NO781813L - PHARMACEUTICAL PREPARATION AND METHOD OF PREPARATION - Google Patents

Description

The present invention relates to a pharmaceutical preparation and method for its preparation.

Sulfasalazine, i.e. 4-hydroxy-4'-(pyrid-2-ylsulfamoyl)-azobenzene-3-carboxylic acid, has been widely used in the treatment of disorders of the digestive tract in mammals, i.e. in humans and dogs, but the agent has the disadvantage is that it causes nausea, skin reactions and haematological complications including neutropenia, thrombocytopenia and haemolysis. Aminosalicylic acids and their pharmaceutically acceptable derivatives (hereafter generally referred to as ASA), i.e. their salts and esters, have likewise been used in mammals, but not for the same disorders as sulfsalazine. ASA also has the disadvantage that there are unwanted side effects. It has now surprisingly been shown that the side effects for sulfasalazine and for ASA can be reduced by using certain disodium chromium glycate-like compounds together with sulfasalazine or ASA. The combinations are also more effective in certain mammals than the individual components.

According to the invention, a pharmaceutical preparation is therefore provided which consists of a compound which has sodium chromium glycate-like activity, as active ingredient, together with sulfasalazine or ASA.

A compound having sodium chromium glycate-like activity is capable of inhibiting the release of pharmacological mediators resulting from the in vivo combination of certain types of antibody and specific antigen, e.g. the combination of reagin antibody and specific antigen (see Ex. 27 of British Patent No. 1,292,601 for the rat passive cutaneous anaphylaxis test).

The active ingredients can be characterized by the following biological tests and their results.

The compound is first tested in the rat passive cutaneous anaphylaxis test. If the preparation does not show a significant inhibition of allergic rashes at 20 mg/kg intraperitoneally (i.p.) or intravenously (i.v.) in this test, the activity is usually too low. Various other biological tests can be used to show that the preparation exhibits its anti-allergic activity as an inhibitor in the release of mediators of anaphylaxis, rather than as e.g. an end organ antagonist or anti-cholinergic or adenyl cyclase stimulator. Therefore, tests to see if the compound antagonizes the action of histamine, serotonin, acetylcholine and slow-reacting substance of anaphylaxis (SRSA), i.e. if the preparation is an end-organ antagonist for the mediators, can be used. Such samples are well known. Active ingredients according to the invention are not end-organ antagonists.

Specific groups of active ingredients are found among chromium-2-carboxylic acids and suitable derivatives thereof, e.g. those described in British Patent Nos. 1,368,243, 1,144,905, 1,230,087 and West German Patent No. 2,553,688. Other active ingredients can be found among xanthones, e.g. in Belgian Patent Nos. 759,292 and 787,843 and Dutch Patent Nos. 72,09622 and 73,06958; among the compounds in Belgian Patent No. 809,935; among nitroindanions, e.g. in Belgian Patent No. 792,867; among phenanthrolines, e.g. in Belgian Patent No. 773,200; among aza-purines, e.g. in Belgian Patent No. 776,683; oxazoles, e.g.

in West German interpretation document no. 2,459,380; flavones, e.g. in Belgian Patent No. 823,875 and oxamic acids in West German Patent No. 2,360,193 and US Patent No. 4,038,398..

Particularly preferred are chromones and chromone-like compounds in British Patent Nos. 1,144,905 and 1,230,087 and West German Patent No. 2,553,688. More specifically, 1,3-bis(2-carboxychromon-5-yloxy)propan-2-ol or a pharmaceutically acceptable derivative, i.e., a salt such as the disodium salt thereof, is preferred; the latter compound is commonly known as sodium cromoglycate or cromolyn sodium. André preferred compounds which may be mentioned are 6,7,8,9-tetrahydro-4-oxo-10-propyl-4H-naphtho[2,3-b]pyran-2-carboxylic acid, 5-(2-hydroxyprop-oxy )-8-propylchromone-2-carboxylic acid, 6,7,8,9-tetrahydro-5-hydroxy-4-oxo-10-propyl-4H-naphtho[2,3-b]pyran-2-carboxylic acid and pharmaceutically acceptable derivatives thereof.

Pharmaceutically acceptable derivatives of the above-mentioned chromium-one-2-carboxylic acid include pharmaceutically acceptable salts, esters and amides of the 2-carboxylic acid group. Suitable salts include ammonium, alkali metal (e.g. sodium, potassium and lithium) salts and salts with suitable organic bases, e.g. salt with

>hydroxylamine, lower alkylamines, such as methylamine or ethylamine with substituted lower alkylamines, e.g. hydroxy-substituted alkylamines, such as tris(hydroxymethyl)methylamine, or with simple monocyclic nitrogen heterocyclic compounds, e.g. piperidine and morpholine. Suitable esters include simple lower alkyl esters, e.g. ethyl esters, esters obtained from alcohols containing basic groups, e.g. di-lower-alkyl-amino-substituted alkanols, such as 3-(diethylamino)-ethyl ester, and acyloxyalkyl esters, e.g. lower acyloxy lower alkyl ester, such as pivaloyloxy methyl ester, or a bis ester obtained from a dihydroxy compound, e.g. a di(hydroxy-lower alkyl) ether, e.g. bis-2-oxapropane-1,3-diyl ester. The pharmaceutically acceptable salts of basic esters, e.g. hydrochloride, can also be used.

Preparations containing only one active ingredient are preferred.

From the group of compounds referred to as ASA, it is preferred to use 4-aminosalicylic acid or 5-aminosalicylic acid, or a pharmaceutically acceptable salt or ester thereof. Specific salts which may be mentioned include sodium, potassium and calcium salts. A specific ester that can be mentioned is phenyl ester.

The ratio between sulfasalazine or ASA to the active ingredient will vary with the particular active ingredient used, ASA or sulfasalazine, the specific disorders to be treated and the individual patient. However, for specific active ingredients, the following ratios have been shown to be suitable, where the parts are parts by weight of active ingredient calculated as the sodium salt:

The daily dosage of sulfasalazine for humans is

for most purposes up to 12 g, preferably 1-8 g and most preferred is 2-4 g. Sulfasalazine can be added from 1-4 times per day.

The daily dosage of ASA (calculated as free acid) for humans is for most purposes up to 5 g, preferably 0.4-3.5 g and most preferably 0.8^-2.0 g. ASA can be administered from 1-4 times per day.

Each dose of sulfasalazine or ASA may comprise one or more unit dosages, i.e. tablets or capsules.

The daily dose of the active ingredient will naturally vary according to which particular active ingredient is used. For specifically active ingredients, however, it has been shown that the following daily doses (calculated as the sodium salt) are suitable:

For use in humans in a dosage form suitable for single administration, i.e. in the form of unit dosages, the amount of active ingredient (calculated as the sodium salt) and of sulfasalazine or ASA (calculated as free acid) amounts to the amounts indicated below:

(a) Sulfasalazine

Up to 12 g, preferably 250 mg to 8 g and most preferably 500 mg to 4 g.

(b) ASA

Up to 5 g, preferably 0.1-3.5 g and most preferably 0.2-2.0 g.

(c) 1, 3- bis-(2- carboxychromon-5- yloxy) propan- 2-ol

0.1-500 mg, preferably 1-200 mg and most preferably 1-50 mg. Preparations in the form of unit dosages comprising up to 100 mg are particularly preferred, as higher unit doses tend to cause an increase in irritation in the digestive tract.

(d) 5-( 2- hydroxypropoxy)- 8- propylchromone- 2- carboxylic acid

25 mg to 2.5 g, preferably 25-500 mg..

(e) 6, 7, 8, 9- tetrahydro- 4- oxo- 10- propyl- 4H- naphtho[ 2, 3-b] pyran- 2-carboxylic acid or 6, 7, 8, 9- tetrahydro- 5- hydroxy - 4- oxo- 10-propyl- 4H- naphtho[ 2, 3-b] pyran- 2- carboxylic acid

0.5-200 mg, preferably 0.5-100 mg.

Specific disorders that can be successfully treated with the preparation according to the invention include Crohn's disease, atrophic gastritis, ulcerative colitis, proctitis, distal proctocolitis, blunt proctitis, disease in the abdominal cavity, local ileitis, peptic ulceration, gastrointestinal allergy and irritable bowel syndrome.

According to the invention, a method is also provided for the treatment of disorders in the digestive system which comprises the administration of a preparation according to the invention to individual mammals, e.g. people who suffer from this. Administration is preferably by mouth or rectum.

According to the invention, a method for the treatment of disorders in the digestive system is also provided which comprises subsequent or simultaneous administration of the active ingredient and sulfasalazine or ASA to the individual mammals, e.g. people who have such a disorder.

The active ingredient is preferably added in such a way that it is available in the digestive tract, i.e. in the large intestine, at the same time as sulfasalazine or ASA. Optionally, the active ingredient can be administered before or after sulfasalazine or ASA.

When subsequent or simultaneous administration of active ingredient and sulfasalazine or ASA is used, the proportions and dosages are as described above with regard to the mixtures.

The present invention therefore also provides a pharmaceutical package comprising at least one dose of the active ingredient and at least one dose of sulfasalazine or ASA. The doses are preferably unit dosages, and they are preferably arranged in a package in a particular order with written or printed instructions, so that the instructions and the packaging method provide guidance with regard to taking the unit dose of the active ingredient and the unit dose of sulfasalazine or ASA in a specific order or together, i.e. a dose of the former together with a dose of the latter. The package is preferably a sealed package and may comprise a tube or box in which the unit doses are packed. The unit doses are preferably suitable for oral intake and preferably contain the doses of the active ingredient

del and sulfasalazine or ASA in the conditions mentioned above.

In order to prepare suitable preparations of the active ingredient and sulfasalazine or ASA, either individually or as a mixture, the ingredients are processed together with organic or inorganic pharmaceutically acceptable additives or diluents. Examples of such additives are: For tablets and dragées: Binders, e.g. cellulosic materials, such as microcrystalline cellulose and methylcellulose; means of distribution, e.g. starches, such as corn starch; stabilizers, such as hydrolysis of the active ingredient; flavoring agents, e.g. sugars, such as lactose; fillers; stearates and inorganic diluents, such as talc.

For syrups, suspensions and dispersions: A liquid carrier in which the active ingredient can be dissolved or suspended, e.g. water and suspending agents, i.e. cellulose derivatives, gums, etc.

For hard or soft capsules: Diluents, e.g. lactose; lubricants, e.g. stearates; inorganic materials, such as silicon oxide or talc, and stabilizing and dispersing agents.

For suppositories: Natural or hardened oils and waxes. A large number of emulsifying bases are available and are suitable for use in suppositories. These include "Witepsol" bases consisting of hydrogenated triglycerides of lauric acid with added monoglycerides and "Massupol" bases consisting of glyceryl esters of lauric acid with a very small amount of glyceryl monostearate.

For enemas: Water, sodium chloride, buffers, etc.

Preparations that can be administered orally or as enemas, e.g. retention enemas, preferred.

The preparation may also contain additional additives, e.g. can a preparation to be used in tablets contain lubricants and lubricants that facilitate tablet production, e.g. magnesium stearate or wetting agents that facilitate granulation, e.g. dioctyl sodium sulfosuccinate. The preparation may also, if desired, contain a pharmaceutically acceptable dye and may be coated with a conventional film using the techniques

which is used for sugar coating.

If desired, the preparation, or one or more of the preparation's components, can be prepared so that a controlled or restrained ejaculation is obtained, e.g. by coating some or all of the drug particles or granules thereof, with e.g. sucrose, and of a. size up to 2 mm in diameter, with a layer of e.g. beeswax, Carnuba wax, stearic or palmitic acids, cetyl alcohol or similar substances which can be assumed to dissolve slowly, or which act as semi-permeable membranes, through which the medicine can diffuse when the preparation is digested. The preparation may contain drug particles or granules that are not coated together with particles or granules that have one or more coatings of a coating medium, or they may be in the form of a capsule containing the particles or granules, or possibly a tablet that will require other additives, e.g. lubricants or lubricants. The mixture can be supplied as a preparation that is coated in such a way that it is absorbed at a specific place in the intestinal tract. This can be provided by coating the tablet with a continuous film of a material which is resistant to and impermeable,

for secretions in the stomach, but which is sensitive to secretions in the intestine. Typical film materials are shellac and its derivatives, and cellulose acetate phthalate.

The active ingredient and sulfasalazine or ASA can,

if desired, used in specific form, i.e. have a mass-average diameter of less than 10 microns.

The active ingredient and sulfasalazine or ASA can also be prepared as an aqueous solution, e.g. a water-chloroform solution (400:1) containing from 0.001-10.0% by weight of the total amount of the active ingredient, and sulfasalazine or ASA.

Preparations containing disodium chromium glycate are preferred.

The preparations preferably contain from 0.1-85% by weight

of each active ingredient, and preferably from 0.1-10% by weight.

The invention is illustrated, but not limited, by the following examples.

Example 1 - (Retention enema)

Composition:

0.2% by weight disodium cromoglycate and 0.4% sulfasalazine

in "USP Isotonic Vehicle Buffer" pH 7.4. Unit dose 100 ml.

Packed in a flexible PVC package and sterilized by heating in a balanced autoclave at 115-116°C for 30 min.

Example 2 .- Granulate

Composition:

An appropriate amount of disodium cromoglycate and sulfasalazine was mixed to give a dose of respectively 0.5 and 1.0 g. Sufficient water to produce a granular mass was sprayed into a. suitable mixer with cooling jacket to keep the temperature below 35°C.

The wet pulp was passed through an 8 mesh bed on an oscillating granulator. The granulate was dried in a "fluidised bed" dryer at 70°C. When the pulp was dry, it was passed through a 16 mesh bed on an oscillating granulator.

The granules can be filled loosely in casings or capsules.

Claims (14)

1. Process for the production of a pharmaceutical preparation, characterized by using a compound that has a sodium cromoglycate-like activity as active ingredient, together with sulfasalazine or an ASA. 2. Method according to claim 1, characterized in that the active ingredient is 1,3-bis(2-carboxychromon-5-yloxy)propan-2-ol or a pharmaceutically acceptable salt thereof. 3. Method according to claim 2, characterized in that the active ingredient is sodium cromoglycate. ' 4. Method according to any one of the preceding claims, characterized in that the ASA is 4-amiriosalicylic acid or 5-aminosalicylic acid, or a pharmaceutically acceptable salt or ester thereof. 5. Method according to any one of claims 1-3, characterized in that the preparation comprises sulfasalazine. 6. Method according to claim 1, characterized in that the preparation comprises from 0.5-80,000 parts by weight of sulfasalazine for each part by weight of 1,3-bis(2-carboxychromon-5-yloxy)propan-2-ol, or a pharmaceutically acceptable salt thereof, calculated as the sodium salt. 7. Method according to claim 1, characterized in that the preparation comprises from 0.8-35,000 parts by weight of ASA for each part by weight of 1,3-bis(2-carboxychromon-5-yloxy)propan-2-ol, or a pharmaceutically acceptable salt thereof, calculated on the sodium salt. 8. Method according to claim 1, characterized in that the preparation comprises from 250 mg to 8 g of sulfasalazine in a dosage form suitable for single administration. 9. Method according to claim 1, characterized in that it comprises from 0.1-3.5 g of ASA in a form suitable for administration at once. 10. Method according to claim 1, characterized in that the preparation comprises from 0.1-500 mg of 1,3-bis(2-carboxychromon-5-yloxy)propan-2-ol, or a pharmaceutically acceptable salt thereof, calculated as the sodium salt in a form suitable for one-time administration. 11. Method according to any one of the preceding claims, characterized in that the preparation has a shape that makes it suitable for taking in by mouth. 12. Method according to any one of claims 1-10, characterized in that the preparation is in the form of a suppository or an enema. 13. Method according to any one of the preceding claims, characterized in that the preparation, or one or more of the preparation's components, is prepared so that a gradual release is obtained. 14. Pharmaceutical package, characterized in that it contains at least one dose of active ingredient and at least one dose of sulfasalazine or ASA.