CA2254411A1 - Ticlopidine hcl formulations - Google Patents

Abstract

Ticlopidine hydrochloride solid dosage formulations are stabilized against oxidation by incorporating therein effective amounts of phosphoric acid.

Description

CA 022~4411 1998-11-18 TICLOPIDINE HCL FORMULATION

FIELD OF THE INVENTION

This invention relates to pharmaceutical formulations. More specifically, it relates to orally administrable dosage formulations of ticlopidine and similar compounds, an to processes for inhibiting the degradation of ticlopidine over time.
BACKGROUND OF THE INVENTION

Ticlopidine, the generic name of the pharmaceutical substance 5-[(2-chlorophenyl)methyl]-4,5,6,7-tetrahydrothieno-[3,2c]pyridine, of chemical formula:

~ ~

is a known pharmaceutical substance, useful as a platelet aggregation inhibitor. It is marketed commercially as its hydrochloride addition salt, in the form of orally administrable tablets. As an amine compound, it is desirable to stabilize it against oxidation, by protonation of its amine group, i.e. by preparing formulations which include an acid stabilizing compound. Without such stabilizer, and in the presence of common tablet excipients such as magnesium stearate, polyvinyl polyvinylpyrrolidone and the like, it discolors, from white to a grey/brown color through oxidation.

CA 022~4411 1998-11-18 BRIEF DESCRIPTION OF THE PRIOR ART

Ticlopidine HCl formulations commonly include a stabilizing amount of an organic acid to enhance it:s stability and hence increase its storage life. Thus, Canadian Patent 1,176,170 Chowhan (Syntex) discloses stabilized ticlopidine HCl compositions using non-volatile organic acid, especially citric acid, as a stabilizer.
Canadian Patent Application 2,100,836 Sherman proposes the use of stearic acid, without any other organic acid, as stabilized in ticlopidine HCl formulations.

There are significant disadvantages to the use of these organic acids in ticlopidine HCl formulations. Citric acid, which is soluble in water so that mixing in compounding processes using it are relatively simple, is nevertheless expensive, and relatively large quantities of citric acid are needed in order to bring the aqueous solution pH of the formulation into the correct acidity range, pH 3-4. As a naturally solid, crystalline material, it tends to crystalize out of solution and upset solution blending procedures.
Stearic acid, on the other hand, is largely insoluble in water, so that processes which use aqueous formulations for homogeneous mixing and dispersing of the ingredients cannot conveniently be used when stearic acid is chosen as stabilizer. Over-mixing of compositions containing stearic acid can result in reduced bio-availability, owing to the fact that stearic acid can act in part as an emulsifier, to coat and separate individual particles of the mixture from the bio-available bulk of particles. Organic stabilizers in general, and stearic and citric acid stabilizers in particular, have a negative impact on the compressibility of the final composition, leading to brittle materials which are very much harder to compress. This is particularly so when CA 022~4411 1998-11-18 the acid has to be used in substantial amounts to be effective as a stabilizer, as in the case of citric acid.

It is an object of present invention to provide novel formulations of ticlopidine HCl which exhibit good storage stability without significant discoloration and without significantly affecting the ln vivo rate and extent of release of the active ingredient after storage.

SUMMARY OF THE INVENTION

The present invention provides stable, solid, orally administrable dosage compositions of ticlopidine HCl and a stabilizing amount of phosphoric acid, along wit:h pharmaceutically acceptable carrier materials. It has been found according to the present invention that phosphoric acid is an effective stabilizer for ticlopidine HCl, and can readily be incorporated in dosage formulations thereof to provide storage stable solid compositions such as tablets, with acceptable bio-availability after storage.

Phosphoric acid is approved as acceptable for use in various formulations of edible products. However, as far as is known, it has not been used in practice in any pharmaceutical formulations. It does however exhibit significant advantages in practice. As a normally liquid, water soluble/miscible compound, it is very easy to mix into intimate, homogeneous mixtures with solid pharmaceutical compositions. It is inexpensive, readily available, adequately biocompatible and does not interfere with the bio-availability of the active pharmaceutical ingredients. As a strongly acidic compound, only small amounts are required to bring the ticlopidine HCL formulation pH into the required low range for stability.

CA 022~4411 1998-11-18 DESCRIPTION OF THE ~RED EMBODIMENTS

To be effective as a stabilizer, the phosphoric acid used in the formulations of the invention should be used in amounts effective to provide formulations having pH from about l to about 5.5 in aqueous solution. Thus, the precise amount of phosphoric acid to be used depends upon the tablet size, the amount of active ingredient and the acidity of any other ingredients included in the formulation. When all of the ingredients except the ticlopidine HCl and the phosphoric stabilizing agent are substantially neutral, such an effective amount of phosphoric acid is from about 0.5 to about 3 parts by weight of 85% phosphoric acid per l00 parts by weight of ticlopidine HCl, preferably from about l-l.5 parts by weight per l00 parts by weight of ticlopidine HCl.
Some routine experimentation may be required to determine the optimum amount of phosphoric acid, for each individual dosage formulation, but this is well within the skill of the art.

Typical additional ingredients for use in formulations according to the invention are those commonly used in pharmaceutical tablets, such as microcrystalline cellulose or other cellulose derivatives, starch and starch derivatives, crosslinked polyvinylpyrrolidone (povidone), to act as carriers or excipients, vegetable oils to provide the necessary binding characteristics for the tablets, and magnesium stearate and the like, to act as a lubricant in forming the tablets. Typically, the active ingredient ticlopidine HCl constitutes more than 50% of the total weight, preferably from 55-75%, of the formulation.

Mixing procedures for preparing compositions according to the invention are generally in accordance with standard procedures known in the art. Typically, the active CA 022~4411 1998-11-18 ingredient, ticlopidine HC1 and carriers, e.g.
microcrystalline cellulose, corn starch and sodium starch glycolate, are initially mixed to form a dry homogeneous powder. The phosphoric acid stabilizer and the povidone are added slowly to water, and mixed at slow speed to form a solution. Then the solution is added slowly to the powder mixture in, for example, a ribbon blender and mixed to form a uniform wet mass, optionally with the addition of more water. After thorough mixing in this way, the wet mass is dried, e.g. on trays in a forced air drying oven, to obtain dry granules of the mixed formulation.

The preparation of tablets from such a granular formulation can be conducted in standard tableting apparatus, e.g. by compression into cores of appropriate size. After tablets have been prepared, they are suitably film coated, using a solution of film forming colored or clear material.
The coating solution or suspension is appropriately sprayed onto the tablets, followed by drying.
Specific examples of the most preferred embodiments of the invention will now be described in detail, these to be viewed as illustrative of the present invention and not limiting.

Film coated tablets of ticlopidine HCl active ingredient 250 mg were prepared according to the following formulation:

Ticlopidine HCl 250 mg (63.29%) Microcrystalline cellulose 66.60 mg (16.86%) Corn Starch 33.57 mg (8.50%) CA 022~4411 1998-11-18 Sodium Starch Glycolate 9.88 mg (2.5) Purified Water (Retained) 7,90 mg (2.00%) Phosphoric acid (85%) 3.35 mg (0.85%) Povidone 15.80 (4.00%) Hydrogenated vegetable oil (Sterotex) 5.93 mg (1.50%) Magnesium Stearate 1.97 mg (0.50%) Initially, there was prepared a dry granular mixture of the microcrystalline cellulose, ticlopidine HCl, corn starch and a portion of the sodium starch glycolate, in a ribbon blender, with mixing for 15 minutes, in a batch size sufficient to make 150,000 tablets (59.25 kg of active ingredient). There was separately prepared, in a mixer, a solution of phosphoric acid and povidone in purified water, the phosphoric acid and povidone being added slowly into the water during mixing, and mixing being continued until a clear solution was obtained. Then the solution was slowly added evenly over the mixing powders in the ribbon blender, and mixing was continued, at room temperature, until a uniform wet mass was obtained. The wet granules were screened and then spread evenly onto drying trays and placed on racks for forced air drying at 43~C. for 2-5 hours. After further screening, the granules were fed into a ribbon blender and mixed for a further three minutes. Then the remainder of the sodium starch glycolate was added and mixed in, followed by the addition of the hydrogenated vegetable oil and magnesium stearate, with mixing for a further minute. This composition was tableted into round modified concave tablets with a conventional punch tableting apparatus, to give tablets of 395 mg average individual weight. The tablets were film coated by spraying with an aqueous solution of Dri-Klear-042 ~Trade-mark CA 022~4411 1998-11-18 (825 g in 5525 g water) for sealing purposes. Dri-Klear-042 is a commercially available, proprietary composition of hydroxypropyl methylcellulose, talc and triethyl citrate. The tablets had acceptable hardness and disintegration S resistance.

Tablets prepared as described above in Example 1 were tested for stability in an accelerated stability test.
For this test, the tablets were stored for 4 weeks at 40"C
under conditions of 75% relative humidity, to represent accelerated storage conditions.

15Assays of the tablets before and after the accelerated stability test showed no difference in their bio-availability, and no significantly difference in their appearance. Whilst the initial appearance of the tablets was, in color, white to off-white, after the 4 week stability test they were more off-white. Otherwise there was no difference, indicating that the formulation is stable.

25A stock standard solution of ticlopidine HCl reference standard was prepared, by accurately weighing out 55.5 mg of the solid material and transferring it to 200 mL
volumetric flask. It was dissolved in 50 mL water and diluted to 300 mL volume, with thorough mixing, to give a 30concentration of 0.2775 mg/mL. The solution was filtered through a 1.2 ~m Acrodisc filter, discarding the first 100 mL
of filtrate.

A working standard solution was prepared from the CA 022~4411 1998-11-18 stock standard solution, by transferring 5.0 mL of stock standard solution filtrate to a 500 mL volumetric flask, diluting to 50 mL volume with water and thorough mixing (concentration - 0.02776 mg/mL).

Sample preparation was conducted using a standard USP Apparatus 2 (paddles). One 250 mg tablet was placed into each of the six dissolution vessels, the paddles lowered to a distance of 2.5 cm from the bottom of each vessel, with the 10shaft centered. 900 mL of water at 37~C+0.5~C was added to each vessel, and the paddles rotated at 50 rpm to effect dissolution. An aliquot of solution was withdrawn, from the mid-zone, filtered immediately through 1.2 ~m Acrodisc filters, and the first 10 mL of each filtrate was discarded.
The remainders were collected in individual containers. 5.0 mL of each filtrate solution was transferred to a 50 mL
volumetric flask, diluted to 50 mL with water and thoroughly mixed. Concentration - 0.02778 mg/mL.

20The amount of ticlopidine HCL dissolved was determined by UV spectrophotometry, measuring UV absorbances of solution under test at the wavelength of maximum ticlopidine HCl absorbance, about 232 nm, in comparison with the working standard solution.
In all samples, not less than 95% of the active ingredient had dissolved after 45 minutes (range 95-99%).
Comparative, similar testing on a commercial ticlopidine HCl formulation stabilized with citric acid showed almost exactly the same dissolution characteristics - of six separate samples, not less than 95% of the active ingredient had dissolved at 45 minutes in each case, range 95-100%.

Assays conducted on tablets promptly after their CA 022~4411 1998-11-18 manufacture and on tablets after the four week accelerated storage described in Example 2, showed no differences in their dissolution rates. Also, very similar results were obtained when the dissolving medium was O.lN hydrochloric S acid instead of water.

Claims (10)

1. An orally administrable dosage formulation of ticlopidine hydrochloride comprising ticlopidine hydrochloride as active ingredient and phosphoric acid as stabilizer.

2. The formulation of claim 1 in the form of a tablet.

3. The formulation of claim 2 comprising from about 0.5-3 parts of 85% phosphoric acid per 100 parts ticlopidine HCl.

4. The formulation of claim 3 comprising from about 1-1.5 parts of 85% phosphoric acid per 100 parts ticlopidine HCl.

5. The formulation of claim 3 wherein the active ingredient ticlopidine HCl constitutes at least 50% by weight of the formulation.

6. The formulation of claim 3 wherein the active ingredient ticlopidine HCl constitutes from about 55-75% by weight of the formulation.

7. The formulation of claim 6 further including at least one excipient, at least one binder and at least one lubricant.

8. A process of stabilizing a ticlopidine hydrochloride dosage formulation to inhibit oxidation of the ticlopidine hydrochloride on storage, which comprises adding to the formulation an effective amount of phosphoric acid.

9. The process of claim 8 comprising the steps of dry mixing ticlopidine HCl with a carrier to form a dry homogeneous powder, adding an aqueous phosphoric solution to said powder, mixing the powder and solution to form a slurry, drying the slurry to obtain dry granules, and pressing the granules into tablets.

10. The process of claim 9 including the additional, final step of film coating the tablets.