Note: Descriptions are shown in the official language in which they were submitted.
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This invention relates to a novel formulation.
It has for a number of years been known to formulate
a variety OL anti-allergic drugs with various excipients in
order to present the drugs in convenient pharmaceutically ac-
S ceptable form. However a number of the excipients have beenfound to be, or contain, materials to which some patients are
allergic. Thus the anomolous situation has arisen in which it
has been proposed that a group of patients who may be particu-
larly prone to allergies should be treated with an anti-
allergic drug which has been formulated with a material capableof causing an adverse, e.g. allergic, reaction.
According to the invention we provide a pharmaceutical
tablet formulation comprising an anti-allergic drug having so-
dium cromoglycate like activity, as active ingredient, wherein
the formulation is (a) a tablet formulation comprising the
drug in combination with a lubricant and a diluent, the lubri-
cant and diluent containing no material capable of causing an
adverse reaction in an allergic patient, (b) a formulation
comprising from 2 to 12 mg (determined as the free acid) of
20 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, or (c) a formulation
comprising from 10 to 50 mg (determined as the free acid) of
6,7,8,9-tetrahydro-4-oxo-lO-propyl-4H-naphtho-[2,3,b]pyran-2-
carboxylic acid, or a pharmaceutically acceptable derivative
thereof, in unit dosage form.
The formulation preferably also contains a flow aid
and/or a binder, the flow aid and/or binder containing no
5~335
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material capable of causing an adverse reaction in an allergic
patient.
The material capable of causing an adverse reaction
in the patient may be a material, e.g. lactose, which can cause
an adverse reaction through an enzyme deficiency in certain
individuals or may be a material which contains residual traces
of an anti-biotic such as penicillin or may be a material con-
taining an actually or - -
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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 originr e.g.
lactose; or method of manufacture, e.g. maltose-dextrose oombinations
produced by enzyme treatment (and 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 oomposition which can be compressed into a
tablet directly without an intermediate, e.g. a wet or dry
granulation, stage.
The flow aid may bel for example, purified talc or silicon
dioxide and especially colloidal silicon dioxide having a mean
particle size of about 12 nm.
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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 ~icarbonate
or dibasic calcium phosphate. The formulation may also comprise
a disintegrant as anentity separate from the diluent. When the
disintegrant is a separate entity it should contain no material
capable of causing an adverse, e.g. 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 ma~ then be
compressed in a tablet forming machine.
The active ingredient may be any suitable anti-allergic drug,
having sodium cromoglycate like activity. A drug having sodium
cromoglycate like activity is able to inhibit the release of
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5835
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pharmaoological mediators which result from the in vivo combination
of certain types of ~nti-body and specific antigen, for example
the ccmbination of reaginic antibody and specific antigen (see
Example 27 of British Patent Specification No 1,292,601 - the rat
passive cutaneous anaphylaxis test).
The active ingredients may be characterised by the following
biological tests and results thereof.
The compound is first tested in the rat passive cutaneous
anaphylaxis test. If the oompound does not show significant
inhibition of allergic manifestations at 20 mg/kg intraperitoneally
(i.p) or intravenously (i.v) in this test, its activity is
generally too low. Various other biological tests may be used to
show that the compound exhibits its anti-allergy activity as an
inhibitor of mediators of anaphylaxis rather than as, for example
an end oryan antagonist, cholinergic or anti-cholinergic and
adenyl cyclase stimulator. Therefore, tests to see if the compound
inhibits the effect of histamine, serotonin, and slow reacting
substance of anaphylaxis (SRSA), that is, that the compound is an
end organ antagonist of the mediators, may be employed. Such tests
are well known and include contraction of guinea pig ileum in the
presence of methylsergide for serotonin activity. If activity is
still observed in these systems, it is due to histamine action. A
further check on histamine is through the spectrafluorimetric assay
descriked by Shore, Burkhalter and Cohn, Journal of Pharmacology
and Experimental Therapeutics/ Vol 127 page 182. ~ctive ingredients
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according bo the invention are not end organ antagonists.
If the results frcm these tests show that the active ingredient
is not an end organ antagonist further tests may be run to show that
the co~pound is not exhibiting its activity through cholinergicity
or anti-cholinergicity, e.g. by the reversal of acetylcholine
induced guinea pig tracheal chain contraction. An active
ingredient will not be a cholinergic or anti-cholinergic.
Specific groups of active ingredients are b~ be found among
the chrcmone-2-carboxylic acids, and suitable derivatives thereof,
e.g. those described in British Patent Specifications Nos 1,368,243;
1,144,905; 1,230,087 and West German Patent Specification
No 2,553,688. Other active ingredients are to be found among the
xanthones, e.g. of Belgian Patent Nos 759,292 and 787,843 and Dutch
Patent Specification Nos 72,09622 and 73,06958; among the compounds
of Belgian Patent No 8~9,935; among the nitroindanediones, e.g. of
Belgian Patent No 792,867; among the phenanthrolines, e.g. of
Belgium Patent No 773,200; among the azapurines, e.g. of Belgian
Patent No 776,683; the oxazoles, e.g. of West German OLS 2,459,380;
and the flavones, e.g. of Belgian Patent No 823,875.
Partlcularly preferred are the chrcmones and chromone like
oompounds of British Patent SpecificationsNos 1,144,905; and
1,230,087 and West German Patent Specification No 2,553,688. More
specifically we prefer 1,3-bis(2-carboxychrcmon-5-yloxy)propan-2-ol
or a pharmaceutically acceptable derivative, e.g. salt such as the
disodium salt, ther~of; this latter is commonly kncwn as sodium
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~5835
c~omoglycate or cromolyn sodium. As further preferred co~pounds
there may be mentioned 6,7,~,9-tetrahydro-4-oxo-10-propyl-4H-
naphtho[2,3-bjpyran-2-carboxylic acid and pharmaceutically
acceptable derivatives thereof (oollectively referred to herein
as 'active ingredient B') and 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 (oollectively
referred to herein as 'active ingredient A'). When using the
chromone and chromone like compounds described in this paragraph
we prefer the oomposition not to oontain di- or tri- basic cations.
Pharmaceutically acceptable derivatives within the meaning
of active ingredient A or B 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. salts
with hydroxylamine, lcwer 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 ccmpounds, e.g.
piperidine or morpholine. Suitable esters include simple lcwer
alkyl esters, e.g. the ethyl ester, esters derived from alcohols
containing basic groups, e.g. di-lcwer alkyl amino substituted
alkanols such as the ~-(diethoxyamino)-ethyl ester, and acyloxy
alkyl esters, e.g. a lcwer acyl-lcwer alkyl ester such as the
pivaloyloxymethyl ester, or a bis-ester derived from a dihydroxy
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compound, e.g. a di(hydroxy-lcwer alkyl) ether, e.g. the bis-2-
oxapropan-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 scdium 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 oomprise up to 4.0%
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
oomprise 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 oomposition.
We prefer tablet formulations containing an active ingredient
A to contain frcm 3 to 15%, and more preferably from 4 to 10% by
weight of water as such formulations have advantageous flow and
oompression characteristics.
Aocording to a further feature of our invention we provide a
pharmaceutical formulation oomprising from 2 to 12 mg (determined
as the free acid) of an active ingredient A in unit dosage form.
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In particular we prefer a unit dosage form comprising from 3 to
12 mg (determined as the free acid) and re 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
the 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
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 t~me.
Thus the patient only has to take one unit dose (or posssibly two
unit doses, depending on the patient's ability to swallcw 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
belcw 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
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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
dragées; microcrystalline cellulose, lactose, starch, talc or
stearic acid; for capsules, tartaric acid, starch, stearic acid or
lactose. 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 oomprises 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.
According to our invention we also provide a pharmaceutical
tablet ccrposition ccmprising an active ingredient A or B, in
combination with a lubricant and a diluent, and also, preferably,
a flow aid, a binder and a disintegrant.
We prefer that none of the ingredients oontain actually or
potentially allergenic material and in particular no proteinaceous
material. Thus we prefer tablet formulations as described above
and containing an active ingredient A or B.
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583~
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
S 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 lcw 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 OE Journal of the American Pharmaceutical Association
(1956) Vol 45 pages 114-116) at 25 rpm for 8 minutes, and are then
re-dusted, the tablet weight 106s shàll be less than 3%, and more
preferably less than 1%.
The unit dosages and other compositions of this invention, and
in particular compositions containing sodium cromoglycatè or an
active ingredient A or B, 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 oolitis and proctitis. The unit dosages and other
compositions 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 and other compositions
- are also indicated for use in the treatment of hay fever, urticaria
and eczema.
We particularly prefer formulations containing 1,3-bis(2-
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carboxy-chromon-5-yloxy)propan-2-ol or 6,7,8,9-tetrahydro-5-
hydroxy-4-oxo-10-propyl-4H-naphtho[2,3-b]pyran-2-carboxylic acid,
oe a pharmaceutically acceptable derivative of either thereof.
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-prop~1-4H-naphtho[2,3-b]
pyran-2-carboxylic acid 3.0
Colloidal silicon dioxide 'Aerosil 200'
(Aerosil is a Trade Mark~ 0.5
Polyvinylpyrrolidone 'Plasdone' K29-32
(Plasdone is a Trade Mark) 2.0
Stearic acid 60 mesh O.S
Microcrystalline cellulose IAvicel PH 101'
(Avicel is a Trade M~rk) 94.0
Approximately 100.0
The micronised or milled 6,7,8,9-tetrahydro-5-hydroxy-4-oxo-
10-propyl-4H-naphtho[2,3-b]pyran-2-carboxylic acid was mixed with
the oolloidal silicon dioxide, polyvinylpyrrolidone, stearic acid
and the microcrystalline oe llulose in a high speed powder blender.
The walls of the blender and its impeller blade were scraped 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
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835
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disintegration time) the moisture content of the blend was
oontrolled within the range 3-15% w/w, and preferably within the
range 4-10~ w/w.
The final mixture was then compressed in a tablet forming
5 machine to a diametral crushing strength of 5 kp Schleuniger.
ExamPle 2
Tablet mg/tablet
Sodium Cromoglycate B.P. 200
Sodium Bicarbonate B.P. 150
Purified Talc 16
Total weight dry 366
The sodium cromoglycate and sodium bicarbonate were dry mixed
together in a planetary mixer, then moistened with purified water,
approximately 20 parts of water being added to 100 parts by weight
solids. The moistened material was passed through a 16 mesh screen
then dried in a fluid bed drier. The purifier talc was blended
into the dry granules and the tablets compressed on 10 mm punches
on a rotary tablet machine to a diametral crushing strength of
6-8 kp Schleuniger.
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ExamPle 3
Tablet mg/tablet
6,7,8,9-Tetrahydro-4-oxo-10-propyl-4H-
naphtho[2,3-b]pyran-2-carboxylic acid
micronised or milled 25.0
Sodium bicarbonate B.P. 75.0
Microcrystalline cellulose 'Avicel PH 101' 50.0
Methyl oe llulose 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-4EI-naphtho[2,3-b]-
pyran-2-carboxylic acid, half the microcrystalline cellulose and
the sodium bicarbonate were dry mixed together and moistened witll
a 5~ aqueous solution of the methyl oe llulose, 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 dried using an inlet air temperature of 60C.
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.
