CA1241918A - Sustained release intranasal formulation and method of use thereof - Google Patents
Sustained release intranasal formulation and method of use thereofInfo
- Publication number
- CA1241918A CA1241918A CA000479316A CA479316A CA1241918A CA 1241918 A CA1241918 A CA 1241918A CA 000479316 A CA000479316 A CA 000479316A CA 479316 A CA479316 A CA 479316A CA 1241918 A CA1241918 A CA 1241918A
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- Prior art keywords
- freon
- formulation
- sustained release
- oleic acid
- dobutamine
- Prior art date
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0043—Nose
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
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- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
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- General Health & Medical Sciences (AREA)
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- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Otolaryngology (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
Abstract
Abstract Administration of a catecholamine by a novel intranasal delivery system provides prolonged blood levels of the drug.
Description
SUSTAINED RELEASE INTRANASAL FORMULATION
AND METHOD OF USE l'~REOF
Catecholamines are a class of chemical com-pounds known for their cardiotonic activity. Dobuta-mine, one of the most potent compounds of the class, is principally used in the short-term treatment of low output acute heart failure which may occur after myocar-dial infarction or after cardiopulmonary bypass surgery.
Dobutamine is biotransformed very rapidly by catechol-O-methyltransferase. Because the compound has a half-life of only 2 minutes in the body, the drug currently must be given by continuous intravenous inusion. This method of administering the drug requires careful monitoring, and typically admission of the patient to a hospital. Because of the short half-life of the com-pound, an oral route of administration is impractical.
The present invention relates to an intranasal sustained release formulation of a catecholamine, such as dobutamine, which affords in a warm-blooded animal prolonged blood levels of such compounds. Sustained inotropic effects of intranasal administration of this formulation also have been observed. The present formulation has the added advantage of being adminis-tered easily without admitting the patient to thehospital.
The present invention provides a sustained release intranasal formulation which comprises a cate-cholamine, a sustained release agent, an emulsifying agent and a dispersion medium.
, 24~9~3 In particular, there is provided a sustained release intranasal ormulation which comprises a cate-cholamine, an emulsifying agent, a dispersion medium and a sustained release agent of formula (I):
Rl-CH=CH(CH2)7CO2R2 (I) in which s Cg C10 alkyl or C8-C10 alkenyl; and R2 is hydrogen or Cl-C4 alkyl. specially preferred is a sustained release formulation in which the catecholamine is dobutamine, or a pharmaceutically-acceptable salt thereof.
This invention also relates to a method for lS increasing cardiac contractility in a warm-blooded animal in need of such therapy which comprises adminis-tering to said animal a therapeutically-effective amount of a sustained release intranasal formulation of the invention.
Brief Description of The Drawings Figure 1 is a semi-logarithmic plot of plasma levels of dobutamine hydrochloride in rats obtained when the drug was administered at a dose of 2.5 mg/kg.
Dobutamine hydrochloride was administered as an intrave-nous bolus and by an intranasal saline solution. The graph represents the average of three trials.
Figure 2 compares the cardiac contractility of an intravenous infusion of dobutamine hydrochloride with the prolonged release obtained my a sustained release intranasal composition of dobutam~ne hydrochloride with oleic acid and the same composition without oleic acid.
.
X-6360A -3~
Figure 3 shows the effect, in anesthetized dogs after nasal administration, of various concentra-tions of oleic acid in the sustained release formulation containing dobutamine hydrochloride at various dose S levels.
Amounts and percentages are described in weight units unless stated otherwise.
The term "Cl-C4 alkyl" represents a straight or branched alkyl chain having from one to four carbon atoms. Typical Cl-C4 alkyl groups include methyl, ethyl, _-propyl, isopropyl, _-butyl, isobutyl, sec-butyl and t-butyl.
The term ''C8-ClO alkyl" represents a straight or branched alkyl chain having either 8, 9 or 10 carbon atoms. Typical C8-C10 alkyl groups include n-octyl, isooctyl, n-nonyl, isononyl, n-decyl, isodecyl and the like.
The term ''C8-ClO alkenyl" represents a straight or branched alkenyl chain having one or more carbon-carbon double bonds. Typical C8-C10 alkenyl groups include 5-octenyl, 1,3-octadienyl, 1,3,5-octatrienyl, 3,6-nonadienyl, 6-nonenyl, 5-decenyl, 4,8-decadienyl and the like.
The active ingredient employed in the present composition is a catecholamine, preferably dobutamine.
The active ingredient will be present in the composition at a concentration at about 0.5 to about 20.0 percent by weight, preferably at a concentration in the range of about 2.0 to about lO.0 percent by weight.
'' .
~24~9~8 Dobutamine is the generic name given to thepreferred active ingredient employed in the present composition. The term "dobutamine", is intended to encompass any pharmaceutically-acceptable form of the drug, for example either the free base or preferably, a pharmaceutically-acceptable salt thereof. Exemplary salts of this type include those prepared with phosphor-ic acid, sulfuric acid, hydrobromic acid and preferably hydrochloric acid. Dobutamine has the chemical name (+,-) 4-[2-[[3-(~-hydroxyphenyl)-1-methylpropyl]amino]-ethyl]pyrocatechol, and is represented by the following chemical structure:
H0\
\\ H2-CH2-NH-CH-CH2-CH2 _ /~ \--0H
Processes for preparing dobutamine, as well as a de-tailed description of its use, are taught in U.S. Patent No. 3,987,200, R.R. Tuttle et al, issued October 19, 1976.
Other catecholamines contemplated for use in the present formulation may include the following:
., , HO
HO -CH-CH-NH
R R R
AND METHOD OF USE l'~REOF
Catecholamines are a class of chemical com-pounds known for their cardiotonic activity. Dobuta-mine, one of the most potent compounds of the class, is principally used in the short-term treatment of low output acute heart failure which may occur after myocar-dial infarction or after cardiopulmonary bypass surgery.
Dobutamine is biotransformed very rapidly by catechol-O-methyltransferase. Because the compound has a half-life of only 2 minutes in the body, the drug currently must be given by continuous intravenous inusion. This method of administering the drug requires careful monitoring, and typically admission of the patient to a hospital. Because of the short half-life of the com-pound, an oral route of administration is impractical.
The present invention relates to an intranasal sustained release formulation of a catecholamine, such as dobutamine, which affords in a warm-blooded animal prolonged blood levels of such compounds. Sustained inotropic effects of intranasal administration of this formulation also have been observed. The present formulation has the added advantage of being adminis-tered easily without admitting the patient to thehospital.
The present invention provides a sustained release intranasal formulation which comprises a cate-cholamine, a sustained release agent, an emulsifying agent and a dispersion medium.
, 24~9~3 In particular, there is provided a sustained release intranasal ormulation which comprises a cate-cholamine, an emulsifying agent, a dispersion medium and a sustained release agent of formula (I):
Rl-CH=CH(CH2)7CO2R2 (I) in which s Cg C10 alkyl or C8-C10 alkenyl; and R2 is hydrogen or Cl-C4 alkyl. specially preferred is a sustained release formulation in which the catecholamine is dobutamine, or a pharmaceutically-acceptable salt thereof.
This invention also relates to a method for lS increasing cardiac contractility in a warm-blooded animal in need of such therapy which comprises adminis-tering to said animal a therapeutically-effective amount of a sustained release intranasal formulation of the invention.
Brief Description of The Drawings Figure 1 is a semi-logarithmic plot of plasma levels of dobutamine hydrochloride in rats obtained when the drug was administered at a dose of 2.5 mg/kg.
Dobutamine hydrochloride was administered as an intrave-nous bolus and by an intranasal saline solution. The graph represents the average of three trials.
Figure 2 compares the cardiac contractility of an intravenous infusion of dobutamine hydrochloride with the prolonged release obtained my a sustained release intranasal composition of dobutam~ne hydrochloride with oleic acid and the same composition without oleic acid.
.
X-6360A -3~
Figure 3 shows the effect, in anesthetized dogs after nasal administration, of various concentra-tions of oleic acid in the sustained release formulation containing dobutamine hydrochloride at various dose S levels.
Amounts and percentages are described in weight units unless stated otherwise.
The term "Cl-C4 alkyl" represents a straight or branched alkyl chain having from one to four carbon atoms. Typical Cl-C4 alkyl groups include methyl, ethyl, _-propyl, isopropyl, _-butyl, isobutyl, sec-butyl and t-butyl.
The term ''C8-ClO alkyl" represents a straight or branched alkyl chain having either 8, 9 or 10 carbon atoms. Typical C8-C10 alkyl groups include n-octyl, isooctyl, n-nonyl, isononyl, n-decyl, isodecyl and the like.
The term ''C8-ClO alkenyl" represents a straight or branched alkenyl chain having one or more carbon-carbon double bonds. Typical C8-C10 alkenyl groups include 5-octenyl, 1,3-octadienyl, 1,3,5-octatrienyl, 3,6-nonadienyl, 6-nonenyl, 5-decenyl, 4,8-decadienyl and the like.
The active ingredient employed in the present composition is a catecholamine, preferably dobutamine.
The active ingredient will be present in the composition at a concentration at about 0.5 to about 20.0 percent by weight, preferably at a concentration in the range of about 2.0 to about lO.0 percent by weight.
'' .
~24~9~8 Dobutamine is the generic name given to thepreferred active ingredient employed in the present composition. The term "dobutamine", is intended to encompass any pharmaceutically-acceptable form of the drug, for example either the free base or preferably, a pharmaceutically-acceptable salt thereof. Exemplary salts of this type include those prepared with phosphor-ic acid, sulfuric acid, hydrobromic acid and preferably hydrochloric acid. Dobutamine has the chemical name (+,-) 4-[2-[[3-(~-hydroxyphenyl)-1-methylpropyl]amino]-ethyl]pyrocatechol, and is represented by the following chemical structure:
H0\
\\ H2-CH2-NH-CH-CH2-CH2 _ /~ \--0H
Processes for preparing dobutamine, as well as a de-tailed description of its use, are taught in U.S. Patent No. 3,987,200, R.R. Tuttle et al, issued October 19, 1976.
Other catecholamines contemplated for use in the present formulation may include the following:
., , HO
HO -CH-CH-NH
R R R
2 3 Compound R, R2 R3 norepinephrine OH H H
epinephrine OH H CH3 isoproterenol OH H CH
dopamine H H H
methyl-dopamine H H CH3 ethyl-dopamine H H CH2CH3 25 propyl-dopamine H H CH2CH2CH3 isopropyl-dopamine H H CH
35 ~-methyl-isopropyl- H CH3 CH
dopamine CH3 40 ~-ethyl-isoproPYl- H CH2 CH
dopamine CH3 CH3 Compound Rl R2 / 2 5 cyclopropyl-dopamine H H CH¦
sec.-butyl-dopamine H H CHCH2CH3 15 phenyl-ethyl-dopamine H H CH2CH2~
phenyl-isopropyl- H H CHCH2 I-dopamlne I =-phenyl-sec.-butyl- H H CHCH2CH2 dopamine I .=~
hydroxyphenyl-ethyl- H H CH2CH2--~ I- H
dopamine I=.
hydroxyphenyl- H H CHCH2 H
isopropyl-dopamine CH3 hydroxyphenyl-ethyl- H CH3 CH2CH2--~ OH
~-methyl-dopamine =-hydroxyphenyl-propyl- H H CH2CH2CH~ --OH
dopamine =-The active agent employed in the formulation also may be a combination of one or more of the cate-cholamines defined above. An exemplary combination of this type includes dobutamine and dopamine.
The sustained release agent employed in the present intranasal formulation will be an oil or liquid at room temperature, that is, at a temperature of about 25C. This agent is a compound of formula (I):
Rl-CH=CH(CH2)7CO2R2 (I) in which C8 C10 alkyl or C8-C10 alkenyli and R2 is hydrogen or C1-C4 alkyl.
Exemplary sustained release agents suitable for use in the present formulation may include the following:
trivial name formula linoleic acid CH3(CH2)4CH=CHCH2CH=CH(CH2)7C02H
linolenic acid CH3(CH2CH=CH)3(CH2)7C02H
ethyl linoleate CH3(CH2)4CH=CHCH2CH=CH(CH2)7C02CH2CH3 methyl linolenate CH3(cH2cH=cH)3(cH2)7co2cH3 ethyl oleate CH3(CH2)7CH=CH(CH2)7C02CH2CH3 The preferred sustained release agent employed in the present intranasal formulation is oleic acid.
Oleic acid has the following structural formula:
CH3(CH2)7CH=CH(CH2)7C02H
This compound may be obtained by the hydrolysis of various animal and vegetable fats and oils, however, the compound is more readily available commercially. Its synthesis has been well-documented in the literature.
See, e.q., Robinson et al. in J. Chem. Soc. 127, 175 (1925).
The sustained release agent may also exist as a combination of more than one of the specific agents described. Typical combinations may include oleic acid and linoleic acid, oleic acid and linolenic acid, oleic acid and ethyl oleate, methyl linoleate and methyl linolenate, and other combinations in ratios so as to provide the desired sustained release effect.
The amount of sustained release agent employed in the formulation will be from about 0.5 to about 50.0 percent by weight, more preferably about 2.0 to about 10.0 percent by weight of the formulation.
One or more emulsifying agents are added to the composition in order to improve its stability. The emulsifier employed may be chosen from among those generally known to be suitable for use in pharmaceutical formulations. Typical emulsifiers employed may include synthetic emulsifying agents. Depending on the charge possessed by the surfactant, this group may be divided into anionic, cationic, and nonionic types. The pre-ferred emulsifier will be nonionic, and in particular a polyoxyethylene derivative. This type of emulsifier is commercially available under the trademark"Tween'.' The most highly preferred emulsifier employed is"Tween 85"
which is polyoxyethylene 20 sorbitan trioleate, ,~
' .
' ~.24~918 available from ICI Americas. Other suitable emulsifiers may include the poloxamers including the"Pluronic"l emulsifiers from BASF Wyandotte such as"Pluronic L81".
Blends of emulsifiers are common and may be used also.
S The reader is referred to REMINGTON PHARMACEUTICAL
SCIENCES, Chapter 21, 16th Edition (1980) for a general discussion of suitable types of emulsifiers and their uses. The amount of emulsifier employed will be in the range of about 0.005 to about 5.0 percent by weight, more preferably at a rate in the range of about 0.1 to about 0.2 percent by weight of the formulation.
A dispersion medium also will be used in the sustained release intranasal composition. This medium may be composed of a variety of substances such as water, alcohols and other similar substantially non-toxic materials. This medium preferably is composed of one or more substances also capable of acting as a propellant for the system. Exemplary substances which may be used include the"Freons" from E.I. DuPont de Nemours and Company such as"Freon 114"3~1,2-dichloro-1,1,2,2-tetrafluoroethane),"Freon 12n4(dichlorodifluoro-methane) and"Freon l~'S(trichlorofluoromethane). These substances preferably are used in combination. While a variety of ingredients in assorted concentrations may be employed in the combinations, preferred combinations include about a 1:1 mixture of'~reon 11~ and'~reon 12"by weight and about a 5:4:1 mixture of"Freons"11:12:114 by weight. The amount of ingredients comprising the dispersion medium will be from about 40.0 to about 98.5 1 Trademark 2 Trademark
epinephrine OH H CH3 isoproterenol OH H CH
dopamine H H H
methyl-dopamine H H CH3 ethyl-dopamine H H CH2CH3 25 propyl-dopamine H H CH2CH2CH3 isopropyl-dopamine H H CH
35 ~-methyl-isopropyl- H CH3 CH
dopamine CH3 40 ~-ethyl-isoproPYl- H CH2 CH
dopamine CH3 CH3 Compound Rl R2 / 2 5 cyclopropyl-dopamine H H CH¦
sec.-butyl-dopamine H H CHCH2CH3 15 phenyl-ethyl-dopamine H H CH2CH2~
phenyl-isopropyl- H H CHCH2 I-dopamlne I =-phenyl-sec.-butyl- H H CHCH2CH2 dopamine I .=~
hydroxyphenyl-ethyl- H H CH2CH2--~ I- H
dopamine I=.
hydroxyphenyl- H H CHCH2 H
isopropyl-dopamine CH3 hydroxyphenyl-ethyl- H CH3 CH2CH2--~ OH
~-methyl-dopamine =-hydroxyphenyl-propyl- H H CH2CH2CH~ --OH
dopamine =-The active agent employed in the formulation also may be a combination of one or more of the cate-cholamines defined above. An exemplary combination of this type includes dobutamine and dopamine.
The sustained release agent employed in the present intranasal formulation will be an oil or liquid at room temperature, that is, at a temperature of about 25C. This agent is a compound of formula (I):
Rl-CH=CH(CH2)7CO2R2 (I) in which C8 C10 alkyl or C8-C10 alkenyli and R2 is hydrogen or C1-C4 alkyl.
Exemplary sustained release agents suitable for use in the present formulation may include the following:
trivial name formula linoleic acid CH3(CH2)4CH=CHCH2CH=CH(CH2)7C02H
linolenic acid CH3(CH2CH=CH)3(CH2)7C02H
ethyl linoleate CH3(CH2)4CH=CHCH2CH=CH(CH2)7C02CH2CH3 methyl linolenate CH3(cH2cH=cH)3(cH2)7co2cH3 ethyl oleate CH3(CH2)7CH=CH(CH2)7C02CH2CH3 The preferred sustained release agent employed in the present intranasal formulation is oleic acid.
Oleic acid has the following structural formula:
CH3(CH2)7CH=CH(CH2)7C02H
This compound may be obtained by the hydrolysis of various animal and vegetable fats and oils, however, the compound is more readily available commercially. Its synthesis has been well-documented in the literature.
See, e.q., Robinson et al. in J. Chem. Soc. 127, 175 (1925).
The sustained release agent may also exist as a combination of more than one of the specific agents described. Typical combinations may include oleic acid and linoleic acid, oleic acid and linolenic acid, oleic acid and ethyl oleate, methyl linoleate and methyl linolenate, and other combinations in ratios so as to provide the desired sustained release effect.
The amount of sustained release agent employed in the formulation will be from about 0.5 to about 50.0 percent by weight, more preferably about 2.0 to about 10.0 percent by weight of the formulation.
One or more emulsifying agents are added to the composition in order to improve its stability. The emulsifier employed may be chosen from among those generally known to be suitable for use in pharmaceutical formulations. Typical emulsifiers employed may include synthetic emulsifying agents. Depending on the charge possessed by the surfactant, this group may be divided into anionic, cationic, and nonionic types. The pre-ferred emulsifier will be nonionic, and in particular a polyoxyethylene derivative. This type of emulsifier is commercially available under the trademark"Tween'.' The most highly preferred emulsifier employed is"Tween 85"
which is polyoxyethylene 20 sorbitan trioleate, ,~
' .
' ~.24~918 available from ICI Americas. Other suitable emulsifiers may include the poloxamers including the"Pluronic"l emulsifiers from BASF Wyandotte such as"Pluronic L81".
Blends of emulsifiers are common and may be used also.
S The reader is referred to REMINGTON PHARMACEUTICAL
SCIENCES, Chapter 21, 16th Edition (1980) for a general discussion of suitable types of emulsifiers and their uses. The amount of emulsifier employed will be in the range of about 0.005 to about 5.0 percent by weight, more preferably at a rate in the range of about 0.1 to about 0.2 percent by weight of the formulation.
A dispersion medium also will be used in the sustained release intranasal composition. This medium may be composed of a variety of substances such as water, alcohols and other similar substantially non-toxic materials. This medium preferably is composed of one or more substances also capable of acting as a propellant for the system. Exemplary substances which may be used include the"Freons" from E.I. DuPont de Nemours and Company such as"Freon 114"3~1,2-dichloro-1,1,2,2-tetrafluoroethane),"Freon 12n4(dichlorodifluoro-methane) and"Freon l~'S(trichlorofluoromethane). These substances preferably are used in combination. While a variety of ingredients in assorted concentrations may be employed in the combinations, preferred combinations include about a 1:1 mixture of'~reon 11~ and'~reon 12"by weight and about a 5:4:1 mixture of"Freons"11:12:114 by weight. The amount of ingredients comprising the dispersion medium will be from about 40.0 to about 98.5 1 Trademark 2 Trademark
3 Trademark
4 Trademark
5 Trademark * Trademark it ' ,' percent by weight, more preferably from about 80.0 toabout 95.0 percent by weight of the total formulation.
One or more compounds having antioxidant properties preferably are used in the present composi-tion to provide additional stability to the system.
Suitable antioxidants may include Vitamin E and particu-larly, butyrated hydroxy anisole (BHA). When employed in the formulation, the compound will be present at a concentration in the range of from about 0.001 to about 0.5 percent by weight of the composition, more prefera-bly from about 0.1 to about 0.5 percent by weight.
Because the present formulation is adminis-tered nasally, a scenting agent also may be added, if desired. When used, the scenting agent will be present 15 in the range of about 0.001 to about 1.0 percent by weight. Exemplary scenting agents may include pepper-mint oil, lemon oil, olive oil and other similar sub-stances having a soothing effect on the olfactory system .
The formulations of the present invention may be prepared by procedures well-known to those skilled in the art. Preferably the formulations are prepared as follows. Prior to formulating, the active ingredient employed is micronized with any one of several devices employed in the art such as a mechanical micronizer.
The particles should be in the range of about 0.1 to about 100 microns in diameter. Next, a stock solution is prepared by dissolving the emulsifying agent and any scenting agent or antioxidant into the sustained release agent. This mixture is mixed thoroughly, typically at 2~
room temperature, and combined with the active ingredi-ent in a suitable cannister or container. The cannister may be metal or glass, capable of being pressurized, and is typical of those employed in the art for this pur-pose. The cannister then is charged with one or morepropellants while cooling the cannister to a temperature in the range of from about 5C to about -50C, more preferably from about 0C to about -20C. The cannister then is sealed, typically with an aerosol type valve, and warmed to determine if there is leakage of the cannister. This formulation is then suitable for administration to a warm-blooded animal in need of an increase in cardiac contractility.
A particularly preferred sustained release composition of the invention is as follows:
Formula 1 percent 20 Inaredient Concentration (bv weiqht) dobutamine hydrochloride about 2.0-4.0 sustained release agent about 2.0-12.0 emulsifier about 0.01-0.1 antioxidant about 0.05-0.2 dispersion medium about 80.0-93.9 Those skilled in the art will recognize that the per-centage of a particular component of the formulatlon is dependent on the other constituents present and in no 9~
event can the total percentage of all components exceed 100%.
More highly preferred compositions of the present invention may be represented by the following:
Formula 2 percent Ingredient Concentration (bY weight) 10 dobutamine hydrochloride about 2.0 oleic acid about 4.0 Tween~85 about 0.01 BHA about 0.1 Freon 11 about 46.945 Freon 12 about 46.945 100 . 00 Formula 3 percent Inqredient Concentration (bY weiqht) dobutamine hydrochloride about 2.0 oleic acid about 10.0 Tween~85 about 0.05 25 BHA about 0.1 Freon 11 about 43.925 Freon 12 about 43.925 100 . 00 f Formula 4 percent InqredientConcentration (bY weight) 5 dobutamine hydrochloride about 2.0 oleic acid about 10.0 Tween 85 about 0.1 BHA about 0.1 peppermint oil about 0.3 Freon 11 about 43.75 Freon 12 about 43.75 100 . 00 Formula 5 percent Inqredient Concentration (bv weiqht) dobutamine hydrochloride about 4.0 oleic acid .about 10.0 20 Tween 85 about 0.1 BHA about 0.1 Freon 11 about 42.9 Freon 12 about 34.32 Freon 114 about 8.58 100.00 The following non-limiting Examples further illustrate specific sustained release intranasal compo-, sitions of the invention and methods for their prep-aration.
Example 1 Five hundred and sixty milligrams (4% by weight) of dobutamine hydrochloride were micronized in a mechanical micronizer to provide particles with a diameter of approximately 2 to 3 microns. A stock solution was prepared by dissolving 140 mg of BHA, 141 mg of Tween 85, 420 mg of peppermint oil and 700 mg of Pluronic L81 in 14.0 g of oleic acid at room tempera-ture. The micronized dobutamine hydrochloride and 1.56 g (11.12% by weight) of the stock solution were added to an aerosol cannister. The cannister was previously cleaned by blowing pure nitrogen gas in the can while it was in an inverted position. The cannister was cooled to 0C and charged with 5.95 g (42.41% by weight) of Freon 11 and 5.96 g (42.48% by weight) of Freon 12. A valve was added immediately and sealed onto the cannister. The cannister was placed in a hot water bath for several minutes to allow the contents to reach room temperature. The cannister was checked for leaks.
The cannister was dried and the valve actuated several times to prime the valve. The valve was then protected with a suitable cap and the cannister was labeled and stored until ready for use.
The following Examples were prepared by the general procedure outlined in this procedure.
Example 2 percent by weiqht weight (g) dobutamine hydrochloride 0.89 0.14 oleic acid 2.17 0.34 Tween 85 0.45 0.07 Freon 11 9.88 1.55 Freon 12 86.61 13.58 Freon 114 J
100 . O
Example 3 percent by weight weiqht (q) dobutamine hydrochloride 1.0 0.14 oleic acid 2.0 0.28 Tween 85 0.5 0.07 Freon 11 48.25 6.75 Freon 12 48.25 6.75 100 . O
., 3~3 Example 4 percent by weiqht weiqht (g) dobutamine hydrochloride 1.0 0.142 oleic acid 10.00 1.404 Tween 85 0.58 0.081 Freon 11 44.14 6.205 Freon 12 44.28 6.224 100 . O
Example 5 percent by weiqht weiqht (g) dobutamine hydrochloride 0.86 0.142 oleic acid 8.5 1.4 Tween 85 0.5 0.083 Freon 11 37.61 6.201 Freon 12 52.53 8.663 100 . O
Example 6 percent by weight weiqht (q) dobutamine hydrochloride 0.96 0.14 oleic acid 9.64 1.403 Tween 85 0.55 0.079 Freon 11 42.61 6.202 Freon 12 46.24 6.73 100 . 00 ~L2~
Example 7 percent by weiqht weiqht (g) dobutamine 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 . O
ExamPle 8 percent by weiqht weight (g) dobutamine 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 5.987 100 . O
9~
Example 9 percent by weight weight ~g) dobutamine hydrochloride 2.01 0.282 oleic acid 10.01 1.403 Tween 85 0.5 0.07 Freon 11 43.73 6.125 Freon 12 43.75 6.130 100 . O
Example 10 percent by lS weig t weiqht (q) dobutamine 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 6.211 100 . O
Example 11 percent by _ weiqhtweiqht (q) dobutamine hydrochloride 3.96 0.561 oleic acid 9.89 1.4 Tween 85 0.51 0.073 Freon 11 42.35 5.996 Freon 12 43.29 6.129 100 . O
~L2~
Example 12 percent by weiqht weight (q) dobutamine hydrochloride 1.96 0.283 oleic acid 9.69 1.406 Tween 85 0.49 0.071 peppermint oil 0.41 0.060 Freon 11 42.03 6.098 10 Freon 12 45.42 6.590 100 . O
Example 13 lS percent by weight weight (g) dobutamine hydrochloride 1.9 0.282 oleic acid BHA 1 9.93 1.472 Tween 85 peppermint oil Pluronic L81 4.86 0.72 Freon 11 41.15 6.096 Freon 12 42.16 6.248 100.0
One or more compounds having antioxidant properties preferably are used in the present composi-tion to provide additional stability to the system.
Suitable antioxidants may include Vitamin E and particu-larly, butyrated hydroxy anisole (BHA). When employed in the formulation, the compound will be present at a concentration in the range of from about 0.001 to about 0.5 percent by weight of the composition, more prefera-bly from about 0.1 to about 0.5 percent by weight.
Because the present formulation is adminis-tered nasally, a scenting agent also may be added, if desired. When used, the scenting agent will be present 15 in the range of about 0.001 to about 1.0 percent by weight. Exemplary scenting agents may include pepper-mint oil, lemon oil, olive oil and other similar sub-stances having a soothing effect on the olfactory system .
The formulations of the present invention may be prepared by procedures well-known to those skilled in the art. Preferably the formulations are prepared as follows. Prior to formulating, the active ingredient employed is micronized with any one of several devices employed in the art such as a mechanical micronizer.
The particles should be in the range of about 0.1 to about 100 microns in diameter. Next, a stock solution is prepared by dissolving the emulsifying agent and any scenting agent or antioxidant into the sustained release agent. This mixture is mixed thoroughly, typically at 2~
room temperature, and combined with the active ingredi-ent in a suitable cannister or container. The cannister may be metal or glass, capable of being pressurized, and is typical of those employed in the art for this pur-pose. The cannister then is charged with one or morepropellants while cooling the cannister to a temperature in the range of from about 5C to about -50C, more preferably from about 0C to about -20C. The cannister then is sealed, typically with an aerosol type valve, and warmed to determine if there is leakage of the cannister. This formulation is then suitable for administration to a warm-blooded animal in need of an increase in cardiac contractility.
A particularly preferred sustained release composition of the invention is as follows:
Formula 1 percent 20 Inaredient Concentration (bv weiqht) dobutamine hydrochloride about 2.0-4.0 sustained release agent about 2.0-12.0 emulsifier about 0.01-0.1 antioxidant about 0.05-0.2 dispersion medium about 80.0-93.9 Those skilled in the art will recognize that the per-centage of a particular component of the formulatlon is dependent on the other constituents present and in no 9~
event can the total percentage of all components exceed 100%.
More highly preferred compositions of the present invention may be represented by the following:
Formula 2 percent Ingredient Concentration (bY weight) 10 dobutamine hydrochloride about 2.0 oleic acid about 4.0 Tween~85 about 0.01 BHA about 0.1 Freon 11 about 46.945 Freon 12 about 46.945 100 . 00 Formula 3 percent Inqredient Concentration (bY weiqht) dobutamine hydrochloride about 2.0 oleic acid about 10.0 Tween~85 about 0.05 25 BHA about 0.1 Freon 11 about 43.925 Freon 12 about 43.925 100 . 00 f Formula 4 percent InqredientConcentration (bY weight) 5 dobutamine hydrochloride about 2.0 oleic acid about 10.0 Tween 85 about 0.1 BHA about 0.1 peppermint oil about 0.3 Freon 11 about 43.75 Freon 12 about 43.75 100 . 00 Formula 5 percent Inqredient Concentration (bv weiqht) dobutamine hydrochloride about 4.0 oleic acid .about 10.0 20 Tween 85 about 0.1 BHA about 0.1 Freon 11 about 42.9 Freon 12 about 34.32 Freon 114 about 8.58 100.00 The following non-limiting Examples further illustrate specific sustained release intranasal compo-, sitions of the invention and methods for their prep-aration.
Example 1 Five hundred and sixty milligrams (4% by weight) of dobutamine hydrochloride were micronized in a mechanical micronizer to provide particles with a diameter of approximately 2 to 3 microns. A stock solution was prepared by dissolving 140 mg of BHA, 141 mg of Tween 85, 420 mg of peppermint oil and 700 mg of Pluronic L81 in 14.0 g of oleic acid at room tempera-ture. The micronized dobutamine hydrochloride and 1.56 g (11.12% by weight) of the stock solution were added to an aerosol cannister. The cannister was previously cleaned by blowing pure nitrogen gas in the can while it was in an inverted position. The cannister was cooled to 0C and charged with 5.95 g (42.41% by weight) of Freon 11 and 5.96 g (42.48% by weight) of Freon 12. A valve was added immediately and sealed onto the cannister. The cannister was placed in a hot water bath for several minutes to allow the contents to reach room temperature. The cannister was checked for leaks.
The cannister was dried and the valve actuated several times to prime the valve. The valve was then protected with a suitable cap and the cannister was labeled and stored until ready for use.
The following Examples were prepared by the general procedure outlined in this procedure.
Example 2 percent by weiqht weight (g) dobutamine hydrochloride 0.89 0.14 oleic acid 2.17 0.34 Tween 85 0.45 0.07 Freon 11 9.88 1.55 Freon 12 86.61 13.58 Freon 114 J
100 . O
Example 3 percent by weight weiqht (q) dobutamine hydrochloride 1.0 0.14 oleic acid 2.0 0.28 Tween 85 0.5 0.07 Freon 11 48.25 6.75 Freon 12 48.25 6.75 100 . O
., 3~3 Example 4 percent by weiqht weiqht (g) dobutamine hydrochloride 1.0 0.142 oleic acid 10.00 1.404 Tween 85 0.58 0.081 Freon 11 44.14 6.205 Freon 12 44.28 6.224 100 . O
Example 5 percent by weiqht weiqht (g) dobutamine hydrochloride 0.86 0.142 oleic acid 8.5 1.4 Tween 85 0.5 0.083 Freon 11 37.61 6.201 Freon 12 52.53 8.663 100 . O
Example 6 percent by weight weiqht (q) dobutamine hydrochloride 0.96 0.14 oleic acid 9.64 1.403 Tween 85 0.55 0.079 Freon 11 42.61 6.202 Freon 12 46.24 6.73 100 . 00 ~L2~
Example 7 percent by weiqht weiqht (g) dobutamine 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 . O
ExamPle 8 percent by weiqht weight (g) dobutamine 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 5.987 100 . O
9~
Example 9 percent by weight weight ~g) dobutamine hydrochloride 2.01 0.282 oleic acid 10.01 1.403 Tween 85 0.5 0.07 Freon 11 43.73 6.125 Freon 12 43.75 6.130 100 . O
Example 10 percent by lS weig t weiqht (q) dobutamine 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 6.211 100 . O
Example 11 percent by _ weiqhtweiqht (q) dobutamine hydrochloride 3.96 0.561 oleic acid 9.89 1.4 Tween 85 0.51 0.073 Freon 11 42.35 5.996 Freon 12 43.29 6.129 100 . O
~L2~
Example 12 percent by weiqht weight (q) dobutamine hydrochloride 1.96 0.283 oleic acid 9.69 1.406 Tween 85 0.49 0.071 peppermint oil 0.41 0.060 Freon 11 42.03 6.098 10 Freon 12 45.42 6.590 100 . O
Example 13 lS percent by weight weight (g) dobutamine hydrochloride 1.9 0.282 oleic acid BHA 1 9.93 1.472 Tween 85 peppermint oil Pluronic L81 4.86 0.72 Freon 11 41.15 6.096 Freon 12 42.16 6.248 100.0
6~
Example 14 percent by weiqht weight (q) dobutamine hydrochloride 6.00 0.849 oleic acid - .
BHA _10.41 1.471 Tween 85 peppermint oil Pluronic L81 0.49 0.07 Freon 11 41.13 5.814 Freon 12 41.95 5.930 100 . O
ExamPle 15 percent by weiqht weiqht (q) dobutamine hydrochloride 1.96 0.28 oleic acid 9.78 1.4 butylated hydroxy anisole 0.1 0.014 Tween 85 0.1 0.014 peppermint oil 0.29 0.042 Freon 11 44.02 6.3 Freon 12 43.75 6.26 100 . O
ExamPle 16 percent by weiqht weiqht (g) 5 dobutamine hydrochloride 7.0 0.98 oleic acid 10.0 1.4 BHA 0.1 0.014 Tween 85 0.1 0.014 Pluronic L81 0.5 0.07 Freon 11 41.15 5.76 Freon 12 41.15 5.76 100 . O
Example 17 percent by weight weiqht (g) dobutamine hydrochloride 1.99 0.280 oleic acid 1.01 0.143 Tween 85 0.1 0.014 Pluronic L81 0.5 0.07 Freon 11 47.9 6.75 Freon 12 48.50 6.836 100 . O
X-6360A -22- ~24~918 ExamPle 18 percent by weiqht weiqht (g) dobutamine hydrochloride 1.97 0.28 oleic acid 3.95 0.56 Tween 85 0.14 0.02 Pluronic L81 0.49 0.07 Freon 11 46.07 6.54 Freon 12 47.33 6.725 100 . O
Example 19 percent by weight weight (g) dobutamine hydrochloride 1.98 0.28 oleic acid 6.94 0.98 Tween 85 0.11 0.016 Pluronic L81 0.5 0.072 Freon 11 44.85 6.329 Freon 12 45.62 6.435 100 . O
Example 20 percent by weiqht weiqht (q) dobutamine hydrochloride 1.98 0.28 oleic acid 2.01 0.285 Tween 85 0.12 0.017 Pluronic L81 0.49 0.07 Freon 11 47.16 6.683 10 Freon 12 48.24 6.835 100 . O
Example 21 percent by weiqht weiqht (g) dobutamine hydrochloride 2.0 0.28 oleic acid 6.99 0.981 Tween 85 0.11 0.015 20 Freon 11 45.39 6.369 Freon 12 45.51 6.386 100 . O
Example 22 percent by weight weight (g) dobutamine hydrochloride 1.99 0.28 linoleic acid 7.0 0.983 BHA 0.1 0.14 Tween 85 0.1 0.14 Freon 11 45.28 6.359 Freon 12 45.53 6.394 100 . O
Example 23 percent by weiqht weiqht (q) dobutamine hydrochloride 1.87 0.28 ethyl oleate 9.39 1.402 Tween 85 0.48 0.071 Freon 11 40.99 6.123 Freon 12 47.27 7.06 100 o O
~4~ 8 X-6360~ -25-ExamPle 24 percent by weight weight (q) dobutamine hydrochloride 1.99 0.281 ethyl oleate 9.94 1.4 Tween 85 0.55 0.078 Freon 11 43.50 6.127 Freon 12 44.02 6.2 100 . O
Example 25 percent by weight weiqht (g) dobutamine hydrochloride 1.99 0.281 ethyl oleate 9.95 1.403 l'ween 85 0.50 0.07 Freon 11 43.43 6.126 Freon 12 44.13 6.225 100 . O
The present invention also provides a method for increasing cardiac contractility in a warm-blooded animal which comprises administering to said animal a therapeutically effective amount of a sustained release intranasal formulation of the invention. The term "therapeutically-effective amount" refers to an amount of a catecholamine formulated for intranasal sustained release capable of ameliorating a degenerative cardiac condition. Typically, a catecholamine is administered as described at a rate in the range of about 175 mcg/kg to about 7 mg/kg in order to restore the contractile force of the heart muscle.
It has been unexpectedly discovered that a S catecholamine can be formulated for nasal administration which upon administration will achieve equivalent bioavailability to that of intravenous administration.
The following study examines the bioavailability of the catecholamine dobutamine when administered intranasally and intravenously.
Six male rats weighing 280 g were anesthetized with sodium pentobarbital (50 mg/kg I.P.). Three rats were dosed intravenously with dobutamine hydrochloride at 2.5 mg/kg. Blood samples were taken at 0.5, 2, 4, 6, 10, 15, 20 and 30 minutes for plasma analysis for dobutamine. The three remaining rats received dobuta-mine, at 2.5 mg/kg, intranasally in a saline solution.
Blood samples from these rats were taken at 1, 5, 10, 20, 30, 60 and 120 minutes.
Figure 1 shows the results of this study as the average plasma level of dobutamine observed from each method of administration over the duration of the study. As is known, the one time intravenous adminis-tration of dobutamine hydrochloride at 2.5 mg/kg pro-duced a very high dobutamine blood level (greater than 1000 ng/ml) within 30 seconds after administration. The duration of dobutamine in the blood as a result of this method of administration was brief however, lasting only for a period of approximately 30 minutes. For compari-son, 1.456 mg of dobutamine hydrochloride was dissolved ~2~
in 0.2 ml of saline solution and 0.1 ml of this solutionwas administered intranasally to a 291 g rat to provide a dose of 2.5 mg/kg. This route of administration shows the prolonged effect afforded by intranasal delivery in comparison to the intravenous bolus administration. The intranasal delivery of dobutamine produced a moderate dobutamine blood level of 100 ng/ml after 20 minutes.
Surprisingly, however, this effective blood level remained after two hours.
The area under the curve (AUC) was calculated with computer assistance employing the trapezoidal method for each route of administration. These results are reported below in Table I.
Table I
Area Under the Curve After Intravenous Bolus and Intranasal Saline Solution Administration Route AUC nq-min/ml IV 2223.3 111.4 Nasal 11269 i 1390.4 The following study was also conducted to evaluate the bioavailability of dobutamine hydrochloride formulated as a sustained release intranasal formulation of the invention.
Mongrel dogs of mixed sex weighing 8.0 to 20.0 kg were anesthetized with sodium thiopental (15 mg/kg, ~2419~3 i.v.) and sodium phenobarbital (100 mg/kg, i.v.). Apositive pressure pump provided ventilation through a cuffed endotracheal tube (18 strokes/min, 20 mg/kg/stroke) and a heating pad maintained the body temperature of the dog at 37-38C. Both vagus nerves were sectioned through an incision in the neck. Arterial blood pres-sure was monitored using a Statham pressure transducer attached to a cannula filled with heparinized saline (16 units/ml) inserted into the abdominal aorta via the right femoral artery. A cannula connected to a three-way stopcock was inserted in the right femoral vein for drug administration. The heart was exposed through the fifth right intercostal space and a precalibrated Walton-Brodie strain gauge arch was sutured on the right ventricle.
The strain gauge was adjusted to a tension of 50 g at systole and a dynograph recorder was set so that the 50 g tension produced a pen deflection of 10 mm.
Heart rate was derived electronically from the blood pressure pulse using a'~eckma~'*cardiotachometer coupler.
Figures 2 and 3 above represent data obtained from this study.
Figure 2 represents a comparison of the inotropic effect observed by the intravenous infusion of dobutamine hydrochloride at a rate of 2 mcg/kg/min with an intranasal formulation without oleic acid and an identical intranasal formulation except with oleic acid.
The sustained release intranasal formulation without oleic acid was prepared by combining 0.420 g of dobuta-mine hydrochloride, 0.21 g of'~ween 85" 20.685 g of 'Freon ll"and 20.685 g of"Freon 12" The sustained * Trademark (each instance) ~2~
release intranasal formulation with oleic acid isrepresented by Example 10 above. The results indicate that the pharmacodynamics of intravenous and intranasal sustained release routes of administration are similar.
The oleic acid formulation provides a sustained release effect 41~ hours after administration.
Figure 3 illustrates the dobutamine cardiac contractility responses produced by changing the concen-tration of oleic acid in a sustained release formulation of the invention. The formulation containing no oleic acid consisted of 0.420 g of dobutamine hydrochloride, 0.21 g of Tween 85, 20.685 g of Freon 11 and 20.685 g of Freon 12. The formulation containing 1% oleic acid by weight is described in Example 17 and the formulation containing 2% oleic acid by weight is described in Example 20. Example 18 illustrates the formulation containing approximately 4% oleic acid while the formu-lation containing 7% oleic acid is described in Example 21. Two advantageous effects are apparent upon increas-ing the concentration of oleic acid in the compositionfrom 0% to 7%. First, a prolonged response of cardiac contractility is observed as the amount of oleic acid is increased to a maximum duration of approximately 5 hours. Second, the initial dobutamine effect which manifests itself as a sharp peak during the first 30 minutes following administration is greatly reduced for the sustained release compositions containing both 4%
and 7% oleic acid by weight.
Example 14 percent by weiqht weight (q) dobutamine hydrochloride 6.00 0.849 oleic acid - .
BHA _10.41 1.471 Tween 85 peppermint oil Pluronic L81 0.49 0.07 Freon 11 41.13 5.814 Freon 12 41.95 5.930 100 . O
ExamPle 15 percent by weiqht weiqht (q) dobutamine hydrochloride 1.96 0.28 oleic acid 9.78 1.4 butylated hydroxy anisole 0.1 0.014 Tween 85 0.1 0.014 peppermint oil 0.29 0.042 Freon 11 44.02 6.3 Freon 12 43.75 6.26 100 . O
ExamPle 16 percent by weiqht weiqht (g) 5 dobutamine hydrochloride 7.0 0.98 oleic acid 10.0 1.4 BHA 0.1 0.014 Tween 85 0.1 0.014 Pluronic L81 0.5 0.07 Freon 11 41.15 5.76 Freon 12 41.15 5.76 100 . O
Example 17 percent by weight weiqht (g) dobutamine hydrochloride 1.99 0.280 oleic acid 1.01 0.143 Tween 85 0.1 0.014 Pluronic L81 0.5 0.07 Freon 11 47.9 6.75 Freon 12 48.50 6.836 100 . O
X-6360A -22- ~24~918 ExamPle 18 percent by weiqht weiqht (g) dobutamine hydrochloride 1.97 0.28 oleic acid 3.95 0.56 Tween 85 0.14 0.02 Pluronic L81 0.49 0.07 Freon 11 46.07 6.54 Freon 12 47.33 6.725 100 . O
Example 19 percent by weight weight (g) dobutamine hydrochloride 1.98 0.28 oleic acid 6.94 0.98 Tween 85 0.11 0.016 Pluronic L81 0.5 0.072 Freon 11 44.85 6.329 Freon 12 45.62 6.435 100 . O
Example 20 percent by weiqht weiqht (q) dobutamine hydrochloride 1.98 0.28 oleic acid 2.01 0.285 Tween 85 0.12 0.017 Pluronic L81 0.49 0.07 Freon 11 47.16 6.683 10 Freon 12 48.24 6.835 100 . O
Example 21 percent by weiqht weiqht (g) dobutamine hydrochloride 2.0 0.28 oleic acid 6.99 0.981 Tween 85 0.11 0.015 20 Freon 11 45.39 6.369 Freon 12 45.51 6.386 100 . O
Example 22 percent by weight weight (g) dobutamine hydrochloride 1.99 0.28 linoleic acid 7.0 0.983 BHA 0.1 0.14 Tween 85 0.1 0.14 Freon 11 45.28 6.359 Freon 12 45.53 6.394 100 . O
Example 23 percent by weiqht weiqht (q) dobutamine hydrochloride 1.87 0.28 ethyl oleate 9.39 1.402 Tween 85 0.48 0.071 Freon 11 40.99 6.123 Freon 12 47.27 7.06 100 o O
~4~ 8 X-6360~ -25-ExamPle 24 percent by weight weight (q) dobutamine hydrochloride 1.99 0.281 ethyl oleate 9.94 1.4 Tween 85 0.55 0.078 Freon 11 43.50 6.127 Freon 12 44.02 6.2 100 . O
Example 25 percent by weight weiqht (g) dobutamine hydrochloride 1.99 0.281 ethyl oleate 9.95 1.403 l'ween 85 0.50 0.07 Freon 11 43.43 6.126 Freon 12 44.13 6.225 100 . O
The present invention also provides a method for increasing cardiac contractility in a warm-blooded animal which comprises administering to said animal a therapeutically effective amount of a sustained release intranasal formulation of the invention. The term "therapeutically-effective amount" refers to an amount of a catecholamine formulated for intranasal sustained release capable of ameliorating a degenerative cardiac condition. Typically, a catecholamine is administered as described at a rate in the range of about 175 mcg/kg to about 7 mg/kg in order to restore the contractile force of the heart muscle.
It has been unexpectedly discovered that a S catecholamine can be formulated for nasal administration which upon administration will achieve equivalent bioavailability to that of intravenous administration.
The following study examines the bioavailability of the catecholamine dobutamine when administered intranasally and intravenously.
Six male rats weighing 280 g were anesthetized with sodium pentobarbital (50 mg/kg I.P.). Three rats were dosed intravenously with dobutamine hydrochloride at 2.5 mg/kg. Blood samples were taken at 0.5, 2, 4, 6, 10, 15, 20 and 30 minutes for plasma analysis for dobutamine. The three remaining rats received dobuta-mine, at 2.5 mg/kg, intranasally in a saline solution.
Blood samples from these rats were taken at 1, 5, 10, 20, 30, 60 and 120 minutes.
Figure 1 shows the results of this study as the average plasma level of dobutamine observed from each method of administration over the duration of the study. As is known, the one time intravenous adminis-tration of dobutamine hydrochloride at 2.5 mg/kg pro-duced a very high dobutamine blood level (greater than 1000 ng/ml) within 30 seconds after administration. The duration of dobutamine in the blood as a result of this method of administration was brief however, lasting only for a period of approximately 30 minutes. For compari-son, 1.456 mg of dobutamine hydrochloride was dissolved ~2~
in 0.2 ml of saline solution and 0.1 ml of this solutionwas administered intranasally to a 291 g rat to provide a dose of 2.5 mg/kg. This route of administration shows the prolonged effect afforded by intranasal delivery in comparison to the intravenous bolus administration. The intranasal delivery of dobutamine produced a moderate dobutamine blood level of 100 ng/ml after 20 minutes.
Surprisingly, however, this effective blood level remained after two hours.
The area under the curve (AUC) was calculated with computer assistance employing the trapezoidal method for each route of administration. These results are reported below in Table I.
Table I
Area Under the Curve After Intravenous Bolus and Intranasal Saline Solution Administration Route AUC nq-min/ml IV 2223.3 111.4 Nasal 11269 i 1390.4 The following study was also conducted to evaluate the bioavailability of dobutamine hydrochloride formulated as a sustained release intranasal formulation of the invention.
Mongrel dogs of mixed sex weighing 8.0 to 20.0 kg were anesthetized with sodium thiopental (15 mg/kg, ~2419~3 i.v.) and sodium phenobarbital (100 mg/kg, i.v.). Apositive pressure pump provided ventilation through a cuffed endotracheal tube (18 strokes/min, 20 mg/kg/stroke) and a heating pad maintained the body temperature of the dog at 37-38C. Both vagus nerves were sectioned through an incision in the neck. Arterial blood pres-sure was monitored using a Statham pressure transducer attached to a cannula filled with heparinized saline (16 units/ml) inserted into the abdominal aorta via the right femoral artery. A cannula connected to a three-way stopcock was inserted in the right femoral vein for drug administration. The heart was exposed through the fifth right intercostal space and a precalibrated Walton-Brodie strain gauge arch was sutured on the right ventricle.
The strain gauge was adjusted to a tension of 50 g at systole and a dynograph recorder was set so that the 50 g tension produced a pen deflection of 10 mm.
Heart rate was derived electronically from the blood pressure pulse using a'~eckma~'*cardiotachometer coupler.
Figures 2 and 3 above represent data obtained from this study.
Figure 2 represents a comparison of the inotropic effect observed by the intravenous infusion of dobutamine hydrochloride at a rate of 2 mcg/kg/min with an intranasal formulation without oleic acid and an identical intranasal formulation except with oleic acid.
The sustained release intranasal formulation without oleic acid was prepared by combining 0.420 g of dobuta-mine hydrochloride, 0.21 g of'~ween 85" 20.685 g of 'Freon ll"and 20.685 g of"Freon 12" The sustained * Trademark (each instance) ~2~
release intranasal formulation with oleic acid isrepresented by Example 10 above. The results indicate that the pharmacodynamics of intravenous and intranasal sustained release routes of administration are similar.
The oleic acid formulation provides a sustained release effect 41~ hours after administration.
Figure 3 illustrates the dobutamine cardiac contractility responses produced by changing the concen-tration of oleic acid in a sustained release formulation of the invention. The formulation containing no oleic acid consisted of 0.420 g of dobutamine hydrochloride, 0.21 g of Tween 85, 20.685 g of Freon 11 and 20.685 g of Freon 12. The formulation containing 1% oleic acid by weight is described in Example 17 and the formulation containing 2% oleic acid by weight is described in Example 20. Example 18 illustrates the formulation containing approximately 4% oleic acid while the formu-lation containing 7% oleic acid is described in Example 21. Two advantageous effects are apparent upon increas-ing the concentration of oleic acid in the compositionfrom 0% to 7%. First, a prolonged response of cardiac contractility is observed as the amount of oleic acid is increased to a maximum duration of approximately 5 hours. Second, the initial dobutamine effect which manifests itself as a sharp peak during the first 30 minutes following administration is greatly reduced for the sustained release compositions containing both 4%
and 7% oleic acid by weight.
Claims (8)
1. A sustained release intranasal formulation which comprises a catecholamine, an emulsifying agent, a dispersion medium and a sustained release agent of formula (I):
R1-CH=CH(CH2)7CO2R2 (I) in which R1 is C8-C10 alkyl or C8-C10 alkenyl; and R2 is hydrogen or C1-C4 alkyl.
R1-CH=CH(CH2)7CO2R2 (I) in which R1 is C8-C10 alkyl or C8-C10 alkenyl; and R2 is hydrogen or C1-C4 alkyl.
2. A formulation as claimed in Claim 1 in which the catecholamine is dobutamine, or a pharma-ceutically-acceptable salt thereof.
3. A formulation as claimed in Claim 2 in which the catecholamine is dobutamine hydrochloride.
4. A formulation as claimed in Claim 3 in which the emulsifying agent is poloxyethylene 20 sorbitan trioleate.
5. A formulation as claimed in Claim 4 in which R1 of formula (I) is C8-C10 alkyl.
6. A formulation of Claim 5 in which the sustained release agent is oleic acid or a C1-C4 alkyl ester thereof.
7. A formulation as claimed in Claim 4 in which R1 of formula (I) is C8-C10 alkenyl.
8. A formulation of Claim 7 in which the sustained release agent is linoleic acid, or a C1-C4 alkyl ester thereof.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US60380884A | 1984-04-25 | 1984-04-25 | |
| US603,808 | 1984-04-25 | ||
| US695,491 | 1985-01-28 | ||
| US06/695,491 US4581225A (en) | 1984-04-25 | 1985-01-28 | Sustained release intranasal formulation and method of use thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1241918A true CA1241918A (en) | 1988-09-13 |
Family
ID=27084522
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000479316A Expired CA1241918A (en) | 1984-04-25 | 1985-04-17 | Sustained release intranasal formulation and method of use thereof |
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| Country | Link |
|---|---|
| US (1) | US4581225A (en) |
| EP (1) | EP0160501A3 (en) |
| AU (1) | AU570555B2 (en) |
| CA (1) | CA1241918A (en) |
| DK (1) | DK178285A (en) |
| IL (1) | IL74954A (en) |
| NZ (1) | NZ211835A (en) |
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Families Citing this family (25)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA1291036C (en) * | 1986-04-23 | 1991-10-22 | Edwin I. Stoltz | Nasal administration of drugs |
| DE3640544A1 (en) * | 1986-11-27 | 1988-06-01 | Goedecke Ag | Norfenefrine-containing pharmaceutical formulation |
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| US5248493A (en) * | 1988-08-27 | 1993-09-28 | Fisons Plc | Pharmaceutical composition |
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| US2222976A (en) * | 1937-11-15 | 1940-11-26 | Sharp & Dohme Inc | Nasal drops |
| US2196322A (en) * | 1937-12-04 | 1940-04-09 | Squibb & Sons Inc | Pharmaceutical |
| BE556587A (en) * | 1957-01-31 | 1957-04-11 | ||
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| NL262354A (en) * | 1960-03-17 | |||
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| BE632504A (en) * | 1962-05-24 | |||
| BE629985A (en) * | 1962-11-29 | |||
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| US3608065A (en) * | 1969-09-11 | 1971-09-21 | Merck & Co Inc | Aerosol composition containing a vasoconstrictor |
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| BE786200A (en) * | 1971-07-13 | 1973-01-12 | Boehringer Sohn Ingelheim | INHALATION TREATMENT OF BRONCHIAL DISEASES |
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| US4175128A (en) * | 1979-01-03 | 1979-11-20 | Pfizer Inc. | Method for treating congestive heart failure |
| DE2903957A1 (en) * | 1979-02-02 | 1980-08-07 | Boehringer Sohn Ingelheim | AGENT FOR TREATING NASAL HYPERSECRETION |
| US4284648A (en) * | 1979-08-03 | 1981-08-18 | The University Of Kentucky Research Foundation | Nasal administration of propranolol |
-
1985
- 1985-01-28 US US06/695,491 patent/US4581225A/en not_active Expired - Fee Related
- 1985-04-10 PH PH32165A patent/PH21194A/en unknown
- 1985-04-17 CA CA000479316A patent/CA1241918A/en not_active Expired
- 1985-04-17 IL IL74954A patent/IL74954A/en unknown
- 1985-04-18 NZ NZ211835A patent/NZ211835A/en unknown
- 1985-04-22 DK DK178285A patent/DK178285A/en not_active Application Discontinuation
- 1985-04-23 AU AU41616/85A patent/AU570555B2/en not_active Ceased
- 1985-04-24 EP EP85302850A patent/EP0160501A3/en not_active Withdrawn
Also Published As
| Publication number | Publication date |
|---|---|
| NZ211835A (en) | 1988-02-12 |
| AU4161685A (en) | 1985-10-31 |
| DK178285D0 (en) | 1985-04-22 |
| IL74954A (en) | 1988-05-31 |
| EP0160501A3 (en) | 1986-12-30 |
| EP0160501A2 (en) | 1985-11-06 |
| US4581225A (en) | 1986-04-08 |
| DK178285A (en) | 1985-10-26 |
| AU570555B2 (en) | 1988-03-17 |
| PH21194A (en) | 1987-08-19 |
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| MKEX | Expiry |