GB1570994A - Pharmaceutical formulation - Google Patents

Description

(54) PHARMACEUTICAL FORMULATION (71) We, FISONS LIMITED, a British Company, of Fison House, 9 Grosvenor Street, London WIX OAH, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- This invention relates to a novel formulation.

According to the invention we provide a pharmaceutical formulation comprising from 2 to 50 mg (determined as the free acid) of a compound of formula I,

in which R5 is hydrogen or hydroxy, or a pharmaceutically acceptable derivative thereof, in unit dosage form.

We prefer the formulation to be a tablet formulation comprising the compound of formula I, or the pharmaceutically acceptable derivative thereof, as active ingredient, in combination -with a lubricant and a diluent, the lubricant and diluent containing no material capable of causing an allergic reaction in an allergic patient.

The formulation preferably also contains a flow aid and/or a binder, the flow aid and/or the binder containing no material capable of causing an allergic reaction in an allergic patient.

The -material capable of causing an allergic reaction in the patient may be a material, which contains residual traces of an anti-biotic such as penicillin or may be a material containing an actually or potentially allergenic material.

Material which is not actually or potentially allergenic is material which will not result in increased hypersensitivity of the individual treated to the material. The material should not be capable of eliciting an immune response, either anti-body or cell mediated. The material should also not combine with protein to form a hapten carrier system and should not activate the complement pathways in formation of C5a or C3a.

We particularly prefer there to be no proteinaceous material in the formulation.

Examples of materials which should be excluded from the formulation are gelatin, starch, starch derivatives (e.g. sodium starch glycollate) and acacia. Materials which contain traces of protein because of their origin, e.g. lactose; or method of manufacture, e.g. maltose-dextrose combinations produced by enzyme treatment (e.g. as sold under the Trade Mark Emdex) should also be excluded from the formulation.

The formation of the tablet may comprise the steps of wet granulation, dry granulation, melting, moulding, enteric coating, film coating or formation into controlled release form. However we prefer to use a composition which can be compressed into a tablet directly without an intermediate, e.g. a wet or dry granulation, stage.

The flow aid may be, for example, purified talc or silicon dioxide and especially colloidal silicon dioxide having a mean particle size of about 12 mm.

The binder may be, for example polyvinylpyrrolidone or methyl cellulose.

The lubricant -may be, for example, stearic acid, a metallic stearate, a polyethylene glycol of molecular weight of 4,000 or more, or purified talc.

The diluent, which may also serve as disintegrant, may be microcrystalline cellulose, or a cellulose derivative, e.g. a cellulose ether such as methyl cellulose; or sodium bicarbonate or dibasic calcium phosphate. The formulation may also comprise a disintegrant as a entity separate from the diluent. When the disintegrant is a separate entity it should contain no material capable of causing an allergic reaction in an allergic patient.

The formulation may be made by dry mixing the active ingredient with the other ingredients, e.g. the flow aid, binder, lubricant and diluent/disintegrant, for example in a powder blending machine. The mixing may be carried out in two stages, the blend, or parts thereof, being sieved through an appropriate screen (e.g. 60 mesh, 250 micron) at the end of a first stage in order to disperse any persistant aggregates. The sieved powder may then be mixed further.

The resulting mixture may then be compressed in a tablet forming machine.

The active ingredient may be 6,7,8, 9 - tetrahydro - 4 - oxo - 10 - propyl - 4H naphtho[2,3-b]pyran-2-carboxylic acid and pharmaceutically acceptable derivatives thereof (collectively referred to herein as 'active ingredient B') or 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 (collectively referred to herein as 'active ingredient A'). We prefer the composition not to contain di- or tri- basic cations.

By pharmaceutically acceptable derivatives within the meaning of active ingredient A or B we mean 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. salts with hydroxylamine, lower alkylamines such as methylamine or ethylamine, with substituted lower alkylamines, e.g. hydroxy substituted alkylamines such as tris(hydroxy methyl)methylamine, or with simple monocyclic nitrogen heterocyclic compounds, e.g. piperidine or morpholine.

Suitable esters include simple lower alkyl esters, e.g. the ethyl ester, esters derived from alcohols containing basic groups e.g.

di-lower alkyl amino substituted alkanols such as the p-(diethoxyamino)-ethyl ester, and acyloxy alkyl esters, e.g. a lower acyllower alkyl ester such as the pivaloyloxymethyl ester, or a bis-ester derived from a dihydroxy compound, e.g. a di(hydroxy-lower alkyl) ether, e.g. the bis-2oxapropan-1,3-diyl ester. The pharmaceutically acceptable salts of the basic esters, e.g. the hydrochloride, may also be used.

We prefer to use as active ingredient A or B the free carboxylic acid or the sodium salt thereof. In particular we prefer to use the free carboxylic acid as it is more orally acceptable than the derivatives thereof.

We prefer the formulation to contain less than 50%, and preferably between about 0.5 and 18% by weight of active ingredient A or B. Unexpectedly even with very small proportions of active ingredient A or B we have found that a lubricant is highly desirable. We prefer the lubricant to comprise up to 4.00/,, and preferably 0.2 to 4.0%, by weight of the composition. We also prefer the composition to contain between about 0.1 and 5.0 /", e.g. about 0.5 /", by weight of the flow aid. We prefer the binder to comprise from about 0.5 to 5% by weight of the composition, and the diluent/disintegrant to comprise from about 80 to 99% by weight of the composition.

We prefer tablet formulations containing an active ingredient A to contain from 3 to 15%, and more preferably from 4 to 10% by weight of water as such formulations have advantageous flow and compression characteristics.

According to a further feature of our invention we provide a pharmaceutical formulation comprising from 2 to 12 mg (determined as the free acid) of an active ingredient A in unit dosage form. In particular we prefer a unit dosage form comprising from 3 to 12 mg (determined as the free acid) and more preferably from 3 to 6 mg (determined as the free acid) of an active ingredient A. Suitably unit dosage forms comprising 3, 6 or 12 mg (determined as free acid) of the active ingredient A may be used.

We also provide a pharmaceutical formulation comprising from 10 to 50 mg (determined as the free acid) of an active ingredient B in unit dosage form. In particular we prefer a unit dosage form comprising from 10 to 30 mg (determined as the free acid) of active ingredient B.

The unit dosages of this invention are advantageous in that they represent the dosage the patient is to take at any one time.

Thus the patient only has to take one unit dose (or possibly-two unit doses, depending on the patient's ability to swallow the larger unit doses) at any one time, thereby leading to consistent and convenient therapy through the elimination of dosage errors.

Dosages above a single dose of 20 mg of active ingredient A (determined as the free acid) or above 50 mg of active ingredient B (determined as the free acid) at any one time have a tendency to cause some stomach irritation in some patients and doses below 2 mg of active ingredient A (determined as the free acid) or below 10 mg of active ingredient B (determined as the free acid) tend to produce an increasing failure of the patient to respond therapeutically.

In addition to the active ingredient A or B the unit dosages may also contain (preferably a major proportion of) a pharmaceutically acceptable adjuvant, diluent or carrier. Examples of suitable adjuvants, diluents or carriers are: for tablets and drawees; microcrystalline cellulose, talc or stearic acid; for capsules, tartaric acid or stearic acid. The unit dosages may also be formulated in controlled release form.

We also provide a process for the production of unit dosage forms according to the invention, which comprises forming an active ingredient A or B, optionally in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, into discreet and separate units each of which comprises the required unit dosage. The forming into discreet units will normally be effected by filling an appropriate volume (or weight) of the finely divided or granulated active ingredient, optionally in combination with an adjuvant, diluent or carrier into a defined space, e.g. a capsule, or the die of a tabletting machine. Tablets according to the invention preferably have a diametral crushing strength of at least 1.5, and preferably from 3 to 7, kp Schleuniger (Dr.

K. Schleuniger and Co, Zurich, Switzerland). We also prefer that the tablets are such that when tested using the disintegration test apparatus of the United States Pharmacopoeia XIX, using water as the medium, they disintegrate in less than 30 minutes. We also prefer that the tablets have a low friability. In particular we prefer that, when 20 pre-dusted and weighed tablets are rotated in a Roche Friabilator drum (Shafer EGE, Wollish EG and Engel CE Journal of the American Pharmaceutical Association (1956) Vol 45 pages 114116) at 25 rpm for 8 minutes, and are then re-dusted, the tablet weight loss shall be less than 3%, and more preferably less than 1.

The unit dosages and other compositions of this invention are indicated for use in the treatment of allergic conditions, e.g.

asthma, (notably allergic asthma) and conditions of the gastrointestinal tract such as Crohn's disease, ulcerative colitis and proctitis. The unit dosages are also indicated for use in the treatment of so called 'intrinsic' asthma (in which no sensitivity to extrinsic antigen can be demonstrated). The unit dosages are also indicated for use in the treatment of hay fever, urticaria and eczema.

Pharmaceutical tablet formulations comprising in anti-allergic pyran-4-one having sodium cromoglycate like activity, in combination with a lubricant and a diluent, the lubricant and diluent containing no material capable of causing an allergic reaction in an allergic patient are described and claimed in our co-pending application No. 20984/76 Serial No. 1,570,993.

The invention is illustrated, but in no way limited by the following Examples.

Example 1 Tablet mg/tablet Micronised or milled 6,7,8,9- tetrahydro- 5 hydroxy - 4- oxo - 10 - propyl- 4H naphtho[2,3-b]pyran - 2 - carboxylic acid 3.0 Colloidal silicon dioxide 'Aerosil 200' (Aerosil is a Trade Mark) 0.5 Polyvinylpyrrolidone 'Plasdone' D29-32 (Plasdone is a Trade Mark) 2.0 Stearic acid 60 mesh 0.5 Microcrystalline cellulose 'Avicel PH 101' (Avicel is a Trade Mark) 94.0 Approximately 100.0 The micronised or milled 6,7,8,9tetrahydro - 5 - hydroxy - 4 - oxo - 10 propyl - 4H - naphtho[2,3 - bipyran - 2 carboxylic acid was mixed with the colloidal silicon dioxide, polyvinylpyrrolidone, stearic acid and the microcrystalline cellulose in a high speed powder blender.

The walls of the blender and its impeller blade were scrapped down with a spatula after about 5 minutes mixing and the mixing was then continued until a suitable degree of mixing had been achieved.

To improve the. flow and compression properties and to improve tablet stability on storage (with respect to crushing strength and disintegration time) the moisture content of the blend was controlled within the range 3-15% w/w, and preferably within the range 410% w/w.

The final mixture was then compressed in a tablet forming machine to a diametral crushing strength of 5 kp Schleuniger.

Example 2 Tablet mg/tablet 6,7,8,9 - Tetrahydro - 4 - oxo - 10 - propyl - 4H naphtho[2,3 - bipyran - 2- carboxylic acid micronised or milled 25.0 Sodium bicarbonate B.P. 75.0 Microcrystalline cellulose 'Avicel PH 101' 50.0 Methyl cellulose 20 B.P.C. (added as 5% aqueous solution) 1.5 Stearic acid 60 mesh 3.0 154.5 The 6,7,8,9 - tetrahydro - 4 - oxo - 10 propyl - 4H - naphtho[2,3 - b] - pyran 2 - carboxylic acid, half the microcrystalline cellulose and the sodium bicarbonate were dry mixed together and moistened with a 5% aqueous solution of the methyl cellulose, adding appropriately 20 parts of solution to 100 parts by weight of powder. The moistened powder was granulated through a 16 mesh (1,000 micron) screen and fluid bed dries using an inlet air temperature of 60"C. The dried granules were passed through a 16 mesh (1,000 micron) screen and mixed with the remaining microcrystalline cellulose and the stearic acid. The blend was compressed on a tablet forming machine to a diametral crushing strength of 4-7 kp Schleuniger.

WHAT WE CLAIM IS: 1. A pharmaceutical formulation comprising from 2 to 50 mg (determined as the free acid) of a compound of formula I.

in which R5 is hydrogen or hydroxy, or a pharmaceutically acceptable derivative thereof, in unit dosage form.

2. A pharmaceutical formulation according to Claim 1. comprising from 2 to 12 mg (determined as the free acid) of 6,7,8,9 - tetrahydro- 5 - hydroxy - 4 - oxo - 10 - propyl - 4H - naphtho[2,3 b]pyran - 2- carboxylic acid or a pharmaceutically acceptable derivative thereof, in unit dosage form.

3. A formulation according to Claim 2 comprising from 3 to 12 mg (determined as the free acid) of 6,7,8,9 - tetrahydro - 5 hydroxy - 4 - oxo - 10 - propyl - 4H - naphtho[2,3 - b]pyran -2 - carboxylic acid, or a pharmaceutically acceptable derivative thereof.

4. A formulation according to Claim 3 comprising from 3 to 6 mg (determined as the free acid) of 6,7,8,9 - tetrahydro - 5 hydroxy - 4 - oxo - 19 - propyl 4H naphtho[2,3 - bipyran - 2 carboxylic acid, or a pharmaceutically acceptable derivative thereof.

5. A pharmaceutical formulation according to Claim 1 comprising from 10 to 50 mg (determined as the free acid) of 6,7,8,9 - tetrahydro - 4- oxo - 10 propyl - 4H - naphtho[2,3 - b]pyran - 2 carboxylic acid, or a pharmaceutically acceptable derivative thereof, in unit dosage form.

6. A formulation according to Claim 5 comprising from 10 to 30 mg (determined as the free acid) of 6,7,8,9 - tetrahydro - 4 oxo - 10 - propyl- 4H - naphtho[2,3 - b]pyran - 2- carboxylic acid, or a pharmaceutically acceptable derivative thereof.

7. A formulation according to any one of the preceding claims which is a tablet formulation.

8. A formulation according to Claim 1 and substantially as hereinbefore described.

9. A formulation according to Claim 1 and substantially as hereinbefore described in any one of the Examples.

10. A process for the production of a unit dosage form according to any one of the preceding claims which comprises filling an appropriate volume or weight of the finely divided or granulated compound of formula I, or a pharmaceutically acceptable derivative thereof, into a defined space.

**WARNING** end of DESC field may overlap start of CLMS **.

Claims (10)

**WARNING** start of CLMS field may overlap end of DESC **. Example 2 Tablet mg/tablet 6,7,8,9 - Tetrahydro - 4 - oxo - 10 - propyl - 4H naphtho[2,3 - bipyran - 2- carboxylic acid micronised or milled 25.0 Sodium bicarbonate B.P. 75.0 Microcrystalline cellulose 'Avicel PH 101' 50.0 Methyl cellulose 20 B.P.C. (added as 5% aqueous solution) 1.5 Stearic acid 60 mesh 3.0 154.5 The 6,7,8,9 - tetrahydro - 4 - oxo - 10 propyl - 4H - naphtho[2,3 - b] - pyran 2 - carboxylic acid, half the microcrystalline cellulose and the sodium bicarbonate were dry mixed together and moistened with a 5% aqueous solution of the methyl cellulose, adding appropriately 20 parts of solution to 100 parts by weight of powder. The moistened powder was granulated through a 16 mesh (1,000 micron) screen and fluid bed dries using an inlet air temperature of 60"C. The dried granules were passed through a 16 mesh (1,000 micron) screen and mixed with the remaining microcrystalline cellulose and the stearic acid. The blend was compressed on a tablet forming machine to a diametral crushing strength of 4-7 kp Schleuniger. WHAT WE CLAIM IS:

1. A pharmaceutical formulation comprising from 2 to 50 mg (determined as the free acid) of a compound of formula I.

in which R5 is hydrogen or hydroxy, or a pharmaceutically acceptable derivative thereof, in unit dosage form.

2. A pharmaceutical formulation according to Claim 1. comprising from 2 to 12 mg (determined as the free acid) of 6,7,8,9 - tetrahydro- 5 - hydroxy - 4 - oxo - 10 - propyl - 4H - naphtho[2,3 b]pyran - 2- carboxylic acid or a pharmaceutically acceptable derivative thereof, in unit dosage form.

3. A formulation according to Claim 2 comprising from 3 to 12 mg (determined as the free acid) of 6,7,8,9 - tetrahydro - 5 hydroxy - 4 - oxo - 10 - propyl - 4H - naphtho[2,3 - b]pyran -2 - carboxylic acid, or a pharmaceutically acceptable derivative thereof.

4. A formulation according to Claim 3 comprising from 3 to 6 mg (determined as the free acid) of 6,7,8,9 - tetrahydro - 5 hydroxy - 4 - oxo - 19 - propyl 4H naphtho[2,3 - bipyran - 2 carboxylic acid, or a pharmaceutically acceptable derivative thereof.

5. A pharmaceutical formulation according to Claim 1 comprising from 10 to 50 mg (determined as the free acid) of 6,7,8,9 - tetrahydro - 4- oxo - 10 propyl - 4H - naphtho[2,3 - b]pyran - 2 carboxylic acid, or a pharmaceutically acceptable derivative thereof, in unit dosage form.

6. A formulation according to Claim 5 comprising from 10 to 30 mg (determined as the free acid) of 6,7,8,9 - tetrahydro - 4 oxo - 10 - propyl- 4H - naphtho[2,3 - b]pyran - 2- carboxylic acid, or a pharmaceutically acceptable derivative thereof.

7. A formulation according to any one of the preceding claims which is a tablet formulation.

8. A formulation according to Claim 1 and substantially as hereinbefore described.

9. A formulation according to Claim 1 and substantially as hereinbefore described in any one of the Examples.

10. A process for the production of a unit dosage form according to any one of the preceding claims which comprises filling an appropriate volume or weight of the finely divided or granulated compound of formula I, or a pharmaceutically acceptable derivative thereof, into a defined space.