IE50400B1 - Gelatin capsule dosage unit containing triamterene - Google Patents

Description

The invention relates to gelatin capsule dosage forms which contain triamterene as the active ingredient.

Triamterene is a nonmercurial, orally effective diuretic which does not enhance the excretion of potassium. Further, triamterene potentiates the action of other diuretics and the combinations also restrict the loss of potassium due to their action. A still further utility for triamterene is the lowering of blood pressure, i.e. an antihypertensive agent.

Gelatin capsule dosage units comprising triamterene and triamterene and hydrochlorotriazide are known (see Chem. Abs. 1967, No. 11345k and U.S. Patent 3,081,203 respectively.

The formulation of a poorly soluble-low dose medicament such as triamterene in a gelatin capsule presents several problems. Due to the dose of the medicament, it is necessary to add diluents in order to get the bulk required to fill the capsule. A disadvantage of this is that many diluents interfere with the release of the medicament.

A further disadvantage in the release of a poorly soluble medicament such as triamterene from gelatin capsules is that during the hydration, the gelatin forms a viscous barrier. This results in the formation of a plug or coagulation of the capsule ingredients which in turn, results in poor dispersion and dissolution of the active ingredient. Instead of obtaining a maximum surface area for the drug, which is one of the prerequisites for increased solubility, a minimum surface area is obtained. A very erratic dissolution rate of the medicament results.

It has been unexpectedly discovered that the combination of a surfactant and carbonate or bicarbonate salt as diluents in a triamterene gelatin capsule dosage form overcomes the above stated problems. Instead of a plug of the ingredients forming upon hydration of the gelatin, rapid dispersion of the ingredients takes place. A maximum surface area of triamterene is provided which results in a dramatic increase in dissolution.

According to the present invention there is provided a gelatin capsule containing triamterene, a pharmaceutically acceptable surfactant and a calcium, ammonium or alkali metal nontoxic carbonate or bicarbonate salt.

The advantage of this invention is that it provides a significantly better dispersion and faster dissolution of the medicament resulting in better absorption and bioavailability.

The compositions of this invention as described above are advantageously carried out in conjunction with another non-pteridine diuretic, particularly with a thiazide diuretic. Exemplary of such thiazide derivatives are chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, benzylhydroflumethiazide, trichloromethiazide or benzthiazide.

Advantageously the triamterene will be present in the capsule in an amount of from 10 mg to 100 mg and the thiazide compound of from 2 mg to 250 mg.

Following are in vitro test results comparing the dissolution rate of capsule dosage forms containing triameterene with a variety of diluents.

Table I Ingredients (mg /capsule) I II Ill IV V VI VII Triamterene 50 50 50 50 50 50 50 5' Hydrochlorothiazide 25 - 25 - 25 25 25 Lactose 91.8 101 44 - - - - Magnesium Stearate 3.2 1.5 1.6 1.6 1.6 x. 6 1.6 10 Calcium Carbonate - - 44 44.2 44.2 - 44.2 Sodium Carboxymethyl starch - - - 69.2 47.6 88 44.2 Cetyldimethyl15 pyridinium Chloride - - 3.4 3.4 - 3.4 3.4 All formulas were tested in a #4 hard gelatin capsule Table XI Percent Triamterene Dissolved Formula 5 minutes 10 minutes 20 minutes 30 minutes I 0 0 5 8 II 0 0 2 4 III 15 70 93 97 IV 53 89 97 99 25 V 6 37 54 67 VI 45 65 74 85 VII 55 82 97 98 The above dissolution rate studies were performed by the USP Paddle Method in 900 ml of artificial gastric fluid without enzyme at 37° C and 50 RPM. This test is detailed under Dissolution, Method II of the 4th Supplement, United States Pharmacopeia XIX, National Formulary XIV, page 194, released January 31, 1978.

Referring specifically to the above Table I, it can be seen that Formulas I and II contain triamterene with hydrochlorothiazide and triamterene alone respectively. Both of these formulas have conventional capsule diluents present, i.e., lactose and magnesium stearate. It will be noted from Table II that only 8% and 4% of triamterene dissolves over a 30 minute period.

When calcium carbonate is present without the surfactant, Formula V, 67% of the triamterene dissolves in 30 minutes. When the surfactant is present without the carbonate, Formula VI, 85% dissolves in 30 minutes.

However, when calcium carbonate and a surfactant such as cetyldimethylpyridinium chloride are added to the formulas (III and IV), the dissolution rate of triamterene is increased to 99%.

The results of these tests clearly demonstrate that when both the carbonate and surfactant are added in combination to the gelatin dosage unit, a very dramatic increase in dissolution of the tfiamterene results, i.e., from 4% to 99% in 30 minutes.

In addition to calcium carbonate, it will be evident to one skilled in the pharmaceutical art that any nontoxic ammonium or alkali metal carbonate or bicarbonate salt may also be employed in this invention. Exemplary of such carbonates or bicarbonates are magnesium carbonate, sodium carbonate, potassium carbonate, or sodium bicarbonate. The salts will be present from 6% to 52% of the capsule formation.

Preferably the salts will be present from 12% to %.

Exemplary of surfactants other than cetyldimethylpyridinium chloride which may be employed in this invention are polysorbate derivatives such as polysorbate 80, sodium lauryl sulfate and dioctyl sodium sulfo10 succinate. The surfactant may be present in an amount of from 0.15% to 3.0% of the composition.

Preferably the surfactant will be present from 0.5% to 3.0%.

If desired, disintegrants such as starch or Veegum 15 which are standard pharmaceutical excipients commonly used in capsule manufacturing may also be employed.

Since these ingredients are not an essential aspect of this invention, the amount can be varied.

Advantageously the ingredients present in the 20 Formulas of I to VII of Table I are mixed together and filled into a# 4 (n° 4 capsule — 50-175 mg powder capacity) hard gelatin capsule. If desired, these ingredients may also be encapsulated as granules.

The granules may be producted by wetting the triamterene with a suitable granulating agent such as, for example, solutions of gelatin or polyvinylpyrrolidone. The wetted powder is passed through a 3.4 mm screen and dried overnight. The dried granules are then passed through a 1.4 mm standard screen, mixed with the diluents and filled into a #4 hard gelatin capsule.

Claims (9)

1. A gelatin capsule dosage unit containing triamterene wherein it further contains a pharmaceutically acceptable surfactant and a calcium, ammonium or alkali metal non-toxic carbonate salt in amounts sufficient 5 to produce a more rapid dispersion of the ingredients.

2. A dosage unit as claimed in claim 1 wherein the surfactant is cetyldimethylpyridinium chloride.

3. A dosage unit as claimed in claim 1 or claim 2 wherein the surfactant is present in an amount of from 0.5% to 3.0%. 10

4. A dosage unit as claimed in any one of claims 1 to 3 wherein the carbonate salt is calcium carbonate.

5. A dosage unit as claimed in any one of claims 1 to 4 wherein the carbonate is present in an amount of from 6% to 52%.

6. A dosage unit as claimed in any one of claims 1 to 5 wherein the 15 triamterene is present in an amount of 10 to 100 mg, the surfactant is present in an amount of from 0.5 to 3.0% and the salt is present in an amount from 12% to 35%.

7. A dosage unit as claimed in any one of claims 1 to 5 further containing hydrochlorothiazide. 20

8. A dosage unit as claimed in claim 7 wherein the triamterene is present in an amount of from 10 to 100 mg and the hydrochlorothiazide is present in an amount of from 2 mg to 250 mg.

9. A gelatin capsule dosage unit substantially as described herein by way of Example.