ACTIVE INGREDIENT CONTAINING STABILISED SOLID FORMS AND METHOD FOR THE PRODUCTION THEREOF

Abstract

The invention relates to solid medicinal forms containing at least one active ingredient and at least one pharmaceutically compatible, water soluble drying agent which is selected from the group consisting of trimagnesium dicitrate and/or calcium chloride, the solid medicinal form having a drying loss of at most 6% and a relative equilibrium moisture content of 25% or less. The invention also relates to solid medicinal forms containing a moisture-sensitive active ingredient and trimagnesium dicitrate.

Claims

1. A non-effervescent solid medicinal form comprising a hydroxypropylmethylcellulose (HPMC) capsule filled with a capsule filling comprising: a. 30 to 40% by weight of a moisture-sensitive active ingredient, wherein said active ingredient is not trimagnesium dicitrate; b. 20 to 50% by weight of trimagnesium dicitrate acting as a drying agent that stabilizes the moisture sensitive agent against hydrolysis during storage; and c. 5 to 30% by weight of a microcrystalline cellulose; wherein said medicinal form exhibits a drying loss, measured at 120° C./30 min, of 0.5 to 2.5% and a relative equilibrium moisture, measured at 25° C., of at most 15%.

2. The non-effervescent solid medicinal form of claim 1, wherein said microcrystalline cellulose comprises 10 to 20% by weight of the capsule filling.

3. The non-effervescent solid medicinal form of claim 1, wherein said medicinal form exhibits a relative equilibrium moisture, measured at 25° C., of at most 10%.

4. The non-effervescent solid medicinal form of claim 1, wherein said capsule filling further includes 0.3 to 2% by weight of stearic acid.

5. The non-effervescent solid medicinal form of claim 1, wherein said capsule filling further includes 1 to 2% by weight of stearic acid.

6. The non-effervescent solid medicinal form of claim 1, wherein said capsule filling further includes 0.2 to 2% by weight of silica.

7. The non-effervescent solid medicinal form of claim 1, wherein said solid medicinal form is packaged together with an external drying agent in a tight packaging that is substantially impermeable to water.

8. The non-effervescent solid medicinal form of claim 1, wherein the moisture-sensitive active ingredient and the trimagnesium dicitrate drying agent are dry granulated together.

Description

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0083] The invention is specified by the below examples without being limited thereto.

Example 1

[0084] If the preferred drying agent trimagnesium dicitrate is dried at 130° C. for several hours, a product is obtained which to the skilled person's surprise has an equilibrium moisture content having a hardly measurable value of 0.6% at 25° C.

[0085] Sodium sulfate which has a drying loss at 130° C. (testing period 30 min) of 0.06%, still yields a value of 32.7% when the equilibrium moisture content is determined. This value proves that sodium sulfate cannot adsorb either a water amount worth mentioning or firmly bonds these adsorbed amounts. This substance is fully unsuited to stabilize moisture-sensitive active ingredients.

TABLE-US-00001 TABLE 1 weight increase drying loss (%) with storage at 130° C./ equilibrium at 15% relative 30 min moisture humidity/25° C. microcrystalline 0.5 <1.0 2.2 cellulose trimagnesium 0.2 <1.0 8.6 dicitrate calcium chloride 0.02 <1.0 45.9 sorbitol 0.1 9.0 0.1 silica 0.5 <1.0 6.4

[0086] The substances were dried at 130° C. for 5 hours (sorbitol: 70° C.) and the drying loss was determined. Then, the weight increase of the individual substances was determined at 25° C./15% relative humidity over 27 days.

[0087] The table proves that even with a very low humidity of 15% calcium chloride can absorb major amounts of water and that to the skilled person's surprise the preferred trimagnesium dicitrate bonds more water than the generally known drying agent silica (silica gel).

Example 2

[0088] In a tightly sealing glass vessel, two Arcellas having 3.5 g trimagnesium dicitrate, dried at 130° C., or having 1.264 g amoxicilline trihydrate (water content 13.1%) are placed side by side and stored at 25° C. After 14 days, the weight of amoxicilline is only 1,105 g whereas the weight of trimagnesium dicitrate is 3.66 g. The amoxicilline released 12.6% water of crystallization which was absorbed by the drying agent. The new drying agent is active such that it virtually split off the entire water of crystallization of amoxicilline (theoretical value: 12.9%).

[0089] If this experiment is repeated with the known drying agent silica gel, the antibiotic only loses 0.1% weight after 25 days. This means that the dried trimagnesium dicitrate according to the invention represents an extremely potent drying agent.

[0090] Under precisely equal test conditions, the amoxicilline only loses 9.0% with calcium chloride dried at 130° C. after 26 days/25° C.

Example 3

[0091] Two dry mixtures having the following composition were produced:

TABLE-US-00002 TABLE 2 a) b) acetylsalicylic acid 500 mg 500 mg sorbitol 950 mg 950 mg citric acid 59 mg 59 mg magnesium oxide 25 mg 25 mg aspartame 10 mg 10 mg lemon flavor 25 mg 25 mg trimagnesium dicitrate — 125 mg (TOTAL 1694)

[0092] The components were mixed, filled into aluminum-coated bags and stored at 40° C. for three months.

[0093] In case a), a disintegration caused by water of acetylsalicylic acid occurred while 3.2% salicylic acid and glacial acetic acid were formed. The pattern was uneatable.

[0094] Pattern b) showed a disintegration of 0.6% and virtually no odor of glacial acetic acid. The pattern was still o.k. as regards taste.

[0095] The equilibrium moisture of pattern a) was 34% (25° C.) and that of pattern b) 8.4% due to the addition of trimagnesium dicitrate. The low equilibrium moisture according to the invention markedly stabilizes the active ingredient due to its water bond.

Example 4

[0096] Trimagnesium dicitrate, calcium chloride x 2H.sub.2O are dried at 130° C. for several hours. The drying loss, measured at 150° C./30 min, is:

Trimagnesium dicitrate: 1.6%; equilibrium moisture content <0.5%
Calcium chloride: 3.4%; equilibrium moisture content <0.5%
clavulanic acid 3.0 kg
trimagnesium dicitrate (mean particle size 0.25 mm) 4.0 kg
microcrystalline cellulose 1.5 kg
mannitol 1.0 kg
silica (Syloid AL 1) 0.2 kg
povidone K25 0.2 kg
magnesium stearate 0.1 kg

[0097] The components were sieved in a room at 22° C., 19% relative humidity and then compacted to a slug in a roll compactor. The slug was dry granulated over 2.5 mm and 1.0 mm. The granules were kept in a sealingly closing container prior to the encapsulation.

[0098] The drying loss of the granules, measured at 105° C./30 min, was 2.4%, the equilibrium moisture content was 4.6% (25° C.). Under exactly the same conditions, the test was repeated with 3.0 kg dried calcium chloride as described above. The calcium chloride was similarly well processed into granules.

Drying loss: 1.7% (105/30 min)
Equilibrium moisture: 5.4% (25° C.)

[0099] Both granules were filled at 21° C./22% relative humidity in undried HPMC capsules (filling weight 417 mg per capsule size 1) and under the same room conditions into glass vials (20 items) and closed with sealingly closing PE plugs. Some plugs contained 2.0 g molecular sieve.

[0100] The patterns were subjected to a stress test at 40° C./75% relative humidity for 6 months.

TABLE-US-00003 TABLE 3 3 6 6 Test parameters Start months months months* appearance capsule white white almost almost content white white disintegration time 8.5 min 9.2 min 9.1 min 8.8 min capsule in water, 37° C. drying loss 2.8% 2.6% 2.9% 2.5% capsule content equilibrium moisture 5.2% 4.8% 5.5% 4.2% content capsule content drying loss 2.7% 2.3% 2.2% 2.1% HPMC capsule drying loss 1.2% — — 1.6% drying agent/plug content clavulanic 101.4% 99.8% 96.1% 96.7% acid *pattern with dry plug All drying losses measured at 105° C./30 min, Drying loss drying agent/plug at 200° C./30 min

[0101] Results (clavulanic acid capsules with calcium chloride):

TABLE-US-00004 TABLE 4 3 6 6 Test parameters start months months months* appearance capsule white almost yellow white/ content white yellow disintegration time 7.9 min 8.2 min 8.6 min 8.4 min capsule in water, 37° C. drying loss 2.1% 2.3% 2.2% 1.7% capsule content equilibrium moisture 5.9% 6.9% 7.2% 5.2% content capsule content drying loss 3.1% 3.2% 2.9% 2.5% HPMC capsule drying loss 1.2% — — 6.4% drying agent/plug content clavulanic 100.7% 98.7%  93.1%  94.6% acid *pattern with dry plug All drying losses at 105° C./30 min Drying loss drying agent/plug at 200° C./30 min

[0102] Although the drying losses of the capsule content increase in both test examples due to the exposition time during the capsule filling and the water content of the undried capsule, the equilibrium moisture content of the capsule content does virtually not change in both test examples. This proves that the water absorbed during filling and extracted from the capsule is absorbed by the drying agent without the equilibrium moisture content decisive for the stability of the moisture-sensitive clavulanic acid changing. Due to the dense packaging agent, the drying losses of the capsule content and the accompanying equilibrium moisture contents hardly change during stress storage for 3 and 6 months. This is an essential precondition for the stabilization of the active ingredient. The results on the drying loss of the drying agent in the plugs are very interesting. Although the person skilled in the art knows that molecular sieve is an extremely severe drying agent, it hardly removed water from the capsules with content to the skilled person's surprise in the case of the drying agent trimagnesium dicitrate and the drying loss only increased from 1.2 to 1.6%. This is a clear evidence for the strong bond of the water to trimagnesium dicitrate. Again to the skilled person's surprise, the water absorption of the molecular sieve markedly increased from 1.2% to 6.4% in the case of the clavulane capsules with the drying agent calcium chloride. Although calcium chloride is considered a strong drying agent, the molecular sieve absorbed over 5% water from the capsules. This in turn proves that although to the skilled person's surprise trimagnesium dicitrate can bind less water than calcium chloride, the strength of the water bond is markedly higher. This makes trimagnesium dicitrate the preferred drying agent for active ingredients highly sensitive to water since the new drying agent can so to speak irreversibly bond the water up to the conditions of about 40° C. and largely dry the sensitive active ingredient by ensuring in the solid form equilibrium moisture contents around 5% up to temperatures of 40° C.

[0103] If the clavulanic acid granules are produced without one of both drying agents, they have an equilibrium moisture content of 28.9% after the production, which is an equilibrium moisture content very low for capsule granules. The active ingredient in this mixture loses, when stored at 40° C. in a sealed vial, over 25% content within one week and changes its color to light brown. Normal capsule mixtures have an equilibrium moisture content of 35 to 55%. Thus, clavulanic acid is indeed an extremely moisture-sensitive active ingredient which even in the presence of small amounts of water rapidly loses activity.