JPS60252410A - Slow-release nasal medicine and use - Google Patents

Abstract

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

Description

DETAILED DESCRIPTION OF THE INVENTION Background of the Invention Catecholamines are a group of chemicals that are said to have cardiotonic effects. One of the most potent compounds of these, dobutamine, is used in the short-term treatment of hypovolatile acute heart failure, which can occur after a streptococcal infarction or after cardiopulmonary bypass surgery. Dobutamine undergoes very rapid biotransformation by catechol-0-methyltransferase. Because this compound has a half-life in the body of only 2 minutes, the drug must currently be administered by continuous intravenous infusion.

This method of drug administration requires careful monitoring, typically hospitalization of the patient. The short half-life of this compound makes oral administration impractical.

The present invention relates to nasal sustained release formulations of catecholamines, such as dobutamine, which prolong blood levels of such compounds in warm-blooded animals. Furthermore, a sustained inotropic effect was also observed when this formulation was administered intranasally. This formulation has the further advantage that it can be easily administered without hospitalizing the patient.

The present invention provides a sustained release nasal preparation comprising a catecholamine, a sustained release agent, an emulsifier, and a dispersion medium.

More particularly, the present invention relates to catecholamines.

Emulsifier, dispersion medium and formula (■): R1-CH=CH(CH) COR2 ((1272 [In the formula, %R1 is 08 to C1o alkyl group or axis 4 Ding Peng'T
V≠Misaki-→1 豐 Mata is C8-C1o alkenyl, R2 is hydrogen or C-C alkyl] 4 This provides a sustained-release nasal preparation consisting of a sustained-release agent represented by be. Particularly preferred are sustained release formulations of catecholamines or dobutamine, or pharmaceutically acceptable salts thereof.

Furthermore, the invention relates to a method of increasing U contractility in a warm-blooded animal in need of treatment, comprising administering to the animal a therapeutically effective amount of a sustained release nasal formulation according to the invention.

FIG. 1 is a semi-logarithmic plot of plasma levels of dobutamine hydrochloride in rats administered at doses of 2.5-/&g. Dobutamine hydrochloride was administered intravenously all at once (-0-) and in nasal saline solution <-c''-). The graph shows the average of three tests.

Figure 2 shows an intravenous infusion of dobutamine hydrochloride (2 mcg//
Dophtamine hydrochloride (r) sustained release g#1m composition with coexistence of oleic acid (724mCgA9-1m-) and the same composition without oleic acid (450mCg/
kg, −·−] compared with the sustained release obtained by

FIG. 3 shows the effect of varying concentrations of oleic acid in dogs anesthetized after intranasal administration of sustained release formulations containing dobutamine hydrochloride at various end dose levels.

11-0% 1 900-.-1% 1 724-Rho 2% 1 612-■-4% 1 663 Unless otherwise indicated, amounts and percentages are expressed in units of weight.

The term "01-C4 alkyl" refers to a straight or branched alkyl chain having 1 to 4 carbon atoms, including T0 lopropyl, isopropyl, n-butyl, imbutyl, crown-butyl and [-butyl]. be done.

The term "08-C1o alkyl" means 8.9 or 1
Indicates a straight or branched alkyl chain with 0 carbon atoms. Typical C8-C1o alkyl groups include n-octyl, inoctyl, n-nonyl, isononyl, n-decyl, isodecyl, and the like.

The term "C8-C1o alkenyl" refers to a straight or branched gamma alkenyl chain having one or more carbon-carbon double bonds. Typical 08-C1° alkenyl groups include 5-octenyl, 1,3-octagenyl, 1.3
．． Included are 5-octagenyl, 3.6-nonajenyl, 6-nonenyl, 5-decenyl%4,8-decadienyl, and the like.

The active ingredient used in the compositions of the invention is a catecholamine, preferably dobutamine. The active ingredient is about 0.
It is present in preferred compositions at a concentration of 5 to about 20.0% by weight.

Dobutamine is the common name given to the preferred active ingredient used in the present compositions. The term "dobutamine" is intended to encompass all pharmaceutically acceptable forms of this drug, including either the free base or preferably the pharmaceutically acceptable salts thereof. Examples of salts of this type include those made with phosphoric, sulfuric, hydrobromic, and preferably hydrochloric acids. Dobutamine has the chemical name (+,-)4-[2-[3-(P-hydroxyphenyl)-1-methylpropyl]amino]-ethyl]pyrocatechol.

It is represented by the following chemical structure: I3 A detailed description of methods for making dobutamine and its uses can be found in US Pat. No. 3,987,200, which is incorporated herein by reference.

Other catecholamines that may be used in the formulation according to the invention include: % Norepinephrine OI (HH Epinephrine OH I CIH3 Dopamine H)-I H Methyl-dopamine Positive-I I-1 3Ejirudopamine 14■-1CH20H37”Lopiludopamine H
I-I CH2CHzQ(a Compound RIRZ Ra Mark 3 Compound 1 (□R2R3) The active substance used in the formulation may be a combination of one or more of the catecholamines defined above. Combinations of this type Examples include dobutamine and dopamine.

The sustained release agent used in the nasal preparation of the present invention is oily or liquid at room temperature, ie, at a temperature of about 25°C. This substance has the formula (■); l2R-CH=CH(CH2)7002R(1) [in the formula, R
1 is C-C alkyl or C-8 10 8 C10 alkenyl, and k is hydrogen or C1-C4
is alkyl] This is a compound represented by the following formula.

Examples of sustained release agents suitable for use in the present formulation include the following:

Methyl linoleate C■13(CH2CH-0])3(C
H2]7CO2CTI3Ethyl oleate (CH2
]7CH:0((a■2)7002CH2C■)3 The preferred sustained release agent used in the nasal preparation according to the present invention is
It is oleic acid. Oleic acid is.

It has the following structural formula: %formula%. This compound can be obtained by hydrolysis of various animal and vegetable oils, but commercially available products are more readily available. Its synthesis is detailed in the literature. For example, Robinson et al., J. Chem.

See SOC, ) l 27 , ] 75 (1925).

Sustained release agents may also be present as a combination of one or more of the individual substances listed. Typical combinations include oleic acid and linoleic acid, primary/inic acid and lylunic acid, oleic acid and ethyl oleate, methyl linoleate and methyl hyllinate, in proportions to produce the desired sustained release effect. as well as other combinations.

The amount of sustained release agent used in the formulation is approximately 0.5 per formulation.
to about 50.0% by weight, more preferably about 2.0 to about 10
．． It has 0 weight.

One or more emulsifiers are added to the composition to improve stability. What emulsifier to use?

It may be selected from among those commonly known as suitable for use in pharmaceutical formulations. Typical emulsifiers that can be used include synthetic emulsifiers. This group can be divided into anionic, cationic, and nonionic types depending on the charge carried by the surfactant.

Preferred emulsifiers are nonionic, especially polyoxyethylene derivatives. Emulsifiers of this type are commercially available under the trademark of Towin.

The most preferred emulsifier used is Tween 85, a polyoxyethylene 20 sorbitan trioleate, available from ICI Americas.
available from mericas). Other suitable emulsifiers include Beenienisf Wyandotte (E A
Included are poloxamers including Pluronic emulsifiers such as Pluronic L81 available from S.F. Wyandoc'e. Incorporation of emulsifiers is common and may also occur. For an overview of suitable emulsifier types and their use, see Remington Pharmaceutical Sciences (RE
M I N'GTONPHARMACEU'rICAL
5CIENC:ES), Chapter 21.

See 16th edition (1980). The amount of emulsifier used ranges from about 0.005 to about 5.0%, more preferably from about 0.1 to about 0.2% by weight of the formulation.

A dispersion medium may also be used in this sustained release nasal composition. This medium is comprised of a variety of materials such as water, alcohols, and other similar substantially non-toxic materials. This medium preferably consists of one or more substances that can also act as the propellant of the system. Examples of materials that can be used include E.I. Dupont Dounanemooru & Company (E, I, Dupont [dCN
Cmours and Company, ). These substances are preferably used in combination. Although various components can be used in this combination at various concentrations, a preferred combination is a mixture of Freon 11 and Hyfreon 12 in an approximately 1:1 ratio by weight, as well as Freon 11 and Freon 11.
:12:114 in a ratio of about 5:4:1 (by weight).The weight of the ingredients, including the dispersion medium, is about 40.0
~about 98.5% by weight, more preferably about 80.0% to about 9% by weight
It is outside the weight of 5.0.

It is preferred to use one or more compounds with antioxidant properties in the composition in order to impart more stability to the system. Suitable antioxidants include vitamin E and especially butylated hydroxyanineol (BHA). When used in formulations.

The compound is about 0.001% to about 0.5% by weight of the composition.
, more preferably in the range of about 0.1 to about 0.5% by weight.

Since the formulation is administered nasally, additional flavoring agents may be added if desired. If used, the flavoring agent is approximately 0.001
It is added in a range of about 1.0% by weight.

Examples of flavoring agents include peppermint oil, lemon oil, olive oil and other similar substances that have a pleasurable effect on the olfactory system.

The formulations according to the invention can be manufactured by methods known (preferably) by those skilled in the art.

This formulation is manufactured as follows. Prior to formulation, the active ingredient to be used is micronized using one of several devices currently in use, such as mechanical micronization equipment. The particles should be about () in diameter, ranging from 1 to about 100 microns. A stock solution is then prepared by dissolving the emulsifier and the flavoring agent or antioxidant, if any, in the sustained release agent. This mixture is thoroughly mixed, typically at room temperature, and combined with the active ingredient in a suitable can or container.

The can can be metal or glass, can be pressurized, and is typical of those used for this purpose in the art. Next, the can is heated to A5℃~about -5℃.
One or more propellants are loaded therein while cooling to a temperature range of 0°C, more preferably about 0°C to about -20°C. The can is then sealed, typically with an aerosol-type valve, warmed, and checked for leaks. Thus, this formulation
This makes it suitable for administration to warm-blooded animals that require increased cardiac contractility.

Particularly preferred sustained release compositions according to the present invention are as follows.

Prescription 1 Component Concentration (weight palpitation) Dobutamine hydrochloride Approx. 2.0-4.0 Sustained release agent Approx. 2.0-12.0 Emulsifier Approx. 0.01-0.1 Antioxidant Approx. 0.05-0. 2 Dispersion medium about 80.0-932 g Those skilled in the art will understand that the percentages of certain components of this formulation will depend on the other components present, and that the sum of the percentages of all components will never exceed 100. Will.

More highly preferred compositions according to the present invention may be particularly indicated below.

Formulation 2 Dobutamine hydrochloride approximately 2.0 Oleic acid approximately 4.0 Tween 85 approximately 0.01 B) (A approximately 0.1 Freon 11 approximately 46.945 Freon 12 approximately 46.945 00 Formulation 3 Dobutamine hydrochloride approximately 2.0 Olein Acid approximately 10.0 Tween 85 approximately 005 BHA approximately 0.1 Freon 11 approximately 43.925 Freon 12 approximately 43.925 100.00 Formulation 4 Dobutamine hydrochloride approximately 2.0 Oleic acid approximately 10.0 Tween 85 approximately 0.I B LI A approx. 0.1 Peppermint oil approx. 0.3 Freon 11 approx. 43.75 Freon 12 approx. 43.75 100.00 Prescription 5 Doptamine hydrochloride approx. 4.0 Oleic acid approx. 10.0 Tween 85 approx. 0.1 B l) A about 0.1 Freon 11 about 42.9 Freon 12 about 34.32 7 Leon 114 about 8.58 100.00 The following non-limiting example shows one example of the composition of an individual X-77 menstrual sm composition according to the present invention and The manufacturing method will be further explained.

Dobcumin hydrochloride 560 ~ (4% by weight) is micronized using a mechanical micronizer into particles approximately 2-3 microns in diameter. BHA140”lf, Tween 85 141+
11f, Jasmine oil 420~ and Pluronic L817
A stock solution is prepared by dissolving ~00~ in 14.0 g of oleic acid at room temperature. Micronized dobutamine and stock solution (1.569C11,12%) are placed in a T-Rosol can. The can was previously cleaned by venting pure nitrogen gas into the can while inverted. 0 cans
℃ and packed with 25.96 g (42.48 wt.%) of Fremen 115.959 (42.41 weight percent) and Freon.

Second, apply a valve and seal the can. Immerse the can in a hot water bath for a few minutes to bring the contents to room temperature. Check the can for leaks. Dry the can and test the valve by operating it several times. Next, protect the bulb with a suitable lid, label the can, and store it until use.

The following examples were prepared by the general method outlined in this method.

Dobcumin hydrochloride (1,890,14 Oleic acid 2.17 0.34 Tween 85 0.45 0.07 Freon 11 9.88 1.55 Example 3 Dobcumin hydrochloride 1.0 0.14 Oleic acid 2.0 0. 28 Towin 85 0.5 0.07 Freon 11 48.25 6.75 Freon 12 48.25 6.75 100.0 Example 4 Dobcumin hydrochloride 1.Q O,142 Oleic acid 10,00 1.404 Tween 85 0.58 0.081 Freon 11
44. ], 4 6.205 Freon 12 44.28
6.224100.0 Example 5 Dobucumin hydrochloride 0.86 0.142 Oleic acid 8
．． 51.4 Tween 85 0.5 0.083 Freon 11 37.61 6.201 Freon 1,2
52.53 8.663100.0 Example 6 Doptamine hydrochloride 0.96 0.14 Oleic acid 9,64 1.403 Tween 85 0.55 0.079 Freon 11
42.61 6.202 Freon 1,2 46.24
6.73000 Example 7 Dobcumin hydrochloride 2.0 0.282 Oleic acid 10,12 1.42 Tween 85 0,55 0.077 Freon 11
43.63 6.12 Freon 12 43.70 6.13 100.0 Example 8 Dobutane hydrochloride 4.0 0.561 Oleic acid 10.0 1.402 Tween 85 0.51 0.072 Freon 11
42.76 5.993 Freon 12 42.73 5
．． 987100゜0 Example 9 Dobcumin hydrochloride 2.01 0.282 Oleic acid 1
0.01 ], 403 Tween 85 0.5 0.
07 Freon 11 43.73 6.125 Freon 12
43.75 6.130100.0 Example 10 Dobcumin hydrochloride 2.0 0.281 Oleic acid 10,00 1.408 Tween 85 0.54 0.076 Freon 11
43.34 6.10 Freon 12 44.12 6.211000 Example 11 Dobcumin hydrochloride 3,96 0.561 Oleic acid 9
．． 89 1.4 Tween 85 0.51 0.073 Freon 11
42.35 5.996 F1 Noon 1,2 43,29
6.129 Example 12 Dobutamine oleic acid 1,96 0.283 Oleic acid 9
．． 69 1.406 Tween 85 0.49 0.071 Heart Oil 0.
41 0.060 Freon 11 42.03 6.098 Freon 1,2
45.42 6.590100.0 Example 13 Dobcumin hydrochloride 1.9 0.282 Pluronic L81 4.86 0.72 Freon 11
41. ．． 15 6.096 Freon 12 42.16
6.248100゜0 Example 14 Dobcumin hydrochloride 6,00 0,849 Pluronic L
81 0.49 0.07 Freon 11 41.13
5.814 Freon 12 41.95 5.93010
0.0 Example 15 Dobcumin hydrochloride 1.96 0.28 Oleic acid 9.78 1.4 Butylhydroxyanisole 0.1 0.014 Tween 85 0.1 0.014 Hatsurikoku 0.29 0.042 Freon 11 4.4.02 6.3 Freon 12 43.75 6.26 100.0 Example 16 Dobcumin hydrochloride 7.0 0.98 Oleic acid 10.0 1.4 Bi(A O, 10,014 Tween 85 0 .1 0.014 Pluronic L81 0.5 0.07 Flare A″711
41.15 5.76 Freon 12 41.15 5
．． 76 000 Example 17 Dobcumin hydrochloride 1.99 0.280 Oleic acid]
,,01 0.143 Tween 85 0.1 0.014 Pluronic I, 81 0.5 0.07 Freon 11
47.9 6.75 7 Leon 12 48.50 6.836000 Example 18 Dobcumin hydrochloride 1,97 0.28 Oleic acid 3,95 0.56 Tween 85 0.1.4 0.02 Pluronic L
81 0.4.9 0.07 Freon 11 46.07
6.54 Freon 12 47.38 6.725000 Example 19 Dobcumin hydrochloride 1.98 0.28 Oleic acid 6,94 0.98 Tween 85 0.11 0.016 Pluronic L
81 0.5 0.072 Freon 11 44.85
6.329 Freon 12 45.62 6.435 Example 20 Dobcumin hydrochloride 1,98 0.28 Oleic acid 2,01 0.285 Tween 85 0. ], 2 0.017 Pluronic L81 0.49 0.07 Freon 11 47.16
6.683 Freon 12 48.24 6.8351
00.0 Example 21 Dobcumin hydrochloride 2.0 0.2B Oleic acid 6,99 0.981 Tween 85 0,11 0.015 Freon 11
' 45,39 6.369 Freon 12 45.51
6.386100.0 Example 22 Dobcumin hydrochloride 1.99 0.28 Linoleic acid 7.0 0.983 BLIA O,10,14 Tween 85 0.1 0.14 Freon 11 45.28 6.359 Freon 12
45.53 6.394000 Example 23 Dobutamia hydrochloride 1,87 0.28 O, I, acid ethyl,, 9,39 1.402 Towie:
/85 048 o, o71 Freoni/114.0.9
9 6.123 Freaux/], z 47.27 7.0
6000 Example 24 Dobcumin hydrochloride 1.99 0.281 Edyl oleate 9.94], 4 Tween 85 0,55 0
．． 078 Freon 11 43.50 6.127 Freon 12' 44.02 6.2000 Example 25 Dobcumin hydrochloride 1,99 0.281 Ethyl oleate 9.95 1.403 Tween 85 0,50
0.07 Flemen 11 43.43 6.126 Flemen 12
44.13 6.225000 The present invention further provides a treatment for warm-blooded animals, which comprises administering to the animal a therapeutically effective amount of the sustained-release nasal preparation according to the present invention.
I) Provides a method of increasing contractility.

The term "therapeutically effective" means: - able to improve the degenerative condition of the viscera; Refers to the amount of catecholamine formulated for sustained release nasal use. Typically, catecholamines are administered at approximately 175 m to restore myocardial contractility.
Administer as indicated at a rate ranging from 7 kg to about 7 kg.

It has been unexpectedly discovered that catecholamines can be formulated for intranasal administration such that upon administration, bioavailability is comparable to intravenous administration. The following study investigated the bioavailability of catecholamide butamine during nasal and intravenous administration.

Six male rats weighing 280 g are anesthetized with bentoparbital sodium (50 to 41 ip administration). 3
Dobcumin hydrochloride 2.5 MQ/kg is administered intravenously to one rat. Blood samples at 0, 5. 2. 4. 6. 10% 15. 20 and 30 minutes are taken for analysis of dovcumin in plasma. The remaining three rats receive 2.5~/kg of dobcumin in saline solution intranasally. Blood samples are taken from these rats at 1.5.10°20.30.60 and 120 minutes.

First, the results of this study are presented as the mean plasma levels of dobcumin observed during the study period for each dosing regimen. As is clear from the figure, dobcumin hydrochloride 2.5
Intravenous temporary administration of FlyI//kH is administered at 30 days after administration.
Very high blood dobcumin levels (1000n) within minutes
g/1tt1 or more]. However, this method of administration results in a short-lived Dobukumin in the blood, lasting only about 30 minutes. On the contrary,
Dobukumin hydrochloride 1.456 W was dissolved in saline water 0.1 liter and 0.1 liter of this solution was intranasally administered to 291 g rats (2.5 ~/kg (7) dose). This route of administration shows a sustained effect via nasal delivery compared to intravenous administration. Nasal delivery of Dovcumin is 100% after 20 minutes.
It results in moderate blood dobcumin levels of ng/ltl. However, surprisingly this effective blood level was maintained up to 2 hours later.

For each route of administration, the area under the curve (AUG) was calculated with the aid of a calculator using the trapezoidal method. These results are shown in Table ■ below.

Table I Area on the curve after intravenous administration and nasal saline solution administration AUG (ng min/dt) I V 2223.3:l-111,4 Nasal 1126
9±1390.4 To evaluate the bioavailability of dobcumin hydrochloride formulated as a sustained release nasal preparation according to the present invention.

Furthermore, the following tests were conducted.

Mongrel dogs of both sexes weighing between 8.0 and 20.0 kg are anesthetized with sodium thiobental (15 kg/kg intravenously) and sodium phenoparbital (100 kg/kg intravenously). Ventilation via a cuffed endotracheal duplex with a positive pressure pump (18 beats/min, 20 cm/minute)
kg/pound) and use a heating plate to bring the dog's body temperature to 37-38.
Maintain at °C. Both vagus nerves are cut through a facial incision.

Arterial blood pressure is monitored using a StaIham pressure transducer attached to a cannula filled with heparinized saline (16 units/ml) inserted into the abdominal aorta via the right femoral artery. For drug administration,
Insert one cannibal connected to a three-way cock into the right femoral vein. The heart was exposed at the right fifth intercostal space, and a Walton-Prody tension measuring bow with corresponding scales was cut and sutured into the right ventricle. 50 on the tension meter during systole
Adjust the tension so that the tension is 9, and adjust the Beckman Dynobluff recorder so that the pen swings 10 tarts at a tension of 509. 1 u beats are electrically derived from the blood pressure wind using a Beckman cardiac tachometer coupler.

Figures 2 and 3 show the data obtained in this test.

Figure 2 shows the effects of dobcumin hydrochloride injected intravenously at a rate of 2 tg/kg/min, with a nasal formulation that does not contain oleic acid and with the same nasal formulation except that it co-occurs with oleic acid. A comparison of the inotropic effects is shown. The sustained-release nasal preparation, which does not contain oleic acid, is dobcumin hydrochloride 0.420 g.
, Towie 7850.21g1 Freon 11.20.6
85g and Flemen] 220.684M. A sustained release nasal formulation containing oleic acid is shown in Example 10 above. The results indicated that the pharmacokinetics of intravenous and nasal sustained release routes of administration were similar. The oleic acid formulation provided a sustained release effect for 41/2 hours after administration.

FIG. 3 shows the cardiac contractile response of dovcumin induced by varying the oleic acid concentration in the sustained release formulation according to the present invention. Preparations containing no oleic acid include dobcumin hydrochloride 0.4209g, Tween 85 0.21g,
Composed of Freon 1120.685g and Freon 1220°685g. A formulation containing 1% by weight oleic acid was described in Example 17 and a formulation containing 2% by weight oleic acid was described in Example 20. Example 18 describes a formulation containing approximately 4% oleic acid, while a formulation containing 7% oleic acid was described in Example 21. Two beneficial effects are evident when increasing the oleic acid concentration in the composition from 0% to 7%. First, a % prolonged cardiac contractile response is observed as the amount of oleic acid increases, up to a maximum duration of approximately 5 hours. Second, the initial effects of dovcumin, appearing as a sharp peak during the first 30 minutes following administration, were
There is a significant reduction for both sustained release compositions containing % oleic acid.

[Brief explanation of the drawing]

Figure 1 is a T-graph showing the plasma concentration of dovcumin hydrochloride administered to rats, and Figure 2 is a T graph showing the plasma concentration of dovcumin hydrochloride administered to dogs.
Figure 3 is a graph showing the effect of oleic acid content on the change in cardiac contraction relative to the control when dobcumin hydrochloride is administered to dogs. . Patent applicant Eli Lilly & Company Agent Patent attorney 1 person FIG, 18 hours (minutes) FIG, 2 days - FM (hours)

Claims (1)

[Scope of Claims] 1 catecholamine, 1 emulsifier, 1 dispersion medium, and formula () % formula % ([in the formula, is c -c alkyl or C8 to C1°8
10 alkenyl, and k is hydrogen or 01-04 alkyl.] A sustained release nasal preparation comprising a sustained release agent represented by the following formula. 2. The catecholamine is dobutamine or its pharmaceutically acceptable salts. The formulation according to item 1. 3. The catecholamine is dobutamine sulfate. The formulation according to item 1 or 2. 4. The formulation according to any one of items 1 to 3, wherein the emulsifier is polyoxyethylene 20 sorbitan trioleate. 5. The first, where R1 of formula ill is c -c alkyl
8 10 6. The formulation according to item 5, wherein the sustained release agent is oleic acid or a C□-C4 alkyl ester thereof. 7. K of formula (1) is C8-C1o alkenyl,
The formulation according to any one of items 1 to 4. 8. The formulation according to item 7, wherein the sustained release agent is linoleic acid or a C1-C4 alkyl ester thereof. 9. A method for increasing contractility in a warm-blooded animal, which comprises administering to the animal a therapeutically effective agent of the sustained-release nasal preparation according to any one of items 1 to 8. 10. The method for increasing cardiac contractility according to item 9, wherein the nasal preparation contains dobutamine hydrochloride.