WO1996000389A1

WO1996000389A1 - Method of determining the amount of active substance released from solid or semi-solid preparations administered to humans or animals

Info

Publication number: WO1996000389A1
Application number: PCT/EP1995/002269
Authority: WO
Inventors: Joel Sinnreich
Original assignee: Ciba-Geigy Ag
Priority date: 1994-06-24
Filing date: 1995-06-12
Publication date: 1996-01-04
Also published as: AU2791295A

Abstract

Described is a method of determining the amount of active substance released from preparations administered to humans or animals, the method comprising the following operations: the preparation under test is placed in a test solution which reproduces the physiological conditions which exist when the preparation is introduced into a human or animal body; the preparation is dissolved in the test solution under controlled conditions, the active substance in the preparation thus passing into the solution; the test solution containing the dissolved active substance is analysed at given intervals, preferably by measuring the optical absorbance, in order to determine at given times the active-substance concentration in a given volume of the test solution; the preparation under test is completely enclosed in a membrane bag which is permeable to the test solution but retains essentially all water-insoluble constituents of the preparation and any undissolved active substance.

Description

Method for determining the active ingredient release from solid or semi-solid dosage forms for use in humans and animals

The invention relates to a method for determining the release of active substance from solid or semi-solid dosage forms for use in humans and animals according to the preamble of claim 1.

Dosage forms that are to be used on the human or animal organism must be adapted to the physiological conditions prevailing on or in the living organism, for example on the skin or in the gastrointestinal tract, in order, for example, with regard to their dissolution rate and the release behavior of a pharmacological active ingredient to be optimal on the living Organism and the therapeutic requirements to be coordinated. For this purpose, analysis regulations (e.g. "United States Pharmacopoeia XXII, 1990") have been recommended by the authorities, which are based on the real physiological conditions of the living organism and should allow a comparison of the dosage forms. The determination of the dissolution rate and the release of active substance is used, for example, to test different production batches of one dosage form for their similarity. Such analyzes are also used regularly for stability tests of dosage forms depending on the storage period and climatic load

To determine the release of active substance, solid or semi-solid dosage forms are introduced into an environment adapted to the physiological conditions, for example when simulating the gastrointestinal tract in gastric or intestinal fluid, in which the pharmacological active substance contained in the dosage form is converted into solution. After that, the change of Drug concentration determined over time and recorded. The active substance concentration is usually determined by measuring the optical absorption behavior of the solution. Methods and devices are described in "United States Pharmacopoeia XXII, 1990", pages 1577-1583, with which the described determination of the active substance concentration can be carried out, for example.

While the determination of the active substance concentration in solutions is theoretically relatively easy to accomplish, in practice there are serious problems with many solid and semi-solid dosage forms. The dosage forms intended for use in humans or animals generally do not only consist of the pure active ingredient, but rather they mostly comprise a relatively large amount of fillers and carriers, auxiliaries or binders etc. a solid dosage form, for example in the case of a tablet, large amounts of starch (disintegrant), modified starch, for example carboxymethyl starch or sodium starch glycolate, or on ion exchangers, acrylates, acrylic derivatives and copolymers, crosslinked polyvinylpyrrolidone, talc, calcium carbonate, calcium sulfate, modified cellulose, crosslinked Sodium carboxymethyl cellulose (eg Nymcel® from Nyma, Nijmegen, the Netherlands) or silicon oxide, which contribute to clouding of the test solution when the tablet disintegrates. The solid suspended matter contained in the test solution interferes with the optical absorption measurement and must therefore be removed before the measurement, for example by repeated filtration or by centrifugation.

When dissolved, other solid or semi-solid dosage forms release, for example, fatty or waxy or oily excipients. These can form emulsions in the test solution, which can cloud the test solution and are very difficult to remove. In semi-solid dosage forms, for example suppositories, the active ingredient is embedded in a fat-like mass. If the dosage form (the suppository) disintegrates, the test solution may become cloudy or separate phases, which makes it difficult or even impossible to determine the active ingredient release. The preparation of the test solution before the actual measurement requires additional equipment, time and personnel. In addition, the extraction apparatus, the filtration or centrifuging devices or the flow cells used must be carefully cleaned each time after use. The object of the invention is to remedy these disadvantages of the test methods of the prior art. In particular, a method for determining the release of active substance from solid or semi-solid dosage forms for use in humans and animals is to be improved so that the test solution can be analyzed optically reliably and without additional effort. Additional separation stages, filtration or centrifugation steps or other possible cleaning steps should be dispensed with.

According to the invention, these objects are achieved by a method for determining the release of active substance from solid or semi-solid dosage forms for use in humans and animals, which comprises the method steps specified in the characterizing part of patent claim 1. Particularly preferred variants of the procedure are the subject of the dependent claims. The method according to the invention for determining the active substance release from solid or semi-solid dosage forms for use in humans and animals has in particular the following method steps:

- The solid or semi-solid dosage form to be examined is introduced into a test solution which corresponds to the physiological conditions when the dosage form is administered to the human or animal organism;

- The dosage form is dissolved in the test solution under controlled conditions, the active ingredient contained in the dosage form being converted into solution;

- The test solution containing the dissolved active substance is subjected to an analysis, preferably an optical absorption measurement, at certain time intervals, by which the active substance concentration contained in a certain volume of the test solution is determined at certain times;

- In order to prevent impurities, in particular turbidity, from getting into the test solution, the solid or semi-solid dosage form to be tested is completely covered with a membrane bag that is permeable to the test solution, but which, on the other hand, is water-insoluble components of the dosage form and, if necessary, still essentially retains undissolved active ingredient The membrane bag completely envelops the dosage form to be tested and retains impurities in the membrane bag, but allows a largely unhindered inflow and the outflow of the test liquid or test solution. The active ingredient contained in the dosage form can be converted into solution without hindrance, while the fillers and carriers, auxiliaries or binders are essentially retained in the membrane bag. This enables the concentration of the released active ingredient in the test solution to be determined directly. Lengthy filtrations, extractions and chromatographic preparation of the test solution are no longer necessary. The test equipment remains free and free from grease or other water-insoluble substances. At the end of the measurement, the membrane bag can be easily removed from the test solution and disposed of. Because the fillers and carriers, auxiliaries or binders contained in the solid or semi-solid dosage form are retained within the membrane bag, this residue can also be checked very easily if necessary.

Depending on whether the drug release behavior is to be investigated for water-soluble drugs in an aqueous test solution or for lipophilic drugs in a lipophilic test medium, the solid or semi-solid dosage form to be tested is made from a hydrophilic material (for water-soluble drugs) or from a membrane bag lipophilic membrane (for lipophilic active substances) coated This allows the most diverse types of solid or semi-solid dosage forms to be investigated by carefully selecting the covering membrane. Single or multilayer laminates that are porous or teabag-like are used as materials for the membrane bag, for example.

In the case of water-soluble active substances, the preferred material for the membrane bag is polymeric films, especially films made of cellulose ethers such as methyl or ethyl cellulose, hydroxypropyl cellulose, methyl or ethyl hydroxyethyl cellulose, methyl or ethyl hydroxypropyl cellulose, carboxymethyl cellulose, polyvinyl acetate, polyvinyl pyrrolidone, or copolymer made from polyacrylonitrile, made from copolymeric, polyacrylonitrile several of the polymers mentioned, for example, from copolymers of acrylic and methacrylic acid esters with a low content of quaternary ammonium groups (such as EUDRAGIT® RL 12.5 or RS 12.5 from Röhm Pharma GmbH, Germany), from mixtures of polyvinylpyrrolidone with polyvinyl alcohol, resins based on phthalic anhydride-polyhydroxy alcohol , Urethanes, polyamides or from polyvinyl alcohol. These materials are particularly known for that they are very permeable to body fluids (e.g. gastric or intestinal fluids).

Highly saponified polyvinyl alcohol with a degree of hydrolysis higher than 92% is particularly preferred, for example MOWIOL of the 98 series from Hoechst, Germany.

Further auxiliaries, in particular plasticizers, can be added to the film materials. This is particularly advantageous if a test apparatus is used which simulates the peristaltic kneading movements of the gastrointestinal tract. The plasticizer ensures that the membrane bag material has sufficient elasticity that the membrane bag does not burst during the simulated kneading movements.

Glycerol, polyethylene glycol fatty acid esters such as polyethylene glycol 400 stearate or polyethylene glycol 2000 stearate, triethyl citrate, diethyl phthalate or diethyl sebacate are preferably added as plasticizers.

The layer thickness of the membrane bag is selected to be approximately 5 μm to approximately 1000 μm, preferably approximately 20 μm to approximately 200 μm. This ensures that the membrane bag has sufficient strength so that it is not damaged during manipulation. On the other hand, the layer thickness is selected in such a way that the permeability to the sample solution is not or only insignificantly impaired. The selected layer thickness also allows the membrane bag to be easily closed after a dosage form has been coated with it. The closure forms, depending on the material type and layer thickness of the membrane bag, are tied, Sealing, stapling, gluing, folding, etc. in question.

The exchange of sample solutions from outside and inside the membrane bag is preferably influenced by adding additives, such as salts and / or enzymes and / or wetting agents, preferably additives that change the pH value, to the test liquid. The invention is explained in more detail below with reference to examples and the associated diagrams. The diagrams show:

1 shows the time course of the drug release of a first solid

Dosage form without membrane pouch envelope,

FIG. 2 shows the time course of the release of the active ingredient of the dosage form from FIG. 1 with a membrane bag covering, and

Fig. 3 W solder release curves of several samples of a semi-solid

Dosage form and corresponding placebos.

In all examples, the solid or semi-solid dosage forms are tested in a test solution made of synthetic gastric juice. The test apparatus and test method used for this corresponds, for example, to the "paddle apparatus" or "United States Pharmacopoeia XXπ, 1990", pages 1577-1583 "Paddle method".

example 1

In a first experiment, the drug release behavior of a solid dosage form containing 25 mg of active ingredient is investigated, which is introduced directly into the test solution without a coating. The test components containing the test solution are separated, and then the substance concentration in the test solution is determined at regular intervals of, for example, one hour via optical absorption measurement. The active substance release curve over time is shown in FIG. 1. Curves A and B relate largely to two identical samples of the solid dosage form.

Example 2

A sample identical to the solid dosage form according to Example 1 is first completely encased and sealed with a membrane bag made of polyvinyl alcohol (Moviol 28/99 from Hoechst, Germany) and then the membrane bag with the solid dosage form is added to the test solution and directly via optical Absorption measurement determines the active substance concentration in the test solution, that is, extractions or filtrations are omitted before the actual measurement process, since the test solution remains clear. The results of the measurement are shown in FIG. 2. Curve C therein shows the active substance release in percent. The bar chart display shows the actually measured concentration.

A comparison of the active ingredient release curves in Fig. 1 and Fig. 2 makes it clear that the wrapping of the solid dosage form with a membrane bag that is permeable to the test solution (with and without dissolved active ingredient), but retains the auxiliary substances of the dosage form, most qualitatively Drug release behavior doesn't change anything. At most, a slight delay effect can be observed.

Example 3

A squeeze containing 25 mg of active ingredient and 120 mg of polyethylene glycol stearate is placed in a test solution made of synthetic gastric juice. A cloudy mixture with excessive UV extinction is formed. An optical absorption measurement to determine the active substance concentration in the test solution is not possible.

Example 4

A squeeze according to Example 3 is first enveloped and sealed with a membrane bag made of polyvinyl alcohol. The membrane bag with the dosage form contained therein is used in synthetic gastric juice. The test solution remains clear and is subjected directly to an optical absorption measurement in order to determine the active ingredient concentration in the test solution over time ( one measurement every two hours). In FIG. 3, the material release curves of three such samples are designated D, E and F. The curve shape corresponds qualitatively to the curve shapes from FIGS. 1 and 2.

Example 5

For comparison with the results from Example 4, a placebo seedling is first encased and sealed with a membrane bag made of polyvinyl alcohol. The membrane bag with the placebo pressing contained therein is used in synthetic gastric juice. The test solution remains clear and becomes an optical absorption measurement directly subjected. The measurement curves for two placebo samples are labeled G, H and in FIG. The low "active substance concentration" registered after 6 hours is due to a slight leakage of auxiliary substances through the membrane bag. Nevertheless, it is clearly evident that the method according to the invention, even in the case of dosage forms with fatty auxiliaries, can be used to determine the active ingredient release behavior in a reproducible manner without complex cleaning and separation processes.

The membrane bag completely envelops the dosage form to be tested and retains impurities in the membrane bag, but allows a largely unimpeded inflow and the outflow of the test liquid or the test solution. The active ingredient contained in the dosage form can be converted into solution without hindrance, while the fillers and carriers, auxiliaries or binders are essentially retained in the membrane bag. As a result, the concentration of the released active ingredient in the test solution can be determined directly, lengthy filtration, extractions and chromatographic preparation of the test solution are unnecessary. The test equipment remains free and free from grease or other water-insoluble substances. At the end of the measurement, the membrane bag can be easily removed from the test solution and disposed of. Because the fillers and carriers, auxiliaries or binders contained in the solid or semi-solid dosage form are retained within the membrane bag, this residue can also be checked very easily if necessary.

Claims

claims

1. A method for determining the release of active ingredient from solid or semi-solid dosage forms for use in humans and animals, in which

the dosage form to be examined is introduced into a test solution which corresponds to the physiological conditions when the dosage form is administered to the human or animal organism,

the dosage form is dissolved in the test solution under controlled conditions, the active ingredient contained in the dosage form being converted into solution,

- The test solution containing the dissolved active substance is subjected to an analysis, preferably an optical absorption measurement, at certain line intervals, whereby the active substance concentration contained in a certain volume of the test solution at certain times is determined, characterized in that

- The solid or semi-solid dosage form to be tested is completely covered with a membrane bag which is permeable to the test solution, but which on the other hand essentially retains water-insoluble components of the dosage forms and possibly still undissolved active ingredient, which components impair the measurement and in particular turbidity in the test solution can cause.

2. The method according to claim 1, characterized in that the dosage form to be tested is coated with a membrane bag made of a hydrophilic material.

3. The method according to claim 2, characterized in that hydrophilic polymer films are selected as the material of the membrane bag.

4. The method according to claim 2, characterized in that single or multi-layer laminates are used as films, which are porous or teabag-like tight.

5. The method according to claim 3 or 4, characterized in that films of cellulose ethers such as methyl or ethyl cellulose, hydroxypropyl cellulose, methyl or ethyl hydroxyethyl cellulose, methyl or ethyl hydroxypropyl cellulose, carboxymethyl cellulose, polyvinyl acetate, polyvinyl pyrrolidone, polyacrylonitrile, from Copolymers, cocondensates or polymer mixtures from several of the polymers mentioned, from copolymers from acrylic and methacrylic acid esters with a low content of quaternary ammonium groups (such as EUDRAGIT® RL 12.5 or RS 12.5 from Röhm Pharma GmbH, Germany), from mixtures of polyvinylpyrrolidone with polyvinyl alcohol , Resins based on phthalic anhydride-polyhydroxy alcohol, urethanes, polyamides or polyvinyl alcohol.

6. The method according to claim 5, characterized in that highly saponified polyvinyl alcohol with a degree of hydrolysis higher than 92% is used.

7. The method according to any one of claims 4 to 6, characterized in that auxiliary materials, in particular plasticizers, are added to the film materials.

8. The method according to claim 7, characterized in that glycerin, polyethylene glycol fatty acid esters such as polyethylene glycol 400 stearate or polyethylene glycol 2000 stearate, triethyl citrate, diethyl phthalate or diethyl sebacate are added as plasticizers.

9. The method according to any one of the preceding claims, characterized in that the layer thickness of the membrane bag to about 5 microns to about 1000 microns, preferably about 20 microns to about 200 microns, is selected.

10. The method according to any one of the preceding claims, characterized in that the transport of the test solution through the membrane bag is influenced with the aid of additives in the test liquid.

11. The method according to claim 11, characterized in that salts and / or enzymes and / or wetting agents, preferably pH-changing additives, are added to the test solution.

12. The method according to any one of the preceding claims, characterized in that the dosage form enclosed in the membrane bag is exposed to a simulated peristaltic kneading movement in the test solution.