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Publication numberUS20050147671 A1
Publication typeApplication
Application numberUS 11/030,537
Publication dateJul 7, 2005
Filing dateJan 5, 2005
Priority dateMay 17, 1996
Also published asUS6974595, US7482377, US20050214363, US20050215643, US20130142874
Publication number030537, 11030537, US 2005/0147671 A1, US 2005/147671 A1, US 20050147671 A1, US 20050147671A1, US 2005147671 A1, US 2005147671A1, US-A1-20050147671, US-A1-2005147671, US2005/0147671A1, US2005/147671A1, US20050147671 A1, US20050147671A1, US2005147671 A1, US2005147671A1
InventorsAlberto Reiner, Giorgio Reiner
Original AssigneeAlberto Reiner, Giorgio Reiner
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
A fast-release dosage of diclofenac or diclofenzc salts in the form of a packet of powder for dissolving or suspending in water or a high-speed release layer in a bilayered tablet that comprises a fast and a slow layer; palatable and free from aftertaste and side effects; consistancy; uniformity
US 20050147671 A1
Abstract
New pharmaceutical compositions for oral use containing Diclofenac together with alkali metal bicarbonates in amounts of from 20 to 80 by weight with respect to Diclofenac are described. These compositions are entirely palatable and free from any unpleasant taste or other side effects; in particular, these formulations permit to obtain in human patients higher Cmax of the active principle and shorter Tmax together with a lower coefficient of variation.
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Claims(27)
1) A fast-release diclofenac composition, in the form of a unit dose packet of powder for dissolving or suspending in water, or in the form of a fast release layer in a two layered diclofenac tablet that comprises a fast layer and a slow layer, wherein said composition comprises diclofenac in acid and/or salt form.
2) The composition of claim 1 wherein said diclofenac is present as diclofenac potassium.
3) The composition of claim 1 wherein said diclofenac is present in an amount ranging from about 10 to about 60 mg.
4) The composition of claim 1 in the form of a unit dose packet of powder wherein said diclofenac is present in an amount of about 50 mg.
5) The composition of claim 1 in the form of a unit dose packet of powder wherein said diclofenac is present as diclofenac potassium in an amount of about 50 mg.
6) The composition of claim 1 in the form of a unit dose packet of powder, wherein said composition is capable of yielding an average Tmax of diclofenac in a human patient between 5 and 30 minutes after administration of said diclofenac to said patient, said average Tmax having a coefficient of variation (CV %) less than about 70%.
7) The composition of claim 1 in the form of a unit dose packet of powder, wherein said composition is capable of yielding an average Tmax of diclofenac in a human patient between 13 and 27 minutes after administration of said diclofenac to said patient, said average Tmax having a coefficient of variation (CV %) less than about 70%.
8) The composition of claim 1 in the form of a fast release layer in a two layered diclofenac tablet.
9) The composition of claim 1 in the form of a fast release layer, wherein said composition comprises about 15 mg. of diclofenac potassium salt, and said slow release layer comprises about 70 mg. of diclofenac potassium salt.
10) The composition of claim 1, further comprising means for potentiating the bioavailability of said diclofenac.
11) The composition of claim 10 wherein said means decreases the Tmax of said diclofenac.
12) The composition of claim 10 wherein said means increases the Cmax of said diclofenac.
13) The composition of claim 10 wherein said means decreases the coefficient of variation of the Cmax of said diclofenac.
14) The composition of claim 10 in the form of a unit dose packet of powder wherein said diclofenac is present in an amount of from about 10 to about 60 mg.
15) The composition of claim 10 in the form of a unit dose packet of powder wherein said diclofenac is present in an amount of about 50 mg.
16) The composition of claim 10 wherein said means comprises one or more alkali metal carbonates or bicarbonates.
17) The composition of claim 10 wherein said means comprises one or more alkali metal carbonates or bicarbonates in an amount greater than about 20 wt. % based on the weight of said diclofenac.
18) The composition of claim 10 in the form of a unit dose packet of powder wherein said diclofenac is present in an amount of about 50 mg. and said means comprises one or more alkali metal carbonates or bicarbonates in an amount greater than about 20% based on the weight of said diclofenac.
19) The composition of claim 10 in the form of a unit dose packet of powder wherein said diclofenac is present as diclofenac potassium in an amount of about 50 mg. and said means comprises potassium bicarbonate in an amount greater than about 20% based on the weight of said diclofenac.
20) The composition of claim 10 in the form of a unit dose packet of powder wherein said diclofenac is present as diclofenac potassium in an amount of about 50 mg. and said means comprises potassium bicarbonate in an amount of from about 40 wt. % to about 80 wt. % based on the weight of said diclofenac.
21) A fast-release diclofenac composition, in the form of a unit dose packet of powder for dissolving or suspending in water, or in the form of a fast release layer in a two layered diclofenac tablet comprising a fast layer and a slow layer, wherein the composition comprises diclofenac in acid and/or salt form and means for potentiating the bioavailability of said diclofenac.
22) The composition of claim 21 wherein said means comprises greater than about 20 wt. % of one or more alkali metal carbonates or bicarbonates based on the weight of said diclofenac.
23) A fast-releasing diclofenac composition, in the form of a unit dose packet of powder for dissolving or suspending in water, comprising about 50 mg. of diclofenac in acid and/or salt form.
24) The composition of claim 23 wherein said diclofenac is present as diclofenac potassium.
25) The composition of claim 23 wherein said diclofenac is present as diclofenac potassium, further comprising from about 40 to about 80 wt. % of potassium bicarbonate.
26) A fast-release diclofenac composition, in the form of a fast release layer in a two layered diclofenac tablet comprising a fast layer and a slow layer, comprising from about 10 to about 60 mg. of diclofenac in acid and/or salt form.
27) The composition of claim 26 wherein said diclofenac is present as diclofenac potassium.
Description

The present application is a continuation of U.S. Ser. No. 09/524,747, filed Mar. 14, 2000 (pending), which is a continuation in part of U.S. Ser. No. 09/192,493, filed Nov. 17, 1998 (abandoned).

The present invention relates to new immediate release pharmaceutical compositions containing [(2,6-dichloro-anilino)-2-phenyl]-2-acetic acid (more commonly known as Diclofenac) in acid and/or salt form.

Diclofenac is a non-steroidal drug which was invented at the end of the sixties by A. Sallmann and R. Pfister (NL-6,604,752 and U.S. Pat. No. 3,558,690 both to Ciba-Geigy) and whose structural formula is indicated below.

Diclofenac is widely dispensed and used owing to its well-known analgesic, anti-pyretic, anti-arthritic, anti-phlogistic and anti-rheumatic properties and it is generally taken orally in the form of normal tablets or tablets covered with coatings resistant to gastric juices, or rectally, or by injection, or topically.

The possibility of taking it in the form of sweets, tablets dissolving in the mouth, drages, chewing gum or other similar pharmaceutical forms or in formulations for the extemporary preparation of Diclofenac-based aqueous solutions and/or suspensions would represent a different mode of administration which is definitely more suitable, especially for children and elderly persons.

Owing to its poor solubility in water, Diclofenac is normally used in salt form; the salts of Diclofenac customarily used are those of sodium, potassium or other alkali and alkaline earth metals, together with salts of organic nature, such as the salts of basic amino acids, such as lysine, arginine and ornithine, or other pharmacologically acceptable organic bases which have the ability to render the resulting salt soluble in water.

The pharmaceutical compositions of the Diclofenac salts for oral use are generally 25 accompanied by side effects of not inconsiderable consequence: Diclofenac salts are in fact characterised by a particularly unpleasant and bitter taste and by the fact that they produce a sensation of strong astringency and cause an especially intense form of irritation in the buccal cavity, especially in the area of the larynx.

Although the first problem has been partly solved by using flavourings which are able in some manner to mask the taste, satisfactory solutions have still not been proposed for the two remaining problems.

Therefore, the pharmaceutical compositions containing Diclofenac salts still have a poor palatability which limits their adoption and possible fields of application, despite the excellent therapeutic effect with which they are associated.

A second problem connected to Diclofenac is that, when it is orally administered by means of immediate release formulations, the corresponding Tmax (the time to the maximum plasma concentration) is usually located at about 1 hour since administration, this being of course a not completely satisfactory result when a prompt and strong analgesic/anti-pyretic effect is sought for. Furthermore, the corresponding coefficient of variation is normally in the range of 70-90%, which means that the Tmax is strongly variable and dependent on the physical characteristics of the patient (Physicians' Desk Reference, 52 edition, 1998, pag. 1831). Attempts are therefore still being made in order to enhance the rate of absorption of Diclofenac and to provide an earlier onset of the therapeutical effect (N. Davies, K Anderson; Clinical Pharmacokinetic of Diclofenac, Clin. Pharmacokinet., 1997, Sep. 33(3).

The object of the present invention is therefore that of providing a fully palatable formulation of Diclofenac which is able to generate a more rapid, uniform and foreseeable release of the active principle if compared to the compositions known in the art and presently available on the market. For the purposes of the present invention Tmax means the time to the maximum plasma concentration whereas Cmax is the maximum plasma concentration of the active principle, namely Diclofenac. It has now been found that, by adding alkali metal bicarbonates or mixtures thereof to the Diclofenac in its acid and/or salt form, in amounts of from 20 to 80% by weight based on the acid-form of Diclofenac, pharmaceutical compositions an be obtained which are substantially free from the side effects mentioned above. The first object of the present invention is therefore represented by a pharmaceutical formulation for oral use containing Diclofenac in acid and/or salt form together with alkali metal bicarbonates or mixtures thereof and customary excipients and adjuvants, wherein said alkali metal bicarbonates are present in amounts of from 20 to 80% by weight based on the weight of Diclofenac.

It has in fact been surprisingly demonstrated that the use of alkali metal bicarbonates in the above-mentioned ratio permits to achieve constant, reproducible and foreseeable blood levels of the active ingredient, with the consequent indisputable advantages from the therapeutic point of view, furthermore, it has also been found that the combined use of Diclofenac together with alkali metal bicarbonates yields Diclofenac-based pharmaceutical compositions in which the active ingredient is released more rapidly compared with normal formulations, bringing about higher blood levels and therefore a more immediate therapeutic effect; finally the so-obtained immediate release formulations are substantially palatable and free from aftertaste.

According to the preferred embodiment of the present invention, the amount of alkali metal bicarbonates to be added is comprised between 40 and 80% by weight, based on the weight of the acid-form Diclofenac, whereas the alkali metal bicarbonates are selected from sodium and/or potassium bicarbonates, Diclofenac being normally present in the form of its sodium and/or potassium salts.

It has also been found, and forms a second subject of the present invention, that the addition of flavouring substances selected from mint, aniseed, ammonium glycyrrhizinate and mixtures thereof to the compositions containing the Diclofenac salts and alkali metal bicarbonates produces a synergistic effect which completely eliminates all the above-mentioned palatability/astringency effects, providing pharmaceutical compositions which are entirely palatable (and/or drinkable in the case of those used for the preparation of solutions and/or suspensions) and free from aftertaste.

The flavouring substances may be used as such or supported on inert materials, for example maltodextrin, in order to obtain a better distribution of the granulates and to facilitate excellent dispersibility of the flavouring in solution. Preferably, they are absorbed on maltodextrin with a power of 1 to 2000 and 1 to 1000.

The amount of flavouring substances in its pure form is also preferably from ⅕ to 3 times the weight of the acid-form Diclofenac.

These flavouring substances are used in the implementation of the present invention without altering their organoleptic properties and without depriving them of their intrinsic qualities of flavourings which are liposoluble and generally oily in the pure state.

As it will be clear from the examples, the immediate release formulations for oral use of the present invention conning from 10 to 60 mg of Diclofenac in acid and/or salt form together with alkali metal bicarbonates or mixtures thereof in amounts of from 20 to 80% by weight based on the weight of Diclofenac permit to generate in human patients an average Cmax of Diclofenac comprised between 400 and 2500 ng/ml independently on the age, sex or weight of the patients themselves.

Secondly, the formulations according to the present invention permit to obtain in humans an average Tmax of Diclofenac after 5÷30 minutes since administration, generally 13÷27, independently on the amount of Diclofenac contained therein and also independently on the age, sex, weight of the patient.

Furthermore, the Tmax of the formulations of the present invention show a coefficient of variation which is about 44-86% lower than the presently marketed formulations; this is evidently an extremely important result from the clinical point of view as it is now possible to have a therapeutical effect of Diclofenac which is foreseable, reproducible and independent on the sex, weight and health conditions of the patient.

Thus, the presently claimed Diclofenac-based formulations permit to achieve a higher Cmax in a shorter Tmax and with a lower corfficient of variation if compared to the formulations available on the market, with therapeutical advantages which do not need to be commented.

According to the best mode for carrying out the present invention the pharmaceutical formulations will contain from 10 to 60 mg/dose of diclofenac in its potassium or sodium salt form together with 40 to 80% by weight of potassium or sodium bicarbonate based on the weight of Diclofenac in its acid form, together with the usual excipients and adjuvants; even more preferably they will packaged as:

    • a sachet or tablet formulation containing 50 mg of Diclofenac potassium salt and 22 mg of potassium bicarbonate or 50 mg of Diclofenac sodium salt and 19 mg of sodium bicarbonate;
    • a sachet or tablet formulation containing 12.5 mg of Diclofenac sodium salt and 5.5 mg of potassium bicarbonate or 25 mg of Diclofenac sodium salt and 11 mg potassium bicarbonate.

It will be by the way evident to any skilled in this art that the present formulations can also be used as immediate release layers of multilayered release pharmaceutical formulations containing Diclofenac as one of the active ingredients; said formulations are therefore a further object of the present invention.

The following Examples are given purely by way of non-limiting illustration.

EXAMPLE 1 Composition Dissolving Instantly in Water

Active ingredients
1) Diclofenac potassium salt*:  50 mg
2) Potassium bicarbonate:  22 mg
3) Mint flavouring on maltodextrin(1:2000)**:  60 mg
4) Aniseed flavouring on maltodextrin (1:1000)***: 104 mg
Excipients and adjuvants
5) Saccharin:  4 mg
6) Aspartame:  10 mg
7) Mannitol:  50 mg
8) Saccharose****q.s.:  2 g

*If it is desired to prepare compositions based on Diclofenac sodium salt, it is advantageous to use sodium bicarbonate in a quantity of approximately 38% by weight based on the weight of the Diclofenac sodium salt present. Sodium carbonate may also be added to the sodium bicarbonate, maintaining the following optimum proportions: 27% of sodium bicarbonate and 4-5% of
# sodium carbonate, always based on the amount by weight of Diclofenac sodium salt present.

**The title of the pure mint essence, as obtained according to the Dean-Stark method, is of 18% by weight; the related amount is therefore in this case of 10.8 mg.

***The title of the pure anise essence, as obtained according to the Dean-Stark method, is of 14.5% by weight, the related amount is therefore in this case of 16 mg.

****The presence of saccharose is not strictly necessary; in its absence, a composition having a very limited granulate content is obtained which is perfectly soluble in contact with water. In that case, nothing is changed from the point of view of tolerability in contact with the mucosa and from the point of view of the palatability of the drinkable solution.

    • Preparation

Components 1, 2, 5, 6 and 7 are mixed in a suitable mixer, and the mixture so obtained is wetted with 95% ethanol. Granulation is carried out with a 66 mm mesh and the granulate is preferably dried in a current of air.

Components 3, 4 and 8, which have already been granulated using a mesh of the same granulometry, are then added and the whole is mixed.

The mixture is then introduced into a metering machine filling packets or similar containers.

EXAMPLE 2 Tablet for Dissolving in the Mouth

Active ingredients
1) Diclofenac potassium salt*:  50 mg
2) Potassium bicarbonate:  35 mg
3) Mint flavouring on maltodextrin**  50 mg
  (1:2000) + gum arabic (E 414):
4) Aniseed flavouring (1:1000) 120 mg
  on maltodextrin*** + silicon
  dioxide (E 551):
Excipients and adjuvants
5) Saccharin:  50 mg
6) Aspartame:  12 mg
7) Mannitol:  20 mg
8) Saccharose****: 300 mg

* to **** see Example 1

EXAMPLE 3 Gum Tablet

Active ingredients
 1) Diclofenac potassium salt*:   50 mg
 2) Potassium bicarbonate:   35 mg
 3) Mint flavouring on maltodextrin**:   30 mg
 4) Aniseed flavouring on maltodextrin***:   80 mg
Excipients and adjuvants
 5) Mannitol:   30 mg
 6) Menthol: 0.01 mg
 7) Gum base:  600 mg
 8) Sorbitol:  700 mg
 9) Saccharin:   3 mg
10) Hydroxypropylmethylcellulose:   33 mg
11) Colouring agent:   7 mg

* to *** see Example 1

EXAMPLE 4 Comparative Test

The packaged composition containing 50 mg of Diclofenac potassium of Example 1 (formulation C) was subjected to a pharmacokinetic test for comparison with a similar composition not containing alkali metal carbonates and bicarbonates (formulation B), and with a second composition in tablet form (formulation A) produced by Ciba-Geigy (Voltaren Rapid®), also in this case not containing alkali metal carbonates and bicarbonates, both formulations A and B containing 50 mg of Diclofenac potassium.

This comparative evaluation was carried out on the same 6 healthy volunteers in accordance with the experimental plan described hereinafter.

    • Experimental scheme: Single-dose study using three methods in randomised cross-over with a wash-out of three days.
    • Sampling times: 0 h (before administration), 5 min, 10 min. 30 mm, 45 min, 1 h, 1.5 h, 2 h, 3 h, 4 h, 6 h, 8 h, after each administration.
    • Blood sample treatment: 8 MI in heparinised test tubes, centrifugation for 15 min at 1500 rev/min, subdivided into two factions and subsequently frozen at −20° C.
    • Times: wash-out of two days between treatments.
    • Determination method: HPLC, with internal standard, sensitivity 10 ng/ml.

Analysis Method

    • Column: Nova Pak C18, 3.9×150 mm, 4 μm Waters S.p.A.—Vimodrone, Italy.
    • Eluant: NaH2PO4 0.01 M+0.1% TEA, pH 3.0 (H3P04)/acetonitrile, 60/40.
    • Flow: 1.2 ml/min
    • Detection: TV/275 nin
    • Temperature: 30° C.
    • Injection: 50 al
    • Analysis time: 16 min.

Sample Preparation

10 al of the internal standard methanolic solution, and flufenamic acid (corresponding to 1320 ng) are added to 1 ml of defrosted plasma in 10 ml glass test tubes. The tubes are agitated in a Vortex mixer for 1 minute. 0.5 ml of a 0.5N HCl/1N NaCl solution is added. The whole is agitated in a Vortex mixer for 1 minute. 6 ml of a 95/5 n-hexane/isopropanol solution are added

The mixture is then agitated in the Vortex mixer for a further 15 minutes. Centrifugation is carried out at 3000 rev/min for 15 minutes and the organic phase is transferred to fresh 10 ml glass test tubes and evaporated to dryness in a centrifugal evaporator under vacuum at ambient temperature. The whole is taken up in 200 al of a 70/30 acetonitrile/water solution, and the precipitate is dissolved under ultrasound for 2 minutes.

FIGS. 1, 2 and 3 show the concentrations of Diclofenac in the blood of the six volunteers as regards formulations A, B (Ciba-Geigy comparative formulations) and C (formulation corresponding to the composition of Example 1), respectively. As will be appreciated the blood concentration of the formulation of the present invention has, compared with the comparative formulations, a more constant and uniform pattern. This characteristic is also found in FIGS. 4, 5 and 6 which show the average values corresponding to the blood levels of the six volunteers together with the corresponding standard deviation.

The result is clear and surprising: compared with the sample compositions, the compositions of the present invention permit constant, reproducible and foreseeable blood levels of the active ingredient, irrespective of the characteristics of the volunteer (weight, age, etc), with the consequent indisputable advantages from the therapeutic point of view.

Finally, FIG. 7 shows, by comparison, the graphs relating to the average values of the six volunteers (that is to say, the preceding FIGS. 4, 5 and 6); as will be noted, the formulation of the present invention permits, in addition to the advantages already mentioned, the attainment of a blood peak higher than that of the other formulations.

EXAMPLE 5 Two Layered Tablet (Fast and Slow Release)

Fast release layer
 1) Diclofenac potassium salt:   15 mg
 2) Potassium bicarbonate:   30 mg
 3) Lactose: 13.2 mg
 4) Maize starch (intragranular):   6 mg
 5) Methyl cellulose: 0.12 mg
 6) Sodium laurylsulfate: 0.06 mg
 7) Maize starch (extragranular):   9 mg
 8) Crospovidone:  0.6 mg
 9) Sodium carboxtmethylstarch:  1.5 mg
10) Magnesium stearate:  2.7 mg
11) Colloidal silicon dioxide:  0.6 mg
Slow release layer
 1) Diclofenac potassium salt:   70 mg
 2) Potassium bicarbonate: 30.8 mg
 3) Lactose: 32.2 mg
 4) Polyvinylpyrrolidone: 1.16 mg
 5) Hydrpxypropylmethylcellulose:   70 mg
 6) Magnesium stearate: 0.84 mg
 7) Colloidal silicon dioxide: 0.21 mg
 8) Talc: 3.92 mg
 9) Polyethylene glycol: 0.56 mg

EXAMPLE 6 Drops

1) Diclofenac potassium salt:   75 g
2) Methyl p-oxybenzoate:  2.7 g
3) Propyl p-oxybenzoate:  0.3 g
4) Aspartame:  37.5 g
5) Potassium bicarbonate:  37.5 g
6) Glycerol:   300 g
7) Ethyl alcool:   450 g
8) Water q.s.:  1500 g
Possible modifications:
a) Addition of sodium metabisulfite (0.06%)
b) Addition of sodium metabisulfite (0.06%)
  Mint flavouring (1.25%)
  Strawberry flavouring (0.75%)

EXAMPLE 7 Drops

1) Diclofenac potassium salt:  37.5 g
2) Methyl p-oxybenzoate:  2.7 g
3) Propyl p-oxybenzoate:  0.3 g
4) Aspartame:  37.5 g
5) Potassium bicarbonate: 18.75 g
6) Saccharin:  6.0 g
7) Glycerol:   300 g
8) Ethyl alcool:   450 g
9) Water q.s.:  1500 g
Possible modifications:
a) Addition of sodium metabisulfite (0.03%)
b) Addition of sodium metabisulfite (0.03%)
  Mint flavouring (1.25%)
  Strawberry flavouring (0.75%)

EXAMPLE 8 Mouthwash

 1) Diclofenac potassium salt: 0.75 g
 2) Glycerol:   50 g
 3) Sorbitol:   12 g
 4) Saccharin:  0.5 g
 5) Aspartame:  1.0 g
 6) Methyl p-oxybenzoate:  0.5 g
 7) Propyl p-oxybenzoate:  0.1 g
 8) Mint flavouring:  1.0 g
 9) Ethyl alcool:  100 g
10) Potassium bicarbonate: 0.33 g
11) Water q.s.:  500 ml

EXAMPLE 9 Gum-Paste

 1) Diclofenac potassium salt:  5.0 g
 2) Glycerol:  630 g
 3) Sodium benzoate:  5.0 g
 4) Silica (Wessalon S ® - Degussa):  120 g
 5) Silica (Siddent 9 ® - Degussa):   80 g
 6) Cellulose gum:  3.0 g
 7) Polyethylenglycol 600:   30 g
 8) Sodium lauroyl sarcosinate   60 g
  (or sodium lauryl sulfate):
 9) Mint flavouring:   10 g
10) Sodium saccharin:  1.0 g
11) Aspartame:  3.0 g
12) Potassium bicarbonate:  2.2 g
13) Water q.s.:   1 kg

EXAMPLE 10 Tooth-Paste

 1) Diclofenac potassium salt:  5.0 g
 2) Glycerol:  630 g
 3) Sodium benzoate:  5.0 g
 4) Silica (Wessalon S ® - Degussa):   20 g
 5) Silica (Siddent 9 ® - Degussa):   80 g
 6) Cellulose gum:  3.0 g
 7) Polyethylenglycol 600:   30 g
 8) Sodium lauroyl sarcosinate   60 g
  (or sodium lauryl sulfate):
 9) Mint flavouring:   10 g
10) Sodium saccharin:  1.0 g
11) Aspartame:  3.0 g
12) NaF:  1.0 g
13) Na2FPO3:  4.0 g
14) Potassium bicarbonate:  2.2 g
15) Water q.s.:   1 kg

EXAMPLE 11 Tablet

 1) Diclofenac potassium salt:  50 mg
 2) Mannitol:  50 mg
 3) Potassium bicarbonate:  22 mg
 4) Maize starch (intragranular):  10 mg
 5) Methyl cellulose: 0.2 mg
 6) Sodium laurylsulfate: 0.1 mg
 7) Maize starch (extragranular):  15 mg
 8) Crospovidone: 1.0 mg
 9) Sodium carboxymethylstarch: 2.5 mg
10) Magnesium stearate: 4.5 mg
11) Colloidal silicon dioxide:  10 mg

EXAMPLE 12 Comparative Test

In the present experiment a sachet formulation containing 50 mg of Diclofenac potassium was compared to a bioequivalent sugar coated fast release tablet also containing 50 mg of Diclofenac potassium, produced and marketed in Italy by Novartis as Cataflam®.

The sachet formulation according to the present invention had the following Composition:

1) Diclofenac potassium salt:  50 mg
2) Potassium bicarbonate:  22 mg
3) Mint flavour:  50 mg
4) Anice flavour  100 mg
5) Saccharin sodium:   4 mg
6) Aspartame:  10 mg
7) Mannitol:  50 mg
8) Sucrose sugar crystals: 1714 g

The above test formulation and the Cataflam® formulation were administered as a single dose to 24 healty volunteers of both sexes. The pharmacokinetic parameters obtained with the two different formulations are reported in table 1 and in FIG. 5. As it will be easily appreciated, the rate of absorption was considerably faster with the sachet formulation of the present invention than with Cataflam®, the sachet formulation having a higher average Cmax (2213 vs 1071 ng/ml) and a shorter average Tmax (0.228 vs 0.885 hours); furthermore, the Tmax of the sachet formulation shows a coefficient of variation lower than the reference formulation (16% vs 97%), this being an extremely important result from the clinical point of view regarding the healing of the pain in terms of quick time and repeteability inter-subjects in order to reach the Cmax.

EXAMPLE 13 Comparative Test

Following to the excellent results obtained in example 12, two tablet formulations containing 12.5 or 25 mg of Diclofenac sodium salt and potassium bicarbonate (in the same weight ratio) have been prepared.

The tablet formulations had the following composition (in mg):

Cores
Diclofenac sodium 12.5 25
Mannitol 25 50
Lactose monohydrate 23.75 47.5
Potassium bicarbonate 5.5 11
Maize starch 22.5 45
Methylcellulose 0.075 0.15
Sodium laurylsulphate 0.125 0.25
Crospovidone 3 6
Ultramyl 5 10
Coloidal silica 0.55 1.1
Cellulose microcrystalline 0.5 1
Magnesium stearate 1.5 3
Purified water q.s. 100 200
Coating
Opadry OY-35009 red 2 4
Macrogol 400 0.25 0.5

A four-way comparative bioavailability study was carried out on 18 healty volunteers of both sexes in order to evaluate the in vivo results of the pharmaokinetic profiles of the present formulations if compared to those of bioequivalent fast release formulations such as Cataflam® (25 mg of Diclofenac potassium) and Voltarol® (50 mg of Diclofenac sodium), both by Novartis. The results, which are summarized in FIG. 6, indicate that Tmax is prompter with the present formulations (T=26 min, T2=24.6 min vs R1=71.4 min and R2=40.8 min) and that Cmax is higher (T1=847 ng/ml and T2=861 ng/ml vs R1=452 ng/ml and R2=703 ng/ml); furthermore, the Tmax of both present formulations shows a coefficient of variation lower than reference formulations (T1=46% and T2=49% vs R1=87% and R2=96%).

EXAMPLE 14 Comparative Test

A further comparative test was carried out on immediate release formulations according to the present invention, containing 50 mg of Diclofenac potassium and 22 mg of potassium bicarbonate, manufactured with different that is, respectively: T1=wet granulation using alcohol, T2=dry granulation by direct compression. The composition in mg of the two formulations is herebelow reported:

Diclofenac potassium 50 50
Potassium bicarbonate 22 22
Mannitol/pearlitol 400 DC 119.9
Mannitol EP cf 50
Maize starch 25
Methocel A4C 0.2
Sodium laurylsulphate 0.1 0.1
Polyplasdone XL 6 1
Ultramyl 2.5
Magnesium stearate 2 4.5
Silicium aerosil 1
Core mass 200 156.3

A comparative bioavailability study was carried out on 6 healty volunteers of both sexes in order to evaluate the in vivo results of the pharmaokinetic profiles of the present formulations if compared to those of a bioequivalent fast release formulation such Voltarene Rapid® (50 mg of Diclofenac potassium), both by Novartis. The results, which are reported in FIGS. 7-10 are also in this case excellent: the Tmax is in fact prompter with the present formulations (T1=18.6 min, T2=16.8 min vs R1=40.8 min) and the Cmax is higher (T1=1878.3 ng/ml and T2=1744.8 ng/ml vs R1=1307 ng/ml); furthermore, also in this case the Tmax of both present formulations shows a coefficient of variation lower than reference formulation (T1=12.9% and T2=25% vs R1=95.6%).

TABLE 1
Pharmacokinetic parameters for two different diclofenac
formulations: test (Diclofenac potassium salt sachets)
and reference (Diclofenac potassium salt sugar
coated tablets)
tmax Cmax t1/2 AUC
(h) (ng/mL) (h) (ng · mL−1 · h)
Vol. no. Test Ref. Test Ref. Test Ref. Test Ref.
Vol. 1 0.250 0.500 1573.000 1186.211 1.505 0.939 1024.511 885.549
Vol. 2 0.250 4.000 2382.368 965.100 0.875 1.358 1653.124 2092.036
Vol. 3 0.184 1.000 2614.655 1352.400 0.796 1.610 1687.529 1763.484
Vol. 4 0.250 3.000 2404.848 735.454 0.996 1.132 1881.944 1834.958
Vol. 5 0.250 0.500 2971.457 1405.000 1.667 1.903 1819.756 1687.075
Vol. 6 0.250 0.750 2158.700 1351.500 0.843 0.650 1197.716 1091.996
Vol. 7 0.250 0.750 1739.200 1741.717 0.596 0.658 1448.713 1301.887
Vol. 8 0.250 0.500 1715.350 534.300 0.818 1.111 991.864 1126.414
Vol. 9 0.250 0.750 444.112 747.800 0.787 1.188 669.084 886.300
Vol. 10 0.267 0.750 2350.100 1110.400 0.960 1.070 1327.808 1020.286
Vol. 11 0.167 0.500 1867.200 1465.502 1.141 0.762 1337.821 892.870
Vol. 12 0.167 0.500 4273.026 1432.200 1.052 0.697 1703.655 1139.003
Vol. 13 0.250 0.500 2097.089 1155.371 1.313 1.198 1486.526 1233.531
Vol. 14 0.167 0.250 2242.684 967.795 0.997 0.837 987.522 927.726
Vol. 15 0.184 0.500 2040.247 1129.957 0.724 0.804 1213.725 1040.424
Vol. 16 0.250 0.750 2143.692 818.200 0.560 1.199 1186.603 1250.221
Vol. 17 0.250 1.500 1527.845 480.900 2.752 1.309 958.821 978.797
Vol. 18 0.250 1.000 1859.608 666.500 1.630 1.383 1131.413 933.008
Vol. 19 0.250 0.750 1537.508 770.100 1.726 1.137 980.348 906.275
Vol. 20 0.250 0.250 1956.004 655.100 0.853 0.883 1309.289 1036.836
Vol. 21 0.250 0.500 3551.360 2421.060 1.322 1.233 2147.217 1639.619
Vol. 22 0.167 0.500 2464.978 1274.648 0.611 0.624 1038.817 816.924
Vol. 23 0.167 0.750 2304.351 453.500 2.066 0.862 1161.414 1049.327
Vol. 24 0.250 0.500 2901.504 894.337 0.970 1.279 1645.384 1086.512
Mean 0.228 0.885 2213.370 1071.461 1.148 1.076 1332.942 1192.544
SD 0.037 0.860 743.099 450.780 0.523 0.320 358.048 350.116
CV % 16.300 97.091 33.573 42.072 45.557 29.700 26.862 29.359
Min. 0.167 0.250 444.112 453.500 0.560 0.624 669.084 816.924
Max. 0.267 4.000 4273.026 2421.060 2.752 1.903 2147.217 2092.036
Geom. Mean 0.225 0.692 2070.719 987.180 1.056 1.032 1287.195 1150.713
Median 0.250 0.625 2151.196 1039.098 0.983 1.122 1261.507 1067.920
AUC
AUC Cmax/AUC extrapolated
(ng · mL−1 · h) C46 (h−1) (%)
Vol. no. Test Ref. Test Ref. Test Ref. Test Ref.
Vol. 1 1050.137 910.868 11.800 18.700 1.498 1.302 2.37 0.00
Vol. 2 1693.172 2092.036 31.700 13.500 1.407 0.461 1.82 1.38
Vol. 3 1718.755 1788.111 27.200 10.600 1.521 0.756 0.83 1.15
Vol. 4 1897.754 1856.346 11.000 13.100 1.267 0.396 1.39 1.88
Vol. 5 1845.486 1719.478 10.700 11.800 1.610 0.817 1.56 1.90
Vol. 6 1216.693 1113.146 15.600 22.500 1.774 1.214 2.50 1.79
Vol. 7 1485.867 1325.661 43.200 25.000 1.170 1.314 1.46 1.78
Vol. 8 1006.522 1146.775 12.400 12.700 1.704 0.466 3.08 2.75
Vol. 9 690.354 911.329 18.700 14.600 0.643 0.821 1.74 1.80
Vol. 10 1351.357 1038.971 17.000 12.100 1.739 1.069 3.01 3.01
Vol. 11 1379.311 920.579 25.200 25.200 1.354 1.592 1.62 2.03
Vol. 12 1731.709 1162.638 18.500 23.500 2.468 1.232 1.26 1.56
Vol. 13 1505.454 1253.088 10.000 11.300 1.393 0.922 2.58 2.26
Vol. 14 1013.665 949.163 18.200 17.700 2.212 1.020 1.91 2.86
Vol. 15 1237.399 1071.029 22.700 26.400 1.649 1.055 1.33 1.58
Vol. 16 1202.653 1270.280 19.900 11.600 1.782 0.644 4.16 2.80
Vol. 17 1000.433 1006.986 10.500 14.900 1.527 0.478 5.51 2.26
Vol. 18 1197.411 954.597 28.100 10.800 1.553 0.698 2.57 2.11
Vol. 19 1006.229 925.835 10.400 11.900 1.528 0.832 2.03 2.02
Vol. 20 1336.472 1058.242 22.400 16.800 1.464 0.619 1.19 1.07
Vol. 21 2173.030 1657.372 13.500 10.000 1.634 1.461 1.75 1.68
Vol. 22 1057.293 830.908 21.000 15.500 2.331 1.534 3.13 1.80
Vol. 23 1198.950 1068.588 12.600 15.500 1.922 0.424 2.19 1.94
Vol. 24 1682.290 1108.024 26.400 11.700 1.725 0.807 2.10 1.78
Mean 1361.600 1214.169 19.113 15.725 1.620 0.914 2.213 1.883
SD 358.359 348.108 8.244 5.160 0.377 0.365 1.035 0.641
CV % 26.319 28.671 43.134 32.812 23.277 39.991 46.795 34.056
Min. 690.354 830.908 10.000 10.000 0.643 0.396 0.833 0.000
Max. 2173.030 2092.036 43.200 26.400 2.468 1.592 5.512 3.010
Geom. Mean 1316.580 1173.325 17.609 15.011 1.573 0.841 2.023 //
Median 1286.936 1089.527 18.350 14.050 1.582 0.827 1.974 1.843

Referenced by
Citing PatentFiling datePublication dateApplicantTitle
US7687542Feb 10, 2006Mar 30, 2010Kowa Pharmaeuticals America, Inc.Rapidly bioavailable tablet and capsule formulations of diclofenac
US7700125Feb 7, 2006Apr 20, 2010Kowa Pharmaceuticals America, Inc.Moisture resistant container systems for rapidly bioavailable dosage forms
US7759394Jun 16, 2006Jul 20, 2010Apr Applied Pharma Research SaDiclofenac formulations and methods of use
US7939561Feb 7, 2006May 10, 2011Apr Applied Pharma Research S.A.Blister packaging for acute pain regimens
US8097267Sep 9, 2009Jan 17, 2012Apr Applied Pharma Research S.A.Moisture resistant container systems for rapidly bioavailable dosage forms
US8097651Jan 7, 2010Jan 17, 2012Apr Applied Pharma Research S.A.Diclofenac formulations and methods of use
WO2007059591A1 *Nov 28, 2006May 31, 2007Imaginot Pty LtdOral therapeutic compound delivery system
WO2012172413A1 *Jun 15, 2012Dec 20, 2012Abbott Healthcare Pvt. Ltd.Pharmaceutical composition comprising a combination of eperisone and diclofenac and process for preparing thereof
Classifications
U.S. Classification424/464, 514/567
International ClassificationA61Q11/00, A61K9/20, A61K47/02, A61K31/196, A61K8/44
Cooperative ClassificationA61Q11/00, A61K8/44, A61K47/02, A61K31/197, A61K31/196, A61K9/2009
European ClassificationA61Q11/00, A61K47/02, A61K8/44, A61K9/20H2, A61K31/196
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