DE102009024949B3 - Remote drug delivery assembly - Google Patents

Abstract

The invention relates to an arrangement for the remote-controlled release of active substances. The object of the invention to provide an arrangement for the remote-controlled release of active substances which avoids the disadvantages of the prior art is achieved in that the arrangement contains a permanent magnetic component rotating under the influence of an external magnetic field and two chemical substances separated from one another by a separating layer which form a propellant gas when they come into contact with one another, at least one mass body being arranged on / in the surface of the permanent magnetic component, which acts mechanically on the separating layer when the component rotates and thereby destroys the separating layer.

Description

The The invention relates to a remote release device of drugs according to the genus of the claims.

The Application of medications to predefined and locally defined Digestion in the gastrointestinal tract is a target that has been used for many years Aimed at medical and pharmacists. Practically applied So far, variants of the physiologically triggered release. Because of the differences the physiological situation between different persons and even with one and the same person under different conditions however, the probability of missing the target area is high and thereby the intended effect with the dose used not achievable [Van den Mooter G (2006): Colon drug delivery, Expert Opin. Drug Deliv. 3, 111-125]. To compensate for this disadvantage, some overdoses applied in which the risk of harmful side effects in purchasing must be taken.

Another way is the remote controlled release. Numerous research and development work has been carried out in this field for years [Wilding IA, Prior DV (2003): Remote controlled capsules in human drug absorption (HAD) studies, Critical Reviews in Therapeutic Drug Carrier Systems, 20, 405-431, Andrä W , Werner C (2007): Remote-controlled drug delivery in the gastrointestinal tract. In: Andrä W, Nowak H (eds.) Magnetism in Medicine, Second Edition, Wiley-VCH Verlag, pp. 499-510]. Typical examples are the Eriksen capsule [Eriksen SP, Swintowsky JV, Serfass EJ, Lin TH, Abrams J, Sturtevant FM (1961): Equipment and methodology for relating gastrointestinal absorption to site of drug release, J. Pharm. Sci. 50, 151-156], the small intestine capsule [Hemmati A (1968): The determination of the absorption site of iron in the intestinal canal with a remote-controlled intestinal capsule, Dtsch. Med. Wochenschr. 93, 1468-1472], the RF capsule [ DE 29 28 477 C3 ], the InteliSite ^® capsule [ US 5, 167, 626 ] and the Enterion ^™ capsule [ WO 01/45789 A2 ].

Other capsule constructions have been proposed which have not yet been used in practice. This also includes capsules in which the release mechanism used is the heating of a capsule part by magnetic rotary or alternating fields [ DE 197 45 890 . DE 10 2004 034 355 B4 . DE 103 10 825 B3 ]. Further, a capsule is known which utilizes the movement of a screw coupled with a permanent magnet as a release mechanism [ JP 2003-325438 A ].

Capsules are also known in which the active ingredient is expelled by a gas generated in the capsule. So z. For example, within a capsule, a gas evolution cell is used which is remotely controlled to produce gas by a magnetic switch [Groening R. (1997): Computer-controlled drug release from small-sized dosage forms, Journal of Controlled Release 48, 185-193, Danco I (2002) Development of new concepts and dosage forms for the release of active ingredients in the colon (colon targeting). Dissertation, IPT-Verlag, Münster]. Also, the gas formation by combining two previously separated substances has been proposed to cause the release of the drug from the capsule [ US 5,279,607 ]. The gas-forming process used for this is long known and z. In effervescent tablets or in a variant of the so-called gastroretentive dosage forms [Arora S, Ali J, Ahuja A, Khar RK, Baboota S (2005) Floating drug delivery systems: AAAPS PharmSciTech 6 (3) //www.aapspharmscitech.org)], which, however, are not used for remote drug delivery. These dosage forms are only intended to have a prolonged length of stay in the stomach, which is, for. B. is realized by a drastic reduction in the density of tablets that can swim after the density reduction in the stomach contents. Such tablets contain sodium bicarbonate and an organic acid from which CO ₂ evolves after diffusion of aqueous gastric juice through a permeable layer [ US 4,844,905 ].

Capsules are known that are not intended for remote drug delivery but for their magnetic location in which spherical magnetic bodies are rotatably mounted, the surface of which are provided with projections or depressions, which obviously is the friction of these bodies to change in the surrounding liquid [ US 6,168,780 B1 ].

• 1. Die Kapseln besitzen eine harte Hülle, die sich im Verdauungstrakt nicht auflösen kann. Dadurch besteht die Gefahr, dass die Kapseln an Stenosen stecken bleiben und möglicherweise operativ entfernt werden müssen. Diese Gefahr besteht sogar dann, wenn durch vorangegangene Röntgen-Untersuchungen keine Stenosen festgestellt worden sind [Rösch T, Ell C (2002): Derzeitige klinische Indikationen der Kapsel-Endoskopie, Zeitschrift für Gastroenterologie, 40, 971–978].
• 2. In den Kapseln befinden sich Teile (z. B. Metallfedern, Batterien, elektronische Bauelemente oder Schaltkreise), die toxisch wirken können, wenn bei einer Beschädigung der Kapselhülle Kontakt mit der Darmwand eintritt.
• 3. Um die Position der Kapsel zu bestimmen, muss ionisierende Strahlung eingesetzt werden.
• 4. Der Volumenanteil der Kapsel, der für den Mechanismus der ferngesteuerten Freisetzung benötigt wird, ist relativ groß und schränkt das für den Wirkstoff-Transport benötigte Volumen stark ein.

All known embodiments of capsules for the remote controlled drug release have at least one of the following disadvantages:

• 1. The capsules have a hard shell that can not dissolve in the digestive tract. There is a risk that the capsules will stick to stenoses and may need to be removed surgically. This risk exists even if no stenoses have been detected by previous X-ray examinations [Rösch T, Ell C (2002): Current Clinical Indications of Capsule Endoscopy, Journal of Gastroenterology, 40, 971-978].
• 2. The capsules contain parts (eg metal springs, batteries, electronic components or circuits) which may be toxic if contact occurs with the wall of the intestine if the capsule shell is damaged.
• 3. To determine the position of the capsule must be used ionizing radiation.
• 4. The volume fraction of the capsule required for the remote release mechanism is relatively large and severely restricts the volume needed for drug delivery.

The invention is based on the object to provide an arrangement for the remote release of active ingredients, which avoids the aforementioned disadvantages. This object is achieved by the characterizing features of the first claim. For triggering the process of drug release, a comparatively low energy is needed. This is transmitted by a magnetic rotating field on a permanent magnetic body, which is provided on / in its surface with a suitable structure, is freely rotatably mounted in the capsule and is rotated by the rotating field. The transmitted energy is sufficient to destroy a separation layer that separates two chemical substances that form a gas upon contact. The destruction of the separation layer takes place by the rotating permanent magnetic body (rotor) is brought with the suitable surface structure to rubbing movement on the separation layer and mechanically destroyed or by at least one connected to the rotor mass body when exceeding a certain rotational speed by the centrifugal effect its distance from Enlarged center of the rotor and pressed against the separation layer, the latter is destroyed and the separated chemical substances come together and can form a propellant. One of these substances may, for. As sodium bicarbonate, the other dilute acetic acid. These two substances form CO ₂ upon contact. Other substance pairs can be used, which also form CO ₂ or another gas upon contact. A particular advantage of the centrifugal force is that it increases with the square of the rotational frequency and thus the onset of the destructive effect is not gradual but occurs suddenly and is better defined in terms of time. It is advantageous that the rotor is designed as a ball which has the above-mentioned structure on / in its surface. Furthermore, it is advantageous that the at least one mass body attached to the magnetic poles of the rotor and z. B. is connected by elastic means to the rotor or incorporated in a surface connected to the rotor surface layer. Furthermore, it is advantageous that the rotor is surrounded by the separating layer and connected to it and contains one of the chemical substances, while the other chemical substance is outside the separating layer. Further, it is advantageous if the rotor is freely movable in a housing within the one of the chemical substances, wherein the housing is located in the capsule containing the active ingredients and the other chemical substance. It is also advantageous that the capsule has outlet means, through which the at least one active substance escapes to the outside under the pressure of the resulting propellant gas, or that the capsule has at least one predetermined breaking point, which breaks open under the pressure of the resulting propellant gas and after the at least one active ingredient outside releases, or that the capsule consists of telescoped parts that move apart under the propellant gas pressure and release the drug. It is also advantageous that the rotor is located in a cage within the capsule.

The The invention will be described below with reference to the schematic drawings some embodiments explained in more detail. It demonstrate:

1 a capsule according to the invention in longitudinal section, containing a rotating body (rotor) made of pressed powder, which is equipped near its surface with mass bodies,

2 a section through a rotor, which consists of concentrically arranged substances and mass bodies,

3 a longitudinal section through a capsule according to the invention with cage-like additional device and tear seam,

4 a longitudinal section through a capsule according to the invention, which contains a rotating body (rotor) with a shell with embedded mass bodies and a hollow cylinder of pressed effervescent powder,

5 a section through a rotor with attached to springs mass bodies and

6 a section through a rotor with a suitable surface structure.

In 1 is a rotor in spherical shape 10 represented, which has a diameter of 7 mm, in a liquid 11 freely floating. The permanent magnetic rotor 10 consists of a pressed mixture of about 80% by volume of magnetite powder, which has a coercive force of more than 25 kA / m, and effervescent powder. The surface of the rotor 10 is with a thin water-impermeable layer 101 (For example, made of polymethyl methacrylate) covered at two diametrically located locations 103 circular predetermined breaking points (eg in the form of reduced thickness) contains. Below each of these places is a small mass body 102 in a corresponding recess of the rotor 10 loosely inserted. These mass bodies are through the layer 101 held in their position. After production, the rotor becomes 10 by a magnetic field (field strength> 100 kA / m) and then has a permanent magnetic moment of about 0.02 Am ² , whose poles, designated by the letters N and S, on the mass bodies 102 are located. The direction of the magnetic moment is indicated by an arrow. The liquid 11 consists of water in which a substance, eg. As sugar is dissolved to set a desired viscosity. rotor 10 and liquid 11 are in a warehouse 12 (For example, made of hard gelatin), the inner wall by a thin layer 121 (eg from Eudragit) is protected against dissolution. The warehouse 12 contains at least one valve 122 that the spontaneous escape of the liquid 11 prevented under normal pressure conditions. The warehouse 12 is from a folded bag 13 surrounded, for example, consists of polyethylene. The remaining volume of the capsule 15 contains the active substance 14 , The wall 151 the capsule 15 exists z. B. hard gelatin and is against the dissolution in the aqueous intestinal fluid through a thin shell 152 (eg from Eudragit or ethyl cellulose or polyvinyl acetate). In the capsule wall there is at least one valve 153 , which prevents the escape of the drug under normal pressure conditions. The rotor 10 becomes through a magnetic rotating field 16 (Amplitude> 100 A / m), the z. B. by a rotating permanent magnet 17 is generated, set in rotation. As soon as the rotation frequency exceeds a critical value, it will be on the mass body 102 acting centrifugal force so great that this is the layer 101 break through and off the rotor 10 be thrown away. At the resulting holes, the contact between the aqueous liquid 11 and the effervescent powder portion of the rotor 10 produced. CO _{2 is} formed through the valve 122 the folded bag 13 bloat, which is the active ingredient 14 through at least one valve 153 squeezes out of the capsule.

2 shows a modification of the rotor 10 , which differs from the type described above in that the rotor is not made of a mixture of two substances, but an inner spherical magnetic core 104 with a diameter of 5 mm from the permanent magnet substance NdFeB, so that the rotor has a magnetic moment of about 0.07 am ² . The core is protected by a layer of gold approximately 50 micrometers thick against possible contact with the intestinal fluid. On top of that is a 0.5 mm thick layer 105 made of pressed effervescent powder. Also in this example, when a critical rotation frequency is exceeded, the centrifugal force acting on the mass bodies 102 acts so strong that these are the predetermined breaking points 103 break up and thus initiate the formation of CO ₂ , which leads to the release of the active substance 14 from the capsule 15 leads.

3 schematically shows a capsule 15 whose wall 151 z. B. consists of hard gelatin. There is a mixture in the capsule 141 from the active ingredient and water. The rotor 10 according to 1 or 2 is stored in this drug-water mixture, including optionally a cage-like additional device 18 for positioning the rotor 10 can be used. Also in this case, when a critical rotation frequency is exceeded, the mass bodies 102 from the rotor 10 thrown away and a contact between the water-active substance mixture 141 and the effervescent powder of the rotor. The resulting CO ₂ pushes the mixture 141 through at least one valve 153 in the capsule wall 151 from the capsule 15 or causes the breakup of the capsule wall 151 along a tear seam 154 , In a modified form, the capsule, as is common in drug capsules, consist of two assembled capsule parts, which are not glued together, but can be pushed apart by the pressure of the resulting CO ₂ . To avoid premature dissolution of the hard gelatin, is the wall 151 the capsule 15 inside and outside with a thin protective layer 155 and 152 (eg from Eudragit, ethyl cellulose or polyvinyl acetate). After the active substance has been expelled, water-containing intestinal fluid can penetrate into the interior of the capsule, reach the unprotected gelatin surfaces and dissolve the walls.

4 shows a capsule 15 in which the camp 12 a part, preferably in the form of a hollow cylinder 123 , which is pressed from effervescent powder, has a wall thickness of about 1 mm and a thin water-impermeable layer 124 from the aqueous storage liquid 11 is disconnected. In this example, the rotor is 10 with a layer 105 covered, in the small mass body 102 (eg, crystals of titanium dioxide) are embedded. The layer 105 consists of a material (eg paraffin) with which the mass bodies do not bond tightly. When forced by an external magnetic rotating field rotation of the rotor 10 As with the examples described above, the centrifugal force increases with increasing frequency. It acts on the mass body and causes the tearing out of the mass body when a critical rotation frequency is exceeded 102 out of the shift 105 , The ejected mass bodies rub against the separating layer 124 and cause destruction of this layer. This will cause the contact between the effervescent powder of the hollow cylinder 123 and the aqueous storage liquid 11 produced. The CO ₂ produced thereby, as in the examples described above, the active ingredient 14 from the capsule 15 pressed.

In 5 a modification of the rotor is shown in 4 is shown. In this case, the rotor 10 with a layer about 0.5 mm thick 106 (for example made of polyethylene), which has an annular groove lying in the plane of the drawing. This groove contains two thin curved strips 107 made of elastic material (eg polypropylene), which are each attached with one end to the rotor, but otherwise can lift off under the action of radially acting forces. The Stripes 107 each carry a mass body at their free end 108 (eg glass) with small tips. Both peaks are on the axis of the magnetic moment of the rotor 10 arranged. When a critical rotational frequency is exceeded, the centrifugal force causes the free ends of the elastic strips to lift off 107 , The mass bodies 108 come out of the groove of the layer 106 out, destroy the separation layer 124 and make the contact between the effervescent powder 123 and the aqueous liquid 11 which leads to the production of CO ₂ . This initiates the release process as in the other examples.

In 6 is shown a further modification of the rotor. This rotor 10 consists of a solid permanent magnet material, which is on its surface 112 with protrusions (mass bodies) 109 is provided. Through the projections 109 the surface gets a certain roughness. This causes the rotation of the rotor destruction of the separation layer 124 , in the 4 the hollow cylinder 123 from effervescent powder from the aqueous storage liquid 11 separates.

All in the description, the embodiments, The drawings and the claims presented below can both individually and in any combination with each other invention essential be.

LIST OF REFERENCE NUMBERS

10

magnetic body (Rotor)

101

layer

102

mass body

103

Breaking point

104

magnetic core

105

topcoat

106

layer with ring groove

107

feather

108

mass body

109

projections

110

magnetic Pole

111

magnetic moment

112

surface

11

liquid

12

storage sleeve

121

inner protective layer

122

Valve

123

bearing part

124

Interface

13

bag

14

active substance

141

mixture from active ingredient and water

15

capsule

151

capsule wall

152

outer protective layer

153

Cartridge valve

154

tear seam

155

inner protective layer

16

magnetic rotating field

17

rotating permanent magnet

18

Positionierkäfig

Claims (13)

Arrangement for the remote-controlled release of active substances from a drug capsule which contains active ingredients, a permanent magnet component rotating under the influence of an external magnetic field and two chemical substances separated from each other by a separating layer, which together form a propellant gas upon contact with each other, characterized in that on / in the surface of the permanent magnetic component at least one mass body is arranged, which acts mechanically upon rotation of the component on the separation layer and thereby destroys the separation layer. Arrangement according to claim 1, characterized that the at least one mass body the separating layer destroyed by mechanical rubbing. Arrangement according to claim 1, characterized that the at least one mass body due to the centrifugal force acting on it its distance from the center of the component is enlarged and while the separation layer destroyed. Arrangement according to claim 1, characterized that the permanent-magnetic component is designed as a ball and a suitable surface structure having. Arrangement according to claim 3, characterized that two mass bodies, preferably each at the magnetic poles of the magnetic component, are attached. Arrangement according to claim 3, characterized that the mass bodies over elastic Means are connected to the permanent-magnetic component and themselves located at the magnetic poles. Arrangement according to claim 3, characterized that the at least one mass body in a surrounding the permanent magnetic component and with the component bonded layer is in and out of rotation can move. Arrangement according to claim 2 or 3, characterized in that the permanent-magnetic component surrounded by the separating layer and with this ver is bound and contains one of the chemical substances while the other chemical substance is outside the separation layer. Arrangement according to claim 2 or 3, characterized that the permanent magnet component in a housing within one of the chemical substances is mounted freely movable, wherein the housing is located in a capsule, contains the active substances and the other chemical substance. Arrangement according to claim 1, characterized in that the capsule has preferred exit means through which the at least one active ingredient under the pressure of the resulting propellant gas outward escapes. Arrangement according to claim 9, characterized that the capsule has at least one predetermined breaking point, the lower breaks the pressure of the resulting propellant gas and the at least an active substance to the outside releases. Arrangement according to claim 9, characterized that the capsule consists of telescoped parts that are under the pressure of the resulting propellant gas slide apart and Release the least one active ingredient. Arrangement according to claim 3, characterized in that the permanent-magnetic component in a cage located inside the capsule.

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