JPS63238018A - Pharmaceutical composition - 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 The present invention relates to pharmaceutical compositions, methods of making them, and methods of treatment using them.

GB 2022078 discloses a number of pyranoquinolines which may be used, among other things, to treat reversible airway obstruction. These compounds are described as being administered by esophageal administration or by inhalation. British Patent Application No. 2157291 describes one of these pyranoquinolines, known as nedo-cromil sodium (which is 9-ethyl-6,9-dihydro-4,6-dioxo-l).
O-propyl-4H-pyrano(3,2-g)quinoline-
Also disclosed are pressurized aerosol compositions of the potassium salt of 2,8-dicarboxylic acid for treating reversible airway obstruction.

Generally, the pyranoquinoline compounds disclosed in the above-mentioned documents are extremely polar hydrophilic molecules.

As such, they are unlikely to be absorbed sufficiently through the skin to provide therapeutic levels of the compound in the subepithelial tissue.

However, surprisingly, the present inventors have now discovered that 9-ethyl-6,9-dihydro-4,6-dioxo-lO-propyl-4H-pyrano (3,2-g)
It has been discovered that compositions containing quinoline-2,8-dicarboxylic acid or a pharmaceutically acceptable derivative thereof are effective in treating certain dermatological disorders when applied topically to the skin.

According to the invention, 9-ethyl-6,9-
dihydro-4,6-dioxo-IO-propyl-4H-
comprising pyrano(3,2-g)quinoline-2,8-dicarboxylic acid or a pharmaceutically acceptable derivative thereof in admixture with a pharmaceutically acceptable adjuvant or excipient; Pharmaceutical compositions are provided that are suitable for administration, but not for oral administration or for administration to the eye of a patient.

Pharmaceutically acceptable derivatives of the active ingredients include pharmaceutically acceptable metal ion salts, such as alkali metal salts, such as di-sodium and di-potassium salts, and alkaline earth metal salts, such as calcium and magnesium salts. Included. Particularly preferred is the disodium salt commonly known as nedocromil sodium.

The composition is 0.5-20% w/w, preferably 1.0-20% w/w.
It may contain 10% w/w of active ingredient, for example 4% w/w.

Preferably, the composition is a cream. The cream may be a water-in-oil cream or, more preferably, an oil-in-water cream.

The cream preferably contains one or more emulsifiers. Suitable emulsifiers for oil-in-water creams include sodium, potassium, ammonium and triethanolamine soaps; polysorbates; and cationic, anionic and nonionic emulsifying waxes. Suitable emulsifiers for water-in-oil creams include calcium soaps, wool fat, wool alcohol, beeswax, and certain sorbitan esters.

Creams generally contain suitable pharmaceutically acceptable preservatives or sterilizing agents in effective proportions. Examples of preservatives that can be used are chlorbutol, chlorocresol, methyl p-hydroxybenzoate (alone or in combination with propyl p-hydroxybenzoate) and thimerosal.

The preservative may be present at a level of about 0.05-1.0% w/w, more preferably about 0.1-0.5%, such as 0.2%.

The cream has a pH of 3.0 to 7.0, preferably 4.0.
A pH of 1 to 6.5, preferably a pH of 5.0 to 6.0
It may be buffered at

Therefore, according to a preferred aspect of the present invention, 3.0 to 7.0
buffered at a pH of An oil-in-water pharmaceutical cream is provided.

The oil phase of oil-in-water creams preferably consists of liquid paraffin. The oil phase preferably contains one or more emulsifiers, such as long chain alcohols such as cetostearyl alcohol,
or fatty acid esters, such as self-emulsifying glyceryl monostearate. The oil phase may contain one or more emollients, such as isopropyl myristate, and one or more additional surfactants, such as one or more cetomacrogol ethers. The oil phase preferably constitutes 20-40% W/W of the cream.

The aqueous phase may contain a buffer, such as a salt of a weak acid.

Suitable acids include carboxylic acids such as acetic acid and especially citric acid. Suitable salts include alkali metal salts,
For example, sodium or potassium salts are included.

The aqueous phase may also contain one or more bactericidal and/or fungicidal preservatives, such as potassium sorbate and methyl hydroxybenzoate.

Compositions according to the invention may be formulated as ointments, lotions or salves or sprays.

For ointments, the active ingredient is preferably finely divided and dispersed in a wax, fat, protein or paraffin base, preferably a liquid paraffin base. The ointment base may include liquid paraffin, solid paraffin and wool fat.

A large proportion (e.g. 70-90% W/W) of white or yellow liquid paraffin and optionally a small proportion of liquid paraffin (5-15% W/W) and solid paraffin (0-1
Preferably, an ointment containing 2% w/v) is used.

The ointment may also contain other liquid ingredients to improve the consistency of the base, provide a solvent for the active ingredient so that it can be sterile filtered, and/or alter the rate of release of the active ingredient from the base. For example, it may contain water or polyethylene glycol.

Lotions and liniments preferably consist of a solution or dispersion of the active ingredient in an aqueous or oily base. Suitable preservatives may also be included in the composition. Thickeners may be incorporated into the aqueous base if a paste, gel or emulsion is desired. Suitable thickening agents include crosslinked polymers, soluble cellulose derivatives and polyvinyl alcohol.

Spraying agents may contain two or more components intimately mixed in finely divided powder form. Alternatively, the active ingredient may be applied to the surface of a solid support as a solution or suspension in a liquid carrier and the coated particles dried. Examples of solid carriers that are normally sterilized include talc, starch, lactose, zinc oxide, light kaolin, and calcium carbonate.

The solid particles of the active ingredient, e.g. in suspension or dispersion,
or when present in powder compositions, their average particle size is 0. Preferably, it is in the range of 10 to 10 micrometers.

The compositions according to the invention can be prepared by mixing the ingredients, for example by dry mixing, or by grinding the solid ingredients together, or by emulsifying an aqueous solution of the active ingredient with a suitable oil base. . The final pH of the solution can be adjusted by adding the appropriate amount of acid or base.

Cream dissolve the active ingredient in buffered water at the desired pn and homogenizer 9 at about 40-90°C.
The solution can be made by adding the solution to the molten oil phase components at a temperature of . After homogenization and cooling, the cream may be filled into suitable containers, such as tubes.

The composition is preferably administered to the patient's skin by simply applying or spreading the cream onto the skin affected or likely to be affected.

The frequency of application of the composition will depend on the severity of the disorder to be treated and the area of skin involved.

Repeated applications may be made at intervals during the day, for example 1 to 6 times, preferably 2 times per day. The composition may be applied prophylactically, but is more commonly applied to already affected areas.

The compositions can be used in the treatment of various dermatological disorders in mammals, particularly humans, cats, dogs and horses, such as conditions involving cutaneous mast cell and/or delayed (cellular) hypersensitivity reactions and/or inflammation. It will be done.

The composition is particularly useful for treating atopic eczema in humans.

Other specific conditions in humans and other animals that can be mapped include contact hypersensitivity, such as contact hypersensitivity to chromium, nickel or antibiotics; drug eruptions; psoriasis; dermatitis; aphthous ulcers; Behcet's syndrome ;
urticaria; pigmented urticaria; ulcers in Crohn's disease; pyoderma gangrene; chronic skin ulcers; burns: bee and wasp stings; herpes infections; and dermatological disorders, such as systemic sclerosis. (also known as systemic scleroderma), morphia (also known as localized or localized scleroderma) and cutaneous nodular fibrous hyperplasia with excessive fibrosis (also known as dermatofibroma). ), etc.

Therefore, according to a further aspect of the present invention, atopic eczema, contact hypersensitivity, drug eruption, psoriatic hemorrhoids, dermatitis, aphthous ulcers, Patchett's syndrome, eczema, urticaria, urticaria pigmentosa, Crohn's disease ulcers, pyoderma gangrenosum, chronic skin ulcers, burns,
A therapeutically effective amount of 9-ethyl-6,9-dihydro on the skin of a patient with a dermatological disorder selected from the group consisting of bee and wasp stings, herpes infections, and dermatological disorders with excessive fibrosis. -4,6-dioxo-
A method of treating the aforementioned dermatological disorders is provided comprising topical administration of 10-propyl-4H-pyrano(3,2-g)quinoline-2,8-dicarboxylic acid or a pharmaceutically acceptable derivative thereof.

The amount of active substance administered will, of course, vary depending on the condition to be treated, the animal or patient to be treated, the particular derivative used and the mode of administration. However, in general the active substance should be added to about 1 kg per kg of animal body weight.
Satisfactory results can be obtained with doses of ~100 mg, preferably 10-75 mg. The indicative daily dose for humans is 11119-3500+++9, preferably 1 mg-1500 mg, more preferably l++
+g~600mg te, and 1~6 g/day
It may also be administered in divided doses. As is usual when treating skin conditions locally, for example with creams,
Adjusting the dosage is difficult and will generally depend on the size and condition of the area to be treated.

The present invention will be illustrated by the following examples, but the invention is not limited thereto.

Example 1 Oil-in-water cream component Oil phase %
w/v glyceryl monostearate BP 4
．． Q Cetostearyl alcohol BP 4.9
Liquid paraffin BP 10.0 Isopropyl myristate BP 5. QCre
mophor A6' 2
．． 0Cremophor A25*2.0 Propyl hydroxybenzoate BP O, 1 Aqueous phase methyl hydroxybenzoate BP O, 1 Potassium sorbate BP O, 2 Purified water B
P (low metal) 67.22 Acidic Sodium Citrate BP 1.3 Sodium Hydroxide BP O,08 Active Ingredients: 4
．． 0 Sodium 9-ethyl-6,9-dihydro-4,6-dioxo-10-propyl-4H-pyrano (3,2-g)
Quinoline-2,8-dicarboxylate 11Cremo
phor A6 and Cremophor A25 are trademarks.

Method The oil phase components are placed in a mixing pole and melted with stirring at 60-70°C.

The active ingredient is added to the buffered aqueous phase and dissolved with gentle heating, and the warm aqueous phase is then added to the oil phase with vigorous stirring. After addition and homogenization are complete, the mixture is allowed to cool with gentle stirring before filling into 20 mQ tubes at ambient temperature.

Example 2 Oil-in-water cream component Oil phase %
w/w Glyceryl Monostearate BP 4.
0 Cetostearyl Alcohol BP 4.0 Liquid Paraffin BP 15.0 Cre
mophor A6° 2.0
Cremophor A25'
2.0 Propyl hydroxybenzoate BP 0
．． 1 aqueous phase methyl hydroxybenzoate BP 0.1 potassium sorbate BP O, 2 purified water B
P (low metal) 67.22 Acidic Sodium Citrate BP 1.3 Sodium Hydroxide BP 0.08 Active Ingredients: 4.
.

Sodium 9-ethyl-6,9-dihydro-4,6-dioxo-IO-propyl-4H-pyrano (3,2-g)
Quinoline-2,8-dicarboxylate “Cremop”
hor A(3) and Cremophor A25 are trademarks.

Method This composition was prepared by the method of Example 1 and also exhibited improved storage properties.

Example 3 Ointment ingredients %
w/w liquid paraffin BP 1
0 Wool fat BP IQ White liquid paraffin BP 7Q Active ingredient = IO Sodium 9-ethyl-6,9-dihydro-4,6-dioxo-lO-propyl-4H-pyrano (3,2-g)
Quinoline-2,8-dicarboxylate Process It is prepared by dispersing the finely divided active ingredient in a molten mixture of the other ingredients in a mixing pole at 60-700C. After homogenization, the mixture is allowed to cool and then filled into 20 mQ tubes at ambient temperature.

Example 4 Oil-based lotion ingredients %
w/w peanut oil 85 Active ingredients: 15 Sodium 9-ethyl-6,9-dihydro-4,6-dioxo-lO-propyl-4H-pyrano (3,2-g)
Quinoline-2,8-dicarboxylate Method It is prepared by dispersing the finely divided active ingredient in oil.

Example 5 Spraying agent component %w
/w Zinc oxide 25 Purified talc 10 Sterilizable corn starch 55 Active ingredients: lO Sodium 9-ethyl-6,9-dihydro-4,6-dioxo-lO-propyl-4H-pyrano (3,2-g)
Quinoline-2,8-dicarboxylate Process It is prepared by grinding the various ingredients together.

Example 6 Skin Penetration Measurement Penetration of the active ingredient through hairless mouse and human skin was demonstrated by the following tests on various compositions: Hairless mice of either sex, aged 8-12 weeks, were subjected to cervical dislocation. The skin was delaminated and the dorsal skin was excised and the subcutaneous fat was removed with minimal manipulation. All human epidermal membranes (epidermis + dermis)
Immerse the skin in water for 30 seconds at 60°C, remove the epidermis using blunt forceps, and gently tease it off.
ng off). Care is taken to ensure that manipulation of this membrane is minimal. The sample was then mounted epidermal side up in a glass horizontal diffusion cell, the donor chamber was secured in place, and tightened. The receiving medium was 50% aqueous ethanol (V/V
), and the cell was placed in a constant temperature water bath at 37°C.

The test composition was applied evenly to the epidermal side of the sample. After a certain period of time, the receiving medium was removed, filtered and analyzed for active ingredients by high performance liquid chromatography (HPLC).

Claims (1)

[Claims] 1) 9-ethyl-6,9-dihydro-4 as an active ingredient
,6-dioxo-10-propyl-4H-pyrano(3,
2-g) comprising quinoline-2,8-dicarboxylic acid or a pharmaceutically acceptable derivative thereof in admixture with a pharmaceutically acceptable adjuvant or excipient and suitable for topical administration to the skin of a patient; A pharmaceutical composition that is suitable for oral administration or for administration to the eye of a patient. 2) Claim 1 wherein the active ingredient is nedocromil sodium
Compositions as described. 3) A composition according to claim 1 or 2 containing 0.5-20% w/w of active ingredient. 4) The composition according to any one of claims 1 to 3, which is a cream. 5) The composition according to claim 4, which is an oil-in-water cream. 6) The composition according to claim 4 or 5, having a pH of 3.0 to 7.0. 7) A composition according to claim 1 in the form of an ointment. 8) A composition according to claim 1 in the form of a liniment or lotion. 9) A composition according to claim 1 in the form of a spray. 10) Atopic eczema, contact hypersensitivity, drug eruption, psoriasis, dermatitis, aphthous ulcer, Behçet syndrome, pemphigus, urticaria, urticaria pigmentosa, Crohn's disease ulcer, pyoderma gangrenosum,
A therapeutically effective amount of 9-ethyl-9-ethyl- 6,9-dihydro-
4,6-dioxo-10-propyl-4H-pyrano(3
, 2-g) A method for treating the above-mentioned dermatological disorders comprising topical administration of quinoline-2,8-dicarboxylic acid or a pharmaceutically acceptable derivative thereof.