Patent Application
20130338569
The invention relates to a polymeric hydrogel composition containing a pharmaceutically active agent or drug which can be implanted subcutaneously at a target site and which is capable of drug release via stimulus activation from an external device.
The management of chronic pain has always proved to be challenging, both for clinicians and patients. The pain arises due to the activation of nociceptors, which convey signals to the brain and are then interpreted as pain (Semenchuk, 2000). This activation may be caused by injury or dysfunction of the neurons. In most cases, relieving the pain completely is rare and difficult. The World Health Organisation (WHO) has set up a three-step ladder algorithm as a guide for the treatment of pain. The ladder aims to treat pain by using a combination of non-opioid analgesics and opioid analgesics and proves to be effective for 80-90% of the cases. However, treatment with such analgesics and opioids results in significant side-effects. Patients may feel severe chronic nausea, vomiting, itching, constipation or drowsiness. In severe cases, patient dependence and addiction may occur, leading to treatment complications. Conventional treatment of chronic pain includes patient-controlled pump administration of oral tablets and drugs which relies on patient compliance and often induces gastric side-effects. Long-term use of non-steroidal anti-inflammatory drugs (NSAIDs) may cause gastric ulceration, increased cardiovascular risk, fluid retention and interactions with anti-coagulants. Oral drugs may have limited dissolution or be strongly ionized which decreases absorption through the intestine. Traditional oral or parenteral drugs may not have adequate therapeutic effects and further metabolism and inactivation of the drug may lower the systemic levels of drug even further.
According to a first embodiment of the invention, there is provided a polymeric hydrogel composition for the delivery of a pharmaceutically active agent to a human or animal when an electrical stimulus is applied to the composition, the composition comprising:
The electrical stimulus may be an electric current.
The polymer which forms the hydrogel may be poly vinyl alcohol (PVA), and may be cross-linked with a cross-linking agent. The cross-linking agent may be diethyl acetamidomalonate (DAA).
The electroactive polymer may be polyaniline, polypyrrole or polythiophene, and is preferably polyaniline.
The hydrogel composition may be for use in relieving or ameliorating chronic pain, and the pharmaceutically active agent may be an analgesic, and is preferably a non-steroidal anti-inflammatory drug (NSAID) such as indomethacin.
The pharmaceutically active agent may cease to be released when the current is no longer applied to the hydrogel composition.
The hydrogel composition may be in an implantable form and is preferably biodegradable.
The hydrogel composition may provide controlled and targeted delivery of the pharmaceutically active agent.
The current may be applied for a time period of from less than about 1 second to about 60 seconds, more preferably from about 1 second to about 5 seconds or from about 30 seconds to about 60 seconds.
The potential difference which is applied may be from about 0.3 volts to about 0.5 volts.
According to a second embodiment of the invention, there is provided a method of preparing a hydrogel composition which is capable of delivering a pharmaceutically active agent to a human or animal when an electrical stimulus is applied to the hydrogel composition, the method comprising the steps of:
According to a third embodiment of the invention, there is provided a method of treating chronic pain in a human or animal, the method comprising the steps of:
A polymeric hydrogel composition is described for the delivery of a pharmaceutically active agent or drug to a human or animal when an electrical current is applied to the hydrogel composition. The hydrogel composition comprises a polymer which forms a hydrogel, an electroactive polymer and a pharmaceutically active agent or drug. The hydrogel composition is typically biodegradable and can be subcutaneously implanted into the human or animal at a targeted site and under normal conditions, the active agent will be entrapped in, attached to or adsorbed onto the hydrogel itself. However, upon the application of a stimulus to the hydrogel, such as an electric current, the hydrogel will undergo structural changes and the active agent will be released into the blood stream of the human or animal. When the electric current is removed, the change is reversed and thus the active agent will cease to be released from the hydrogel composition. The hydrogel composition of the invention will in some instances be referred to as a drug-entrapped electro-liberated polymeric hydrogel system (EPHS).
In one embodiment of the invention, the hydrogel composition is for use in the controlled and targeted delivery of a pharmaceutically active agent into the surrounding tissue for the alleviation of chronic pain. The pharmaceutically active agent is typically an analgesic such as acetaminophen or a non-steroidal anti-inflammatory drug (NSAID). NSAIDs include Aspirin (Anacin, Ascriptin, Bayer, Bufferin, Ecotrin, Excedrin), choline and magnesium salicylates (CMT, Tricosal, Trilisate), Choline salicylate (Arthropan), Celecoxib (Celebrex), Diclofenac potassium (Cataflam), Diclofenac sodium (Voltaren, Voltaren XR), Diclofenac sodium with misoprostol (Arthrotec), Diflunisal (Dolobid), Etodolac (Lodine, Lodine XL), Fenoprofen calcium (Nalfon), Flurbiprofen (Ansaid), Ibuprofen (Advil, Motrin, Motrin IB, Nuprin), Indomethacin (Indocin, Indocin SR), Ketoprofen (Actron, Orudis, Orudis KT, Oruvail), Magnesium salicylate (Arthritab, Bayer Select, Doan's Pills, Magan, Mobidin, Mobogesic), Meclofenamate sodium (Meclomen), Mefenamic acid (Ponstel), Meloxicam (Mobic), Nabumetone (Relafen), Naproxen (Naprosyn, Naprelan), Naproxen sodium (Aleve, Anaprox), Oxaprozin (Daypro), Piroxicam (Feldene), Rofecoxib (Vioxx), Salsalate (Amigesic, Anaflex 750, Disalcid, Marthritic, Mono-Gesic, Salflex, Salsitab), Sodium salicylate (various generics), Sulindac (Clinoril), Tolmetin sodium (Tolectin) and Valdecoxib (Bextra). A particularly suitable NSAID is indomethacin. The hydrogel composition can include more than one pharmaceutically active agent or drug. The pharmaceutically active agent or drug can be loaded onto or into micro- or nano-particles.
The hydrogel can be formed from poly vinyl alcohol (PVA) cross-linked with diethyl acetamidomalonate (DAA). This cross-linking can result in a hydrogel with an irregular shape.
The electroactive polymer is an electrical stimulus actuated polymer such as polyaniline (PANi), polypyrrole or polythiophene, and is typically polyaniline. Electrical stimulus actuated polymers are polymers which undergo structural or behaviour changes when exposed to an electric current or potential difference. Electroactive polymers (EAP) have previously been used as biosensors and in the field of robotics. EAPs such as polyaniline, polypyrrole and polythiophene are well-researched conducting polymers due to their easy synthesis and rich redox reaction. Their drawback, however, is their poor mechanical property.
The hydrogel composition may comprise from about 0.5 g to about 0.8 g PVA, from about 0 g to about 0.30 g DAA and from about 1.0% w/w to about 4% w/w PANi.
The potential difference which is applied may be from about 0.3 volts to about 0.5 volts.
The EAP-based drug delivery system of the present invention can be implanted subcutaneously at a target site and can be capable of drug release via stimulus activation from an external device. For example, a small electrical supply device with, for example, a 1.5 volt battery, could be worn by the user over or in the region of where the composition has been implanted. The user could activate the electrical supply device at the push of a button to send a current through the skin to the composition. The electrical supply device could include a means, e.g. an electronic chip, to control the number of doses that a patient can take a day.
The invention will now be described in more detail by way of the following non-limiting examples.
Poly vinyl alcohol was used to form a hydrogel. Diethyl acetamidomalonate (DAA) was used as a crosslinker for increasing the structural integrity of the hydrogel. A conducting polymer, polyaniline (PANi), was used to ensure that electric current is conducted throughout the entire hydrogel and thus ensures a more rapid, consistent response from the hydrogel. However, other electroative polymers (EAPs), such as polypyrrole or polythiophene, could also be used. Indomethacin was used as a model drug. The PANi used was the PANi emeraldine base, Mw 20 000. The PVA (Mw88 000) and the indomethacin were purchased from Sigma Chemical Company (St Louis, Mo., USA). The DAA had a purity of >98% and was purchased from Fluka Chemie AG (Buchs, Switzerland).
The poly vinyl alcohol (PVA) and diethyl acetamidomalonate (DAA) were mixed together in a 1:1% w/w ratio. The poly vinyl alcohol, Mw approx 88 000, (0.5 g) was dissolved in 10 mL boiling water and allowed to cool for fifteen minutes. DAA (0.5 g), 2% w/w PANi and indomethacin (100 mg) were dissolved in 10 mL acetone until fully dissolved. The dissolved DAA solution was then added into the cooled PVA solution and stirred with a glass rod for one minute until all the polymers had reacted and a drug-loaded hydrogel had formed on the tip of the glass rod. Several other hydrogels with different ratios of PVA: DAA and different molecular weights of PVA were also prepared.
Assessment of Drug Release from the Polymeric Hydrogel in the Presence of an Electric Current
The drug-loaded hydrogels were subjected to an electric current in phosphate buffered saline (PBS) in order to assess release of the drug. This was done by placing the hydrogels into 40 mL of PBS and allowing a potential difference of 1.2 V with a current of 0.3 A to pass through the PBS. The equipment used was a PGSTAT 302N potentiostat/glavanostat (Autolab, Utrecht, Netherlands) with platinum as the working electrode and gold as the counter electrode. The setup of the experiment is depicted in
An electric current was passed through the hydrogel for 45 seconds and 1 mL samples were then taken. This was repeated three times, after which the samples were scanned via UV/visible spectroscopy for any presence of the drug.
Assessment of Indomethacin Release from the Hydrogels in the Presence and the Absence of an Electric Current
The indomethacin-loaded hydrogels were left in 40 mL PBS for 12 hours, and a 1 mL sample was then taken in order to assess for any drug release prior to exposure to an electric current. The results obtained from the UV/visible spectroscopy indicated that there was no drug present in the sample. Further tests for drug release of the indomethacin-loaded hydrogels in the presence of an electric current were performed. The results are summarized in Table 1.
These results show that drug release was achieved when the hydrogels were placed under an electric current. The hydrogels were also assessed in order to ensure that drug leakage did not occur once the hydrogels had been exposed to the electric current due to any possible structural changes which may have occurred. The system was therefore left in 50 mL of PBS for 12 hours, and 1 mL sample was taken and assessed for any presence of drugs. The results obtained from the UV/visible spectroscopy indicated that there was no drug leakage. This suggests that an indomethacin-loaded hydrogel could be used for the purpose of an electroactive drug delivery system. The hydrogels were then assessed for their drug release capacity. They were once again immersed in PBS and an electric current was passed through them. This time, 35 samples were extracted and assessed by UV/visible spectroscopy for the amount of drugs which were released. The results are shown in Table 2.
The amount of drug released ranged from 0.081 mg to 0.160 mg. The hydrogel was then assessed one last time for any leakage of drugs. The hydrogel was immersed in 50 mL of PBS for 12 hours. A 1 mL sample was taken and the UV absorbance indicated that there was no leakage of indomethacin when the hydrogel was left immersed in the absence of electricity.
One challenge with an electroactive hydrogel device such as this is that its response may slowly lag in time. As can be seen in Table 2, there is a slight difference in drug release from the first ten samples as compared to the last ten samples. This is probably due to the slightly lagged response from the hydrogel when it was left immersed and unused in PBS. This phenomenon is possibly due to the ion exchange between the hydrogel and the surrounding medium, which tends to diminish the electrochemical control of the drug release (Lira, 2005). The last step in this study was to determine how much drug could be released before the hydrogel became totally depleted of drug. The hydrogel was therefore continuously exposed to an electric current and samples were assessed for drug until no more drugs were released. The results are indicated in Table 3.
Diclofenac sodium, ibuprofen and indomethacin were used and results indicated that indomethacin was the only suitable drug for this implantable hydrogel, as no leakage occurred when an electric current was not applied to hydrogels containing indomethacin. One possible explanation for this phenomenon is the larger molecular size of indomethacin as compared to diclofenac sodium and ibuprofen. This larger molecular size means that indomethacin is better entrapped inside the three dimensional network of the hydrogel system. Although most diclofenac sodium and ibuprofen molecules were well entrapped in the centre of the hydrogel, the drug leakage may still have occurred on the surface. Since the drug is entrapped in the hydrogel system, it is possible to suggest a release mechanism of passive diffusion outwards of the hydrogel.
Following on from the design of the hydrogels, the next step was to determine the various factors which affected the hydrogels, thus allowing optimization thereof. These factors included internal factors such as the ratio of the constituent polymers, and external factors such as the environmental pH and temperature, as they could affect the physico-chemical or physico-mechanical properties of the hydrogels.
In order to determine the optimum working range of the hydrogels, the internal factors such as a variation in the ratio of constituents and the amount of drugs used were first assessed. By varying the ratio of constituents, the rate of release of the drugs and the physico-mechanical properties of the hydrogel can be altered. The crosslinking should be sufficiently adequate to provide good structural integrity while not hindering drug release significantly. The amount of drugs loaded into the hydrogel should be maximized so that more drug release may be achieved, thereby prolonging the lifespan of the hydrogel. Preliminary results had indicated that the higher the erosion rate, the higher the amount of drug that should be present. Therefore, a good starting point for the testing of this hydrogel system was to begin with a hydrogel with high PANi concentration, high drug loading and intermediate volume. This should yield a high erosion rate while still maintaining the structural integrity of the system. In order to ensure that the hydrogel system that was synthesized was desirable, computer simulation was also performed to ensure that the optimum ratio was chosen. Once the internal factors were established, the hydrogel system was further characterized for its drug release rate under different environmental factors.
All of the tests were initially carried out under physiological pH of 7.4. However, when an infection occurs in the human body, the surrounding tissue becomes acidic. This is a result of anaerobic glycolysis by the bacteria, resulting in lactic acid at the infection site (McCormick, 1983). Furthermore, the blood stasis caused by the infection causes a build-up of carbon dioxide which decreases the pH level even further (Menkin, 1956). It was therefore important to determine whether this change in environmental pH can affect the drug release rate of the hydrogel. Other environmental factors such as temperature and current strength were also investigated in order to determine what affect these factors have on drug release. For example, a change in temperature may affect the visco-elastic property of the hydrogel. This change in physico-mechanical property may, in turn, affect the erosion rate and thus the rate of drug release. Other characterizations included properties such as melting points, glass transition temperature and thermal degradation.
Optimization of the Potential Difference to be Applied to the Hydrogel System in Order to Achieve an Ideal Drug Release Profile
Taking into account the effects that various polymers have on the hydrogel system, a hydrogel system with minimal crosslinking, intermediate volume and high PANi concentration was a favourable starting point for the synthesis of the hydrogel system. A hydrogel composition was therefore synthesized using 0.5 g PVA, 0.5 g 2% w/w PANi and 100 mg indomethacin. The DEE for this hydrogel was 70.25%. The testing conditions were first standardized. Thus far, all the experiments had been carried out at room temperature under 1.2V for 45 seconds. Therefore, an experiment was conducted by immersing the hydrogel system in 20 mL of PBS followed by exposure to an electric current for 45 seconds. The hydrogel was then left in the PBS for an hour before another electric current was passed through the PBS. Samples were taken before and after the electric current in order to assess the amount of drug released and if there was any leakage of drugs during the absence of the electric current. This experiment was conducted over three hours in order to assess the response of the hydrogel system under these circumstances.
From
From the results shown in
Murdan (2003) has suggested methods by which drugs are released via electro-responsive methods. These methods are forced eviction of drug due to deswelling; electrophoresis of drugs towards charged electrodes; and erosion of hydrogel leading to liberation of drugs. The drug release mechanism from the hydrogel of the present invention may be one of these three possible mechanisms. When the hydrogel system was evaluated, a change in structure was visible before and after exposure to an electric current (
The hydrogel system in
Spherical erosions can be seen at sites where the electrodes had been placed on the hydrogel. The colour of the hydrogel became lighter in places where PANi was now absent, appearing as translucent areas on the hydrogel in
The FTIR Spectroscopy of the PANi-Hydrogel System with and without Indomethacin
The applicant also investigated whether any reaction occurred between the hydrogel and the indomethacin. This is important from a release mechanism point of view because if indomethacin does have any interaction with the hydrogel system, there is a possibility that indomethacin may affect the structural integrity of the hydrogel and therefore the erosion rate. This would ultimately affect the release rate of indomethacin from the hydrogel system. In order to determine if there was any reaction between the indomethacin and the PANi-hydrogel system, Fourier Transform Infra-Red (FTIR) was performed using a Spectrum 100 (PerkinElmer, Waltham, Mass., USA). The experiment was conducted in order to assess for any structural changes in a hydrogel system which was loaded with indomethacin compared to the same hydrogel system without indomethacin.
As shown in
The surface morphology was analysed to see if there were any differences between the hydrogel system and the erosion sites, thus determining the possible causes of the erosion.
The hydrogel at the erosion site was lighter than other areas. This may be attributed to the decrease in PANi as erosion takes place, since it is the PANi that gives this hydrogel system its distinctive black colour. It was therefore possible to link PANi to the erosions which occur at these sites. As previous experimentation has shown, the hydrogel system which was formed without PANi did not undergo any erosion when exposed to electric current, strongly suggesting that the attraction of PANi towards the gold counter electrode plays an important role in the erosion of the hydrogel system.
Electron Microscopy of the Eroded PANi-Hydrogel System
Scanning electron microscopy (SEM) was used in order to examine the surface morphology of the erosion site at 300-400× magnification. A Phenom™ (FEI Company, Hillsboro, Oregon, USA) SEM was used.
The presence of any nano-spheres in the hydrogel was determined via light scattering at 37° C. at varying angles. The equipment used for this technique was the Zetasizer NanoZS (Malvern Instruments Ltd, Malvern, Worcestershire, UK). The hydrogel was formulated, cut in half and immersed in distilled water for 24 hours to allow adequate diffusion of nano-sphere from the hydrogel system into the distilled water. Samples were then taken from the hydrogel-immersed distilled water and analyzed with the ZetaSizer NanoZS. The results indicated that nano-spheres were present, with a size range of approximately 138 nm (
The effects that PVA and DAA have on the erosion of the hydrogel system were determined. For this experiment, 5 hydrogel systems with varying constituents were synthesized and exposed to an electric current. Each hydrogel contained 100 mg indomethacin and 2% w/w, PANi, with varying amounts of PVA and DAA. The 5 hydrogel systems which were synthesized are shown in Table 4.
Each of the devices were then immersed in 25 mL of PBS and exposed to 1.2 V of potential difference for 10 minutes. The devices were then assessed for the extent of erosion and hence the effect which PVA and DAA have on the hydrogel system. Hydrogel 1 had the highest erosion rate, whereas hydrogels 2, 3 and 4 exhibited only a minimal erosion rate, with hydrogel 2 having the lowest erosion rate. Hydrogel 5 had a considerable erosion rate compared to hydrogels 2, 3 and 4 but less than hydrogel 1. The results observed in Table 3 can be explained by the crosslinking mechanism between DAA and PVA. The erosion rate is dependent on two factors: the degree of crosslinking and the concentration of PANi in the hydrogel. The lesser the degree of crosslinking and the higher the concentration of PANi, the higher the rate of erosion is going to be. In hydrogel 1, DAA was not present, which decreased the degree of crosslinking between the PVA. Since there was no DAA, the volume of the hydrogel was smaller, and thus the concentration of PANi was higher and the rate of erosion was the highest. In hydrogel 2, the amount of DAA was twice that of the PVA and the volume of the hydrogel was three times that of hydrogel 1. Therefore, the concentration of the PANi in the hydrogel system was decreased and the erosion rate was the lowest. Hydrogel 3 also included DAA, but in a smaller volume compared to hydrogel 2, and therefore had a higher degree of crosslinking and a higher concentration of PANi. The erosion rate was thus minimal but still higher than that of hydrogel 3. Hydrogel 4 was the opposite of hydrogel 3. In this hydrogel, the PVA was much higher than the DAA, therefore reducing the degree of crosslinking between the two. However, the volume of the entire hydrogel was equivalent to hydrogel 2, thus lowering the concentration of PANi in the hydrogel system. This lowered the erosion rate of the system. Hydrogel 5 showed a higher erosion rate than hydrogels 2, 3 and 4 because the PVA was dominant over DAA, thus lowering the degree of crosslinking as compared to hydrogel 3. The volume of this hydrogel system was also half of that of hydrogels 2 and 4. The concentration of PANi, however, was not higher than that that of hydrogel 1, and therefore, although it exhibited a higher erosion rate when compared to hydrogels 2, 3 and 4, it was still lower than that of hydrogel 1.
In order to demonstrate the effect that volume has on the concentration of PANi, the hydrogel systems with various volumes of PANi were observed using a light microscope. In this experiment, only the amount of PVA was varied, while the rest of the constituents were kept at a constant 0.5 g DAA, 100 mg indomethacin and 2% w/w PANi. These hydrogels are shown in
Another important factor which appeared to determine the erosion rate was the amount of DAA added into the system. The more DAA that was added into the system, the less the rate of erosion This suggested that DAA plays a role in hindering erosion rate, possibly due to the increased crosslinking within the hydrogel system. In order to confirm this, texture analysis was conducted on 3 different hydrogels using a gel compression test. All 3 hydrogels were composed of 2% w/w PANi, 0.5 g PVA and 100 mg indomethacin, with the difference being that the amount of DAA used was 0 g, 0.25 g and 1 g. The hydrogels were compressed to a distance of 3 mm, with a compression rate of 1 mm/second. The force required to compress each hydrogel over a distance of 3 mm was then recorded and is presented in
The results show that there is an increase in the required force to compress the hydrogel by 3 mm when DAA is incorporated into the hydrogel system. The required force for compression is the same for 0.25 g DAA and 1 g DAA, indicating there is an upper limit to the crosslink between PVA and DAA. This increase in force for compression when DAA is added may therefore indicate a crosslink between the DAA and the PVA as opposed to PVA alone. This crosslinked system was also tested by formulating two hydrogel systems, one with DAA and one without DAA. The two hydrogel systems were then assessed for their drug release capability in the presence and absence of electric current. The two hydrogels were immersed in 20 mL of PBS and a potential difference of 1.2V was applied for duration of 5 minutes. 4 mL samples were taken afterwards and assessed for drug release. The PBS was then discarded and the hydrogel systems were immersed in a fresh batch of 20 mL PBS. Samples were taken from 5 different hydrogel systems.
From
This mechanism of erosion would require an even and adequate distribution of PANi throughout the hydrogel in order to achieve optimum drug release. As seen in
Using UV-visible spectroscopy, it was seen that the drug release was enhanced when electric current was passed through the PBS in which the polymeric hydrogel was immersed. The actual mechanism of this enhanced release is attributed to the erosion which causes the drug to be released into the surrounding medium. In contrast to the control, the experiment had a pulse release, as opposed to a first order release from that of the control.
Although the lack of mechanical strength and weak physical property may be a drawback to the hydrogel, it is possible to create an electroactive polymer hydrogel composition for use as an implantable drug delivery system by incorporating different hydrogel polymers, electroactive polymers and drugs.
| Number | Date | Country | Kind |
|---|---|---|---|
| 2010/03746 | Nov 2010 | ZA | national |
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/IB2011/055322 | 11/28/2011 | WO | 00 | 9/5/2013 |
