active compound and a slow-acting effect) can be manufactured. In the latter case, it is possible to produce compositions containing the active compound that can be put into a "protected" form at the intended site of action and/or can be made to act in a manner that sustains the release. The methods of the present invention are applicable to a wide range of biologically active compounds in formulations suitable for ready administration; Alternatively, it can be used to prepare compositions containing cosmetically active compounds, compounds with nutritional value and other compounds used in the treatment of humans or animals. Suitable cosmetically active compounds include skin and hair compounds. protection,
For example, moisturizers, artificial skin creams, (combined with coloring agents if necessary), water-soluble sunscreens, anti-perspirants, deodorants, astringents, freshening agents, toning agents, keratolytic agents, hair removal. agents, perfumes, animal and plant tissue extracts, water-soluble hair dyes, anti-dandruff agents, anti-seborrhea agents,
It is an oxidizing agent (bleaching agent) and a reducing agent. Therapeutically active compounds are vitamins, hormones, active peptides, enzymes, vaccines, anti-inflammatory agents, antibiotics and fungicides. However, the method of the present invention uses bitolterol (
It has particular application in the administration of therapeutically active compounds for use in inhalation therapy, such as those mentioned above) and anti-cancer agents. Such compounds can be incorporated into IJ fosome carriers and penetrated into the bronchi, improving therapeutic efficacy. Similarly, in the treatment of skin wounds, other dermatological conditions, or cosmetic treatments, liposomal carriers can be used to improve effects, such as sustained release effects, allowing a particular treatment to be retained for a longer period of time. . Suitable compounds for use according to the invention are shown below. Active Compound Classification of Compound Route of Administration Cholesterol Anabolic Steroid Topical Chill (e.g. its mesylate) Salbutamol Catecholamines Tracheal Inhalation Dilator Theofili/Xanthine Tracheal Prolonger Inhalation) I
Jum Kuromo Nonsteroidal Antizen Inhalation Glycate Nkung Glutamine Propanolol B-blocking Interventions and Contraceptives Intravaginal/Inhalation Of course, one skilled in the art will be able to use other routes of administration as well as a wide range of other active compounds. be understood. For example, compositions prepared according to the invention can be administered directly to the eye or even intravenously. In addition, antigens and/or antibodies, such as anti-UzagiergG
, active substances useful as markers in blood tests for the presence of disease, can be used. The liposomal materials of the invention are carriers containing specific lipid materials, either positively or negatively charged or neutral and present in the form of an aqueous suspension or dispersion. The lipid material is associated with the active compound required by sb in the form of a monolayer and/or a multilayer. Liposomal materials typically contain phospholipids, including phosphatidylcholines, such as dipalmitoylphosphatidylcholine, phospholipids in the form of lecithin, phosphatidylethanolamine, phosphatidylserine. Liposomal materials can be formed from phospholipids alone or from cholesterol and/or at least one compound capable of imparting a charge to the liposomal material. For example, the siliposome material can be charged by using dicetyl phosphate, which can result in a negatively charged polymer, or phosphatidic acid, or stearylamine, which can result in a positively charged polymer. The use of the above-mentioned materials and the amounts used, as well as the wide selection of materials used and variations in the proportions used, are well known to those skilled in the art. However, by way of example, in a preferred embodiment of the invention, the second component comprises a phospholipid consisting of phosphatidylcholine, cholesterol, cicetyl phosphate;
It typically contains a molar ratio of about 8=about 1 to about 2=about 1 to about 0.05. In another preferred embodiment of the invention, the second component comprises a phospholipid consisting of phosphatidylcholine, cholesterol, and phosphatidic acid, typically from about 8:1 to about 22:1
Contained in a molar ratio of ~0.1. Furthermore, in another preferred embodiment of the present invention, the second component c:
It typically contains phospholipids consisting of phosphatidylcholine, cholesterol, and stearylamine in a molar ratio of about 8:about 1 to about 2:about 1 to about 0,050. The rehomme suspension or dispersion produced by the method of the present invention always maintains a pH within the physiological range, preferably between about 6.8 and about 7.4, preferably between about 7 and 7.4. be. pH
It may also contain an appropriate amount of buffer or buffer system to maintain the . Suitable for this purpose are monobasic sodium phosphate and dibasic sodium phosphate, which are preferably contained in the aqueous solution of the first component. Depending on the composition of the second component, it is preferable or necessary to contain a physiologically suitable liquid excipient in which the lipid substance and the active compound are soluble. Suitable liquid excipients are relatively volatile organic solvents such as ethanol, chloroform (for local control), ethers, inzolovyl alcohol. In a preferred embodiment of the invention, the first and second components are mixed hydrocarbons such as fluoromethane or dichlorotetrafluoroether or halogenated hydrocarbons or mixtures thereof under pressure by the use of an aerosol propellant. The propellant is about 25% of the propellant, such as a 20:80 w/w mixture of dichlorodifluoromethane and dichlorotetrafluoroethane.
It is formulated with a low pressure propellant of ~30 psi. Alternatively, the propellant may be a relatively high pressure propellant up to about 70 psi, such as an 80 to 220 w/w mixture of dichloro-1-cocyfluoromethane and dichlorotetrafluoroethane. Of course, the relative ratio between the two can be adjusted and can be varied depending on the propellant pressure used for each component. The invention also includes a pack for use in the production of liposome aerosols, the puncture being at least between the first and second chambers. One chamber contains a first component containing water, which is a buffered aqueous substance. The other chamber contains a second component containing a lipid substance. One of the components optionally contains a compound for use in the treatment of the human or animal body, for which a suspension or solution is preferred. One or both chambers or the third chamber contains the propellant material. The device includes a reservoir arrangement implemented as an atomizer, and the mixture of first and second components is delivered from each chamber under pressure developed by a propellant or propellants. The proportions of the ingredients can be adjusted within the range of proportions being metered. The desired measured amounts of active compound can thereby be achieved. When the active compound is used, it is preferred that it is in suspension or solution in the second component consisting of a lipid substance, and it is further preferred that the active compound be in solution to avoid precipitation. Generally, the active compound, first and second ingredients, and propellant are those described above for the method of the invention. It is further preferred that the first and second chambers contain a propellant as part of their composition. The pack of the present invention comprises a mixing chamber, an outlet, and a reservoir into which the above-mentioned first and second components are to be applied from their respective chambers to the mixing chamber by means of the pressure created by the propellant, and the ratio of the components within a metered range. Contains pulp for regulating. The desired metered dose of the mixture can be applied from one release via the pulp. In the pack of the present invention, the first chamber is a first aerosol can or bag, the second chamber is a second aerosol can or bag, and these cans or other first and second aerosol cans or bags are The two sealed chambers can be arranged as follows. The respective pulping means and mixing chambers are connected end-to-end by being placed between or on a can or other container. The respective valve means and mixing chambers are connected side-to-side, with the respective valve means and mixing chambers placed between or on top of the can or other container. The first container is placed within the second container (or vice versa) and the valve means and mixing chamber are placed in or on the outer can or other container. Aerosol containers using this type of arrangement have been published, for example in US Pat.
reference. In the device of the present invention, an outer enclosure is provided, and
A sealed chamber is placed therein through which the pulp is manipulated. The present invention further includes compositions for use in the treatment of the human and animal body, e.g. in therapeutic or cosmetic treatments by the delivery of active compounds, the compositions comprising liposomes or liposomal substances and optionally the active compounds being rehomogeneous. It is prepared as a propellant by the method described herein or by the use of the pack described herein. The methods and punctures of the invention can be used to produce and deliver such liposomal aerosols without a single active compound. Such aerosols will find application in numerous ways. Particularly during delivery, newborns with respiratory distress (respiratory poverty syndrome) are able to breathe normally by delivering lipid substances to the tracheal sites to replenish the naturally present low levels of pulmonary surfactant found in these infants. We can help you develop it. The present invention thus describes an alternative method for the production of H-M using a pressurized aerosol system, whether it contains a single active compound or is present as such, and how such production is possible. Contains information about the use of punctures. Translation of the specification (no change in content) In the process of the invention, the first and second components are provided separated [11] from each other, each component being separated from one another under the pressure of the propellant it contains. Preferably, the mixing chamber is fed in controlled discrete doses and the mixture thus obtained is expelled from the mixing chamber through an orifice under pressure from at least one of said propellants. Also,
It is also preferred that the first and second components are mixed in a manner that provides a measured amount of any active substance. More preferably, the second component is added as a measured amount to the measured first component and brought into contact with the first component at multiple locations. Therefore, specifically, the method of the present invention more preferably comprises the following series of steps. feeding a measured amount of a first component into the mixing chamber; a measured amount of a second component;
The second component is preferably fed into the mixing chamber from a plurality of positions in such a manner that turbulent mixing of the two components occurs according to item i'1 of the specification (no change in content). feed into the mixing chamber. Discharge the mixture from the mixing chamber; step 5. Conveniently, the metered quantity of the first component is controlled by supplying the first component to the mixing chamber to fill the mixing chamber and determining the volume of the mixing chamber to give the desired quantity of supply. It is. Preferably, the valve means is a combination (e.g. a two-barrel valve), which is capable of filling one catfish chamber with the first component to be dispensed and metering the second component to be dispensed. amount 2
The two components can be fed into the mixing chamber to cause turbulent mixing and the mixture can be discharged through a discharge orifice. Preferably, the valve means also includes a device capable of supplying the second component from multiple locations in the mixing chamber. (No change in content) If eel is required, separate mixing means may be provided upstream or downstream of the mixing chamber to discharge the eel from the discharge orifice with 1.1 intimate and/or turbulent agitation conditions. It is also possible to promote liposome formation prior to treatment. The locusts of the invention may be provided with an outer covering, such as a can. Inside this a closed chamber can be placed and through which the valve means can be operated. In this pack, the second component contains a propellant and is contained in an internal rigid wall sealed chamber, and the first component is contained in an external plastic wall sealed chamber, preferably a chamber surrounding the internal Fill '+i. Preferably, the outer housing is made of a rigid wall, and the space between the outer chamber and the surrounding housing contains a propellant. . A preferred two-component pack device with these features is disclosed in Isu Patent Application No. 4450/83 (unchanged). As can be understood from the following description, when carrying out the present invention, the amount of active substance supplied by the above-mentioned pack trough operation depends on many factors, such as: It can vary widely. 1. The amount of the active substance in the first component and the second component: and 2. The mixing ratio of the first and 4f-G2 components. In the case of the mixing ratio of each component, the ratio depends on the magnitude of the total amount of the first and second components involved in the mixing, which therefore [depends on the specific mixing and valving equipment accepted. 4. In the above-mentioned particularly preferred (7) apparatus, the mixing chamber has a volume of about 50 to about 100 μl, e.g. 75 to 1
With a volume of 0 (1 μl), approximately 91 actuations of the valve controlling the metering of the second component cause approximately 50 to 100 μl of the component to be added to the mixing chamber V. The dimensions of the discharge or supply orifice of the valve used to supply the mixed components also control the dimensions of the formed hIJ homme.The discharge orifice r is approximately 350 m
Preferably, it has a size of ˜about 450 μm. However, once the above parameters are fixed and determined, the resulting usage level can be easily determined, as well as the degree of incorporation of any active substance and the size of the liposomes produced. As those knowledgeable about incorporating active agents into carriers will appreciate, the level of incorporation of active agents within a liponorm carrier may be selected with respect to the overall composition selected. It has a significant effect on the demonstrated dose VC. Accordingly, a demonstrated dosage level such as 1j'·舊 in Komei 4111 (no change in content) would be a formulation choice depending on the observed range that also fits any particular formulation. The following examples illustrate the method and aerosol batter of the present invention. In the particular examples given, most formulations (containing ammonium molybutate as an electron densifying agent) were formulated to facilitate measuring the diameter of the liposomes using an electron microscopy sharpener. Of course, as has been explained by the Ministry of Pharmaceutical Preparation, the somewhat wild ammonium molybdate should not be part of the actual composition for administration to patients. Example 1
As can be seen from the comparison at 9 and 2°, the omission of ammonium molybdate does not have any negative effect on the level of active ingredient uptake. Facts, implementation 51J 20
In this case, the uptake level is slightly low. Therefore, in any of the formulations shown, the molybutate marker can be omitted without negative effects and the results obtained can be obtained without it. Additionally, although various levels of active ingredient are illustrated, and these levels therefore provide different concentrations of free and incorporated active ingredient for action, the formulation level chosen for the particular puncture. It will be appreciated by those skilled in the art that the type and type of composition will vary depending on the particular intended method of administration undertaken and the required or desired balance of incorporated or unincorporated active agents. . For example, the average person consumes 2.2 nols of Taleem concoction!
9/cn12 (BP implementation level) An average application to the skin would be approximately 5t and - times of aerosol application (i.e.
The following comparison can be made between the example composition and the standard composition, assuming that the R71 shot (shot) covers 25 crn2 of skin (without any changes). Stanozolol cream 2.3 (0,1%) Stanozolol-4,0 of Example 21 Hydrocortesontareem 23 (1,0%) Hydrocortesontareem 23 (1,0%) Hydroco-4,8 of Example 25 TezonoAeroNol Beta Mesazo/ Taleem 2.5 (0.1%) Betamethasone of Example 27 0.64 Aerosol (The active substance may be present at known standard levels or higher or lower total

[J of specific administration and details Q
7Ik (No change in content) Can be added with bell,
The desired degree of effect can be achieved. Changes in effectiveness can be enhanced by changing the degree of blending. Similarly, in the case of preparations for inhalation, the overall dosage will vary depending on the desired effect. Therefore, for example,
As described in Example 31, albutamol is a slow-release material with a single dose of fip 125 μl and 125 μl.
μg of free substance is effectively administered. This compares to 100 μJ per dose from standard dispensers. Furthermore, as illustrated in Examples 29 and 30, respectively, the active agent can be administered at levels significantly higher or lower than the standard. That is, in the case of bitolterol of Example 29, 933μ
I (standard is 200 μg), and in the case of 30 chromoglygates, 200 μg! j (Standard 2
rl+9). However, in both these cases it is also possible to adapt the dosage level to that of the standard by varying the total amount of active substance provided by the first and second components, respectively. Example 1 240 mg of egg yolk leishte/and 28 g of cholesterol are dissolved in 4 ml of ethanol and the solution is added to 25 g of a 20:80 w/w mixture of propellant dichlorodifluoromethane and dichlorotetrafluoroethane. The mixture is then sealed in a container with a metering valve. 25 ml of 3.3mM! Aqueous solution of sodium chloride, 2. into an aluminum container 2
5. Place in a separate container with a valve from the one containing the propellant described above. The vessels are connected through a mixing chamber and a valve mechanism is actuated to release a portion of the lipid solution and a portion of the phosphate solution into the mixing chamber and from there through the constriction to the atmosphere. The resulting aerosol has an average diameter of 1μ
Contains multilamellar and monolamellar liposomes of less than m. Example 2 240 mg of egg yolk lecithin, 28 rng of cholesterol and 4 mg of phosphatidic acid are dissolved in 4 ml of ethanol and the solution is mixed with the propellants dichlorodifluoromethane and dichlorotetrafluoroene (D
Add to 40:60 w/w mixture 259. The mixture is sealed in a container fitted with a metering valve. 25 ml of 3.3mM sodium phosphate aqueous solution, p
H7.2 is placed in an aluminum container and then sealed in a separate valved container containing 25 g of the above propellant. The vessels are connected through a mixing chamber and a pulp mechanism is actuated to release a portion of the lipid solution and a portion of the phosphate solution into the mixing chamber and from there through the constriction to the atmosphere. The resulting aerosol contains negatively charged multilayer and single layer adhesive membranes with an average diameter of less than 1 μm. Example 3 240 mg egg yolk lecithin, 2B11゛1go covy
, 1.6nl of stearylamine f4rnl dissolved in ethanol and its solution total propellant 25.9% of a 20:80 w/w mixture of dichlorodifluoromethane and dichlorotetrafluoroethane.
Add to. The mixture is then sealed in a container fitted with a metering valve. 25rnl of 3.3mM sodium phosphate aqueous solution, pH 7.2, is placed in a k aluminum container and then sealed in a separate valved container containing 25g of the above propellant. The vessels are connected through a mixing chamber and a pulp mechanism is actuated to release a portion of the lipid solution and a portion of the phosphate solution into the mixing chamber and from there through the constriction to the atmosphere. The resulting aerosol contains positively charged multilamellar and unilamellar liposomes with an average diameter of less than 1 μm. Example 4 240 rIQ of egg yolk lecithin and 4 m9 of phosphatidic acid are dissolved in 41 nl of ethanol and the solution is added to 25 g of a 20 to 280 w/w mixture of propellants dichlorodifluorometa/and dichlorotetrafluoroethane. The mixture is then sealed in a container fitted with a metering valve. 25 ml of a 3.3 mM aqueous sodium phosphate solution, pH 7.2, is placed in an aluminum container and then sealed in a valved container separate from the one containing 25.9 of the above propellant. The vessels are connected through a mixing chamber and a pulp mechanism is actuated to release a portion of the lipid solution and a portion of the phosphate solution into the mixing chamber and thence to the atmosphere through the constriction port. The resulting aerosol contains negatively charged multilayer and single layer glue bombs with an average diameter of less than 1 μm. Example 5 24 mg dipalmitoylphosphatidylcholine, 2,
8n1g0 cholesterol, 2 mg of dicetyl phosphate and 211 g of bitolterol mesylate were dissolved in 4 ml of ethanol and the solution was mixed with the propellants dichlorofluoromethane and dichlorotetrafluoroethane at a ratio of 40:60 w/ Add to mixture 25.9. 25 ml of a 3.3 mM sodium phosphate solution, pH 7.2,' is placed in an aluminum container and then sealed in a valved container separate from the one containing 25.9 of the above propellant. The vessels are connected through the mixing chamber and the pulp mechanism is actuated to discharge a portion of the lipid solution and a portion of the acid solution from the mixing chamber and thence to the atmosphere through the constriction. The resulting aerosol contains negatively charged multilamellar and monolamellar liposomes;
More than 0% bitolterolmenate has been introduced into the population. Example 6 2401ψ egg yolk lecithin, 28■ cholesterol,
Dissolve 2 mg of dicetyl phosunate and 20 l of bitolterol mesylate in 4 m13 of ethanol and mix the solution with 40 m of the propellants dichlorodifluoromethane and dichlorotetrafluoroethane:
Add to 25g of 60 w/w mixture. The mixture is then sealed in containers fitted with metered pulp. 25ml of 3.3mM sodium phosphate solution, pH 7.2-. is placed in an aluminum container and sealed in a container with pulp separate from the one containing 25 m9 of the above propellant. The vessels are connected through a mixing chamber and a valve mechanism is actuated to release a portion of the lipid solution and a portion of the chloride/acid solution into the mixing chamber and from there through the constriction to the atmosphere. The resulting aerosol contains multilayered and monolayered polymers with an average diameter of less than 1 μm, and more than 9.50% bitolterol mesylate is incorporated into the liposomes. Example 7 50 n1g of rabbit lecithin was dissolved in ethyl alcohol (96
%BP) and the total volume was adjusted to f 1.0 ml to obtain a lipid component. The resulting solution was transferred to a glass container and 7.0 g of dichlorofluoromethane was added. Next, this glass container t
It was sealed with a 65111 metering valve. This pulp is 75μ
A mixing chamber e is arranged to receive the lipid components discharged through the metering valve, itself forming part of the second pulping apparatus. The apparatus thus constructed was placed in a second plastic container (cylindrical bag) containing 40 ml of ammonium molybdate solution (0.5% w/v deionized/water) to form the aqueous component. This aqueous component is in communication with the mixing chamber in the closed position of the second valve. The second container is then crushed to 2.0
g of dichlorodifluoromethane propellant. In this case, the second valve system (located in the bag and in the mixing chamber), when activated itself, activates the first pulp for releasing lipid components into the mixing chamber, e.g. The entire aerosol can device was inserted in such a way that the mixed components could be released as disclosed in Swiss Patent Application No. 4450/83. The second pulp system was then equipped with a standard button actuator with a 450 μm orifice. The resulting aerosilica/device has a diameter of 40-400 nm.
could be used to provide aerosol sprays containing unilamellar and multilamellar liposomes. Unless otherwise specified, the general method of Example 7 was carried out in the following examples and the same aerosolcan equipment was used. Example 8 50 liters of egg yolk lecithin in ethyl alcohol 96% BP
Dissolve in and bring up the volume to LOrnl with ethyl alcohol. Transfer the solution to a glass container and add 7.0 g of dichlorodifluoromethane. The container is then sealed with 50μ4 of metered pulp and fitted with a 100μl mixing chamber. The assembly was placed in a second flexible container containing 40 ml of ammonium molybdate solution (0.5% w/v in deionized water) and placed in an aerosol can containing 2.0 g of the propellant dichlorodifluoromethane. Shrink it inside. A standard 450 micron button actuator is then installed. The resulting aerosols are 40 nm and 100 nm.
Includes unilamellar and multilamellar liposomes with diameters between. Example 9 50 Tn9 (7) Dissolve egg yolk lecithin in ethyl alcohol 96% BP, make up the volume by 1 with ethyl alcohol,
Q Make it ml. Transfer the entire solution to a glass container, 7.0
g of dichlorodifluoromethane is added. The container is then filled with 100 .mu.g of metered pulp, sealed and fitted with a 100 .mu.e mixing chamber. Add the assembly to 4Q ml of ammonium molybdate solution (05% w/v in deionized water).
and compressed into an aerosol can containing 1 part of 2.0 g of the propellant dichlorodifluoromethane. A standard 450 micron button actuator is then installed. The resulting aerosol is 50nm
and 1000 nm in diameter. Example 11 060 nI of egg yolk lecithin and 7Qlng of cholesterol are dissolved in 1.0 ml of ethyl alcohol 96% BP. Transfer the solution to a glass container and mix with 20:8 dichlorodifluoromethane and dichlorotetrafluoroethane.
Add 6.0 g of 0 V//w mixture. Next, pour the pulp into the container, seal it, and attach the mixing chamber. The assembly is placed in a second flexible container containing 40rnE of 3.3nuM aqueous sodium lysate solution pH 7.2 and compressed into an aerosol containing 20g of propellant dichlorodifluoromethane. The resulting aerosol contains unilamellar and multilamellar liposomes with diameters between 40 nm and 11000 nm. Implementation Reli 11 60, 0 m9 of egg yolk 1/cytin, 10 m9 of phosphatidic acid and 7.0 Tn9 of cholesterol'f:
Dissolve in 1.0 ml of ethyl alcohol 96% BP. Transfer the solution to a glass container and mix with 20:8 dichlorodifluoromethane and dichlorotetrafluoroethane.
Add 6.0 gt of 0 w/w mixture. The container is then filled with metered pulp, sealed and fitted with a mixing chamber. Place the assembly into a second flexible container containing 40 ml of 3.3 mM sodium phosphate aqueous solution pH 7.2;
Squeeze into an aerosol can containing 2.0 g of propellant dichlorodifluoromethane. The aerosol produced is 4
Contains unilamellar and multilamellar liposomes with diameters between 0 nm and 1100 Or1. Example 12 60,0 mq of egg yolk lecithin, Q,4+qy of stearylamine and 7.0 m9 of cholesterol @ 1
．． Orlt. Ether Alcohol Transfer to a glass container and add 20 to 80 w7v of dichlorodifluoromethane and dichlorotetrafluoroethane:
Add 6.0 g of mixture. The container is then filled with pulp, sealed and fitted with a mixing chamber. The assembled product is 40 m
3.3mM ly/acid sodium soluble in water i'ilpH
7.2 into a second flexible container containing 2.0 g of propellant dichlorodifluoromethane and compacted into an aerosol can. The resulting aerosol is 4. It includes single-layer and multilayer adhesive membranes with diameters between 1000 nm and 1000 nm. Example 13 Egg yolk lecithin of 60, 0 1119 and 1. O
n+9 phosphatidic acid 1. Dissolve in 0 mlJ of ethyl alcohol 96% PB. Transfer the solution to a glass container and add 6.0 g of a 20:80 W/W mixture of dichlorodifluoromec/and dichlorotetrafluoroethane. Next, pour the pulp into the container, seal it, and open several mixing chambers. The assembled product is 3.3m in 4Qrrt.
Place in a second flexible container containing an aqueous solution of sodium phosphate pE (7.2) and compress into an aerosol can containing 2.0 g of the propellant dichlorodifluoromethane. The resulting aerosol has a particle diameter of 40 nm. Contains monolamellar and multilamellar liposomes with diameters between 1000 nm. Example 14 0.5 mg bitolterol mesylate, 6. O J
rUi Nodipalmitoylphosphatidylcholine, 0.
5 m9 of dicetyl phosphate and 0.5 m9 of dicetyl phosphate. 7 411
9 cholesterol 1, Qml ethyl alcohol 9
Dissolve 6% BP. Transfer the solution to a glass container and add a 20:80 w/w mixture of dichlorodifluoromethane and dichlorotetrafluoroethane6. 0 g k
Add. The container is then filled with pulp, sealed and fitted with a mixing chamber. The assembly 'Z 40ml 3.3
mMIJ Natritan sodium aqueous solution. 2ff: Place in a second flexible container and collapse into an aerosol can containing 2.0 g of propellant dichlorodifluoromethane. The resulting aerosol is 4. O u m and 1000n
Contains unilamellar and multilamellar liposomes with diameters between m. Example 15 Vitruderol mesylate of 5.0m), 60. Q
m9 egg yolk lecithin% 0.5 m&dicetyl phos7ate and 0 7. O rv's cholesterol't i
．． Dissolve in 0 ml of ethyl alcohol 96% BP. Transfer the solution to a glass container and add 20% of dichlorodifluoromethane and dichlorotetrafluoroether/
: Add 80 w/w mixture. The container is then filled with pulp, sealed, and fitted with a mixing chamber. The assembly was placed in a second flexible container containing a 3.3 mM aqueous solution of sodium phosphate, pH 7.2, in 'Fc40me' for 2 hours.
．． Compress into aerosolization containing 0 g of propellant dichlorodifluoromethane. The aerosol produced was 40
Contains unilamellar and multilamellar liposomes with diameters between nm and 11000 nm. Example 16 100 Tn9 egg yolk lecithin and 6.0 mg stanozolol were dissolved in ethyl alcohol 96% BP,
2. Volume total ethyl alcohol. Set it to Oall. Transfer the solution to a glass container and add 9.09 g of dichlorodifluoromethane. Next, add 50116 old pulp to the container, seal it, and attach a 100 μl mixing chamber. The assembly was placed in a second flexible container containing 401ne of ammonium molybdate (Q, 5% W/V in deionized water) and aerosolized with 2.0g of propellant dichlorodifluoromethane. Shrink it and put it in. A standard button actuator of 450 micron diameter is then installed. The resulting aerosol is 40 nm and 110 nm.
Contains unilamellar and multilamellar liposomes with diameters between m. Of the 50.0 gg of stanozolol released by that mode of operation, 21.6 μg was shown to be associated with liposomes. Example 17 450 rng of egg yolk lecithin and 60 lng of succnozolol were dissolved in ethyl alcohol 96% BP K.
'c volume with ethyl alcohol 3. Q Make it ml. Transfer the solution to a glass container and add 4.5 g of dichlorodifluoromethane. Then add 50 μe to the container.
of metering pulp, seal, and install a 100μ4 mixing chamber. The assembly was placed in a second flexible container containing 40rne of ammonium molybdate (0.5% w/v in deionized water) and aerosolized with 2.0g of the propellant dichlorodifluoromethane. Shrink it and put it inside. A standard button actuator of 360 micron diameter is then installed. The aerosol produced was 44
Contains unilamellar and multilamellar liposomes with diameters between 440 nm and 440 nm. 500. released by the operation of the method. Of the σμg of stanozolol, 35.4μg was shown to be associated with liposomes. Example 18 Dissolve 450 η of egg yolk lecithin and 60 η of suchinozolol in 96'% BP of ethyl alcohol.
3. with jtt ethyl alcohol. Q Make it ml. Transfer the solution to a glass container and add 4.5 g dichlorodifluorometa/total. The container is then sealed with 100 μl of metering pulp and the entire mixing chamber is filled with 100 μl. The assembly was placed in a second flexible container containing 40rnl of ammonium molybdate solution (0.5% w/v in deionized water), which contained 2.0g of the propellant dichlorodifluoromethane. Shrink it into an aerosol. A standard button actuator of 450 micron diameter is then installed. The resulting aerosol contains monolayer and multilayer polymers with diameters between 25 nm and 190 nm. 1000.0 gg released by the operation of the method
of stanozolol was shown to be associated with liposomes. Example 19 9001 ψ of egg yolk lecithin and 60 m9 of stanozolol were mixed in 96% BP of ethyl alcohol, and the volume was diluted with ethyl alcohol for 3. Q Make it ml. Transfer the solution to a glass container and add 4.59 g of dichlorodifluoromethane. The vessel is then fitted with a 50 It l mixing chamber. That assembly? : 40m1! ammonium molybdate solution (0.5% w in deionized water)
/v) into a second flexible container containing
:2.0. ! 9 into an aerosol containing the propellant dichlorodifluoromethane. A standard button actuator of 450 micron diameter is then installed. The resulting aerosol contains monolamellar and multilamellar liposomes with diameters between 40 μem and 350 nm. It was shown that 81.3 μs of the 5000.0 μl of 2-cunozolol released by that mode of operation was associated with liposomes. Example 20 900 m9 of egg yolk lecithin and 60 mg of stanozolol were dissolved in 96% BPK of ethyl alcohol. Q Set it to Tnll. Transfer the solution to a glass container and add 4.5 g of dichlorodifluoromethane. Add. The vessel is then sealed with a 50 μl metering valve and fitted with a 100 μl mixing chamber. The assembly is placed in a second flexible container containing 40 rJ of deionized water and compressed into an aerosolizer containing 2.0 g of propellant dichlorodifluoromethane. A standard button actuator of 450 micron diameter is then installed. Of the 500 μg of stanozolol released by the mode of operation, 85.0
μI was shown to be associated with liposomes. Example 21 900 Ing of egg yolk lecithin and 12 Tng of Stanozolol were dissolved in ethyl alcohol 96% BPK.
Bring up the volume to 3.9 ml with ethyl alcohol. The solution is transferred to a glass container, sealed with a 4.5 g dichlorofluoromethane metering valve, and fitted with a 100 μ4 mixing chamber. The assembly ffi is placed in a second flexible container containing 40 ml of deionized water and compressed into an aerosolization containing 2.0 g of the propellant dichlorofluoromethane. A standard button actuator of 450 micron diameter is then installed. The aerosol contains monolamellar and multilamellar liposomes with diameters between 40 μm and 350 nm. It has been shown that 76.8 μg of the 100 μg of methanazol released by operation of that mode is associated with liposomes. Example 22 900 ~ egg yolk lecithin and 12m9 stanozolol in ethyl alcohol 96% BP 11Cm,
'The volume of C fJt (3. Q m with t-ethyl alcohol
Make it l. Transfer the solution to a glass container and add 4.5 g of dichlorodifluoromethane. Then add 5 to that container.
Attach and seal the 0 μl metering valve and attach the 100 μl mixing chamber. The assembly was placed in a second flexible container containing 4 gme of ethyl alcohol in deionized water (1% v/v), which was f:2. Of! into an aerosol containing the propellant dichlorodifluoromethane. A standard button actuator of 450 micron diameter is then installed. The resulting aerosol contains unilamellar and multilamellar liposomes with diameters between 30 nm and 500 nm. Of the 100 μl of statanozolol released by that mode of operation, 77.3 μμ was shown to be associated with liposomes. Example 23 900#+9 egg yolk lecithin and 12 mg stanozolol in ethyl alcohol 96% BP Ki or L, -'
Make up the volume of t to 3.0 ml with total ethyl alcohol. Transfer the solution to a glass container and add 4.5 g of dichlorofluoromethane. The vessel was then sealed with a 50 μe metering valve and fitted with a 100 μl mixing chamber. Place the assembly in a second flexible container containing 40 ml of ethyl alcohol in deionized water (5% v/y) and place it in e2. og into an aerosol containing the propellant dichlorodifluoromethane. A standard button actuator with a diameter of 450 microns is then installed. The resulting aerosols were 30 nm and 500 nm.
Includes single-layer and multi-layer lipomes with diameters between m. 10 released by the operation of the system
Of the 0μs of stanozolol, 76.3μμ was liposol.
- It was shown that the group was meeting. Example 24 900 mg of egg yolk lecithin and 13 m9 of stanozolol were dissolved in ethyl alcohol 96% BP Ki, -
3.t volume with ethyl alcohol. Set to Q rag. Transfer the solution to a glass container and add 4.59 g of dichlorodifluoromethane. The container is then sealed with a 50μ4 metering valve and a full 100μl mixing chamber is installed. The assembled product 'Z4Q+n1. of ethyl alcohol in deionized water (10% v/v) and compressed into an aerosolization solution containing 2.0 g of the propellant dichlorodifluoromethane. A standard button actuator with a 450 micron aperture is then attached.The resulting aerosol is
Contains unilamellar and multilamellar liposomes with diameters between 00 nm and 00 nm. Out of the 100 μs of methanozolol released by that mode of operation, 66.6 μI was shown to be associated with liposomes. Example 25 900 mg of egg yolk lecithin and 14.4 m9 of hydrocortisol 2B,P,? ! -Ethyl alcohol 96% B
Dissolve in P and reduce its volume to 3.0 m with ethyl alcohol.
Make it l. Transfer the solution to a glass container and add 4.5 g
of dichlorodifluoromethane. Then 50 in that container! Attach and seal the 100μ metering valve.
Write a few verses about the mixing room of l. Add 40ml of ammonium molybdate solution (0.5% w in deionized water) to the assembly.
/v) t-containing second flexible container and compress it into an aerosol can containing 2.0 g of propellant dichlorodifluoromethane. A standard button actuator of 360 micron diameter is then installed. The resulting aerosol has wavelengths of 44nm and 220nm.
Includes unilamellar and multilamellar liposomes with diameters between. 120 released by the operation of the method
54.0 μg of μI pitrocortisone/B, P
was shown to be associated with liposomes. Example 26 8411n9 of egg yolk lecithin, 54.8rr of dicetyl phosphate and 14.4 m9 of hydrocortizoy B
,P. Dissolve 96 liters of ethyl alcohol in BP, and dilute the volume with ethyl alcohol by 3. Q Set to rnl. The melt
Transfer L to a glass container and add 4.59 g of dichlorodifluoromethane. Next, add a 50 μg metering valve to the container. Seal and attach 100 μl mixing chamber. The assembly t 40 ml of ammonium molybdate solution (0.5% w,/v in deionized water)'
jl into a second flexible container containing 2.0.
! 9 into an aerosol can containing the propellant dichlorodifluoromethane. A standard button actuator of 450 micron diameter is then installed. Of the 120 μI of hydrocortisol/B,P released by operation in that manner, 45.6 μI was shown to be associated with liposomes. Example 27 841 m9 of egg yolk lecithin and 4.8 m9 of betamethasone valerate BP/USP/NF are dissolved in 96% of ethyl alcohol and the volume is made up to 3.01 n, l with ethyl alcohol. Transfer the solution to a glass container and add 4.5 g of dichlorodifluoromethane. The vessel is then sealed with a 50 μl metering valve and fitted with a 100 μl mixing chamber. The assembled product k
Place 40 rug of ammonium molybdate solution (0.5% w/v in deionized water) into a second flexible container containing: f: an aerosol can containing 2.0 g of the propellant dichlorodifluoromethane. Shrink it inside. The resulting aerosol contains unilamellar and multilamellar liposomes with diameters between 2011 m and 300 nm. 16 μI of betamethasone parilate is released by the mode of operation. Example 28 84Lm9 of egg yolk lecithin was added to 96% B of ethyl alcohol.
Dissolve the volume in 3'Oml of ethyl alcohol.
Make it. Transfer the solution to a glass container and add 4.5 g of dichlorodifluoromethane. Then add 50μ to the container.
Attach the metering valve No. 4, seal it, and open the 100 μe mixing chamber several times. The assembly was dissolved in 4Qral ammonium molybdate solution (0.5% w/v in deionized water)' (
i- Place the second flexible container containing it and collapse it into an aerosol can containing 2.0 g of the propellant dichlorodifluoromethane. A standard button actuator of 450 micron diameter is then installed. The resulting aerosol was 30rr. n and 1000
Contains unilamellar and multilamellar 1-noposomes with diameters between nmO. Example 29 841 mg egg yolk lecithin and 1 1 2 rnl7
bitolterol mesylate toethyl alcohol 96%
BP to a volume of 3.0 ml. Transfer the solution to a glass container and add 4.5 g of dichlorodifluoromethane. The container is then sealed with a 50 μl metering valve and 100 μg of Install the mixing chamber. Place the assembly in a second flexible container containing 40 ml of ammonium molybdate solution (deionized/0.5% W/v in water) and add 2.0 g. The aerosol containing dichlorodinololomethane is then compressed into a standard button actuator of 450 micron diameter. It was shown that 545 μg of the 933 μl of bitolterol mesile-1 released by actuation of this mode was associated with liposomes. Example 30 841 mg of egg yolk lecithin was dissolved in ethyl alcohol. 96%B
Dissolve in P and dilute its volume with ethyl alcohol to 39 ml.
: to make. Transfer the solution to a glass container and add 4.5 g of dichlorodifluoromethane. Then add 5 to that container.
Attach and seal the 0 μl metering valve and attach the 100 μl mixing chamber. The assembly was washed with sodium chloride in 0.1 M sodium phosphate buffer pH 7.4).
USP XX, BP'80 (2Tnl//:al) and ammonium molybdate C5m9/ml), which was then added to an aerosol containing 2.0g of the propellant dichlorodifluoromethane. Shrink it into a form. A standard button actuator of 450 micron diameter is then installed. The aerosol produced is 3
It includes single-layer and multi-layer adhesive membranes with diameters between 5 nm and 700 nm. Of the 200 μg of sodium chromobrifut released by operation of that mode, 22 μg was shown to be associated with liposomes. Example 31 450m9 egg yolk lecithin and 15rp9 salbutamol base BP' (+: ethyl alcohol 96% BPK
Dissolve and dilute its volume with 3. ethyl alcohol. Q me
Make it. Transfer the solution to a glass container and add 4.5 g of dichlorodifluoromethane. Then put 10 in the container
Attach and seal the 0 μl metering valve and attach the 100 μg mixing chamber. Assembling - Place the C-article into a second flexible container containing an ammonium molybdate solution (0.5% w/v in deionized water) 'i5' and it 't2. Contain the propellant dichlorodifluoromethane' A standard button actuator of 450 micron diameter is then attached. The resulting aerosol contains monolamellar and multilamellar liposomes with diameters between 30 nm and 300 nm. Of the 250 μl of bitolterol mesylate released by operation of that mode, 125 μl was shown to be associated with liposomes. Example 32 841 ml (7) egg yolk 1/cytine in ethyl alcohol 96% BP Dissolve and reduce its volume with ethyl alcohol
, Q ml. Transfer the solution to a glass container and
g of dichlorodifluoromethane is added. The vessel is then sealed with a 50 μg metering valve and fitted with a 100 μl mixing chamber. Place the assembly in deionized water with N
A solution of -acetylmuramyl-L-alanyl-p-inglutamine (NALAG) (lQQμjj/:al) and ammonium molybdate (5mg/ml)] into a second flexible container containing Oml; ! z
Compress into an aerosol containing 2.0 g of propellant dichlorodifluoromethane. A standard button actuator of 450 micron diameter is then installed. The resulting aerosol contains all monolamellar and multilamellar spsomes. A 10 μs NALAG is emitted by the mode of operation. Example 33 Egg yolk lecithin of 841 mt;) was mixed with 9 parts of ethyl alcohol.
Dissolve in 6% PB and its volume 3 with ethyl alcohol.
Q Make it me. Transfer the molten liquid to a glass container,
Add 45y of dichlorodifluorometa/. Next, attach a 50μβ metering valve to the container, seal it, and add 100μβ.
Install the mixing chamber e. Prepare a dilution of anti-rabbit IgC (1/64 titer vs. 1/640 normal rabbit serum agar-block precipitin titration) in total deionized water (50 μl/ml).
)! ? and ammonium molybdate (5my, /:
tLl) into a second flexible container containing tv solution 35me6 and it'! The mixture was compressed into an aerosol containing the propellant dichlorodifluoromethane at r 2.09. A standard 450 micron 10 diameter button actuator is then installed. The resulting aerosol contains unilamellar and multilamellar liposomes. 5μ4 anti-rabbit IgG
(1/64 titer) is released by operation of that mode. It is to be understood that the invention is not limited to the specific example items described above. For example, a variety of lipid materials can be used to make the desired liposome carrier, and a wide variety of active substances can be attached thereto. Many other aerosol arrangements can also be used, in particular one of the other arrangements mentioned above. (Other 5 people) Procedural amendment Showa (October 17, 2013, Director General of the Patent Office, Gakudon Shiga 2, Name of the invention, 91゛ So B, 9 upper n “f title/)　　　　　　　　　　　　　　) Relationship with the person who does the patent application Address of the patent applicant
Shiitte sweat 4, agent

Claims (1)

[Claims] (1) At least two separate components, the first component containing water and the second component containing a lipid substance, are mixed under pressure, and the mixture is passed through a nozzle or the like. A method for producing liposomes, which is characterized by passing the liposomes through another device under pressure to produce an aerosol spray containing liposomes. 2. At least one of the first or second components mentioned above is characterized by a non-lipid active substance that is biologically active and/or useful for the treatment or protection of humans or animals. Manufacturing method. 3. The method of claim 2, wherein the active substance is in solution in the first or second component. 4. The manufacturing method according to claim 2 or 3, wherein the active substance is a biologically active drug. 5. Claim 2, wherein the active substance is an antigen or an antibody.
The manufacturing method according to any one of items g2 to 4. 6. Process according to claim 2 or 3, wherein the active substance is therapeutically or cosmetically active. 7. The manufacturing method according to claim 6, wherein the active substance is a bronchodilator, an anti-inflammatory agent, an anti-cancer agent, an anti-inflammatory agent, a pregnancy regulator, or a solidifying steroid. 8. The active substance is bitolterol and its ester,
Stanzolol, Hi-10 corchicine and hisodiester, betamezazone and its ester, salzutamol,
Claim 6, which is a compound selected from theophylli/, sodium cromoglycate, acetylume dimyl-analyl-isoglutamine or propranotol.
Manufacturing method described in section. 9. The manufacturing method according to claim 2 or 3, wherein the active substance is one or more compounds with nutritional value. 10. The lipid substance of the second component has a positive charge, a negative charge,
or selected to produce neutral liposomes/
The manufacturing method according to any one of claims 1 to 9, which is a lipid. 11. The lipid substance of the second component is phosphatidylcholine,
Phosphatidylethanolamine, phos-7atidylserine alone or with two or more components; cholesterol and/or
or dicetyl phosphate. At least one of phosphatidic acid or stearylamine
11. The method according to claim 10, wherein the phospholipid is a phospholipid consisting of: 12. A claim characterized in that the second component consists of a phospholipid selected to provide a neutral liposome and composed of phosphatidylcholine and cholesterol in a relative molar ratio of about 8:1 to about 2. The manufacturing method according to item 11. 13. The second component is selected to have a negative loading lipome, and the phospholipid is composed of phosphatidylcholine, cholesterol and dicetyl phos7ate in a relative ratio of about 82 about 1 to about 2: about 1 to about 0.05. The manufacturing method according to claim 11, characterized in that: 14. The second component is negatively charged; it gives 1 sonome.5
and a relative molar ratio of about 8=about 1 to about 2:about 1
12. Process according to claim 11, characterized in that it consists of a phospholipid composed of ~0.1 phosphatidyl coli/, cholesterol and phosphatidic acid. 15. The second component is selected to provide positively charged liposomes, and the second component has a relative molar ratio of about 8:1 to about 1.
12. The method according to claim 11, characterized in that the phospholipid is composed of about 2:1 to about 0.5 phosphatidylcholine, cholesterol and stearylamine. 16. The production method according to any one of claims 11 to 15, wherein the phosphatidylcholine is dipalmitoylphosphatidylcholine itself or in the form of lecithin. 17. According to any one of claims 1 to 16, wherein the first component comprises a buffer or buffer system in a suitable amount to bring and maintain the pH within the physiological range. manufacturing method. 18. A method according to any one of claims 1 to 17, wherein the second component comprises a physiologically suitable liquid medium. 19. The production method according to claim 18, wherein the medium is a liquid substance and a volatile organic solvent in which the above-mentioned active substance is soluble. 20. The liquid medium is ethanol, chloroform, ether, isopropyl. Claim 1 which is alcohol
8. Method of manufacturing reconnaissance notes. 21. The method according to any one of claims 1 to 20, wherein the first component comprises, in addition to water, a physiologically suitable liquid medium. 22. The manufacturing method according to claim 21, wherein the liquid medium is a volatile, water-soluble organic solvent. 23. The manufacturing method according to claim 22, wherein the solvent is ethanol. 24. Process according to any one of claims 1 to 23, characterized in that the first and second components are mixed under pressure generated by at least one aerosol propellant. 25. The method of claim 24, wherein the propellant is a constituent of one or both of the first and second components. 26. The manufacturing method according to claim 25, wherein the propellant is a constituent of the second component, and the first component is pressurized with a propellant prepared separately from the propellant. 27. A process according to any one of claims 24 to 26, wherein the or each propellant comprises a halogenated hydrocarbon or a mixture of halogenated hydrocarbons. 28. A process according to any one of claims 24 to 27, wherein one or both propellants are dichlorodifluoromethane. 29. Claims 24 through 27 in which one or both propellants are low pressure propellants of from about 25 to about 3 Qpsi.
The manufacturing method described in any of the paragraphs. 30. One or both propellants are 20:80 w/
Preparation of dichlorodifluoromethane and dichloroI-cotedrafluoroethane of g. 31. A process according to any of claims 24 to 27, wherein one or both propellants are high pressure propellants of up to about 70 psi. 32. One or both propellants are 80:20 W/
32. The method according to claim 31, wherein W is a mixture of dichloro-difluoromethane and dichlorotetrafluoroethane. 33, supplying the first and second components as described above separately from each other, introducing each component in controlled and separate amounts into the mixing chamber under the pressure of its own propellant, and the mixture comprising: 34. A process as claimed in any one of claims 1 to 33, in which the combined propellant is ejected under pressure from a mixing chamber through an orifice. 34. A method according to any one of claims 2 to 33, wherein the first and second components are mixed in a manner that provides a measured amount of said active substance. 35. A first component is introduced into a mixing chamber, and then a measured amount of a second component is introduced into the mixing chamber in such a way that the surrounding components are intensively mixed, and the mixture is injected. Manufacturing method of paragraph 34. 36, having at least a first and a second chamber, the first chamber containing a first component comprising water and the other chamber containing a second component comprising a lipid substance; A lipon room air system, characterized in that the chamber or the third chamber contains a propellant; and further includes a device for distributing as a spray the mixture of the first and second components supplied from the respective chambers under pressure by the propellant. Pack used for sol production. 37. The pack of claim 36, wherein at least one first or second component as mentioned above comprises a non-lipid active substance that is biologically active and/or useful for the treatment or protection of humans or animals. 38. The device according to claim 37, wherein the spraying device adjusts the mixing holes of the ingredients to a predetermined range and sprays the active substance in a suitably measured amount. 39. Under the pressure of a propellant of 1fii or more, the first and second components are sprayed from their respective chambers, and the mixing ratio of the components is adjusted to an amount within that range so that a measured amount of the mixture can be sprayed from the spout. 39. A pack according to one of claims 36 to 38, characterized by a mixing chamber, a spout, and a pulp intended to cause a mixing chamber, a spout and a pulp. 40. The above-mentioned pulp is designed to fill a mixing chamber by supplying the first component, supplying a measured amount of the second component in such a way that the two components can mix vigorously, and injecting the mixture. The pack of claim 39. 41. The pack according to claim 39 or 40, wherein the first and second chambers are sealed chambers and are connected at one end, and the respective pulp and mixing chambers are arranged between the ends. 42. Any one of claims 39 to 40, wherein the first and second chambers are sealed chambers and are side-to-side connected, with respective pulp and mixing chambers arranged between or above the two chambers. Packs listed in the section. 43. The first and second chambers are sealed chambers, one of the chambers is arranged within the other, and the pulp and mixing chambers are arranged in or above the outer chamber, according to claim 39 or 40. Pack of. 44. Claims 40 to 4, wherein each of the above-mentioned chambers is arranged in an outer container and through which the pulp can be operated.
A pack described in any of Section 3. 45. The second component includes a propellant and is contained in an internal rigid wall sealed chamber, and the first component is contained in an external plastic wall sealed chamber and the external bait container is a rigid wall container. 45. The apparatus of claim 44, wherein the propellant is located in the space between the external sealed chamber and the surrounding external container.