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Transdermal Chronopharmaceutical Drug Delivery: Microneedles, Intradermal Infusion Experiments and a Delivery Device

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Transdermal Chronopharmaceutical Drug Delivery: Microneedles, Intradermal Infusion Experiments and a Delivery Device Michael Vosseler Transdermal chronopharmaceutical drug delivery: microneedles, intradermal infusion experiments and a delivery device Dissertation zur Erlangung des Doktorgrades der Technischen Fakultät der Albert-Ludwigs-Universität Freiburg im Breisgau April 3rd 2013 I Dekan Prof. Dr. Yiannos Manoli Gutachter Prof. Dr. Roland Zengerle Prof. Dr. Holger Reinecke Tag der Prüfung 05.02.2014 Michael Vosseler Hahn-Schickard-Gesellschaft für Angewandte Forschung e.V. Institut für Mikro- und Informationstechnik (HSG-IMIT) Villingen-Schwenningen II Erklärung Ich erkläre, dass ich die vorliegende Arbeit ohne unzulässige Hilfe Dritter und ohne Benutzung anderer als der angegebenen Hilfsmittel angefertigt habe. Die aus ande- ren Quellen direkt oder indirekt übernommenen Daten und Konzepte sind unter An- gabe der Quelle gekennzeichnet. Insbesondere habe ich hierfür nicht die entgeltliche Hilfe von Vermittlungs- oder Beratungsdiensten (Promotionsberaterinnen oder Pro- motionsberater oder anderer Personen) in Anspruch genommen. Niemand hat von mir unmittelbar oder mittelbar geldwerte Leistungen für Arbeiten erhalten, die im Zu- sammenhang mit dem Inhalt der vorgelegten Dissertation stehen. Die Arbeit wurde bisher weder im In- noch im Ausland in gleicher oder ähnlicher Form einer anderen Prüfungsbehörde vorgelegt. Ich erkläre hiermit, dass ich mich noch nie an einer in- oder ausländischen wissen- schaftlichen Hochschule um die Promotion beworben habe oder gleichzeitig be- werbe. Datum/date: Unterschrift/signature: III Abstract The beginning of modern chronotherapy was the delivery of cancer medication according to circadian (about 24 h) rhythms in the 70s and 80s of the last century. Nowadays, there is a lot of knowledge on rhythms of medical conditions and especially on the exacerbation of symptoms with time of day. Chronic conditions ranging from asthma to stroke are studied intensively. For a patient suffering from such a disease it is important to get the appropriate amount of his drug at the right time. Typically, this is an outpatient setting. In this case pills are the most accepted delivery technology. However, drug absorption from the gastro intestinal tract is site specific. This is a challenge for the development of time controlled release formulations. Minimal invasive transdermal time controlled drug delivery could be a potential solution for this issue. A new approach was developed within this thesis. Transdermal drug delivery is a discipline that generated impressive success stories in the last two decades. Drug loaded patches enable to deliver a drug without first pass effect and other gastro intestinal adverse effects. However, there are only approximately 20 drug molecules that can be absorbed across the human skin. The reason is the barrier properties of the upper skin layer. One way to circumvent this barrier is the application of microneedles. Hollow microneedles enable the time con- trolled delivery of drug solutions via the skin to the patient. Fabrication of such nee- dles is a challenging task. Within this thesis two approaches were investigated: microneedles generated by thermoforming processes such as hot embossing and injection moulding as well as steel cannulas that were inserted via a small but well defined angle into the skin. Later on the second approach will be named intradermal infusion set. The generation of the lumen of hollow microneedles by thermoforming processes is quite challenging. It was demonstrated that a soft mould in combination with wires can be used. It was proofed that aspect ratios (lumen diameter to needle length) larger than 10 can be realized easily. The outer diameter of a specific moulded microneedle design is 0.36 mm, the inner diameter is 0.13 mm and its length is 0.60 mm. The microneedle is placed on a pedestal with a height of 0.80 mm. The aspect ratio is computed with the height of the microneedle, the height of the pedestal and the lumen diameter. Including the base plate with a thickness of 1.00 mm the aspect ratio increases to approximately 20. The cycle time of the hot embossing process is more than one hour. Fast production is demonstrated by thermoforming with an injection moulding machine. Short fabrication cycles are inherent to this process. However, mould development is quite challenging. As an alternative approach a cannula was inserted at a very low but well-defined angle of 10° into the skin. The tip of the cannula could reliably be placed approximately 0.70 mm ± 0.08 mm below the skin surface during injection and infusion. Parameters for intradermal infusion and injection processes were characterized, which are necessary for the development and selection of small actuators for skin attachable drug delivery devices. Extensive ex vivo and in vivo experiments with the intradermal infusion set demonstrated the feasibility of this approach. Flow rates ranging from 0.1 ml/h to 180 ml/h were studied. Data on back pressure is presented. It ranges from 10 kPa to 700 kPa. Practical leak tightness of IV the delivery process was demonstrated, too. This is of outmost importance for the drug developer. It ensures a precise and consistent delivery mechanism. To realize an electronic and battery free infusion device a hydrogel actuator technology was developed. The design is very simple with less than 5 fabrication steps. If the hydrogel gets in contact with water it starts to swell immediately. Thereby the hydrogel delivers volume work. The influence of the most important design parameters was studied extensively. The dynamics of the actuators is characterized by a fast initial swelling followed by slow continuous increase in volume. Depending on the design parameters a volume of approximately 0.2 ml to 2.0 ml can be displaced within the first 5 min. This is followed by an additional volume displacement of up to 1 ml within the following 4 hours. Finally a chronotherapeutic drug delivery device, called ChronopaDD was realized. It integrates the intradermal infusion set, the hydrogel actuator and an activation mechanism with time delay without the need for electronics or batteries. Fabrication of the ChronopaDD is based on processes well-known from the packaging industry. The activation mechanism consists of three pouches that can be manufactured from suitable films in modified pouching machines. The drug solution is also stored in a pouch. The time delay of the activation mechanism is realized with a sucrose tablet. After activation of the ChronopaDD the swelling agent must dissolve this tablet before it can enter the hydrogel actuator. Delay times between 30 minutes and 280 minutes were demonstrated. The delay mechanism is a critical step because after dissolution of the sucrose tablet a plug of highly concentrated sucrose solution may be formed. This plug can result in additional undesired delay times. Apart from that the hydrogel actuator is able to displace volume at quite high sucrose concentrations, up to 50% by weight. Of course, its power is reduced in this case. Under well defined conditions the ChronopaDD can deliver e.g. 0.5 ml of liquid in combination with a time delay of 30 min. In another configuration it can deliver a volume of 0.4 ml with a time delay of 280 min. Finally, time delayed intradermal delivery of 0.35 ml liquid with the ChronopaDD was demonstrated ex vivo. V Zusammenfassung Die Gabe von Medikamenten gegen Krebs in Abhängigkeit von circadianen (ca. 24 Stunden) Rhythmen in den 70er und 80er Jahren des letzten Jahrhunderts markiert den Beginn der modernen Chronotherapie. Heutzutage ist reichlich Wissen über den rhythmischen Verlauf von Krankheiten und insbesondere über die rhythmisch ausge- prägte Verschlimmerung deren Symptome vorhanden. Chronische Krankheiten von Asthma bis Schlaganfall wurden diesbezüglich intensiv untersucht. Für Patienten, die unter solch einer Krankheit leiden, ist es von Bedeutung, die richtige Menge der rich- tigen Substanz zur richtigen Zeit zu erhalten. Dabei gilt es die Anforderungen der ambulanten Versorgung zu berücksichtigen. In diesem Fall sind Tabletten die am besten akzeptierte Lösung. Jedoch ist die Wirkstoffaufnahme aus dem Verdauungs- trakt ortsabhängig. Dies ist eine Herausforderung für die Entwicklung von zeitgesteu- erten Verabreichungssystemen. Eine mögliche Lösung dieses Problems ist die mini- malinvasive zeitlich gesteuerte Wirkstoffgabe über die Haut. In dieser Forschungsar- beit wird solch ein Ansatz verfolgt. Die transdermale Wirkstoffgabe ist eine Disziplin, die in den letzten zwanzig Jahren beeindruckende Erfolge vorweisen konnte. Mit Wirkstoff beladenen Pflastern können Wirkstoffe unter Umgehung der Leber und ohne direkte Nebenwirkungen im Magen- Darm-Trakt verabreicht werden. Aktuell gibt es jedoch lediglich ca. zwanzig Wirk- stoffe, die der Körper über die Haut aufnehmen kann. Der Grund liegt in den Barrie- reeigenschaften der oberen Hautschichten. Ein Weg, diese Barriere zu umgehen, ist der Einsatz von Mikronadeln. Hohle Mikronadeln ermöglichen die zeitlich gesteuerte Verabreichung von Wirkstofflösung über die Haut an einen Patienten. Die Herstellung solcher Nadeln ist jedoch eine Herausforderung. Die Möglichkeit Thermoformpro- zesse wie Heißprägen und Spritzguss dafür zu verwenden wurde in dieser Arbeit ge- prüft. Darüber hinaus wurden intradermale Verabreichungssysteme auf Basis von Stahlkanülen entwickelt. Die Herstellung des Hohlraums der Mikronadeln im Heißprägeverfahren ist eine große Herausforderung. Es wurde gezeigt, dass eine Form aus Gummi mit eingesetzten Drähten genutzt werden kann. In
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