DD254881A1

DD254881A1 - NON-PARENTERAL APPLICABLE INSULIN PREPARATION WITH DELAYED EFFECT

Info

Publication number: DD254881A1
Application number: DD29566686A
Authority: DD
Inventors: Guenter Losse; Frank Mueller; Joachim Kossowicz; Helga Trebesius; Birgit Griesshammer
Original assignee: Univ Dresden Tech
Priority date: 1986-10-29
Filing date: 1986-10-29
Publication date: 1988-03-16

Abstract

Die Erfindung betrifft ein Verfahren zur Herstellung nicht parenteral, vorzugsweise rektal, anwendbarer Insulinpraeparate mit verzoegerter Wirkung. Um eine Insulinresorption und erhoehte Bioverfuegbarkeit im Magen-Darm-Trakt zu ermoeglichen, werden den an sich bekannten Insulineinbettungen in polymere gelartige Matrices zusaetzlich als Resorptionsvermittler Eiweissfettsaeurekondensat und als Proteaseinhibitor ein Trypsininhibitor zugesetzt. Diese werden in Konzentrationen von vorzugsweise 2-10%, bezogen auf die Gesamtsuppositorienmasse mit in das Gel eingebracht und so in einer mit der Hormonabgabe weitgehend koordinierten Geschwindigkeit und Menge wieder freigesetzt.The invention relates to a process for the preparation of non-parenterally, preferably rectally, applicable insulin preparations with delayed action. In order to enable insulin absorption and increased bioavailability in the gastrointestinal tract, the intrinsic insulin embedding in polymeric gelatinous matrices, which are known per se, are supplemented with egg white fatty acid condensate as absorption promoter and a trypsin inhibitor as protease inhibitor. These are introduced into the gel in concentrations of preferably 2-10%, based on the total suppository mass, and thus released again in a speed and quantity which are largely coordinated with the hormone release.

Description

Erfindungsgemäß zeigte sich weiter, daß die Wirksamkeit der genannten Zusatzstoffe bei diesen Hormon-Geleinbettungen mit immobilisiertem Horman-Anteil nur dann optimal zur Geltung kommt und klinisch verwertbar, rektal anwendbare Präparate gewonnen werden, wenn Agar-Einbettung, Resorptionsvermittler und Proteaseinhibitor in genau aufeinander abgestimmten Mengenverhältnissen angewendet werden und hierbei der Resorptionsvermittler in einer Konzentration von 2-5%, bezogen auf die Gesamtsuppositorienmasse, vorliegt.According to the invention, it has further been found that the effectiveness of said additives in these hormone gel deposits with immobilized hormone content is only optimal and clinically useful, rectally applicable preparations are obtained when agar embedding, absorption and protease inhibitor in exactly matched proportions and in this case the absorption promoter in a concentration of 2-5%, based on the total suppository mass, is present.

embodiments Example 1:

Zur Herstellung der Agar-Insulin-Einbettung wurden 1,0 g gereinigter Agar in 19 ml dest. Wasser bei 90°C gelöst. Nach Abkühlung auf 45°C wurden 80μΙ Insulinlösung (250 mg/ml Phosphatpuffer; pH = 7,5) hinzugefügt und bis zum Erstarren gerührt. Anschließend wurde auf einem Sieb zerkleinert, mit 1000 ml absolutem Aceton entwässert, abgesaugt und mehrmals mit 100 ml absolutem Aceton gewaschen. Die Gele wurden bei 1 Torr und 25°C getrocknet, zerkleinert und nach Korngrößen fraktioniert, wobei vorzugsweise Fraktionen von 0-160μ,ηη und 160-315μ.ηη Korngröße zur Anwendung gelangten. Zur Herstellung der insulinhaltigen Suppositorien wurden 1,9g Zäpfchengrundmasse (Rosupol^R-15) und 0,1 g Agar-Insulineinbettung (20IE) verwendet. Die Agar-Insulineinbettung wurde bei 40°C in die geschmolzene Grundmasse eingebracht und zu Zäpfchen vergossen. Einer repräsentativen Anzahl männlicher Kaninchen von ca. 4kg Körpermasse gleicher Rasse wurden die Suppositorien so appliziert, daß jedes Versuchstier eine Insulindosis von 5IE/kg Körpergewicht erhielt. Den Kontrolltieren wurden Suppositorien gleicher Insulindosierung ohne Einbettung und Resorptionsvermittler appliziert. Die Blutglucosespiegelwerte wurden nach Normierung auf den Anfangblutzzuckerwert im Nüchternzustand mittels des Fermognost^R-Blutzuckerbestecks bestimmt.To prepare the agar insulin embedding, 1.0 g of purified agar in 19 ml of dist. Water dissolved at 90 ° C. After cooling to 45 ° C., 80 μl insulin solution (250 mg / ml phosphate buffer, pH = 7.5) was added and stirred until it solidified. The mixture was then comminuted on a sieve, dewatered with 1000 ml of absolute acetone, filtered off with suction and washed several times with 100 ml of absolute acetone. The gels were dried at 1 Torr and 25 ° C, crushed and fractionated by particle sizes, preferably fractions of 0-160μ, ηη and 160-315μ.ηη grain size were used. For the preparation of the insulin-containing suppositories, 1.9 g suppository base (Rosupol ^R- 15) and 0.1 g agar insulin embedding (20 IE) were used. The agar-insuline embedding was introduced into the molten matrix at 40 ° C and poured into suppositories. A representative number of male rabbits of about 4 kg of body mass of the same breed, the suppositories were applied so that each animal received an insulin dose of 5IE / kg body weight. Suppositories of the same insulin dosage without embedding and absorption mediators were applied to the control animals. Blood glucose levels were determined after standardization to the initial fasting blood glucose level using the Fermognost ^R blood glucose kit.

Es ergab sich eine mindestens 3stündige Blutzuckersenkung um 25% mit Erreichen des Anfangsniveaus nach 6 Stunden. Die Kontrolltiere zeigten keine Wirkung.There was a 25% reduction in blood sugar for at least 3 hours, reaching the initial level after 6 hours. The control animals showed no effect.

Example 2:

0,050g der unter Beispiel 1 erhaltenen Einbettung (= 20lE/Suppositorium) wurden mit 0,050g Resorptionsvermittler (= 2,5% EFK, bezogen auf die Gesamtzäpfchenmasse) innig verrieben und wie unter Beispiel 1 in die Zäpfchengrundmasse eingearbeitet. Bei einer Insulindosierung von 5IE/kg Körpergewicht ergab sich eine über4stündige Blutzuckersenkung um 55% mit Erreichen des Anfangsniveaus nach 24 Stunden.0.050 g of the embedding obtained under Example 1 (= 20 IU / suppository) were intimately triturated with 0.050 g absorption promoter (= 2.5% EFK, based on the total suppository mass) and incorporated into the suppository base as in Example 1. An insulin dose of 5 IU / kg body weight resulted in a more than 4-hour reduction in blood sugar by 55% when reaching the initial level after 24 hours.

Example 3:

Die Herstellung der Agar-Insulineinbettung erfolgte wie unter Beispiel 1, wobei zusätzlich 1 g Resorptionsvermittler in kristalliner Form bei 45⁰C in die Gelphase eingebettet wurde. Die weitere Aufarbeitung bis zum Suppositorium erfolgt wie unter Beispiel 1. Bei einer Insulindosierung von 5IE/kg Körpergewicht ergab sich eine mehr als 6stündige Blutzuckersenkung um 35% mit Erreichen des Anfangsniveaus nach 12 Stunden.The preparation of the agar insulin embedding was carried out as in Example 1, wherein in addition 1 g absorption mediator was embedded in crystalline form at 45 ⁰ C in the gel phase. The further processing up to the suppository takes place as in Example 1. At an insulin dosage of 5 IU / kg body weight, there was a blood glucose lowering by more than 6 hours by 35% with reaching the initial level after 12 hours.

Example 4:

Die Herstellung der Agar-Insulineinbettung erfolgte analog Beispiel 1, wobei 1 g Resorptionsvermittler, gelöst in 3ml80%igem Ethanol, bei 45°C der Gelphase zugegeben wird. Die weitere Aufarbeitung erfolgte entsprechend Beispiel 1. Bei einer Insulindosierung von 5IE/kg Körpergewicht ergab sich eine mindestens 5stündige Blutzuckersenkung um 25% mit Erreichen des Anfangsniveaus nach 8 Stunden.The preparation of the agar insulin embedding was carried out analogously to Example 1, wherein 1 g absorption mediator, dissolved in 3ml80% ethanol, is added at 45 ° C the gel phase. The further work-up was carried out according to Example 1. At an insulin dosage of 5IE / kg body weight resulted in a blood glucose reduction of at least 5 hours by 25% with reaching the initial level after 8 hours.

Example 5:

Die Herrstellung der Agar-Insulineinbettung erfolgte analog Beispiel 3, wobei zusätzlich zum Resorptionsvermittler 0,2g Proteaseinhibitor (= 10% Contrykal^R 50000, bezogen auf die Gesamtzäpfchenmasse) eingebettet wurde. Die weitere Aufarbeitung bis zum Suppositorium erfolgte wie unter Beispiel 1. Bei einer Insulindosierung von 5IE/kg Körpergewicht ergab sich eine mehr als lOstündige Blutzuckersenkung um 40% mit Erreichen des Anfangsniveaus nach 22 Stunden.The production of the agar insulin embedding was carried out analogously to Example 3, wherein in addition to the resorption mediator 0.2 g protease inhibitor (= 10% Contrykal ^R 50000, based on the total suppository mass) was embedded. The further processing up to the suppository was carried out as in Example 1. At an insulin dosage of 5 IU / kg body weight, there was a more than 10-hour reduction in blood sugar by 40% with reaching the initial level after 22 hours.

Claims

1. A process for the preparation of non-parenteral, preferably rectally, administrable insulin preparations by embedding, inclusion or absorption of insulin in gelatinous macromolecular, biodegradable support materials, in particular in polysaccharide, polyamide or Polypeptidmatrices, characterized in that as a resorption promoter protein fatty acid condensate and as ProteaseinhibitorTrypsininhibitor are included.

2. The method according to claim 1, characterized in that egg white lauric acid condensate, preferably in a concentration of 2-5%, is contained as absorption mediator.

3. The method according to claim 1, characterized in that is contained as ProteaseinhibitorContrykal 50000, preferably in a concentration of 5-10%.

Field of application of the invention

The invention relates to a process for the preparation of non-parenteral, preferably rectal, applicable insulin preparations with delayed action.

Characteristic of the previously known solutions

Since the introduction of insulin therapy, suitable and parenteral forms of administration have been sought with adequate, as far as possible continuous insulin delivery, since the usual regular injections are a heavy burden for those affected. For example, the investigations focused on various principles for improving the retardation effect of depot insulins, such as: As the inclusion of matrix in cross-linked bovine serum albumin, the inclusion of insulin in liposomes and the use of phospholipids as a carrier. The chemical fixation of the hormone to polymeric carriers has also been intensively processed in order to achieve favorable reductive effects or an increase in stability. Different chemical immobilization principles such as complex formation or covalent bonding were used.

On the other hand, various principles have been examined in order to arrive at non-parenteral, preferably oral or rectal administration forms. Clinically useful results have not been achieved in this way, however, because the corresponding preparations either require too high doses of insulin or are irreversibly inactivated under the conditions prevailing in the gastrointestinal tract are difficult to absorb or have a short residence time. In contrast, the particular benefits of insulin gel embedding have not yet been considered for therapeutic purposes. Due to the storage and protective function of the gel, the insulin gel embeddings proposed in DD 219673 cause a high bioavailability and stability of the insulin and release the hormone in a strongly delayed form. They thus offer the basic possibility to develop the various application forms adapted pharmacological systems for clinical application.

Object of the invention

The aim of the invention is to develop a non-parenteral, preferably rectal, clinically useful application possibility of insulin gel embedding with simultaneously long-lasting protahierender effect.

Explanation of the essence of the invention

The object of the invention is to develop a process for the preparation of insulin preparations with delayed action, which are not parenteral, preferably rectally, applicable and characterized by a high compatibility. According to the invention the object is achieved in that according to DD 219673 per se known insulin gel embedding additionally be mixed with a Resorptionsvermittler and a trypsin inhibitor. In principle, however, other additives of absorption mediators or protease inhibitors can also be used. The polysaccharide agar, as a matrix in this system, is particularly capable of immobilizing the hormone as well as the additives in high loading rates, releasing them and at the same time exerting a protective function on the hormone. This makes it possible to use gel embeddings for insulin applications in the gastrointestinal tract and at the same time to limit the hormone losses caused by proteolytic degradation. In this way, therapeutically acceptable, low doses are achieved, while at the same time the delay resulting from the matrix embedding is effectively maintained. A particular advantage of insulin gel embedding is - also according to the invention - further in that additives such. B. Resorptionsvermittler and protease inhibitors in exactly metered form with introduced into the gel and so can be released again in a largely coordinated with the hormone release speed and quantity. In this way, substantial gains in glucose lowering over the entire liberation interval are achieved. Particularly suitable in this context, the resorption promoter protein fatty acid condensate whose preparation is described in the patents DD 106783 and DD 117681, in principle, but also other types of absorption promoters and any protease inhibitors into consideration.