Patent Application
20190242863
The present invention relates to a release test system according to the preamble of claim 1.
One important aspect to be considered when developing medical active ingredients is how a medical active ingredient is taken up by the human body. One important influencing factor in this respect is the state of the medical active ingredient or of a given dosage form of the medical active ingredient and its change in the human body. Dosage forms may, for example, assume liquid form from the outset. They may, however, also initially assume solid form, then be present as a liquid-solid mixture, and finally adopt liquid form or complete dissolved form. As a rule, a chain of states of the dosage form, before it can be ultimately absorbed by the body, is longer for solid dosage forms than for dosage forms that are liquid from the outset. This is associated with the fact that solid dosage forms generally have to be finely comminuted and dissolved before absorption by the body. Within the human body, these operations take place, for example, via the masticatory apparatus or through certain conditions inside the human body which lead to a change in state of the medical active ingredients. Examples of this are mechanical, physical and chemical influences in the region of the gastrointestinal passage. A change in the state of the medical active ingredient is brought about as a result of influencing factors prevailing there, such as temperature, presence of body fluids, pH, presence of gases, pressure conditions, presence of further solids and mechanical influences resulting from muscle contractions of the stomach and intestine. This change in state may, for example, be a change from a solid state in the form of a tablet, through finely comminuted fragments of the tablet to the state of being dissolved in liquid.
Since the state of the medical active ingredient at the absorption site in the human body, for example in stomach lining regions, at the gastrointestinal passage or in the intestine, has a major effect on uptake efficiency and thus on the action of the medical active ingredient, medical active ingredients need to be developed in such a way that the change in state thereof in the human body has a defined characteristic which favors uptake. Extensive laboratory investigations are needed in this case, for example to investigate the release behavior of a dosage form in a test liquid.
WO 2013/164629 A1 for example describes a device for testing solubility of a medical dosage form. This device comprises a chamber in which a solvent medium is located. The device comprises means for adjusting pH.
In this case, there are particular challenges when handling the medical active ingredients.
For instance, medical active ingredients may cause undesired toxic, carcinogenic, mutagenic, fertility-compromising or other potentially hazardous effects. This constitutes a risk to health when handling the active ingredients.
It is therefore necessary to prevent the medical active ingredient from exiting a test system and entering the surrounding environment. Conventionally, these challenges are countered by personnel wearing suitable protective clothing and by providing complex environmental monitoring systems and isolated safe working areas.
All this entails significant effort with regard to the technical, organizational and personal protective measures which need to be taken.
The object of the invention is to provide a novel test system for medical active ingredients which can be produced and used with little effort and at the same time is extremely reliable with regard to working conditions and attainable test results.
The object is achieved by the subject matter of independent claim 1. Preferred configurations of the invention are revealed by the remaining features mentioned in the subclaims.
The subject matter of the invention is a release test system for simulating the change in state of medical active ingredients in the region of a human or animal organ, comprising at least:
According to the invention, the lid and at least the stirring mechanism are permanently connected to one another and a nondetachable connection is producible or exists between the main body and the lid.
Inert materials are preferably used for the components of the release test system which may come into contact with medical active ingredients during use. For example, stainless steel may be used, but preferably a plastics material is used as it is inexpensive and easy to work. The lid and the main body are connected or connectable together in such a way that once they have been assembled they can no longer be non-destructively separated from one another. The lid and the main body are then integral components of the release test vessel. The lid and the stirring mechanism are preferably designed as a common unit, further preferably can no longer be disassembled once the lid has been connected with the main body, and further preferably can no longer be non-destructively disassembled once the lid and the stirring mechanism have been fitted together. The release test system as a whole is, due to its structure, particularly suitable for one-off use or as a disposable system.
The release test system according to the invention has the advantage that it is of very simple construction and can be produced with little effort. This is also attributable to the fact that no possibility of disassembly has to be structurally provided, thereby increasing design latitude. The release test system is also particularly safe, since after preparation for the simulation, i.e. after filling of the main body with a test liquid, adjusting the temperature of the test liquid and equipping the main body with the dosage form of the medical active ingredient to be tested, followed by fitting of the lid to the main body, such that the release test vessel is permanently closed, no access to the interior of the release test vessel by releasing the lid is possible any longer. Once the simulation is concluded, the release test vessel or the main body including lid may be disposed of as a unit, meaning that there is no possibility of contaminated material escaping. Conventional systems are not suitable for disposable use due to the cost thereof and therefore must be cleaned, which is a complex and high-risk process. In the case of the present invention, such use is ruled out by the design measures taken.
The release test system is particularly well suited for investigating the dissolution behavior of medical active ingredients under conditions such as those that prevail in the region of the human gastrointestinal passage.
In a preferred configuration of the present invention, provision is made for the lid to be form-lockingly and/or force-lockingly connectable or connected and/or materially bondable or bonded to the main body.
The main body and the lid may preferably be connected to one another by way of a snap-in connection, a press fit, an adhesive bond or ultrasound welding. In this case, a snap-in connection, as an example of a form-locking or form- and force-locking connection, offers the advantage that the release test vessel may initially be delivered in the open state, i.e. without a connection present between the main body and the lid, and then permanently closed at the place of use.
The same is true of an adhesive bond as an example of a flexibly producible bonded connection, this having particular advantages with regard to tightness.
A press fit, as an example of a force-locking connection, offers the advantage that the main body and the lid may be permanently and extremely tightly connected to one another without additional parts or auxiliary substances having to be provided for this purpose. This reduces the design complexity of the release test system.
Ultrasound welding, as a further example of a bonded connection, offers significantly increased tightness, durability and security against undesired separation of the lid from the main body.
In view of the technical teaching disclosed here, a person skilled in the art is henceforth in a position to select further suitable connecting methods.
In a further preferred configuration of the release test system of the invention, provision is made for the lid to be hermetically sealed or sealable relative to the main body. Suitable sealing elements are preferably used in this respect. Flat gaskets, sealing rings and indeed sealing pastes are particularly suitable.
All of this offers several advantages at once. On the one hand, security against contaminated material escaping is significantly increased. On the other hand, defined pressure conditions may in this way be produced inside the release test vessel, for example by the technical control means, to influence the simulation conditions prevailing inside the release test vessel. A vacuum may for example be produced here. This ensures that even in the case of undesired leaks in the release test vessel, no contaminated material can escape. However, an overpressure may also be produced, in order for example to simulate gas accumulation in the stomach.
In a further preferred configuration of the release test system of the invention, provision is made for the stirring mechanism to have a drive interface, which is only accessible from outside the release test vessel. The drive interface may for example comprise a shaft end of a drive shaft of the stirring mechanism. The shaft end may be manufactured to fit or indeed have a parallel key or teeth. The shaft end conveniently projects out of the lid of the release test vessel, wherein the lid may comprise appropriate mechanical interfaces for mounting an electrical drive, for example. The drive shaft is preferably firmly installed in the lid via rolling bearings or plain bearings.
The structure described furthermore reduces the design complexity of the release test system and ensures simple and extremely reliable operability from outside. It is additionally advantageously ensured that the stirring mechanism is always arranged at the same position inside the release test vessel. If, for example, series of simulations are conveniently carried out with different release test systems intended for one-off use, the results may in this way be better compared with one another.
The stirring mechanism may particularly preferably be incorporated into the lid in such a way that it is not released with a view to performing a stirring movement until the permanent connection has been produced between the lid and the main body. To this end, for example, a locking element may be provided which, upon closure of the main body with the lid, is displaced relative to the stirring mechanism from a locking position into a release position.
The locking element may ensure that use of the stirring mechanism is only actually possible when the lid is closed. In this way, improper handling may be ruled out. In practice, it has been known for safety aspects to take a back seat under high cost pressures. The possibility cannot therefore be ruled out of attempts being made to use a system repeatedly which is intended for single use. The locking element reliably prevents such attempts.
The locking element is preferably designed in such a way that the drive interface of the stirring mechanism becomes unusable (purely by way of example through a predetermined breaking point in the drive shaft) if an attempt is made to force the stirring mechanism to start up when the lid is open (i.e. with the locking element in the locking position). In this way, it is ensured that the function of the locking element cannot be bypassed even by applying force.
In a further preferred configuration of the release test system of the invention, provision is made for the sampling device to comprise at least one sampling tube or additionally a sample return tube, these each being arrangeable or arranged in a complementary receptacle in the lid. The respective complementary receptacle is preferably configured such that in no spatial position of the release test vessel can contaminated material escape. The sampling tube and optionally sample return tube may preferably be guided in the lid via tight-fitting plain bearings. The plain bearings may for example be regions of resilient material, through which the sampling tube or sample return tube can be guided with resilient deformation of the material. Purely by way of example, rubber inserts may be provided for this purpose. However, a plurality of sealing rings arranged one behind the other may also be provided. A design requirement for the complementary receptacle is full tightness of the release test vessel even when the entire liquid column of the test liquid located inside the release test vessel and of the medical active ingredient dissolved wholly or partly therein acts on the complementary receptacle. A further safety factor may optionally be added in this case, taking account of overpressure producible in the release test vessel. In light of the technical teaching disclosed here, a person skilled in the art is henceforth in a position to select further suitable sealing methods.
All this has the advantage that a sample may be taken from the release test vessel with little effort. To this end, for example, a hose exposed to a vacuum may be slipped onto the sampling tube. To equalize pressures, the corresponding quantity of air may flow in through the sample return tube. Alternatively, recirculation of a sample which has been taken is also possible in this way.
The sampling tube may also be of a telescopic design. For example, an inner tube may be guided displaceably in an outer tube. Any remaining play between the inner tube and the outer tube may preferably be sealed by a lubricant.
This has the advantage that a small defined sample may be collected by short immersion in the test liquid. Capillary action may be exploited in this respect. It is technically more demanding to collect a sample of very small volume by suction, for example using a pump.
In a further preferred configuration of the release test system of the invention, provision is made for one or more of the following features to be incorporated structurally into the stirring mechanism: a feed path for liquid and/or gaseous substances; technical means for measuring pH; technical means for measuring temperature.
Incorporation into the stirring mechanism first of all offers the advantage that available structural space is utilized effectively and the stated technical means may be directly brought up to the test liquid inside the release test vessel by the stirring mechanism. Feed paths are configured and optionally sealed in such a way that test liquid is always prevented from escaping from the inside of the release test vessel. The feed paths may for example be twisted on themselves in such a way that test liquid cannot flow out for that reason alone. The feed paths may also be of appropriately thin construction. Furthermore, the previously described sealing methods may be used.
The feed path has the advantage that titrimetric substances may for example be guided into the release test vessel.
The technical means for measuring pH and temperature may furthermore advantageously be used to regulate the simulation conditions prevailing inside the release test vessel.
In a further preferred configuration of the release test system of the invention, provision is made for a resilient flask to be arranged or arrangeable inside the release test vessel, said being supplied or suppliable with a pressure medium.
This has the advantage that a wide range of pressure conditions may be simulated inside the release test vessel. In particular, biorelevant pressure conditions may be realistically modeled. The intensity and frequency of pressure waves producible with the resilient flask are advantageously suitable for a close-to-reality simulation of pressure conditions at the human gastrointestinal passage.
In a further preferred configuration of the release test system of the invention, provision is made for an auxiliary substance for transferring mechanical stirring energy to the test liquid to be introduced or introducible into the release test vessel. The auxiliary substance may for example be polystyrene pellets.
The auxiliary substance advantageously brings about an increase in the mechanical loading of the dosage form of the medical active ingredient inside the release test vessel. By adapting a test liquid used and a stirring program, it is possible to simulate postprandial conditions for taking rapid-release dosage forms.
In a further preferred configuration of the release test system of the invention, provision is made for the lid to have one or more predetermined breaking points for producing interfaces in the release test vessel, wherein in the region of the interfaces sealing elements or receptacles are provided for this purpose.
Depending on the configuration of the release test system, for example as a function of technical means arranged inside the release test vessel, such as the resilient flask, structural weaknesses are advantageously produced in the lid only when actually necessary. Otherwise, the lid is materially impermeable in the region of the predetermined breaking points, thereby offering maximum safety. The sealing elements or receptacles present may optionally be configured such that they are adaptable with little effort. Purely by way of example, a sealing element in the form of a flat semi-finished product of rubber may be provided, which is perforated if need be with a needle whose diameter is conveniently smaller than for example the diameter of a sampling tube to be placed in the sealing element.
This makes the release test system extremely flexibly configurable and safe at the same time. Since only a one-off configuration is necessary, due to the disposable nature, such simply configured regions may be implemented for producing the interfaces.
In a further preferred configuration of the release test system of the invention, provision is made for the release test system to further comprise one or more of the following features: a drive for the stirring mechanism; a pump for delivering test liquid from and/or into the release test vessel; an analyzer for analyzing the test liquid; one or more stoppers for closing interfaces of the lid.
All this has the advantage of enabling the release test system to offer a simple, reliable and extensively automatable simulation of the change of state of the medical active ingredients located inside the release test vessel. The pump and the analyzer further have the particular advantage that medical active ingredients which have passed into solution may be recirculated with simultaneous analysis. To this end, using the pump test liquid is sucked out of the release test vessel for example via a sampling tube, passed through the analyzer, analyzed and finally passed by way of the pump output through the sample return tube back into the release test vessel. In this way, test runs of extended duration may also advantageously be implemented, in order to observe the change in state of the medical active ingredients continuously over time.
Provided nothing is stated to the contrary, the various features disclosed in this patent application can be combined with one another.
The invention is described in greater detail below with reference to exemplary embodiments and associated figures, in which:
The lid 14 shown in
The stirring mechanism 20 is incorporated structurally into the lid 14 and thus permanently connected therewith. This mechanism comprises in the present case a paddle stirrer 36, a stirring shaft 38, a bearing portion 40 and a sealing ring 42 arrangeable on the bearing portion 40 and in the lid 14. The bearing portion 40 likewise has in an upper region one of the regions for producing a snap-in connection 34 (cf.
For hermetic sealing of the lid 14 relative to the main body 12 and of the release test vessel 16 relative to the environment, a flat seal 44 is provided in the region of the snap-in connection. Furthermore, the sealing ring 42 described participates in the hermetic sealing. The interfaces 28 are sealed materially impermeably, provided no sampling device 26 or other required additional technical elements are arranged there. In this case, predetermined breaking points 46 are merely provided in the material of the lid 14. If the interfaces 28 are not needed, the lid 14 is thus itself hermetically impermeable. The seal in the case of use of the interfaces 28 is described further below.
In
Through rotation of the stirring mechanism 20, simulation conditions may be mechanically influenced in the release test vessel 16. The temperature control device 22, which is not illustrated here but which may be arranged in or on the release test vessel 16 or indeed separately therefrom, allows the temperature of the test liquid 50 to be adjusted before and/or during and optionally after the simulation.
The sampling device 26 allows simple sampling and recirculation. To this end, either the sample may be taken using the sampling tube 30 and air or another medium added using the sample return tube 32 or indeed the sample taken may be recirculated via the sample return tube 32.
Finally,
In step II at the latest, filling with test liquid 50 proceeds, and placement of the dosage form, then, at the latest, fitting of the lid 14 onto the main body 12, followed by adjustment of the temperature of the test liquid 50.
In step III at the latest, stirring 76 proceeds with the stirring mechanism 20. To this end, a corresponding drive 78 is connected to the stirring mechanism 20. A sample is further taken with the sampling device 26 via a pump 80, for example, and the sample is analyzed using an analyzer 82. As indicated, recirculation of the sample may optionally take place, to perform a continuous test.
Step IV involves disposal of the release test vessel 16 including stirring mechanism 20, sampling and return tubes and the test liquid 50 and the dosage form 54. In this way, all contaminated elements, which are complex and risky to clean, are directly disposed of. The contaminated test liquid 50 in this case remains safely contained inside the release test vessel 16.
| Number | Date | Country | Kind |
|---|---|---|---|
| 10 2016 120 019.0 | Oct 2016 | DE | national |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/EP2017/076403 | 10/17/2017 | WO | 00 |
