DE1178975B - Method of making an inhalant - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

GERMAN

PATENT OFFICE

EDITORIAL

Boarding school Class: A 61 k

Number:
File number:
Registration date:
Display day:

German class: 30 h -2/35

R 22567IV a / 30 h
January 27, 1958
October 1, 1964

The invention is based on the object of providing a self-propelling, solid active ingredient as a solid aerosol to produce a dispensing agent that can be inhaled. The known a solid as a solid aerosol As is well known, dispensing agents consist essentially of a suspension of a finely divided Active ingredient in an organic liquid optionally containing an emulsifier, and the suspension is sprayed by means of a device equipped with fine nozzles.

For the effectiveness of inhalation aerosols, it is crucial that the active ingredient, as possible is intended to penetrate deeply into the pulmonary alveoli, is used in the precisely prescribed dosage, in order to avoid damage caused by overdosing or ineffectiveness caused by underdosing. A constant concentration and quantity withdrawal are a prerequisite for an even dosage of the inhalation aerosol. Both conditions depend essentially on the immutable Particle size of the active ingredient. Namely, the change in the original particle size has a Settling of larger particles and thus a segregation of the suspension as a result; the agglomeration the particles also obstruct the passage through the nozzle of the sprayer, since the nozzle openings are clogged by the larger particles, and these also penetrate less deep into the lungs, so that even if the amount of inhaled agent remains the same, the effect of this is decreased.

It has been found that the dangerous change in the particle size of the active ingredient in the suspension can be prevented by in any order with the practical exclusion of water in a known liquefied propellant with a boiling point ^{below 18.5 ° C. at atmospheric pressure} this soluble liquid, nonionic surface-active substance with a hydrophilic-lipophilic equilibrium ratio below 10, preferably between 1 and 5, and an active substance which is insoluble in the mixture of propellant and surface-active substance and comminuted to an essentially equal particle size of less than 25 μ and one introduces such amounts used that the total weight of the agent accounts for 0.01 to 20 percent by weight of active ingredient and 0.1 to 20 percent by weight of surfactant.

It is expedient to first mix the powdered active ingredient and the surface-active agent, homogenize and dilute the mixture with the propellant. Advantageously, a blowing process is used to produce a
Inhalant

Applicant:

Riker Laboratories, Inc.,

Los Angeles, Calif. (V. St. A.)

Representative:

Dr.-Ing. E. Berkenfeld, patent attorney,

Cologne-Lindenthal, Universitätsstr. 31

Named as inventor:

Charles Gilbert Thiel, Monica, Calif.,

Irving Porush, Los Angeles, Calif.,

Ronald Dee Law, La Mirada, Calif. (V. St. A.)

Claimed priority:

V. St. v. America of January 31st (637 353),

dated August 23, 1957

(680 016),

dated January 3, 1958 (706 908)

medium, the specific weight of which is not greater than that of the active ingredient.

A method for distributing pesticides and antifreeze agents by atomization is known, in which homogenized suspensions of solid substances with a suspended particle size of on average less than 50 μ are atomized in organic, preferably flame-retardant liquids in a manner known per se. These organic liquids are high-boiling liquids, such as diesel oil or ethylene chloride, with which the active ingredient is homogenized. The known emulsions are not self-propelling. The homogenization of a solid active ingredient in a propellant with a ^{boiling point below 18.5 °} C. at atmospheric pressure is practically impracticable, since the propellant would volatilize during the homogenization.

The use of a liquefied propellant is in aqueous emulsions of solid active ingredients, such as Insecticides, pigments and the like are known. These emulsions can also contain nonionic emulsifiers contain. Also only a low solubility of the

409 689/314

3 4

Active ingredient in water can lead to dangerous such compounds for the purposes of the invention

Change in particle size will result in satisfactory results, as this will allow sufficient

Dissolved particles on other crystals have polar groups, such as hydroxyl, amino or carb

grow again and enlarge these, while oxyl groups have, and consequently predominantly

others have become smaller as a result of the solution. Out of 5 are polar. When a compound like phenylephrine

For this reason the process at hand is somewhat soluble in the mixture, it is advisable to

Invention to use the acid salt of this base practically with the exclusion of water,

carried out, and only those liquefied for the process of the invention can be amorphous

Propellants and surfactants used, as well as crystalline active ingredients are used,

in which the active ingredient is insoluble. io The use of crystalline substances is preferable.

The present invention is also based on the knowledge that the lower limit of the particle size is what

is based on the fact that not any non-ionic surface is easily absorbed and on or in the body tissues

surfactants are retained for the purposes of the invention. Particles with a size of

are usable, but those that have a value below 10, less than Ι, μ can be reused by the patient.

preferably between 1 and 5 lying hydro- 15 breathes. The particle size is two-dimensional

have phileslipophilic balance ratio; because wise less than 25 α. preferably less than 10 μ

the risk of agglomeration is on the one hand in diameter. The best results will be then

excluded by a practically anhydrous medium, achieved when the particle size of the powder is practical

on the other hand, the active ingredient can settle, which is uniform.

insoluble in the mixture of the liquefied 20 As examples of for the purposes of the invention Propellants and the nonionic surface active ingredients in question are said to be the following Fabric is. This danger is given by giving: a vasoconstrictive amine or its acid turn of certain ionic surface addition salts, a hormone, enzyme, alkaloid, steroid, active substance overcome. Analgesic, antihistamine, anti-wheezing agent Use of liquefied propellants for aerospace coughs, angina and bronchial diseases sole is known; These aerosols are effective as well as antibiotic, synergistic and sulfonamide Preparations containing agents, if necessary with the help of a solubilizer, also isoproterenol - [«- (isoin Solution brought. It should be taken into account, however, propylaminometnyO-protocatechualkoholj-hydrochlodaß not all pharmaceutically active agents contain or sulfate, phenylephrine, phenylpropanolaniine, sufficient in the usual liquefied propellants 3 ° Glucagon, Adrenochrome, Trypsin, Ephinephrine, Ephegelöst even if there is a solution in it, narcotine, codeine, atropine, morphine, dihydro mediator is used, and also some are morphinone, ergotamine, scopolamine, methapyrilene, Compounds such as ephinephrine, in polar solutions, »cyanocobalamin« and colchicine, as well as antibiotics, agents are not stable, especially when they are in contact with such as neomycin, streptomycin, penicillin, procaine come with the metal from which the 35 penicillin, tetracycline, chlortetracycline and hydroxy valve come of the sprayer. tetracycline and adrenocorticotropic hormone as well When practicing the present invention, adrenocortical hormones, such as cortisone, hydrocortic hormones Medicines are applied, then son, hydrocortisone acetate and prednisolone and except is it especially required that during all of the insulin. The solid active ingredient can also have a Kos level of the process the humidity be under control 40 metikum, such as. B. Talc, antiperspirant is provided. It was found that the total agent such as aluminum chlorohydrate, etc., had a polishing moisture content finely dispersed water-soluble substance, such as polishing red, a dye, e.g. B. for dyeing Medicines less than 300 parts per million ge of food, a lubricant such as graphite, should be parts by weight of the total mixture. Liquefied ones suitable for the purposes of the invention Humidity control is critical, with 45 propellants being the lower to 5 carbon atoms that the suspension also during a long layer containing alkanes, such as butane and pentane, or a tion remains stable. If, for example, in the case of the lower alkyl chloride, such as methyl, ethyl or sample 10 given below, more than 300 parts of water per pyl chloride. The most suitable liquefied propellants A million parts of the mixture are agglomerated, that is, the lower fluorine and chlorofluoroalkanes. Even Drug at room temperature in 1 month and 50 mixtures of the aforementioned propellants settles on the walls of the container, making it usable.

the dose to be delivered is adversely affected, the lower fluorine- and chlorofluoroalkanes should

apart from the fact that from the pharmaceutical standpoint no more than 2 carbon atoms and at least

point there is an objectionable preparation. To contain 1 fluorine atom. The preferred halogenated

to influence or reduce the moisture content. 55 Alkanes can be represented by the following formula.

wrestling, you can give the filling before closing:

of the container small amounts of an anhydrous, inert CmHnCl, F _z , desiccant, such as. B. silica gel or calcium sulfate,

add, reducing the moisture content of the liquid- in this m means an integer that is less than

The phase of the mixture is depressed so far that 60 is 3, η is an integer or zero, y is an integer

that no agglomeration occurs. Generally or zero and ζ an integer such that

100 mg desiccant are enough for one with the _ + _,. _ _{y m} _l?

Mixture-filled 10 ml container. " ¹ ^ '

The finely powdered active ingredient is more appropriate. Examples of such propellants are: dichlorodifluoro-

wise in the liquefied propellant, in the upper 65 methane, dichlorotetrafluoroethane, CClF ₂ · CClF ₂ , tri-

surface-active agents such as chloromonofluoromethane, dichloromonofluoromethane,

of the propellant and surfactant insoluble monochlorodifluoromethane, trichlorotrifluoroethane and

borrowed. It has been found that in most cases monochlorotrifluoromethane. Propellants with better ones

Vapor pressure properties are obtained by using certain mixtures of these compounds applies. So has z. B. dichlorodifluoromethane a vapor pressure of about 0.05 kg / mm atü and 1,2-dichloro-1,2,2-tetrafluoroethane has a vapor pressure of about 0.009 kg / mm at 18.5 ° C, and if if you mix these two compounds in different amounts, you can get one between them Achieve pressure lying at both vapor pressures, which is for a mixture with the HLB ratio in the prescribed Area results.

As examples of nonionic surfactants suitable for the purposes of the invention the following are indicated: the esters or partial esters from 6 to 22 carbon atoms containing fatty acids, such as caproic, octanoic, lauric, palmitic, stearic, Linoleic, linolenic, eleostearic and oleic acid, and an aliphatic polyalcohol or its cyclic

Containers with relatively low pressures io Shem anhydride, such as ethylene glycol, glycerin, ery-

suitable is.

In most cases it will be desirable for the vapor pressure of the propellant itself to be between about 0.018 and 0.046 kg / mm at g, but preferably between 0.021 and 0.028 kg / mm at g at 18.5 ° C. A propellant consisting only of a compound results in a pressure of 0.039 to 0.046 kg / mm at 18.5 ^° C., which can be used for metal containers without impairing safety. One of two connections, e.g. B. equal parts dichlorodifluoromethane and trichloromonofluoromethane, existing propellant gives overpressures of about 0.014 to 0.028 kg / mm at 18.5 ° C, which can be used without damage for particularly reinforced glass containers.

It is generally desirable to keep the gas pressures as low as possible within that desired specific gravity of the propellant set limits to keep the application easier thrit, arabitol, mannitol, sorbitol, the hexitol anhydrides derived from sorbitol and the polyoxyethylene and Polyoxypropylene derivatives of these esters, also mixed esters, e.g. B. mixed or natural glycerides, such as Corn oil. The preferred surfactants are the oleates of sorbitol, e.g. B. sorbitol sesquioleate and Sorbitol trioleate.

Examples of other surface-active agents which can be used for the purposes of the invention are sorbitol monolaurate, Polyoxyethylene sorbitol tetraoleate, polyoxyethylene sorbitol pentaoleate, polyoxypropylene mannitol dioleate. Ever The more soluble a surfactant is in the propellant, the more useful it is in the invention. In order to test the usefulness of surface-active agents, a number of tests were carried out, the results of which are given below. The tests were carried out at a concentration of 0.5% with a suspension of 0.5% hydrocortisone acetate carried out in a mixture containing 30% tri-

and 38.5% dichlorodifluoromethane.

To allow containers and also to entzu too high pressures 30 chloromonofluoromethane and 70% of a mixture avoid a wide spread of the aerosol, which in turn consists of 61.5% dichlorotetrafluoroethane present powdery active ingredient would result. If stronger, e.g. B. made of stainless Existing steel containers are used and the active substance is absorbed by the lungs 35 is to be, it is advantageous to use a propellant with a pressure of 0.028 to 0.036 kg / mm atü, as this achieves complete aerosolization before the current flows backwards Throat area reached. Because the powder is already dispersed in the mixture with the desired particle size is needed in the valve or in the device used to administer the aerosol no further comminution of the powder takes place, so valves of simple construction are used 45 and no special nozzles or expansion chambers are required, to which one is generally dependent when administering agents that are in the propellant or are dissolved in a liquid which is emulsified with the propellant 50.

The liquid, nonionic surfactant is said to have a hydrophilic-lipophilic balance ratio (HLB) less than 10. The HLB ratio is an empirical number that gives an indication of gives the surfactant properties of a surfactant. The lower the HLB ratio, the more lipophilic the agent, and vice versa: the higher the HLB ratio, the more hydrophilic it is the middle. The HLB ratio is known, it is calculated according to that of W. C. G r i f i η in the Journal of the Society of Cosmetic Chemists, Vol. 1, No. 5, pp. 311 bis (1949), described method. It is possible to use surfactants, their HLB ratio is not within the range required for the purposes of the invention if be used in conjunction with other surfactants that have an HLB ratio that

Investigated substances Test results Paraffin wax Deposits as a solid in the
proceed from the extraction valve
the adapter; impairment
the removal; nonhomogeneous
Suspension; Smear
of the valve Stearic acid like paraffin wax Stearyl alcohol
(fixed) like paraffin wax Beeswax like paraffin wax Petrolatum Petrolatum suspended in the propellant
middle ; sufficient emulsification,
but rapid segregation;
sticks to the container wall
gene; Smear of ven
tils; insufficient for an in
halation therapy Oleyl alcohol
(fluid) poor suspension; not much
homogeneous, rapid demixing;
Lubrication of the valve Polyethylene
glycol 300 not miscible with propellant mineral oil poor suspension; Lump
education; rapid segregation;
Lubrication of the valve; U.N
suitable for inhalation therapy Isopropyl
myristate
* adequate suspension,
but not sufficiently homo
gene; Valve stuck

(Continuation) Investigated substances Test results Polyoxyethylene very good suspension; Lump stearate education; adheres to the container; rapid segregation; Ver lubrication of the valve Polyoxyethylene very poor suspension; Klum lauryl alcohol pen formation; Smear of the valve Polyoxyethylene very poor suspension; Klum sorbitol mono- pen formation; Smear oleat of the valve

The beneficial effect of the surface-active substances provided for the purposes of the present invention Agent is believed to be based on the surfactant having a monomolecular film on it finely suspended powder, which prevents agglomeration of the particles when these are dispersed in the propellant or are located in the valve of the spray container. The surprising In turn, good suspension has the advantage that a polar solvent is used is no longer required for the active ingredients, so that the suspension of the active ingredient is practical can be anhydrous.

There is a certain risk of the finely powdered active ingredient becoming deposited or caking when the specific gravity of the powdered active ingredient is significantly lower than that of the propellant is. However, this risk can be avoided by the specific gravity of the liquid Phase z. B. decreased by using a propellant with a lower specific weight, such as butane, or by using the specific weight of the powdered active ingredient increased, e.g. B. in the case of phenylephrine by using the bitartrate salt instead of the hydrochloride used. In many cases, however, it is not possible to use the propellant and / or the form of the active ingredient change. It has now been found that even in such cases there is a risk that the powdery light Active ingredient spreads on the surface of the liquid phase and a deposit or caking occurs, by additionally using a sufficient amount of a finely divided solid excipient can be prevented, the density of which is greater than that of the liquid phase.

The solid excipient must go with the other ingredients of the aerosol and be insoluble in the propellant. He can z. B. from an inorganic Compound such as sodium sulfate, calcium or sodium chloride, or from an organic substance such as powdered lactose, cane sugar, epinephrine bitartrate, neomycin sulfate or graphite. He can too be a desiccant for the self-propelling mixture and e.g. B. from anhydrous sodium sulfate or Consist of calcium chloride; it can also be made from a pharmaceutical compound such as neomycin sulfate and epinephrine bitartrate. The particle size of the solid excipient should be of the same order of magnitude like that of the active ingredient.

It has been found that the amount of adjuvant advantageously remains within certain limits, which are discussed below.

When the symbols listed below have the specified meanings:

qa = specific weight of the solid excipient, qp = specific weight of the propellant,
Qq - specific weight of the total powder components (solid excipient and active component),

ρ υ = specific weight of the active ingredient, a = weight of the excipient,
p = weight of the propellant,

q = weight of the total powdery components,
u = weight of the active ingredient,

then it is obvious

q = u + a. (I)

If deposition on the surface or sticking is to be prevented, then the the following condition must be met:

Qq - qp need not be less than zero. (2)
This condition is met if

ου equal to or greater than Qp (3)

is; then a = zero when q = u . But if ρ υ is smaller than qp then the following relationships hold:

11 a

Qu

Qa

(u + a) Qu qa u Qa + a Qu

For a theoretical minimum, condition (2) applies: Qq - qp = O or Qq = Qp-

Applying this instruction to equation (4) then results

(«+ A) Qu · ti- qa + a ·

= Qp

and therefore

inside =

M * QA {QP - QV)

Qu - (Qa- Qp)

If one proceeds from the symbols explained above, then, if ο υ is equal to or greater than Qp, a perfect mixture is obtained and, without the use of a solid auxiliary substance or additional powder, powder is prevented from settling on the surface or from caking. If ρ υ is less than Qp , then equation (5) gives the minimum amount of solid excipient that is required to prevent solid matter from settling out of the mixture. It has been found that good results are obtained using ten times the minimum amount, but an amount between a _m in and three times the amine is preferred.

If necessary, to avoid surface settling or caking to use a solid or powdered auxiliary, this is then advantageously in the Mixture entered when the powdered active solids are introduced. This procedure is in Examples 20-30 described. The solid excipient can optionally also be added to the mixture.

after it is pre-wetted with the surfactant or the propellant.

The process of the invention is described in more detail in the following examples. The ones in the examples and the amounts given in the description are percentages by weight of the total mixture, as far as nothing else is expressly stated. If an ingredient is labeled "micronized," then it contains 90 percent by weight of particles with a particle size of 1 to 5 μ. Examples 20 to 30 relate to mixtures that contain a solid additive to prevent deposition on the surface or to prevent caking.

example 1

Hydrocortisone acetate, crystalline (more than 90 percent by weight have a particle size of 1 to 5 μ) 3.0 7 ₀

Sorbitol trioleate 1.0 7 "

Trichloromonofluoromethane 30.0 7 ₀

Dichlorotetrafluoroethane 41.07 ₀

Dichlorodifluoromethane 25.0 7o

Example 6 Example 2

Trypsin, amorphous (more than 90 percent by weight have a particle size of 1 to 10 μ) 0.10 g

Sorbitol trioleate 0.05 g

Propellant A 10.00 g

(A blowing agent consists of 2,0 butane 7 ₀ and 98 ° / ₀

a mixture of 61.5% dichlorotetrafluoroethane and 38.5 7o dichlorodifluoromethane.)

Example 3

Prednisolone Acetate, crystalline (more than 90 percent by weight has a particle size from 1 to 5 μ)

Sorbitol trioleate

Propellant B

Insulin, amorphous (more than 90 percent by weight have a particle size of 1 to

5 μ)

Sorbitol trioleate

Propellant consisting of a mixture of dichlorotetrafluoroethane and dichlorodifluoromethane

Example 7

Epinephrine, crystalline (free base) (more than 90 percent by weight has a particle size from 1 to 5 μ)

Sorbitol trioleate

Trichloromonofluoromethane

Propellant consisting of a mixture of dichlorotetrafluoroethane and dichlorodifluoromethane

Example 8

0.257 ₀ 0.257 o

99.507 ₀ 100.007 ₀

0.28% 0.25% 5.00%

94.47% 100.00%

Epinephrine bitartrate, crystalline (more than 90 percent by weight has a particle size from 1 to 5 μ):.

Sorbitol trioleate

Trichloromonofluoromethane 49.50 ° / ₀

Dichlorodifluoromethane 49.50 7 ₀

100.00%

0.50% 0.50%

35

Example 9

0.5% 0.5% 99.0%

100.07 ₀

(Propellant B consists of 10,07ο trichloromonofluoromethane, dichlorotetrafluoroethane 50.4 7o, 31.6% dichlorodifluoromethane and 8.0 ° / ₀ butane.)

Example 4

ACTH, adrenocorticotropin, amorphous (10 USP units / mg) (more than 90 percent by weight have a particle size of 1 to 20 μ)

Sorbitol trioleate

Trichloromonofluoromethane

Propellant consisting of a mixture of dichlorotetrafluoroethane and dichlorodifluoromethane 93.75 7

Isopropylarterenol hydrochloride, crystalline (more than 90 percent by weight have a

Particle size from 1 to 5 μ)

Sorbitol trioleate

Trichloromonofluoromethane 49.75 7o

Dichlorodifluoromethane 49.75 ° / ₀

100.00%

0.25% 0.25%

45

Example 10

l, 007 ₀ 0.25% 5.007 ₀ phenylephrine hydrochloride, crystalline (more than 90 percent by weight have a particle size of 1 to 25 μ) 0.25 7 ₀

Neomycin sulfate 0.11 ° / ₀

Hydrocortisone 0.04 ° / ₀

Sorbitan trioleate 0.25 7 ₀

Trichloromonofluoromethane 49.675 ° / ₀

Dichlorodifluoromethane 49.675 ° / ₀

100.00%

55

100.007 ₀ Example 5

Adrenocorticotropin, amorphous (10 USP units / mg) (greater than 90 percent by weight have a particle size of

1 to 20 μ) 0.25 7 ₀

Sorbitan trioleate 0.25 7 ₀

Propellant consisting of a mixture of dichlorotetrafluoroethane and dichlorodifluoromethane 99.50 7o

Example 11

0.50% 0.25% 4.75%

100.00% neomycin sulfate, crystalline (more than 90 percent by weight have a particle size

from 1 to 25 μ)

Sorbitol trioleate

Trichloromonofluoromethane

g propellant consisting of a mixture of dichlorotetrafluoroethane and dichlorodifluoromethane 94.507 ₀

100.007ο

409 689/314

11 12

Example 12 This agent is suitable for optical polishing

Hydrocortisone acetate, crystalline (more than ^{egg e} '

90 percent by weight have a particle

size from 1 to 5 μ) 0.507o _Tr j · ι · n- ^ ι ι

»Surfactant G-1087« ⁵ Hydrocortisone acetate crystalline (more than

(Polyoxyethylene sorbitol hexaoleate) 0.50% 90 percent by weight have a part

Propellant C 99.00% oifvTnS 0 5%

100.007 ₀ trichloromonofluoromethane 3θ'θ%

(Propellant C consists of 30.00 7o trichloromono propellant, consisting of a mixture

fluoromethane and 70% of a mixture of dichloro from dichlorotetrafluoroethane and dichloro

tetrafluoroethane and dichlorodifluoromethane.) difluoromethane 69.07o

Example 13

_T,. ,. ". , 15 example 20

Hydrocortisone acetate, crystalline (more than
90 percent by weight have a particle- phenylephrine hydrochloride (crystalline),

size from 1 to 5 μ) 0.50% micronized 0.25%

Sorbitol sesquioleate 0.50% phenylpropanolamine hydrochloride

Propellant C (see Example 12) 99.00%, "(crystalline), micronized 0.50%

- - Neomycin sulfate (crystalline), micronized 0.10%

100.00 / ₀ Hydrocortisone (crystalline), micronized .. 0.04% Example 14 Sodium sulfate (anhydrous), micronized .. 0.357o

,. ", Sorbitol trioleate 0.80%

Hydrocortisone acetate, crystalline (more than propellant S 97 96 ° /

90 percent by weight have a particle 25 - '■

size from 1 to 5 μ) 0.50 7 ₀ 100.00%

Sorbitan monooleate 0.50% (propellant composed of 27.0 ° / ₀ Dichlordifluor-

Propellant C (see Example 12) 99.00% methane, 30% trichloromonofluoromethane and 43%

100 007 dichlorotetrafluoroethane.)

'3 °
Example 15. .

At s ρ 1 el 21

Hydrocortisone acetate, crystalline (more than
90 percent by weight have a particle- phenylephrine hydrochloride (crystalline),

size from 1 to 5 μ) 0.50% micronized 0.25 7 ₀

Sorbitol trioleate 0.50% 35 Neomycin sulphate (crystalline), micronized 0.10%

Propellant C (see example 12) 99.00 7 ₀ Hydrocortisone (crystalline), micronized ... 0.04%

Calcium chloride, micronized 0.10%

100.00 / ₀ sorbitol trioleate 0.50%

Example 16 Propellant S, consisting of a mixture _{> r} . ,. ...,,. "" _,. , 40 from dichlorodifluoromethane, trichloro-narcotm, crystalline (more than 90 weight monofluoromethane and dichlorotetrap % have a particle size of ^ fluoroethane (see example 20) 99.01%

Sorbitol trioleate ϊ'θ0 ° / ο 100.00%

Propellant consisting of a mixture. ....

from dichlorotetrafluoroethane and dichloro - ³ examples

difluoromethane 89.00% phenylephrine hydrochloride (crystalline),

100.007 ₀ micronized 0.25%

. - ,, - τ Sodium chloride (crystalline), powdered ... 0.50 7o

^{B e J s} P ' ^{e 1 ll} 5 "Sorbitol trioleate 0.75%

Dihydromorphinone hydrochloride (more than propellant S, consisting of a mixture

90 percent by weight have a particle ^of dichlorodifluoromethane, trichloro

size from 1 to 5 μ) 0.5 7 monofluoromethane and dichlorotetra-

Sorbitan trioleate .'... 'l [o% fluoroethane (s. Example 20) 98.5 ° / ₀

Trichloromonofluoromethane 30.0 ° / ₀ 55 100.00 7 ₀

Propellant consisting of a mixture

from dichlorotetrafluoroethane and dichloro example 23

difluoromethane 68.57o _nL . _u -uj ,,.,.,. ". ,

- ^ - phenylephrine hydrochloride (crystalline),

100.0% _5o micronized 0.25%

Example 18 Epinephrine Bitartrate (Crystalline), Micronized 0.75%

Iron oxide (polished red) (more than 90 Ge sorbitol trioleate 1.00%

weight percent have a particle size propellant S, consisting of a mixture

from 1 to 20 μ) 1.00% ₆ from dichlorodifluoromethane, trichloro

Sorbitol monooleate 0.25 ° / ₀ monofluoromethane and dichlorotetra-

Dichlorodifluoromethane 98.75% fluoroethane (see example 20) 98.00%

100.00% 100.00%

13 14

^In P ^{ieI24 example30}

Phenylephrine hydrochloride (crystalline),. .

micronized 0.25% phenylephrine hydrochloride (crystalline),

Cane sugar (crystalline), powdered 0.50 ° / ₀ micronized. .. ......... 0.25 / ₀

Sorbitan trioleate 0 75 ° / ^{5 Neom} y ^cin sulfate (crystalline), micronized .. 0.08% propellant S, bestehendäus a mixture '° Phenylpyraminhydrochlorid (crystalline)

from dichlorodifluoromethane, trichlorom? T? /, / ■ V W \ V: VVS? 2

monofluoromethane and dichlorotetra- sodium sulfate (crystalline), micronized ... 0.15 %

fluoroethane (see example 20) 98.5% sorbitol trioleate; '''V ··· ■ ···; ·· ·;. · · ■ ■ · · °' ^70%

ίο Propellant X, consisting of a mixture

100.00 7o from dichlorodifluoromethane, trichloro

Example 25 monofluoromethane and dichlorotetra-

Phenylephrine hydrochloride (crystalline), fluoroethane (see Example 29) 98.62%

micronized 1.0% 100.00 7 "

Neomycin sulfate (crystalline), micronized .. 3.07o ^I5

Sorbitol Trioleate 1.07 ₀ Example 31

Propellant S, consisting of a mixture of isoproterenol sulfate (crystalline), micron

from dichlorodifluoromethane, trichloro- j _t 0 15 ° /

monofluoromethane and dichlorotetra-sorbitol trioleaV. "'.'.'.'.'.'.'.'.'.'.'.'.'.'.'.'.'.'.'.'.'.' . '.'. 0, '50% °

fluoroethane (see example 20) 95.0% trichlorotrifluoroethane 0.95%

100.07 ₀ trichloromonomethane 24.60 7 ₀

Example 26 dichlorotetrafluoroethane 24.60 7o

_,,,. _{,, M} -A η ■ * u- λ dichlorodifluoromethane 49.207 ₀

Phenylephrine hydrochloride (crystalline),

micronized 0.25 »/ ₀ ²⁵ 100.00%

Graphite powder 0.25% B e i s D i e 1 32

Sorbitol Trioleate 0.50% Example ^

Propellant S, consisting of a mixture of phenylpropanolamine hydrochloride

from dichlorodifluoromethane, trichloro- (crystalline), micronized 0.49 7 ₀

monofluoromethane and dichlorotetra- ³ ° phenylephrine hydrochloride (crystalline),

fluoroethane (see example 20) 99.00% micronized 9.257 ,,

100 00 ° / Neomycin sulphate (crystalline), micro-treated .. 0.107ο

. Hydrocortisone (crystalline), micronized .. 0.04 7o

B e ι s ρ ι e 1 27 sodium sulfate (crystalline, anhydrous),

Hydrocortisone acetate (crystalline), micronized ³⁵ micronized 0.35 7o

Siert 0.88 ° / ₀ 1,007 ₀ sorbitan

Sodium sulfate (anhydrous), micronized .. 0.88 7o trichlorotrifluoroethane l> 00 7o

Sorbitol trioleate l, 007 ₀ ...

Propellant S-2 97 24 ° / dichlorodifluoromethane 29.03 ° ₀

Propellant ^ ^ f ⁴ Jo

₄₀ trichloromonofluoromethane 29.03%

100.007 ₀ dichlorotetrafluoroethane 38.71%

(Propellant S-2 consists of 50 7 ₀ dichlorodifluoro- 100 00 ° /

methane, 25 7o trichloromonofluoromethane and 25% '°

Dichlorotetrafluoroethane.) Example 33

p., ·. · _n8 ^4S phenylephrine hydrochloride (crystalline),

micronized 0.25%

Phenylephrine hydrochloride (crystalline), phenylpropanolamine hydrochloride

micronized 0.25% (crystalline), micronized 0.50 ° / ₀

Lactose, powdered 0.50% neomycin sulfate (crystalline), micronized .. 0.08 ⁰ J ₀

Sorbitol trioleate 0.75% ⁵ ° methapyrilene hydrochloride (crystalline),

Propellant S, consisting of a mixture micronized 0.10%

made of dichlorodifluoromethane, trichlorosodium sulfate (crystalline), micronized ... 0.35%

monofluoromethane and dichlorotetra- sorbitol trioleate 1.00%

fluoroethane (see example 20) 98.5% trichlorotrifluoroethane 1.00%

inn ο ο / ⁵⁵ trichloromonofluoromethane 29.017o

_. . , -. ' ^{/ 0} dichlorotetrafluoroethane 38.70%

Example 29 dichlorodifluoromethane 29.01%

Phenylephrine hydrochloride (crystalline), 100 00 ° /

micronized 0.25% '

Neomycin sulfate (crystalline), micronized .. 0.08% B e i s ρ i e 1 34

Sorbitol trioleate 0.50% Crystalline glucagon, micronized 0.156%

Sodium sulfate AR, micronized 0.10% sorbitol trioleate 0.468%

Propellant X 99.07% propellant S, consisting of a mixture

100 007 ₀ 6 <; from dichlorodifluoromethane, trichloro

(Propellant X consists of 30% dichlorodifluoromonofluoromethane and dichlorotetra-

methane, 30% trichloromonofluoromethane and 40% fluoroethane (see Example 20) ⁹⁹ ' ³⁷⁶ ° / °

Dichlorotetrafluoroethane.) 100,000%

Claims (1)

15 16 Example 35 claims: 1.Method of making an inhalation Anhydrous cyanocobalamin (crystalline), means, characterized in that micronized 0.039 7o ^{man m} any order under practical Sorbitan trioleate monofluoromethane 0.250% 5 exclusion of water in a known verTreibmittel S consisting flüssigtes of a mixture of blowing agents with a schem at atmosphäriaus dichlorodifluoromethane, trichloro- pressure below 18.5 ⁰ C lying boiling point and Dichlortetra- a soluble in this liquid, non-ionic fluoroethane (see example 20) 99.7117o surface-active substance with a less than 10, 100 000 ⁰ I ¹⁰ preferably between 1 and 5 lying hydro- '° Phile-lipophile equilibrium ratio and one in the mixture of propellant and Example 36 surfactant insoluble, on an essentially same particle size of less than 25 μ Chlortetracyclinehydrochlorid (crystalline), 15 brings crushed active substance and one such micronized 0.5 ⁰ I ₀ amounts that used on total weight Lactose 0.5% of the composition, 0.01 to 20% by weight of the active ingredient Sorbitan trioleate 1.0 ° / ₀ and 0.1 to 20 weight percent surfaces propellant S consisting of a mixture of active substance are eliminated. from dichlorodifluoromethane, trichloro 20 2. The method according to claim 1, characterized in monofluoromethane and dichlorotetra indicate that you should first use the powder fluoroethane (see Example 20) 98.0% active ingredient and the surface-active 100 0 ° / means mixes, homogenizes and the mixture 'diluted with the propellant. 25 3. The method according to claims 1 and 2, Example 37, characterized in that a propellant is used applies whose specific weight is not greater Adrenochrome (crystalline), micronized 1.785% ... ^a ^ ^s is the active ingredient. Sorbitol trioleate 1.0 ⁰ J ₀ 4. The method according to claims 1 and 2, Propellant S, consisting of a mixture 30, characterized in that additionally one made of dichlorodifluoromethane, trichloro finely comminuted auxiliary material, the density of which is greater monofluoromethane and dichlorotetra- than that of the liquid phase of the inhalant fluoroethane (see Example 20) 97.215 7o ^and whose particle size is the same as that of the 100,000 ° / active ingredient, in a minimum amount ³⁵ u-qa {qp - Qv) _Example38 a _min = ρρ. ₍ ^ _ _gJ>) Phenylephrine hydrochloride (crystalline), where means micronized. ... .. ......... 0.253% _{u = weight of the} active ingredient, Neomycin sulfate (crystalline), micronized .. 0.080% _{40 = specific} weight of the excipient, Methapyrileiüiydrochlond (crystalline), _{ρρ = specific} weight of the propellant, micronized ······; ·· ·: ·· ■■■■ ° ^'198/0 _eu = specific weight of the active ingredient. anhydrous sodium sulfate (crystalline), 5. The method according to claim 4, characterized micronized 0.150 / " _by using such quantities of excipient, Sorbitol trioleate ......... 1.0 / _{0 45 that a between} a _min and 10 · a _min , preferably Propellant ^, consisting of a mixture between a _min and 3 · a _min . from dichlorodifluoromethane, trichloro monofluoromethane and dichlorotetra- _{Publications considered} : fluoroethane (see Example 29) ⁹ 8> ^{319 70} British Patent No. 764 862; 100,000% 50 U.S. Patent Nos. 2,440,915, 2,524,590. 409 689/314 9.64 © Bundesdruckerei Berlin