KR820000110B1 - Improvements in or relating to organic compounds ergot peptide composition - Google Patents

Abstract

Ergotpetide alkaloids I(I; R1 = H or halogen; R2 = H C1-4 alkyl; R3 = iso-Pr, sec-Bu or iso-Bu; R4 = Me, Et, or iso-Pr; R5 = H, R6 = H or MeO, or R3 = benyzyl, and R5 forms a bond with R6) are prepd. and used for nasal and pulmonary treatment of respiratory disorders. The compns. contain 0.5-5 % active ingredients which are applicable 1-5 times daily in 0.1-10 mg dosages in forms of aerosols, more sprays or drops and powd. for inhalation. For example, aerosols comprised dihydroergotamine methane-sulfonate 25, EtOH (94%) 520, H2O (distd.) 120, Trigen 335 mg. The active ingredient was dissolved in the alc.-H2O mixt. by stirring and dosaged into aerosol flasks.

Description

Pharmaceutical compositions containing ergot peptide alkaloids

The present invention relates to an ergot peptide alkaloid which is a structural formula (I) compound capable of binding to a pharmaceutically toxic carrier or diluent applied to konape.

From above

(Iii) R ₁ is hydrogen or halogen R ₆ is hydrogen or methoxy and is a single bond.

R ₂ is hydrogen or alkyl having 1 to 4 carbon atoms or

R ₃ is isopropyl, secondary-butyl or isobutyl, R ₃ is benzyl

R ₄ is methyl, ethyl or isopropyl R ₄ is methyl

R ₅ is hydrogen, single bond and R ₅ is hydrogen or methoxy

Satisfactory formulations can be made in conventional manner, with the formulations being different depending on the active agent, carrier, diluent or nasal or lung used. The nasal composition consists of an aqueous solution containing a viscosity increasing agent such as methyl cellulose. Such liquid compositions are made in a container or jetting agent suitable for dropwise addition. The compound is solid and has a particle diameter of up to 10 mu, preferably from 0.5 to 5 mu. Lactose as a carrier or diluent is 87.5 to 97.5% in hard capsules that can be administered to the nose through an air inhaler.

The composition may be in a pharmaceutically toxic jetting agent, such as a halogenated hydrocarbon, or in a pressurized container. The container can hold 0.1 to 5 mg of compound. The container is an aerosol. In aerosols for nasal and fesal administration, the viscosity of the composition is 5 to 40 centipoise.

The present invention provides a compound of formula (I) as an active agent for the administration of naphage.

The container is a conventional one for nasal administration. In general, containers for dry jetting and liquid jetting are as follows.

a) aerosol for inhalation

b) Liquid ejection vessels and dropping vessels for nasal administration

c) powder spray container for inhalation

The container should be suitable for administering a unit dose of the active agent. A convenient one is a container for coadministration.

Various forms of containers or compositions will be described next.

1) Aerosol containers can be used as nebulizers.

For example, supersonic aerosol containers or pressurized gas jet bottles are preferred. Here, the active agent is present in solution or in suspension.

If a supersonic aerosol container is used, it is convenient for the active agent to be a solution. This solution is added to a solution containing sodium chloride and tonicity agent or acetate buffer by dissolving the active agent in a mixture of ethanol and water. The dose of active agent is conveniently in the range of 0.1 mg to 5 mg / ml. The water / ethanol mixture used as a solution is preferably 90:10, with a volume ratio of 98: 2 to 80:20 of water and ethanol. Other additives added for isotonic or buffering are 1% or less by weight of the total solution. Furthermore, stabilizers such as sodium pyrosulphite ascorbic acid or fragrances such as methanol can be added, which also have a weight percentage of the total solution of about 1%.

The same solution used for the supersonic aerosol container can be used when using a blow-out gas pressurized bottle. These solutions can be added to the pressure ejection gear as follows. Fluorinated or chlorinated hydrocarbons, e.g. trichlorofluoromethane (pregen 11),

Dichlorodifluoromethane (Prigen 12)

Trichlorotrifluoromethane (Prigen 113)

Or dichlorotetrafluoroethane (prigen 114)

Instead of a solution in a jet gas pressurized bottle, a suspension of the micronized active agent in a pressurized jet agent can be used. In this case, it is convenient to add an emulsifier such as Tween or polyethylene-glycol esters of fatty acids such as sorbitan monooleate. The dose of active agent is 1 to 10% by weight relative to the total volume of the suspension including the ejector and the dose of emulsifier is 0.1 to 1% by weight.

This aerosol is conveniently used for inhalation of the nose or inhalation of the lungs.

2) The composition for jetting or dropping into the nose consists of an active agent and water, an acetate buffer, an isotonic agent such as sodium chloride, a solubilizer such as auxiliary polyethylene glycol 400 such as nipacombine, and a viscosity increasing agent such as methyl cellulose. The solution can be contained in a nebulizer, a spray container, or a pipette for coadministration. The weight capacity of the active agent in this solution is 1 to 10% of the total solution and other additives is 0.1 to 1%.

Instead of solution, monohydric or polyhydric alcohols such as triethylene glycol / ethanol, polyethylene glycol 300-400 / ethanol, propylene glycol / ethanol or monohydric or polyhydric alcohols such as water / ethanol, water / polyethylene glycol 300-400 and water Suspensions of the active agent in the mixture can be used. Preferred doses of each of the compositions in the solvent mixture are described in Example 3. In the latter, the active agent has a weight percentage of 0.5 to 5% based on the total capacity. Moreover, 1% total amount of emulsifiers such as horse oil, paraffin oil or sorbitan monooleate is used to obtain the organic phase when producing the emulsion.

Each of these suspensions can be conveniently administered via a spray bottle or a plastic bottle, each of which is equipped with a nozzle device, by adding a blowing gas by the pressure wrapping method, and then activating the active agent in the solution that produces the suspension with the liquefied blowing gas.

3) For powder scattering of the nose and lungs, the active agent is used mixed with lactose when the particle diameter is less than 10 μ, ie 2 to 10 μ. The weight percentage of active agent and lactose is from 0.25: 12.5% to 99.75: 87.5%. The mixture can be filled by conventional methods, such as an air aspirator, by filling hard gelatine capsules weighing 20-40 mg per capsule.

The present invention also provides a method of administering a compound of formula (I) to the mucosa of the nose or lung of an animal.

In the formula (I) R ₂ is an alkyl group, in particular methyl or isopropyl. Halogen is fluorine, chlorine, bromine or urethra, especially bromine.

- 및 β- 디하이드로에르고 크립틴, 디하이드로 에르고코르닌인데 디하이드로에르고톡신, 브로모크립틴, 디하이드로 에르고타민 및 디하이드로에르고닌으로 알려진 혼합물의 형태로 사용되는 것이 바람직하다. 구조식(Ⅰ)화합물은 유리 염기 혹은 매탄올설포네이트, 알리에이트 및 타르레이트 같은 산부가염으로 사용된다.Preferred compounds of formula (I) are dihydroergocristine,

-And β-dihydroergo cryptin, dihydro ergocortin, which is preferably used in the form of a mixture known as dihydroergotoxin, bromocriptine, dihydro ergotamine and dihydroergonine. The compound of formula (I) is used as free base or as acid addition salts such as matanolsulfonate, allate and tarate.

The composition shows a significant peak in blood concentration when administered locally to the mucosa of the nasal lungs of rhesus monkeys anesthetized with fenclidine or a short initial time at the peak of blood concentration when administered 1-10 mg. The concentration of blood compounds can be measured by conventional radioimmunoassays in accordance with the principles of J. Rosenthaler and H. Munzer 32, 234 (1976).

Appropriate doses in this test are from 0.1 to 10 mg of the compound of formula (I) and may be administered from one to five times daily if necessary.

In the following examples all percentages are by weight unless otherwise indicated. Nipacombin has a mixing ratio of p-hydroxybenzoyl methyl ester and p-hydroxybenzoyl propyl ester at 67:33.

Tween 80 is a polyethylene (20) sorbitan monooleate (ICI, UK). Frigen 113 is trichloro trifluoroethane. Prigen 11/12/114 has a volume ratio of 25:50:25 of trichlorofluoromethane, dichlorodifluoromethane and dichlorotetrafluoroethane.

Example 1 Dihydroergotamine Solution Aerosol

Basic composition

Dihydroergotamine Methanesulfonate

Ethanol (94%)

Distilled water

Prigen 11/12/114

fair

Dihydroergotamine, ethanol and water are mixed to form a solution and filled into an aerosol bottle. Stop the bottle by aligning the outlet valve. Add the required pill volume through the valve.

This composition is suitable for nasal fetus administration.

Example 2 Dihydroergotamine Suspension Aerosol

Basic composition

Dihydroergotamine Methanesulfonate

Emulsifier:

Sorbitan monooleate or soy lecithin

Fregen 113

Prigen 11/12/114

fair

In the induction of cooling of the dihydroergotamine, pregen 113 is ground with an emulsifier in the presence of a small amount. If it is necessary to use polytrons, pregen 113 is further added to a homogeneous mixture. The mixture is continued to cool and fill into an aerosol bottle with stirring. Cap the bottle with the outlet valve in place. The required volume of blowing gas is added through the valve.

Example 3 Dihydroergotamine-2 Phase Aerosol Suspension

Basic composition

Dihydroergotamine Methanesulfonate

Sorbitan monooleate

Ethanol anhydride

Glycol

Prigen 11/12/114

fair

Dihydroergotamine, ethanol and water are mixed to form a solution and filled into an aerosol bottle. Stop the bottle by aligning the outlet valve. Add the required pill volume through the valve.

Example 4 Liquid Dispersion Container for Dihydroergotamine Nose

Basic composition

Dihydroergotamine Methanesulfonate

Nipacombine

Sodium acetate trihydrate

Glacial acetic acid

Methyl cellulose

Polyethylene Glyph 400

Recall 80

Twin Chlorohepidine Diacetate

Ethanol (94%)

water

fair

Mix the components except dihydroergotamine with water, add dihydroergotamine and add water again to complete the mixture. The resulting solution is isotonic with sodium chloride, mannitol or sorbitan if necessary and filled into the nebulizer.

Example 5 Dihydroergotamine Powder Dispersion Container

A mixture of lactose and fine dihydroergotamine methanesulfonate is filled into gelatin capsules.

For administration to the lungs, the capsules are filled in a conventional powder dispensing container for dosing. Administer when the contents of the capsule can be inhaled deeply.

The contents are sprayed into the nose with a rubber valve or other sprayer.

Example 6 Bromocriptine Suspension Aerosol

Basic composition

Bromocriptine Methanesulfonate

Soybean Oil Lecithin

Anhydrous ethanol

Fregen 113

Prigen 11/12/114

fair

A composition containing such a composition 90 can be prepared by a similar method as in Example 2.

Example 7 Liquid Dispersion for Bromocriptine Nasal Administration

Basic composition

Bromocriptine Methanesulfonate Mannitol

Ascorbic Acid Methyl Cellulose

Glacial acetic acid ethanol (94%)

Sodium acetate water

fair

A 14 ml bottle with a piston spreader is filled with the composition in a CO ₂ atmosphere.

The composition uses a suitable dose of dihydroergonin or dihydroergotoxin in place of the dihydroergotamine of Examples 1-5 or bromocriptine of Examples 6 and 7.

Claims (1)

0.25 to 12.5% by weight of at least one compound of formula (I) is dissolved, suspended or suspended in a pharmaceutically acceptable liquid carrier or diluent suitable for nasal administration, or finely powdered into a container for coadministration. A method for preparing an ergot peptide formulation for nasal administration, characterized in that

Wherein R ₁ is hydrogen or halogen, R ₂ is hydrogen or alkyl of 1 to 4 carbon atoms, (iii) R ₃ is isopropyl, secondary-butyl or isobutyl and R ₄ is methyl, ethyl or isopropyl R ₅ is hydrogen and R ₆ is hydrogen or methoxy or R ₅ and R ₆ together represent a single bond, or (ii) R ₃ is benzyl, R ₄ is methyl and R ₅ is hydrogen and R ₆ is hydrogen Or methoxy.