5 This invention relates to to a tablet comprising an active ingredient selected from tolfenamic acid and pharmaceutically acceptable salts thereof which is capable of rapid release of the active ingredient. In addition the invention relates to a method of preparing 0 such tablet.

Tolfenamic acid, N- (2-methyl-3-chlorophenyl) -an- thramlic acid, and salts thereof are known compounds having antiinflammatory and analgesic activity. The compounds and their aforementioned activities as well 5 as a method of preparing the compounds have been described m DK patent no. 116 061.

During the treatment of patients suffering from rheumatic diseases with tolfenamic acid preparations some patients noticed a reduced occurrence of migraine 0 attacks, and tolfenamic acid is now being marketed both as antiinflammatory and analgesic agent, particularly for the treatment of rheumatic diseases and dysme- norrhoea, and as anti-migraine agent (prophylactic as well as curative) . 5 The tolfenamic acid preparations were originally formulated as capsules consisting of a hard gelatine capsule shell containing a loose powder of the tolfena¬ mic acid m admixture with usual tablet and capsule fillers, the powder being made available for disso- 0 lution m the gastro-intestinal tract, when the gela¬ tine capsule has been dissolved.

The capsule formulation was chosen because of dif¬ ficulties in preparing a tablet containing a therapeu¬ tic dose and still being of a reasonable size, as a 5 tablet of a size which could be easily swallowed by a

patient, turned out to be very difficult to disinte¬ grate .

Later efforts resulted in the development of tab¬ lets being capable of providing a bioavailability of the tolfenamic acid corresponding to that obtained by the tolfenamic acid capsules. Furthermore the maximum plasma concentration was found to be somewhat higher for the tablet formulation than for the capsule formu¬ lation. However, T _max , the time at which the maximum plasma concentration is obtained, was essentially un¬ changed.

The potential of tolfenamic acid of curing a mi- grame attack has accentuated the desire of obtaining a small tablet which is capable of providing a high plasma concentration of tolfenamic acid within a short time.

As a result of extensive research aiming at attaining this object, a tablet having these character¬ istics has now been developed. Thus a tablet has been provided, which is capable of providing a maximum plasma concentration of tolfenamic acid being almost twofold of that obtained with the capsule formulation (mean values of 5.60 μg/ml and 2.95 μg/ml, respective¬ ly, in a cross-over test carried out on 12 test per- sons) , and furthermore within about half the time after administration {T _max median values of 1.0 hours and 1.8 hours, respectively) . As a further essential point, the mean plasma concentration reached half an hour after administration of the tablet according to the invention has been found to be more than twofold of that obtained by the known tablet, 2.60 μg/ml and 1.18 μg/ml, respec¬ tively. Thus a therapeutic level of tolfenamic acid is reached much faster by administration of the tablet according to the invention than by administration of the known tablet, among other things making the tablet

according to the invention particularly suited for acute treatment of a migraine attack.

These surprising results are based on a selection of a particular combination of tablet formulation aids and a particular particle size of the active ingredi¬ ent .

Accordingly the invention provides a tablet com¬ prising an active ingredient selected from tolfenamic acid and pharmaceutically acceptable salts thereof, said active ingredient having a mean particle size of ≤ 10 μm, and said tablet furthermore comprising alginic acid or a pharmaceutically acceptable salt thereof m an amount of 1.5 - 6.0 % by weight and a superdis¬ mtegrant an amount of at least 6 % by weight. The designation superdismtegrant refers to a group of disintegration agents being well-known to a person skilled m the art. Generally speaking, super- dismtegrants are disintegration agents which can be used a fractional amount of normal dismtegrants to obtain the same effect. According to product informa¬ tion provided by the manufacturers of superdismte- grants, the superdis tegrants should be used m amounts of 1 - 8 % with amounts of about 2% to about 4 % being indicated as optimal . Thus the amounts of superdismtegrant used accordmg to the invention are higher than the amounts generally used.

Cross-linked polyvinylpyrrolidones, particularly crospovidone, modified starches, particularly sodium starch glycolate, Starch 1500, modified celluloses, particularly croscarmellose sodium (cross-linked sodium carboxymethylcellulose) , LHPC (Low substituted hydroxy- propylcellulose) and Veegum are examples of preferred superdismtegrants for use m the tablet according to the mvention.

Croscarmellose sodium is f . inst . commercialized under the trade name Ac-Di-Sol and sodium starch glycolate under the trade names Primojel and Explotab.

Kollidon CL and Polyplasdone XL are commercial cross- linked PVP products.

According to the invention, the superdismtegrant will be present in the tablet in an amount of at least 6 % by weight, such as in an amount at least 8 % by weight, particularly in an amount of at least 10 % by weight and preferably in an amount of at least 12 % by weight. The superdisintegrant may be a single superdis¬ mtegrant or a combination of superdisintegrants and will normally be used in combination with one or more common disintegrants, such as starch, f. inst. corn starch.

There is no particular upper limit regarding the amount of superdisintegrant as long as the mechanical properties of the tablet are compatible with its intended use. However, normally the amount of superdis- integrant will not exceed 25 % by weight. From a cost point of view, the amount of superdisintegrant will preferably not exceed 15 -20 % by weight as normally no particular benefits will be achieved beyond this range.

The superdisintegrant may be present as an extra- granular and/or as an intragranular disintegration agent. According to one embodiment of the invention the superdisintegrant is present both as an intragranular disintegration agent and as an extragranular disinte¬ gration agent. Although the sup< "disintegrant may be present solely as an intragranular disintegration agent, it will in most cases be present as an extra¬ granular disintegration agent, either solely as an extragranular disintegration agent or in combination with an intragranular disintegration agent as mentioned above .

The particle size of the active ingredient can be obtained m different ways, such as by milling or micronizmg. The mean particle size can f .inst. be determined by the so-called Malvern technique, f . mst. using a Malvern Instrument of the type M6.10.

Typically milling results in a mean particle size the upper half of the range from zero up to 10 μm whereas micronizmg results in a mean particle size the lower half of said range. In a preferred embodiment of the invention, the mean particle size of the active ingredient is ≤ 8μm.

A typical mean particle size of tolfenamic acid for use as active ingredient the tablet according to the invention as obtained by milling is the range from 5 - 7 μm with a specific surface area the range from 1.0 - 1.8 m ² /cm ³ , particularly m the range from 1.1 - 1.7 πr/cm ³ , as determined by the above mentioned Malvern technique

A typical mean particle size of tolfenamic acid for use as active ingredient the tablet according to the invention as obtained by micronizmg is m the range from 1.5 - 2.5 μm with a specific surface area m the range from 2.5 - 3.5 m ² /cm ³ , as determined by the Malvern technique. Generally the specific surface area of the active ingredient will be in the range from 1.0 - 4.0 m ² /cm ³ .

As the micronizmg process is more expensive than milling and no particular advantages seem to be obtained by a micronized product compared to a milled product, the latter is normally preferred from a cost point of view.

The very hydrophobic nature of tolfenamic acid necessitates the use of an agent being capable of reducing the hydrophobicity of the particles, and alginic acid and pharmaceutically acceptable salts

thereof have been found particularly suited for that purpose. Thus a dissolution of 86 % of the tolfenamic acid included m a tablet as active ingredient has been obtained within 3 minutes by use of algmic acid as granulation agent compared to 32 % and 47 %, respect¬ ively, by use of the conventional granulation agents, polyvinylpyrrolidone and gelatine.

Similarly milling or micronizmg results n an increase of the dissolution withm 3 minutes by about two thirds compared to an unmilled product. Thus also the particle size appears to be of importance.

Finally the use of a superdisintegrant m an amount of at least 6 % by weight has turned out to be an important feature for obtaining the desired rapid release of the active ingredient.

The alginic acid or pharmaceutically acceptable salt thereof is generally included in an amount of 1.5 - 6.0 % by weight and preferably in an amount of 2.5 - 5.0 % by weight. Alkali metal salts, such as the sodium and potas¬ sium salts, are examples of pharmaceutically acceptable salts of algmic acid which may be used according to the invention.

In a preferred embodiment of the invention the algmic acid or pharmaceutically acceptable salt thereof is used as a granulation agent in the prepara¬ tion of the tablet.

A presently preferred embodiment of the mvention relates to a tablet comprising from 40 - 70 % by weight of the active ingredient, from 2.5 - 5.0 % by weight of alginic acid or a pharmaceutically acceptable salt thereof, from 6 - 10 % by weight of intragranular sodium starch glycolate, from 3 - 5 % by weight of extragranular sodium starch glycolate and from 1 - 3 % by weight of extragranular croscarmellose sodium, the

remainder up to 100 % by weight consisting of conven¬ tional tablet formulation aids, such as fillers, binding agents, disintegrants, lubricants, etc.

In a further aspect of the invention a method of preparing a tablet as indicated above is provided, said method comprising the followmg steps:

a) blending an active ingredient selected from tolfenamic acid and pharmaceutically acceptable salts thereof having a mean particle size of ≤ 10 μm with a disintegration agent and optionally other intragranular tablet formulation aids, b) kneading the resulting blend with a solution or dispersion of algmic acid or a pharmaceutically accep- table salt thereof to form a moist homogeneous mass, the algmic acid or pharmaceutically acceptable salt thereof being used in an amount to give a concentration thereof m the resulting tablet of 1.5 - 6.0 % by weight, and granulating the moist homogeneous mass, c) drying the obtained granules, optionally after blending with a filler and/or other tablet formulation aids, d) blending the dried granules with a disintegration agent and optionally other extragranular tablet formu- lation aids, and e) compressing the resulting blend mto a tablet,

with the proviso that the disintegration agent used in step a) and/or step d) comprises one or more superdis- integrants in a total amount to give a concentration of superdis tegrant in the resulting tablet of at least 6 % by weight .

The invention also relates to the use of tolfena¬ mic acid or a pharmaceutically acceptable salt thereof having a mean particle size of ≤ 10 μm in combination

with algmic acid or a pharmaceutically acceptable salt thereof and a superdismtegrant for the preparation of a tablet for treatment of pain, inflammation, migraine, dysmenorrhoea and fever, particularly for acute treat- ment thereof, the algmic acid or pharmaceutically acceptable salt thereof and the superdis tegrant being used in amounts of 1.5 - 6.0 % by weight and at least 6 % by weight, respectively.

The tablets according to the invention comprising tolfenamic acid or a pharmaceutically acceptable salt thereof as active ingredient will usually be admini¬ stered m a daily dose corresponding to 200 - 600 mg of tolfenamic acid with a unit dose of 200 mg per tablet Using the formulation according to the invention, a rapid release tablet containing such unit dose of 200 mg can be made with a total weight as low as about 350 -375 m . If desired, the tablets according to the in¬ vention can also be prepared to contain multiples of such unit doses, in which case the tablets will be provided with means such as notches for easy division mto suitable parts. F. mst. tablets containing a double dose and being provided with a notch for easy division mto two halves can be prepared. Also tablets containing a smgle dose can be notched for easy divi- sion, if desired. Furthermore the tablets can be pro¬ vided with identification codes.

In a preferred aspect, the invention provides a tablet comprising a unit dose of tolfenamic acid or a pharmaceutically acceptable salt thereof, of about 200 mg tolfenamic acid, or a multiple of such unit dose, and having a total weight of 350 - 400 mg per unit dose, preferably about 375 mg per unit dose.

As a further preferred aspect, the invention pro¬ vides a tablet being capable of providing a mean plasma

concentration of tolfenamic acid of about 2.00 μg/ml withm half an hour after administration.

In the drawings

Figure 1 illustrates mean plasma concentration curves for tolfenamic acid tablets accordmg to the invention and tolfenamic acid capsules and tablets according to the prior art, and

Figure 2 dissolution curves for the same tolfen¬ amic acid preparations. In the following the tablet of the invention and its method of preparation will be further illustrated by examples which should not be regarded as limiting.

Example 1.

Rapid release tablets, each containing 200 mg of tolfenamic acid as active ingredient, were prepared using the followmg ingredients and procedure.

Ingredients I . Tolfenamic acid, milled to a mean particle size of about 5.7 μm 1000 g Amyl. maidis (corn starch) 320 - Sodium starch glycolate 150 - II . Algmic acid 60 g

Aq. purificata 100 °C 500 - - Aq. purificata 10 - 12 °C 750 -

III. Cellulose, microcrystalline ad 1530 g

IV. Cellulose, microcrystalline 120 g Polyethylene glycol 6000 75 - Croscarmellose sodium 35 - - Siliciu dioxide 10 -

Sodium starch glycolate 75 - Sodium stearyl fumarate 15 -

I is blended in a suitable intensive blender for 60 sec. after which the prepared solution II is added and worked mto I until adequate wetting.

The wet mass of I + II is passed through a screen havmg a mesh width of 2.5 mm (8 mesh) . Then the pre¬ pared granules are dried to a weight of 1480 - 1530 g in a suitable fluidizer and supplemented to 1530 g with III as necessary.

After drying the granules are screened on a screen having a mesh width of 1.5 mm (12 mesh) .

The ingredients under IV are screened on a screen having a mesh width of 0.15 mm (100 mesh) and then added to the dry-screened granules in a suitable mixing apparatus for final mixing. The resulting granules are formed into tablets of a gross weight of 372 mg and containing 200 mg of tolfenamic acid each, using oval matrices of 7 x 14 mm optionally provided with a dividing notch and an iden¬ tification code on one of its faces. The above amounts are adequate for the preparation of 5000 tablets. Example 2

Using the same procedure as described example 1 tablets of the followmg content were prepared.

Tolfenamic acid, milled to a mean particle size of about 6.2 μm 200

Amylum aidis 64

Sodium starch glycolate 22.5 Polyethylene glycol 15

Algmic acid 12

Cellulose, microcrystalline 24

Croscarmellose sodium A 5.25 - Ξilicium dioxide 2

Sodium starch glycolate 11.25

Sodium stearyl fumarate 3

Comparative example 1

Preparation of tolfenamic acid capsules according to the prior art .

Capsules, each containing 200 mg of tolfenamic acid as active ingredient, were prepared using the followmg ingredients and procedure.

Ingredients Amount

I Tolfenamic acid, unmilled 1000 g

Lactose 403.5 -

Amyl. maidis 167.5 - II. Polyvinylpyrrolidone 16.5 g

Ethanol 160.0 -

Aq. purificata 200.0 -

III. Amyl. maidis ad 1587.5 g

IV Polyethylene glycol 6000 75.0 g - Talc 87.5 -

I is blended a suitable intensive blender for 60 sec after which the prepared solution II is added and worked mto I until adequate wetting. The wet mass of I + II is passed through a screen havmg a mesh width of 2.5 mm (8 mesh) . Then the pre¬ pared granules are dried to a weight of 1550 - 1587.5 g in a suitable fluidizer and supplemented to 1587.5 g with III as necessary. After drying the granules are screened on a screen havmg a mesh width of 1.0 mm (18 mesh) .

The ingredients under IV are screened on a screen havmg a mesh width of 0.15 mm (100 mesh) and then added to the dry-screened granules m a suitable mixing apparatus for final mixing.

The resulting granules are filled mto hard gela¬ tine capsules of size 2 in an amount of 350 mg/capsule corresponding to 200 mg tolfenamic acid/capsule, using a suitable capsule filling apparatus. The above amounts are adequate for the preparation of 5000 capsules.

Comparative example 2

Preparation of tolfenamic acid tablets according to the prior art .

Tablets, each containing 200 mg of tolfenamic acid as active ingredient, were prepared using the following ingredients and procedure

Ingredients Amount

I. Tolfenamic acid, unmilled 1000 g

Lactose 250 -

Amyl. maidis 300 -

II Polyvinylpyrrolidone 75 g - Ethanol 80 -

Aq. purificata 100 -

III. Amyl. maidis ad 1625 g

IV. Cellulose, microcrystalline 100 g Silicium dioxide 10 - - Croscarmellose sodium 35 -

Sodium stearyl fumarate 15 -

Polyethylene glycol 6000 75 -

I is blended in a suitable intensive blender for 60 sec. after which the prepared solution II is added and worked mto I until adequate wetting.

The wet mass of I + II is passed through a screen having a mesh width of 2.5 mm (8 mesh) . Then the pre ^¬ pared granules are dried to a weight of 1600 - 1625 g

in a suitable fluidizer and supplemented to 1625 g with III as necessary.

After drying the granules are screened on a screen having a mesh width of 1.5 mm (12 mesh) . The ingredients under IV are screened on a screen having a mesh width of 0.15 mm (100 mesh) and then added to the dry-screened granules in a suitable mixing apparatus for final mixing.

The resulting granules are formed mto tablets of a gross weight of 372 mg and containing 200 mg of tolfenamic acid each, using oval matrices of 7 x 14 mm optionally provided with a dividing notch and an iden¬ tification code on one of its faces.

The above amounts are adequate for the preparation of 5000 tablets.

Comparative example 3. Bioavailability studies.

Tolfenamic acid tablets according to the mven- tion, prepared as described in example 1 and tolfenamic acid capsules prepared as described in comparative example 1 were compared as to bioavailability of tolfenamic acid after oral administration, a random¬ ized single dose cross-over study carried out on 12 healthy volunteers.

Blood samples were collected after 1/4, 1/2, 1, 1 1/2, 2, 3, 4, 6 and 8 hours and the plasma concentra¬ tion of tolfenamic acid m μg/ml was determined. The individual results are listed tables Ia and Ila below, together with the mean and SEM values of the plasma concentrations obtained after 1/4, 1/2, 1 hour etc.

Table la

Tolfenamic acid tablets 200 mg, according to the invention.

Table Ila

Tolfenamic acid Capsules 200 mg.

In table Ilia below the maximum plasma concentra¬ tion, C _max , and the area under the plasma concentration curve, AUC ₀ ___., for each test person are listed together with the mean and SEM values. Table Ilia

As will be seen, the tablet according to the invention results m a maximum plasma concentration being almost twofold of that obtained by the capsule formulation (5.60 μg/ml vs. 2.95 μg/ml) . In addition, the total area under the plasma concentration curve appears to be larger for the tablet according to the invention than for the capsule preparation, indicating

that the tolfenamic acid is utilized more efficiently m the tablet according to the invention than m the capsule formulation.

As a further important feature, the maximum plasma concentration is obtained in a much shorter time (T _max median values of 1.0 hours and 1.8 hours, respective¬ ly) , as will appear from table IVa below wherein the time, T _max , for each test person to reach C _max is listed together with the median value.

Table IVa

Subject No. Tolfenamic acid Tolfenamic acid tablet, 200 mg, capsule, 200 mg, according to the prior art, T _max invention, T _max (h)

(h)

1 2.0 2.0

2 1.0 2.0

3 1.0 1.5

4 1.0 4.0

5 1.5 1.5

6 0.5 1.5

7 1.0 1.5

8 0.5 3.0

9 2.0 1.5

10 2.0 2.0

11 2.0 8.0

12 0,5 1.0

Median 1.0 1.8

In a corresponding randomized single dose cross¬ over study carried out on 12 healthy volunteers, tolfenamic acid tablets according to the prior art

prepared as described in comparative example 2 was compared to the capsule formulation prepared in com¬ parative example 1 with the results indicated in tables lb - IVb below, table lb corresponding to the above table Ia, etc.

Table I lib

Sub" ect Tolfenamic acid Tolfenamic acid

No. tablet, 200 mg, capsule, 200 mg, prior art prior art

Cmax AUC 0-26h Cmax AUC 0-26h

(μg/ml) (μg/ml) h (μg/ml) (μg/ml) h

1 4.12 11.36 2.31 13.36

2 6.56 14.86 4.68 11.73

3 5.79 15.12 2.31 13.39

4 3.67 15.04 3.21 14.06

5 2.71 16.89 1.91 12.19

6 3.20 9.87 1.61 8.58

7 2.04 7.58 2.35 8.84

8 3.36 13.69 2.57 12.59

9 4.30 10.84 1.16 14.36

10 2.96 19.25 2.76 18.45

11 3.75 13.82 2.05 10.55

12 3.30 15.06 3.50 16.66

Mean 3.81 13.62 2.54 12.90

SEM 0.37 0.93 0.27 0.83

Table IVb

Subject No. Tolfenamic acid Tolfenamic acid tablet, 200 mg, capsule, 200 mg, prior art, T _max prior art, T _max

(h) (h)

1 1.5 2.0

2 1.0 1.0

3 1.0 1.0

4 1.0 1.0

5 1.5 3.0

6 1.5 1.5

7 1.5 1.0

8 1.5 1.5

9 1.0 3.0

10 2.0 4.0

11 1.5 1.5

12 2.0 1.5

Median 1.5 1.5

Although the tablet according to the prior art results m a somewhat higher maximum plasma concentra¬ tion than the capsule preparation, 3.81 μg/ml vs. 2.54 μg/ml, cf . table Illb, the increase is much smaller than that obtained by the tablet according to the invention, resulting m an increase from 2.95 μg/ml to 5.60 μg/ml, as indicated m the above table Ilia. Furthermore, the prior art tablet has the same T _max median value as the capsule preparation.

Thus the tolfenamic acid tablet according to the invention results m a substantively increased maximum plasma concentration being obtained in a substantively reduced period of time, not only compared to the known capsule preparation but also compared to the known

tolfenamic acid tablet. Furthermore the tablet accord¬ ing to the invention results in a higher total area under the plasma concentration curve that the two other preparations meaning that a higher utilization of the active ingredient can be achieved.

The above results are further illustrated in Figure 1 wherein mean plasma concentration curves for the three preparations are shown.

Dissolution tests

The dissolution tests are carried out according to Ph.Eur. V.5.4 using a paddle apparatus operating at 100 rpm.

Initially the following solution is prepared: 40.8 g KH ₂ P0 ₄ is dissolved in 1500 ml of water. pH is adjusted to 7.2 with NaOH (40%) and 4500 ml of water is added.

The tablet/capsule to be tested is added to 1000 ml medium of 37°C prepared by diluting 150 ml 96% ethanol to 1000 ml with the above solution. After 3, 5, 10, 15, 30 and 60 minutes 10 ml samples are withdrawn and analyzed by UV spectrophotometry at 289 nm using medium as reference and a solution of 25 mg tolfenamic acid in 50.00 ml 0.1 N NaOH diluted 2 → 100 with medium as standard.

In Figure 2 dissolution curves for the tablet according to the invention and the prior art tablet and capsule formulations are shown. The much faster dissol¬ ution of the tablet according to the invention is evident.

In the preceding the invention has been described by means of specific examples of preferred embodiments. However it will be appreciated, that various modifica¬ tions can be made by a person skilled in the art

without deviating from the spirit and scope of the invention.