DE3922021A1 - NIFEDIPIN CONTAINING DIGITAL CAPSULES AND THEIR PREPARATION - Google Patents

Abstract

Hard gelatin capsules contain nifedipine (I) dissolved in a water-soluble carrier (II) which does not embrittle the capsule on storage at room temp. (II) is an ethoxylated fatty acid ester, esp. a reaction prod. of 1 mole hydrogenated castor oil with 40 moles ethylene oxide, e.g. 'Cremphor' RH40 (RTM). The (I):(II) ratio is 1:10-70. The capsule shell material contains dyes, pigments or opacifiers esp. Ti02, Fe oxide or CaCO3. The soln. of (I) in (II) is introduced into the capsules and the capsule halves are sealed together with a strip of gelatin film. ADVANTAGE - Embrittlement problems associated with hygroscopic carriers such as polyethylene glycol are avoided (cf. DE3438830 , US4450877 ) Bioavailability and absorption of (I) are as good as with conventional capsules.

Description

The present invention relates to new, Nifedipine-containing hard gelatin capsules and a method for their production.

Hard gelatine capsules have already been known (DE-A- 34 38 830, EP-A-1 82 007), in which the nifedipine in a Mixture of liquid at room temperature, semi-solid and / or solid polyethylene glycols in a particular Ratio is present, so that the solidification point and the Viscosity of the mixture in well-defined areas to come to rest. By the selected mixing ratio the polyethylene glycols and the resulting values the solidification point and the viscosity becomes a mass obtained, which at a slightly elevated temperature liquid is, but solidifies again at room temperature. Thereby The mass at slightly elevated temperature in hard gelatin capsules be filled without the junction the two capsule halves then to prevent a possible oozing out of the mass by banding or gluing must be sealed.

The last mentioned goals could be different Active ingredients can also be achieved by other means (US-A-44 50 877, EP-B-49909). The active ingredient is in dissolved a liquid medium that solidifies so far or gelled, that its flow properties disappear; this creates a thixotropic system that is in hard gelatin capsules also fill and in it solidified or gelled, so that when storing the capsules at room temperature, no leakage or leakage of the capsule contents at the junction of the two capsule halves is to be feared. The liquid  Medium consists of a polyethylene glycol, a mixture of polyethylene glycols of various molecular weights or a mixture of polyethylene glycol (s) with polyvinyl acetate or hydrogenated castor oil or colloidal Silica.

Meet the already known hard gelatin capsules although the purpose insofar as an outflow or leakage of the capsule contents during storage avoided without the connection point of the Both capsule halves would have to be sealed. Together They are characterized by the fact that nifedipine in a liquid medium of polyethylene glycols is. However, this poses a serious disadvantage because the glycols, in particular glycerol, propylene glycol and the polyethylene glycols, known to be hygroscopic are. Because of their hygroscopicity, such glycols are preferred Water from their environment, in the specific case so off the capsule wall. As a result of the progressive dehydration the capsule wall over time, d. H. while the storage, brittle and brittle, what the effective The usefulness of these capsules sets limits.

On the other hand, they are nifedipine-containing soft gelatin capsules has already been proposed (US-A-37 84 684), which should be bitten in the mouth to one to ensure sublingual absorption of the active substance. The capsules contain nifedipine as a liquid mixture in a mixture of polyalkylene glycol (s) and a lower one Alcohol or polyalcohol. To the bitter taste of nifedipine in the mouth, contains the mixture preferably a sweetener and / or a flavoring agent. The gelatin material of the capsule wall contains a Dye and an opaque substance to the To protect nifedipine from the influence of light; as examples  of which the yellow-orange S (Color Index No. 15 985) or the titanium dioxide, an iron oxide or calcium carbonate called.

However, newer pharmacological and clinical have Studies (J. Van Harten et al., Lancet 12. 12. 1987, 1363-1364) the supposed or hoped for Sublingual absorption of nifedipine from soft gelatin capsules can not confirm. The absorption of the Active ingredient is essentially through the stomach, a effective sublingual absorption after biting the capsules in the mouth were not detected.

So far it has not succeeded in containing nifedipine Gelatine capsules, in particular hard gelatine capsules, produce, which on the one hand even with longer Storage duration neither brittle nor brittle, but remain unchanged and on the other hand one ensure rapid uptake of the drug into the bloodstream.

It has now been found that the above described Targets by containing a new kind of nifedipine Hard gelatin capsules can be achieved, in which the nifedipine in dissolved form in one for the human organism there is a compatible water-soluble carrier, which carrier during storage of the capsules at Room temperature does not cause brittleness or brittleness same leads.

As water-soluble carrier in the above sense Particularly suitable are polyoxyethylene glycol fatty acid esters; these are reaction products of fatty acid esters with a certain number of ethylene oxide molecules, too to be found under the name fatty acid polyethylene glycol ester  are. Among these are those under the brand name Cremophor®RH commercially available products (Manufacturer: Badische Anilin- und Sodafabrik, Ludwigshafen on the Rhine, Germany). They are made by reaction for example, about 40 or 60 moles of ethylene oxide 1 mol hydrogenated castor oil (English: PEG 40 or PEG 60-Hydrogenated Castor oil). Accordingly, the majority of products consists Cremophor®RH from esters of hydrogenated castor oil with oxyethylated glycerol; in addition there are polyoxyethylene glycol esters the fatty acids of hydrogenated castor oil.

Also suitable is the product Cremophor®EL (Brand name), which by reacting 1 mole of castor oil is prepared with 35 moles of ethylene oxide and as main components Fatty acid glycerol polyglycol ester and fatty acid polyglycol ester contains. To fulfill the purpose also under the Brand names MYRJ® commercially available polyoxyethylene stearates (Manufacturer: ICI America Inc., Atlas Chemicals Division, Wilmington DE, USA).

The ratio of nifedipine and water-soluble Carrier is advantageously about 1: 10 to 1: 70 parts by weight. For a content of nifedipine for example, 10 mg may be the hard gelatin capsules with advantage about 70 to 700 mg Cremophor®RH 40 or a mixture of about 70 to 200 mg Cremophor®RH 40 and 4 to 20 mg of MYRJ 52 (PEG 40 stearate, see Example 3).

The capsules are made by adding First, the nifedipine in the vehicle dissolves, with light Heating the mixture promotes the dissolution process. As the solidification temperature of, for example, Cremophor®RH 40 in the range of 20 to 30 ° C is recommended heating to about 35 to 60 ° C; at a ratio  of nifedipine / vehicle of, for example, 1: 70 ranges a temperature of about 35 ° C already off, in short Time (about half an hour) to effect complete dissolution. Thereafter, the solution is poured into hard gelatin capsules, why the usual filling devices for hard gelatin capsules are excellent. After closing the Capsules becomes the junction of the two capsule halves with a strip of gelatin film using a Bandolierungsvorrichtung sealed to a possible Prevent leakage of capsule contents - the solution containing does not form thixotropic System.

The material of the capsule wall may be a pigment or Pigments or an opaque substance, for example Titanium dioxide, an iron oxide or calcium carbonate, involve a potentially damaging light effect to exclude nifedipine.

On the other hand, the material of the capsule wall the same reason also a dye, preferably one water-soluble dye.

Because it is the water-soluble carrier not a glycol, you could from the inventive Capsules expect to last even longer Storage period their original satisfactory Appearance and textures would be maintained, as it is in indeed for different fabrication batches after one several months of storage. On the other hand It was not to be expected that the nifedipine would dissolve in it as well as in the already long-tested polyethylene glycols, and that it consists of such Capsules released immediately and in the organism would be absorbed as from the conventional, polyethylene glycols containing capsules.  

The excellent bioavailability of nifedipine from the hard gelatin capsules according to the invention goes out clearly demonstrated in comparative in vivo studies, which was published in December 1987 by Ian W. French and Associates Ltd. in Scarborough (Ontario, CA) on six males Subjects have been performed.

The subjects were transferred before the start of the experiment The nature, purpose and scope of the experiment have been clarified and All have their consent to participate in the exam issued. Thereafter, they were examined by a specialist (with detailed laboratory, drug and alcohol screening) and classified as healthy.

For comparison, the following preparations came in the dose given below for nifedipine:

• A. Capsules to 10 mg nifedipine, according to the invention 2 × 10 mg (2 capsules),
• B. Adalat®, 10 mg capsules, Bayer AG (FRG) 2 × 10 mg (2 capsules),
• C. Procardia®, 20 mg capsules, Pfizer Inc. (USA) 1 x 20 mg (1 capsule).

Each of the six subjects received in each case in the distance from a week per os the above dose one of three preparations in a blindly fixed order. Thereafter, blood samples were taken according to a specific schedule taken and from it the plasma won and on the concentration analyzed on nifedipine; the analyzes are from Enseco Inc., Richmond (VA, USA) by high pressure liquid chromatography Have been carried out. From the measured at different times Concentrations were those in the following table summarized pharmacokinetic parameters calculated:

- the time span up to the maximum concentration t _max (hrs) - the maximum concentration at time t C _max (ng / ml) - the area under the curve of concentrations AUC (ng · hrs / ml)

The area AUC was calculated from the values of concentration measured from time 0 to time t , AUC (0- t) ; from the same values, the total area AUC (0-∞) was also calculated by extrapolation.

Using the values calculated for the parameters C _max and AUC , the relative bioavailability of the nifedipine (in%) from the capsules A according to the invention, based on those of the comparative preparations B and C (A / B or A / C), was then calculated; it is listed in Table 1 under C _max and AUC , respectively.

As already mentioned, the results of the overall, a practically the same high bioavailability of the three included in the comparison Capsule species; in terms of their bioavailability Thus, the capsules according to the invention the already known Equivalent to preparations, they are distinguished against these but by a virtually unlimited shelf life out.  

Table 1

The mentioned biopharmaceutical equivalence of the new Capsules of known preparations are then replaced by a broader, fully dosed in vivo in vivo January-February 1989 by LAB GmbH & Co., Neu-Ulm (FRG) was executed (LAB code: 88533, May 1989).

For this purpose, 24 male, voluntary, healthy Subjects between 19 and 50 years (average age 38.0 years, average weight 73.3 kg). The following preparations were compared in each case below indicated dose:

• A. Capsules to 20 mg nifedipine, according to the invention 1 x 20 mg (1 capsule),
• Procardia®, 20 mg capsules, Pfizer Inc. (USA) 1 x 20 mg (1 capsule).

Each subject received during four days and in the morning of fifth day, three times a day with a time interval of 8 hours each, one capsule each of the preparation A or the preparation B; after a Washout period of seven or eight days, each subject received same type one capsule of the other preparation. Blood samples were taken taken on the 4th and 5th day of the first and the second treatment period and analyzed for plasma content of nifedipine; the analyzes are (also here by high pressure liquid chromatography) of the company LAB GmbH & Co. has been carried out. The calculated from the nifedipine content Pharmacokinetic parameters are the same as those previously described Investigations by Ian W. French and Associates; they are shown in Table 2 summarized.

Based on the values determined for AUC (0-∞), C _max and t _max , a perfect equivalence of the bioavailability can be confirmed between the two investigated preparations. Accordingly, one can expect from the Nifedipinkapseln invention for human use the same therapeutic success as from the known preparations, but these prove to prove the new capsules significantly by their virtually unlimited storage stability.

Table 2

Example 1

In a beaker 90 g of polyoxyethylated hydrogenated castor oil containing about 40 oxyethyl units (National Formulary XVI: PEG 40-Hydrogenated Castor Oil; Commercial product Cremophor®RH 40) and at about 50 ° C. heated. 10 g of crystallized nifedipine are added and the mixture is stirred slowly at the same temperature, until the drug is completely dissolved and a clear yellow solution has formed. The solution is filled by hand into size 4 hard gelatin capsules, so that in each capsule a filling of 200 mg and therefore also 20 mg nifedipine are. The Capsules are at the junction of the two capsule halves using a gelatin strip using a machine of the "Quali-Seal" type of laboratory Company Elanco Products Comp., Indianapolis (IN, USA) sealed.

For these capsules the speed was - in Comparison with that of the commercially available soft gelatin capsules Adalat® from Bayer AG - measured, with which releases the active ingredient from the capsule in the water becomes. For this purpose, the usual dissolution method and the apparatus used under the name "Dissolution Paddle Apparatus" in the US Parmacopoeia XX (1979) at page 959; the agitator was set to 100 rpm, the dissolution medium was from 1000 ml of 0.1 N hydrochloric acid. After 30 minutes were taken from the medium samples and their content of nifedipine examined by high pressure liquid chromatography. It was found by the two types of capsules that 99% of nifedipine in the dissolution medium after only 30 minutes templates.

example 2

In a beaker are 690 g Cremophor®RH 40 placed and heated to about 35 ° C. 10 g crystallized Nifedipine is added and the mixture becomes at the same Temperature slowly stirred until the active ingredient  completely dissolved and formed a clear solution Has. The solution is made by hand into hard gelatin capsules of Size 0 filled, so that in each capsule one Filling amount of 700 mg and therefore also 10 mg nifedipine are located. The capsules are then sealed, as in Example 1 is described.

example 3

Starting from the following components:

10.0 g Nifedipine, crystallized 150.0 g Cremophor®RH 40 (see Example 1)  8.0 g Mixture of polyoxyethylated stearates with about 40 oxyethyl units (National Formulary XVI: PEG 40 stearates, commercial product MYRJ® 52) 168.0 g

is carried out according to the procedure described in Example 1 method and the solution formed in hard gelatin capsules the size 4 filled. After sealing as in Example 1 be capsules containing 10 mg Received nifedipine.

example 4

In a beaker, 150 g of Cremophor®EL (reaction product of 1 mole of castor oil and 35 moles of ethylene oxide; Manufacturer: Badische aniline and soda factory, Ludwigshafen am Rhine, Germany) and heated to about 40 ° C. 10 g crystallized Nifedipine is added and the mixture becomes at the same Slowly stir the temperature until the drug is complete dissolved and formed a clear solution. The solution is hand-made into size 4 hard gelatin capsules introduced so that in each capsule a filling of 160 mg and therefore also 10 mg nifedipine. The capsules are then sealed as described in Example 1.

Claims (10)

1. Nifedipine-containing hard gelatin capsules, characterized in that the nifedipine is present therein in dissolved form in a water-soluble carrier which is compatible with the human organism and which does not lead to brittleness or brittleness of the capsules at room temperature when the said capsules are stored. 2. hard gelatin capsules according to claim 1, characterized characterized in that the water-soluble carrier is a Polyoxyethylene glycol fatty acid ester (or fatty acid polyethylene glycol ester) is. 3. hard gelatin capsules according to claim 2, characterized characterized in that the polyoxyethylene glycol fatty acid ester the reaction product of 1 mol of hydrogenated Castor oil with about 40 moles of ethylene oxide. 4. hard gelatin capsules according to claim 1, characterized characterized in that the nifedipine and the water-soluble Carrier in a ratio of 1: 10 to 1: 70 parts by weight available. 5. hard gelatin capsules according to any one of claims 1 to 4, characterized in that the material of Capsule wall a pigment or pigments or an opaque Contains substance. 6. hard gelatin capsules according to claim 5, characterized characterized in that the pigment or the opaque  Substance made of titanium dioxide, an iron oxide or Calcium carbonate exists. 7. hard gelatin capsules according to any one of claims 1 to 4, characterized in that the material of Capsule wall a dye, in particular a water-soluble Dye containing. 8. Process for the preparation of nifedipine-containing Hard gelatine capsules according to claim 1, characterized that the nifedipine in one for the human organism compatible, water-soluble Carrier, which in storage of said capsules at room temperature, not too brittle or brittle the same leads, dissolves, of the solution a predetermined one Volume in hard gelatin capsules using a usual filling device fills and the connection point the two capsule halves by attaching a Strip of a gelatin film by means of a suitable Device sealed. 9. The method according to claim 8, characterized the water-soluble carrier is a polyoxyethylene glycol fatty acid ester (or fatty acid polyethylene glycol ester) is. 10. The method according to claim 9, characterized in that the polyoxyethylene glycol fatty acid ester the reaction product of 1 mole of hydrogenated castor oil with about 40 moles of ethylene oxide.