WO2001064191A1

WO2001064191A1 - Bodies for the controlled release of active substances

Info

Publication number: WO2001064191A1
Application number: PCT/EP2001/002321
Authority: WO
Inventors: Holger Bengs; Bernd Hahn; Uwe Bayer; Axel Walch
Original assignee: Akzo Nobel N.V.; WALCH, Klaus
Priority date: 2000-02-28
Filing date: 2001-02-27
Publication date: 2001-09-07
Also published as: AU2001237424A1

Abstract

The invention relates to bodies for the controlled release of active substances. The inventive bodies comprise a material surrounding the active substance and one or more active substances, and, if desired, other adjuvants such as swelling agents, expanding agents and the like. The inventive bodies are characterized in that linear organic compounds, preferably stearyl alcohol are used as the low-molecular compounds. The inventive bodies are especially useful for a pulsed release of the active substances.

Description

Body for the controlled release of active ingredients

The invention relates to a body for the controlled release of one or more active substances which are to be released to the surrounding environment in a pulsatile or delayed manner.

The use of certain active substances in humans or animals for therapeutic or prophylactic purposes requires, depending on the intended effect, a specific release profile of the pharmaceutical formulation used in the surrounding environment.

For special agents, e.g. Hormones that are used in veterinary medicine to control reproductive processes in cows (e.g. FSH) require a release at certain intervals to take into account the natural cycle. So here you are not interested in having a constant concentration over a long period of time, but in a discontinuous release. In such cases the delivery should be delayed and pulsed i.e. There must be a certain period of time between different deliveries, within which no or only a little hormone is released.

A pulsed release of an active substance (here an antigen) is also advantageous for vaccination. An antigen is applied to the organism for active immunization. To strengthen the immune response, and thus the duration and resilience of the immunity acquired through the vaccination, a second application of the same antigen (revaccination.) Is often carried out after this first immunization (so-called "prime") at intervals of several weeks to months , so-called "Boost").

In order to avoid this complex process, it would be desirable to apply the second antigen injection in the form of a delayed, discontinuously releasing formulation at the same time as the first injection. The second dose then remains in the body until the further dose of the antigen is released after a defined period of time. There has been no shortage of attempts to develop materials with which the release of the active ingredient can be advantageously controlled and which on the other hand are completely broken down by the surrounding environment into degradation products which are physiologically harmless.

The use of so-called sustained-release formulations for the delayed release of medicaments for oral administration is known and is used in particular for the release of active substances in defined sections of the gastrointestinal tract.

EP 68450 (Meditest) describes e.g. a depot pharmaceutical form for oral administration, in which the active ingredient is present together with water-insoluble, meltable components containing fatty alcohol. In GB 2245492 (Zambon Group S.P.A.) an oral dosage form is described, the hydrophobic coating of which allows active ingredient release in defined intestinal segments after a defined time.

Oral application, however, leads to inactivation with a number of active substances and immunogens, so that they must be administered parenterally. In these cases, the proposed formulations are therefore not applicable.

WO 96/12466 (Daratech PTY. Ltd) describes a body for the controlled and delayed release, in which the active ingredient is surrounded by a capsule made of a non-porous, biodegradable polymer with a defined degradation profile.

However, the production of the body described from biodegradable polymer is complex, so that the use of this technology for food-producing animals does not appear to make sense for economic reasons.

EP 147479 (Merck & Co Inc.) describes a pharmaceutical form for rectal or vaginal administration, which contains the active ingredient and a water-insoluble, meltable fatty alcohol-containing component together with a liquid reservoir. However, this formulation is not suitable for parenteral administration (intramuscular or subcutaneous injection or implantation) because of its structure and composition. Therefore, there is still a need for improved formulations that overcome these limitations in the prior art.

The object of the invention is to provide formulations which have very good mechanical strength, so that they can be easily and easily applied to the body of humans or animals (by injection or implantation), but at the same time are also completely broken down in the body can. These formulations should also be simple, inexpensive and with reproducible properties. In addition, these should enable adjustable controlled release of active substances and should be particularly suitable for the pulsed release of active substances.

This object is achieved by the bodies according to the invention, suitable for parenteral administration, for the controlled release of active substances, comprising a material surrounding the active substance and one or more active substances and, if appropriate, further auxiliaries which are characterized in that the material surrounding the active substance has low molecular weight compounds with a molecular weight of 180 to 440 daltons and a melting point above 35 ° C.

In principle, there are several forms of controlled delivery of an active ingredient. The time or period of release of an active ingredient is predetermined by the pharmaceutical formulation. In one case, the entire active ingredient should be available within a short time. In another case, the active ingredient should be delayed but released evenly. Or it should be released to the surrounding environment with a delay but discontinuously (pulsed or pulsatile). In the latter case, this means that between the phases of the release of the active ingredient there is a certain period of time within which no or only a little active ingredient is released.

It was surprising that the low molecular weight compounds can be processed into suitable bodies for the controlled release of active substances and that it is thus possible not only to use the customary methods of active substance release, for example the slow release of active substance over a certain period of time, but in particular also the pulse-like delivery, and that it is in particular possible to build up systems with time-delayed pulse-like drug deliveries.

It was also particularly surprising that low molecular weight compounds, in particular stearyl alcohol, can be processed so excellently to give the bodies according to the invention. Stearyl alcohol is a substance that belongs to the so-called fatty alcohols, which are easily accessible from higher fatty acids.

The material surrounding the active ingredient can consist entirely or to a greater or lesser extent of the low molecular weight compound.

The expression “comprising” in the context of the invention means that the material does not necessarily have to consist of a single low-molecular compound, but can also contain further additives or also mixtures of two or more low-molecular compounds, optionally with additives.

Suitable homogeneous low molecular weight compounds for the bodies according to the invention are linear organic compounds, e.g. aliphatic alcohols with 14 to 30 carbon atoms.

These compounds include meltable, water-insoluble fats or fat-like melting masses, for example fatty alcohol mixtures with carbon chain lengths> C ₁₂ and melting points above 35 ° C., such as cetyl alcohol, stearyl alcohol, cetylstearyl alcohol, lauryl alcohol, docosanol, behenic acid and mixtures thereof.

Active substances for use in the bodies according to the invention are artificial, natural or recombinant medicinally active substances and / or immunogens for humans or animals, which are also administered in combinations. Medicinally active substances are, for example, antibiotics, antiparasitics or repellents, antiviral and fungicidal or fungistatic substances, hormones, growth promoters, immunopotentiators, vitamins, minerals and trace elements, cardiovascular active substances, antipyretic and anti-inflammatory substances, immunostimulants and immunosuppressants, substances with Effect on the peripheral and central Nervous system (e.g. antidepressants, tranquilizers, anesthetics). Immunogens are, for example, antigens, antibodies, antitoxins, nucleic acids, vaccines, cytokines. Immunogens are particularly preferred.

In principle, the active substances can be administered in various ways. e.g. through oral application (e.g. tablets, drops, powder, capsules, granules, syrup), parenteral application (solutions, suspensions, implants for e.g. intravenous, intramuscular, subcutaneous, application) and topical application (as ointments, creams, "pour - on ", spray, powder, paste, or also for intraocular, intranasaien application).

The type of application is selected in accordance with the characteristics of the active ingredients to be applied and the particular aim of the application. Some active ingredients are e.g. absorbed in the gastrointestinal tract after oral administration, others are ineffective. Another aspect for choosing the application form is the simplicity of the

Administration. This can lead to the preferred application of different application forms in humans and animals. While oral administration is generally the preferred variant for long-term use in humans, this is an injection or implantation in farm animals.

Suitable auxiliaries can furthermore be used in the bodies according to the invention. Auxiliaries are e.g. Swelling and blowing agents, fillers, agents for increasing viscosity, solubilizers and the like.

To produce the bodies according to the invention, the low molecular weight compounds can be mixed with polymers, in particular with biodegradable polymers. Mixtures are preferably used which produce a homogeneous mixture in the melt, in particular those which form a single-phase system. By adding these polymers, the degradation behavior can be controlled on the one hand, and on the other hand the mechanical properties of the body can be influenced. In order to be able to control the onset of the effect, the hydrophilization of the bodies according to the invention can be influenced in a targeted manner. The bodies according to the invention can be modified hydrophilically or hydrophobically. The examples show how the bodies according to the invention can be modified hydrophobically or hydrophilically.

By adding the substances which increase the hydrophilicity, the rate of degradation of the materials enveloping the active substances in aqueous systems can be increased (hydrophilic modification). It is thus possible, for example, to trigger the release of the active ingredient at different times by using several capsules with envelopes by substances of different degrees of hydrophilicity.

Suitable substances used to increase the hydrophilicity of the low molecular weight

Compound can be used in the body according to the invention are aliphatic compounds, preferably hydrophilic aliphatic compounds such as

Example polyols with different chain lengths. Polyglycols, in particular polyoxyethylene-polyoxyethylene glycol such as, for example, Pluronic® F68 from BASF or Poloxamer 188, are particularly preferred. These substances can be used in a proportion of 2 to 70%.

Conversely, the degradation of the material surrounding the active ingredient in aqueous systems can be delayed by increasing the hydrophobicity of the material (hydrophobic modification).

Suitable substances which can be used to increase the hydrophobicity of the low molecular weight compound in bodies according to the invention are, for example, polycaprolactones, polylactic acid, polyglycolic acid and / or copolymers from milk and glycolic acid. Polycaprolactones (PCL) are biodegradable thermoplastic polymers from the chemical synthesis of crude oil. Polycaprolactones, for example poly-epsilon-caprolactone, have a low melting point (58-60 ° C.) and a low viscosity and are completely biodegradable (for example Polyol 0260 from Union Carbide or CAPA ^® polycaprolactones from Solvay). These substances can be used in a proportion of 2 to 70%. The bodies according to the invention can be in the form of spheres, granules, pellets, tablets, projectiles, cylindrical bodies, capsules and in other forms which are known to those skilled in the art for controlled delivery

The excipients can absorb the active ingredient in a matrix or they can coat discrete active ingredient particles as a shell. After the shell has been broken down in the surrounding environment, the active ingredient is released. The same applies to bodies in which the material surrounding the active ingredient is present as a matrix Release of the active ingredient instead, since the surrounding environment slowly breaks down or dissolves the matrix and thereby releases the active ingredient

The bodies according to the invention can be used particularly advantageously in the pulsed release of active substances. Another object of the invention is therefore the use of the bodies according to the invention for the pulsed release of active substances.

Pulse-like (pulsatile) release means in the context of the invention that the body, in particular a cylindrical hollow body, after it has been brought into the environment intended for it, releases the active ingredient very quickly to the surrounding environment after a defined period of time. The pulsatile release is on there is also a delayed release, although a delayed release also includes delivery mechanisms in which, after a certain time, the active ingredient is released more or less gradually to the environment intended for it

The pulse-like release of active ingredients is generally assumed to be a body in which the active ingredient is present together with a swelling agent when the liquid in the surrounding environment has penetrated the cylindrical hollow body filled with the active ingredient, swelling agent and, if necessary, auxiliary agents, and the swelling agent is caused to swell , the pressure inside the body increases continuously. When the pressure set to burst the body is reached, the shell opens and the active ingredient is released Such bodies can be used advantageously in human medicine and veterinary medicine. Further applications can arise in particular in agriculture. The encapsulation of fertilizers or pesticides, insecticides, fungicides and herbicides are important.

EXAMPLES

The invention is explained in more detail by the following examples

Example 1 Production of a pulsartiq-releasing system from stearyl alcohol

3 g of stearyl alcohol were weighed into a 15 ml glass and melted at 110 ° C. The hot melt was pipetted into silicone tube pieces (h = 1 cm D (inside) = 6 mm). After 15 minutes, the cooled blanks were removed from the tube pieces and with the help of a clamping device with a centered hole (D = 2mm, h = approx. 6mm)

Now 5μl of a solution of antigen (tick vaccine) and adjuvant (potentiator for the immune response) (BM86 / Quιl A solution (c (BM86) = 10mg / ml, c (Quil A) = 200mg / ml)) were pipetted in. The tubulars filled in this way Bodies were allowed to dry at room temperature for 2 days

The dried-up BM86 / Quιl A mixture at the top of the bore was detached with a cannula and about 5 mg of swelling agent (polyacrylate absorber, manufacturer e.g. BASF) was poured in. Then the opening of the tube was melted with a hot slide and with a few drops of melted stearyl alcohol in closed the kind that forms a hemispherical on the bore of the tube

After cooling, the tubes were briefly washed in water in order to remove any BM86 / Quιl A adhering to the outside

Finally, the tubes were dried with a cellulose cloth and stored at 4 ° C for further use

Example 2 Production of a pulsartiq-releasing system from stearyl alcohol with hydrophilic modification

2.85 g of stearyl alcohol and 150 mg of Pluronic F68 were weighed into a 15 ml glass and melted at 110 ° C. The hot melt was pipetted into silicone tube pieces (h = 1 cm, diameter (inside) = 6 mm). After 15 minutes, the cooled blanks were removed from the tube pieces and with the help of a clamping device with a centered hole (D = 2mm, h = approx. 6mm) The tubular bodies are filled with a solution of antigen and adjuvant as described in Example 1.

The tubes filled in this way were allowed to dry for 2 days at room temperature. The BM86 / Quil A mixture dried at the top of the hole was detached with a cannula and approx. 5 mg of swelling agent (polyacrylate absorber; manufacturer e.g. BASF or

Stockhausen).

Then the opening of the tube was melted with a hot slide and closed with a few drops of stearyl alcohol / Pluronic melt in such a way that a hemisphere forms on the bore of the tube. After cooling, the tubes were briefly washed in water in order to remove any BM86 / Quil A that was adhering to the outside.

Finally, the tubes were dried with a cellulose cloth and then another

Use stored at 4 ° C.

Example 3: Production of a pulsed-release system from stearyl alcohol with hydrophobic modification

2.1 g stearyl alcohol and 0.9 g polyol 0260 (poly-epsilon-caprolactone from Union

Carbides) were weighed into a 15 ml glass and melted at 110 ° C. The hot melt was pipetted into silicone tube pieces (h = 1cm, D (inside) = 6mm).

After 15 minutes, the cooled blanks were removed from the tube pieces and with

Provide a centered hole (D = 2mm, h = 6mm) using a clamping device.

5 μl of BM86 / Quil A solution (c (BM86) = 10 mg / ml; c (Quil A) = 200 mg / ml) were then pipetted in.

The tubes thus filled were left to dry for 2 days at room temperature. The BM86 / Quil A mixture dried at the top of the hole was detached with a cannula and approx. 5 mg of swelling agent (polyacrylate absorber; manufacturer e.g. BASF) was added.

Then the opening of the tube was melted with a hot slide and closed with a few drops of stearyl alcohol / polyol melt in such a way that a

Hemisphere forms on the bore of the tube.

After cooling, the tubes were briefly washed in water in order to remove any BM86 / Quil A that was adhering to the outside. Finally, the tubes were dried with a cellulose cloth and kept at 4 ° C for further use.

Example 4: Production of a pulsartiq-releasing system from> stearyl alcohol modified with a copolymer of lactic and glycolic acid

1.5 g of stearyl alcohol and 1.5 g of PLGA 65/35 DL (poly-milk-co-glycolic acid from Medisorb) were weighed into a 15 ml glass and melted at 150.degree. The hot melt was pipetted into silicone tube pieces (h = 1cm, D (inside) = 6mm). After 15 minutes, the cooled blanks were moved out of the tube pieces and provided with a centered hole (D = 2mm, h = 6mm) with the aid of a clamping device. 5 μl of BM86 / Quil A solution (c (BM86) = 10 mg / ml; c (Quil) a = 200 mg / ml) were then pipetted in.

The tubes thus filled were left to dry for 2 days at room temperature. The dried BM86 / Quil A mixture at the top of the hole was detached with a cannula and about 5 mg of swelling agent (Sanwet) was added.

Then the opening of the tube was melted with a hot slide and closed with a few drops of stearly alcohol / PLGA melt in such a way that a hemisphere forms on the bore of the tube. After cooling, the tubes were briefly washed in water in order to remove any BM86 / Quil A that was adhering to the outside.

Finally, the tubes were dried with a cellulose cloth and kept at 4 ° C for further use.

Example 5: Use of a hydrophilically modified body for delayed, pulse-like antigen release in sheep

A pulsatile releasing body with hydrophilic modification was produced as described in Example 2. The cylindrical body was made of stearyl alcohol with 3% Pluronic F68. Sanwet® was used as the swelling agent. The cylindrical body contained -50μg Bm86 as antigen and 1 mg Quil A as adjuvant. The sheep were vaccinated by a single, subcutaneous application of an antigen solution (50μg Bm86 and 1 mg Quil A per sheep) (so-called Prime). In the following days, serum samples were taken from the vaccinated animals at regular intervals and the immune response was measured by ELISA.

After the antibody titer had dropped to a minimum titer of 100 (background in the ELISA), the sheep in a group were re-vaccinated by subcutaneous implantation of the cylindrical body (“booster”). The control group was revaccinated with the same antigen / adjuvant solution used for the first vaccination Serum samples were obtained at regular weekly intervals after the revaccination and the antibody titers were determined using an ELISA test.

The average antibody titers after revaccination are summarized in Table 1. As a result, a significant time-delayed immune response was observed due to increased antibody titers of the revaccinated animals implanted with cylindrical bodies compared to the control group.

Table 1: Average antibody titers (n = 3 animals) after revaccination with a cylindrical body or antigen / adjuvant solution

Claims

claims

Body suitable for parenteral administration for the controlled delivery of

Active ingredients, comprising a material surrounding the active ingredient and one or more active ingredients, and optionally auxiliary substances, characterized in that the material surrounding the active ingredient comprises low molecular weight compounds with a molecular weight of 180 Daltons to 440 Daltons and a melting point above 35 ° C

Body according to claim 1, characterized in that the low molecular weight

Connection is a linear, organic connection

Body according to claim 1 or 2, characterized in that the low molecular weight compound is an aliphatic alcohol having 14 to 30 carbon atoms

Body according to claim 3, characterized in that the aliphatic alcohol is stearyl alcohol

Body according to at least one of claims 1 to 4, characterized in that the material contains a substance which increases the hydrophilicity

Body according to one of claims 1 to 4, characterized in that the material contains a substance which increases the hydrophobicity of the material

Body according to at least one of claims 1 to 6, characterized in that the low molecular weight compounds are mixed with a biodegradable polymer

Body according to claim 7, characterized in that the biodegradable polymer is polylactic acid, polyglycolic acid or a copolymer based on lactic acid and glycolic acid

9. Body according to at least one of claims 1 to 8, characterized in that the material surrounding the active ingredient is in matrix form in which the active ingredients are distributed.

10. Body according to at least one of claims 1 to 8, characterized in that the material surrounding the active ingredient is in a cylindrical form in which the active ingredient is enclosed.

1 1. Body according to at least one of claims 1 to 8, characterized in that the active substance surrounding material is in the form of a hollow cylinder, inside the active substance is enclosed and the hollow cylinder is provided at both ends with a closure.

12. Use of the body according to at least one of claims 1 to 11 for the pulsed release of active ingredients.