DD298351A5 - METHOD FOR PRODUCING A CARRIER-RELATED MEDICAMENT - Google Patents

Abstract

The invention relates to a method for producing a carrier-dependent dosage form. Various monocyclic peptides, such as the immunosuppressant cyclosporin, are only effective in the presence of carrier substances when administered perorally. However, the simultaneous, precisely dosed administration of active ingredients and excipients presents difficulties if the carrier is not compactable substances and the active ingredient is virtually water-insoluble. The invention solves the problem by a liquid filling in capsules. {Pharmaceutical form, carrier-dependent; Piece capsule; immunosuppressives; cyclosporine; Carrier substances; Liquid bottling; excipients}

Description

Field of application of the invention

The invention relates to a method for processing cyclic peptides together with Carriersubstanzen to gelatin capsules, which are filled by way of the melt solidification.

Characteristic of the known state of the art

The task of the drug formulation is not only to convert an active substance into a well applicable, stable and compatible preparation, but also to influence the availability in the organism in a therapeutically optimal manner. This is especially true for peroral application. A number of active substances are considered problem substances because they are very difficult to absorb due to their very low solubility in water. These include cyclic peptides such as cyclosporine. For ciclosporin, the very successful use in human medicine could only begin after the problem of dosage form was solved.

Therefore, several patents deal with this question. The method claims are directed to the use of certain excipients. Described were

in DD-PS142149 the use of

a nonionic ester of a triglyceride with a polyalkylene glycol, a saturated fatty acid triglyceride and a mono or diglyceride

- In the CH-PS 375 828 the use of

a nonionic transesterification product of an oil triglyceride with a polyalkylene glycol, a vegetable oil and

ethanol

- in DE-OS 1280435 digV ^ rwendunavor ^, ^^^ ^. ^ "_" ___ ^^ ^ _M ^ " _t .

aqueous surfactant solutions _:

- in WO-PS8706463 theyerweridungyon,. · Ί Omega-3 fatty acid & ter | t '; aJjsi fish oils. * ^v "- ·

Although the Syst | me'p "are in principle good, the intake is difficult and thus solved the problem only unsatisfactory.

Object of the invention

The aim of the invention is a process for the preparation of a preparation which enables a simple and problem-free peroral administration of an immunosuppressant.

Explanation of the essence of the invention

The object of the invention is the preparation of a preparation which enables the peroral administration of a cyclic peptide in single dose with one or more carrier substances at a dosage accuracy of ± 1 to 2% easily ingested.

The essence of the invention is to transfer the active ingredient together with the Carriersubstanzen in a melt and this according to the principle of liquid filling in a gelatin plug capsule. In this case, a system had to be found, which melts in the temperature range up to about 70 ° C and solidifies after filling. If a carrier substance meets these requirements, the drug could be incorporated directly into these excipients. In addition, the active ingredient was to be treated so that it is in the melt in dissolved form.

To realize the melt solidification, it has surprisingly been found that solid organic acids, such as palmitic acid and stearic acid, are very suitable for this purpose. They deliver the desired effect even in small quantities, thus enabling the use of small, well-swallowable capsules. The novel excipient for this task provides even in the acidic environment of the stomach a certain protection and is only converted in the intestinal area in the water-soluble alkali salt. In addition, the acids are readily miscible with the other constituents and give a clear melt.

Suitable carrier substances are in principle surfactants, especially with an HLB value of 10. They improve in a known manner the wetting of solids, their dissolution and their transport in the organism. Both non-ionic "Netzer" and Polysorbate 80 as well as ionic surfactants such as sodium lauryl sulfate were used.

Finally, it was important to incorporate the active ingredient in dissolved form. For ciclosporin, 1,2-propylene glycol, which had advantages over alcohols such as ethanol because of its relatively high boiling point (187.4 "C) in melt processing, proved to be a suitable solvent.

The experiments showed that the principle of melt solidification can also be used in fundamentally different ways for capsule production. As we have surprisingly found, a melt with polyethylene glycols on cooling forms a dense felt from fine needles, i.e. substances such as cyclosporin additionally solidify the system by the elimination of sparingly soluble adducts. A proportion of 20% polyethylene glycol 1500 is sufficient to cause the effect. By combining the active ingredient with a surfactant (carrier) and a polyethylene glycol, a system is created whose phase transition

thermally easy to regulate. ^v

embodiments

example 1

200 g of cyclosporin are dissolved with heating to about 70 ° C in 200g of 1,2-propylene glycol and then treated with 100g polysorbate and 150g stearic acid (finely powdered). All ingredients are held at the elevated temperature until a clear melt is formed. The batch is filled in the liquid state with the aid of a special machine in gelatine capsule size 1, so that the filling amount 325mg (corresponding to 100mg Ciclosporin).

Example 2

200 g Ciclosporin beica.70 ° Cin250g 1,2-propylene glycol are dissolved. The solution is mixed with 50 g of sodium lauryl sulfate and 100 g of stearic acid and brought to the same temperature until a clear melt is formed. The liquid batch is transferred to the tempered storage tank of a liquid-Abmaschien and distributed at a dosage of 300 mg in gelatin gelatin capsules size 1.

Example 3

200 g of cyclosporin are heated with 300 g of polyethylene glycol 600.150 g of polyethylene glycol 4000 and 200 g of polysorbate 80 until a melt is formed. The resulting suspension is filled at about 70 ⁰ C with a single dose of 213 mg (corresponding to 50 mg Ciclosporinjin gelatin capsules size 2.

Example 4

200 g of ciclosporin are heated with 200 g of sorbitan ester (sorbitan monolaurate, monostearate, tristearate) until a melt is formed. The liquefied batch is metered into gelatine cachets using a liquid filling machine. The capacity is measured according to the intended amount of active ingredient.

Claims (6)

1. A process for the preparation of a carrier-dependent drug form, characterized in that the active ingredient, which is dissolved in a lower polyhydric alcohol (C ₃ to C ₅ ), transferred together with one to three Carriersubstanzen in a melt phase and according to the principle of liquid filling in gelatin capsules, wherein the melt solidification with a saturated organic acid of the general formula H ₃ C- (CH ₂ ) _n -COOH _r wherein η = 12 to, is performed. 2. The method according to claim 1, characterized in that is used as the active ingredient Ciclosporin or another cyclic peptide such as a Ciclosporinderivat. 3. The method according to claim 1, characterized in that as carrier substances surfactants, preferably with an HLB value between 10 and 50, is used. 4. The method according to claim 1, characterized in that the melt solidification is preferably carried out with stearic acid. 5. The method according to claim 1 _r characterized in that the active ingredient before the addition of further ingredients in a monohydric or polyhydric alcohol, preferably propylene glycol, is dissolved. 6. The method according to claim 1, characterized in that an addition of further adjuvants such as long-chain alcohols is made.