veterinary drug delivery

Alright, so this afternoon I'm going to talk about veterinary Activity Systems, which is the last lecture before we come back for this course. We do not have any lecture or anything lined up for tomorrow. There will be time for you to prepare for a test and Friday afternoon, Friday to settle with the useful test that's been an online format. 40 questions. You'll get 45 minutes. Look more in the history for last three years you should be able to finish it up I don't think anybody will be 25 minutes so you will not want to you won't be pressured off time. OK let me start with where they live assistance. So it's an interesting area which I picked up on my research about 15 years ago my initial research my master's PhD and initial type work all about humanity systems, but when I. In New Zealand, University of Auckland as in ask, I was contacted by two companies in New Zealand, web companies, and they wanted to solve some of their formulation issues. So I started looking at those and I found that they have to be very fascinating in a couple of ways. 1 Is that everything that we do for human products, all that you have been listening, learning about human products, all of that applies to veterinary products as well. Pharmaceutical science is the same. The only difference is. Human is 70 KG at adult average men, while a horse can be 600 KG. So the formula should be different to what, 50%? But in terms of delivery technology, in terms of all the challenges that you have to deal with, they're very similar. They also have retention problems with the problem, viability issues. We struggle with the food effect on drug adoption. They process horses and sheep and cows will have A and a lot of fiber in their bodies which effects adoption of drug as well. So very similar type of challenges does the ingredients are different. So that was one and second was that when we started. You live with new drugs or deliver assistance for human it takes about 10 to 15 years to get to human. Anything that you develop has to go through a lot of tough studies, safety studies before you can touch a human being, before you can feed out, administer the product in human being. But in case of animals you make something you 12 web companies and during my time at the University of Auckland in eight years I worked with almost every company isn't trying to solve some of their difficult challenges. Now when I came to Adelaide, I have been carrying out research with web companies over all these years and that has been going on very well. In fact, we are one of the very few groups in the world who do work actively into. I don't think there's any other group in Australia and that's why we get contacted by a lot of web companies at this stage this week if I give you a number, I'm talking to four new companies to solve their formulation issues in Australia. So we get a lot of queries from their companies and there are some as part of this lecture. So a lot of things that you will hear from me today are first hand experience of working with. Let me get a sense of you're thinking about web product before I jump into slides. What are some of the concerns, some of the things that come to your mind and I'm sure many of you will have also anything that comes to your mind, curiosity or something as well. Administration chemically, yes, that's absolutely right. It's not easy to feed, but to stand sometimes it can be very difficult for anyone as well as owner or anything else. OK, let's look at the details here then. So what I'm going to talk about? For development issues and some of the best issues, yeah, that's an interesting one. If you use the wrong to administer it, the animal may hurt you. Yes. That's also possible with larger figure animals like horses and cows. And they can definitely hurt you even with small animals I've seen in my lab experiments I've seen. It has not happened to me luckily, but I've seen my students and colleagues getting hurt from bats and also bite them and all those kind of things will happen. So there's a book from. Somebody said what I have been doing, I'll give you a look at Mercedes and that's the infection of other impulse, new antibacterial compounds and formulations, phase masking for aquaculture. We have made a formulation for the company in Port Lincoln. That product has now gone back to the company and they are scaling up at the moment. In fact, this morning we have communication to them, the company they are trying to develop. And for that we have looked at once drug extended release and infected the patient for dog ear transformer preparation for pain in cats. That's what tramadol extended release injection for hosts and I'll talk more about it and some of the oral based formulation process. So all of these products. Have come up because of industrial partnerships. When we work with companies, they come to us and they ask us to develop new products for them. In fact, you will be quite surprised. There's enough of our long term partner we can get them for PTS. Now there's a company called Compounding which is based in Sydney. Sonic Boba, who's owner is a pharmacist and he specializes in red compound and formulations from his lab from his company. I sold all of us. The voting test by the pharmacist obviously talks to vets all the time and they they have come up with a list of products for which they would like. There's a need for new formulations. They talk to someone like me and then he starts manufacturing those and then also he's trying to license some of those. He's also set up a compound in UK so if you search on internet you'll find they want to UK these manufacturing UK is trying to register there and so that's a bit of entrepreneurship that pharmacists can use to because of the gas when you work in pharmacies. OK. So what are the variations in that categories, companion animals, farm animals and wild animals? Companion animals are better working animals. These are family members those administration can determine and some of you have pointed it out. People will go to any extent. I know people pay thousands of dollars worth eating their pets just because they they. And if you're gonna send your members and then context you think that's it's even more difficult because if you want to get sick, our permissions are such as the government part of the bill. While for animals entire money is paid by the owner or by the insurance company. Farm animals is the other category which is managed on officially. Cost is a big issue in health management and losing and discussing as again with a note here it says it will be done a long way. They can hurt you that can be challenged and while that was. But into the problems that you want to solve let's say that's approximate wake up of livestock system contributes to 40% of global GDP, 30 billion U.S. dollars in 2020, 60% livestock, 40% company, that's sort of an approximate data and in the products vaccines from 25%. Somewhere that normally comes because he will use it as an acquired but we we edit it separately do you think anyone has companies? So joy is is Pfizer's animal healthcare branch. They're a big one. Has recently sold their animal health division, but back is a big one and also some of the big players on global scale and. And I'm at the market market. This is what is estimated to be this is from marketing research report about 67 billion by 2025. What are some increasing trends in Emerald Research? So smaller companies are developing innovative technologies and licensing with big pharma. So that's what this company doing. They work with us, they spend money, develop new concepts, and then they license to multinational companies. That's that's that's the smaller players can make money out of it. The success of the technology dictated by IT status normally big. Karma will not talk to anyone unless you have a patient dropping your innovation. So we were recently a couple of weeks ago I was talking to global R&D manager for joints and in the sessions that was the first thing he said. Do you have anything or if you have IP that we can license from you? So now working on your assignments and patents, you know how that works. You have to have innovations, usefulness, non obviousness, all of that mixed up written file, a lot of money. And the companies can speak to you, that's a normal thing. Cost effectiveness is a big factor. Can we talk about cost? As I mentioned about farm animals, like recently as I said, we were developing a product of fish treatment. Now I'm not under vegetarian, so I don't eat fish, but both of you would know how much fish would cost. So let's say any number and if you want to buy a medium sized fish in the market, how much would a fish cost? 20 per kilogram and normal fish would be medium sized fish can be, I mean obviously fish are all different sizes, but let's say the fish was OK. That means the cost of animal, the retail price is $40. That means the the cost of they probably sell it for maybe $15 by the time it goes through full chain and holes and making all that. Make and release and all of that, all these places. So with the bus of fish for a farmer is $15.00, you can imagine how much they can afford. If you tell that it's going to cost you $50.00 to buy an antibiotic for them. So that's the 4-5 in australia and if you have to teach PIC, you will have a similar issue. What's the cost of pig and basically what you've been treating them? That's the cost factor. We don't care so much about human products, but for pets also we can afford to go for a first year product. But for farm animals and others it can be quite a big issue. So you know, market robustness, functionality, scale and reliability, other points of differentiation are very obvious. So in comparing everyone, 75% of total sales come from Europe and US, 62% of US households have a companion animal, over 80% of human families have found a pet fish. So what a big population. If you think of people around you and your friends that you'll find majority of your friends would have some sort of some animals. One Health is a new term which has been going for last probably less than 10 years, collaborative venture between medical and veterinary financial areas and I'll talk a bit more about. So these are examples of drugs which are approved for using animal companion health. So very similar antibiotics like penicillins are used in human as well as animals. Hormones, hydro anesthetics, non steroidal drugs, very similar range but then they are somewhat agency but not for human health and this includes implemented antibiotics is a big market in animals. Because we live on farm and they live in rough trains generally. So those depend with a lot of infections and market antibiotics are only required antibiotics, parasiticides, neuroleptics. So some of these compounds are reserved for using animals and they're not allowed to be used in human. And that's a that's quite interesting data. There's a lot of talks about antibiotic businesses and if you look into details, they would say anyone's act as a big do a big part in development of assistant and cause of cause of infections coronavirus. The theory is that it started with that's in China. So we don't know whether that is right or wrong, but that's what the latest if you ask anywhere in the world of. We've been started for this. So that's the theory. Umm, so typically, uh, in US fixed. I mean, that's all over the world. In fact, animals after a lot of antibiotics, uh, fix pet antibiotics, they pass on to human and they pass on to me and other forms, they get to human system, which leads to resistant Mrs. infection. And so there was a little. Very nicely uninstalled evidence that, uh, if you want to control the antibiotic assistance, we need to be taking care of human and animal at the same time. If you only want, it's not going to solve the problem. And that's what I mean by one time. There's a question here, how do they decide whether to approve? That's what we're doing. So the drug approval process is very similar to human. Generally drugs which are used, they're generally discovered for human and that some people will start using as you have mentioned here. So that's what starts happening in real life and then they find out whether they're working or not and then eventually they will send us some trials. And then that's one way of doing it. Second is there's some drugs which start showing which do not make the human product market and if they're toxic for some reason or there's some different level of tolerance through us and some drugs, you know, we call it in human, but so those tend to become animals. The third category is certain antibiotics, umm, details when apparatus, and that's a new thing with WHO has been talking about that we should have antibiotics which are used only in animals or only implemented and that's a way to protect us from persistence. So not very different. Again, it's very similar to human factors. Alright, now let's look at anatomical features of animals. Obviously each animal is different and it's quite surprising. I mean, when we work with animal products, I find it quite challenging in the lab in terms of deciding on those and delivery systems. Like for human, you know, patriotic population is 1 type of individual system. Then all the adults to 70 years of the ages can more or less to get similar kind of proceed form and then 70 plus may require more. But which can fit in a small handbag and from there to a large animal, which can be probably over 100 KG. Now if you try to develop the same dosage for me, not even the dose may not be you'll have to scale it up and down depending on it. Similarly for fish, you know, the size range can be huge. So that's that's also a good factor. Economically, ruminants which include cheap cattle, goat, and here they are happy words. Umm, So it's very interesting how their system works. So, uh, they take food from Simpson, request for them out, then it goes to his stomach. So they just say that animals have two stomachs, not one. There's one stomach where it's acts as a reservoir. From there it gets sort of a little while and so if you have ever seen a cow eating holiday, they'll go to farm. They'll eat for several hours, 234 hours in one go and then they will sit down and start doing the food. So they put the food out of this, chew it up and then it goes to the real summer to the second summer. And then from there it goes into sign and small. Now this is different to. System again umm, we don't have two summers here, the only one we just connected to someone in case of animals, that's what happens in 2 minutes. So this is a while access umm uh, that is now imagine the effect on the form of relation. So if you have a tablet or a solid. It will go and it might sit in this big, big part for several hours mixed with all the hay and fibers and everything else they eat. And then obviously you can have a different disintegrate and it might be several hours before you want to teach your stomach. And it is fine where you want it to be a job. This part here is not a job. Adoption still happens from the end of 20%. So permission factors can be quite different here we want a permission, it will take much longer. But starting off drug delivery in animals, the animals are susceptible to many of the same diseases and some others. Quality requirement for web pharmacy no less than human products give a safety as part of the development process. So same thing. I mean. Industries, I'm gonna have a look at that. Uh, that will be the system play an important part and need for new development technologies for animals are given by factors such as convenience compliance. Consumer, in this case, interestingly, is both anyone as well as if you have a dog at home, you can call dog if consumers, you can call doggy consumer for systems, but if you have to feed that formulation and it's a difficult one, then your own experience and your own stress level will also come into play to prove fanatics of drug and animal safety. So very similar to human products. Now there's a term called reporting. which is. Which does not exist for human product. So it's about residue. So let's say you are treating a fish, which is let's say with an antibiotic or a cow with amoxicillin. Once the animal is treated, you want animal to be clear of that antibiotic before any of the animal product can be used for human conduction. So that's the time. So we don't agree to the time in which the drug levels get below a certain defined level for that particular animal and whatever so each wet product will have on the labeling. and they will say. Send this, it simply means that if it's S3 days, that means after feeding, after the last dose of the antibiotic, you have to wait for three days before any of the animal product can be used. So whatever you cannot use it for three days. So that's the time which is not applied to human, but it is applied to and that is determined upfront during development phase. So when we develop any new formulation that is given to animals and we then keep collecting. Plug on samples and other tissue systems samples, those are analyzed and we try to figure out the time at which it is completely clear somebody and that has to be stated on the label. That's the requirement. Make sense. Any questions? For the first time in this system, it does not exist in human system. OK. So to do the strategies these are going by diversity of species leads to be treated, wide engine size and optimizations, practices, variations, individual versus group treatment cost constraint as they talk about value of animals to be treated, residues, convenience and compliance. Let's look at some of the location form. It's a very big range a lot of different animals, different type of systems. I've selected some which are common which. Water, liquids, unpleasant taste can be a problem. So that's a sort of done, as you can see in the green here, that's a gun which is used to deliver liquid deep inside clothes so that we cannot throw it up. Time emissions paste is a very common dosage form, so we have been doing a lot of work on paste for horses. This is basically an oily suspension. You make it consistency similar to a toothpaste, you make it thick and you load a bug into it and it's fed into an animal and if the taste is right, they'll just chew it up and. Right. The beauty is you can put particles of large size. Synthesis. So because these can be administered for owners, we've done 3 clinical study on horses with different base and those if the formation is made right, this would have to take the product. It's a common dosage form that doesn't gain significant products. Powders and granules are sometimes used premixes. So premixes are more like feed additives where you mix the compounds with feed. So far like Porter industry they use oxidiosis nutrition mixed with. I mean this is the easiest way to with animals, there is always an issue of those. Uniformity, not also, I mean how do you ensure that each animal gets the right amount of those. So when you're developing information for fish, that would be the question you were asked. So for fish they were simply drop the ballots that we prepared in water and one fish might take two ballots. But it's no how would you control that? Similarly, tha how do you control that amount of plug in? That's an issue. Which funnels?t feed, if you make something with feed, one anyone might f which are wide therapeutic window where differences in those doesn't directly translate to safety. Medicated block is another dosage form which is implemented blocks nutrition supplements. These are packed in cardboard boxes and. Portal modified release systems terminal infestations are very commonly contain supplements parasite besides anti bloating agents production enhancers administered by Bollington release effective longer than 100 days. So four companies that I mentioned that I'm talking about three of them want formulations which will work from six months to one year so. For nutrition product, one is for an antibacterial, 1 is for a contraceptive. All three are different products. But in all cases, I cannot give you details of companies and products, specific products, but all three are asking for us to come up with delivery system which will release over six months to one year, which is pretty challenging. It's not straightforward to ensure. The other issue with developing those products is if you want to test. So if you want to establish that a product will work in dog for six months, you'll have to administer the dog and wait for six months. Now after five months, if it does not work or does not provide the right concentration, you come back and start from there. So the duration it can be done by the time it takes to develop the product can be very long. This is an ad from a company called which is based in Sydney. It's a French company and it's also listed in top ten web companies. This was an announcement from them a few years ago now I think, but 10 years old. So during the conference where they presented this to everyone at any conference, they say we are looking for technologies. Where? 120 days 4 percentile delivery system so they won't 20 percentile is not the continuous type preferably capable of being produced commercially with cost of manufacturing under 10 per unit. So a system which will release photos is over four months but should cost less than $10 per unit capable of being administered individually by the people to a large number of. OK, let's look at some of the order systems. So this is one which is used for Ivormectin, which is a modified release system. It's an authority system where you create a double kind of device. You have a small hole on one end which exists osmotic thing. There's a polymeric osmotic component recording between when the animal takes the tablet or when the formation is to the animal. Water will get permitted to this hole, it will start swelling this membrane and it will start pushing the drug out. And these are pretty good systems. They provide good zero order release profile and there are several human products which are based on osmotic system. So the same technology has been used by animal products. That's another formulation where there are you can see five different ballots here and after administration one release and then that's how. Kept the device a device of this type where this inserted in one pack and after administration this device will get logged in the stomach and it'll keep on leaving 1 tablet at a time. Probably will never come out of anybody. They also use metallic devices which will get lodged in the stomach because of their weight and they will stay there. And there have been cases where animal was even one metric device and after six months another metric device and when animals would walk around the farm, they would hear the sound coming. So they're living with each other. Again, this is something that you cannot do for human products. For human products, you cannot leave a device inside the body for long, and for wet products you can. Telephone solutions similar to human products suspensions have been used. There are a number of solvents which we can use for animals. DMP like is 1 which is used in animals, but we cannot use it for human products. So there are some differences in what kind of formation you can make, but in general, principally they are the same solution suspension emissions and. Drive orders, generally from my experience when I talk to companies, they don't want to deal with this. They don't want, they want a simple solution where the farmer can open the pack, push that formulation and then that's it. Again, because of large number of animals. So imagine if it has to be treated on a farm where they're probably 500 pics infected. Now if you try to create Republic for reconstitution, that's a lot of extra work for a farmer and they don't want to do that. Parental dosage forms. So that's what I mentioned my initial research that we have done that was a mastitis where you try to apply formations to cows other that's a kind of device which I used. So these others get infected and then you have to these are to be with antibiotics. So there are different formulations for electric cows which are milking phase, they have to be fast and distribution of drug. For non lactating or dry calves you can have a system which gets logged in here and it keeps on providing slowly for months together different kind of animals into different kind of building systems which can be used. There's a picture from one of our research projects where we developed a formulation it was tested in those were the research area University School, we collaborate with veterinary school, we do they do all our animal product testing and our permissions were applied to these animals and that was quite effective. So we filed a patent for it and the company is now trying to find the still partners for that product. So that's kind of observation they were conducting there. So they were using thermal camera. As you can see this camera, this is the scale here on the back end side which shows different colours for different temperature. Infection is normally associated with inflammation and which leads to higher temperature. So they were even thermal camera to figure out the progress of improvement of infection after treatment, before and after treatment. This is one of our patent that we filed on that research. It's a method of treating microbial infections including mastitis. We have a US patent, other patents file for this now. And this was a publication which we, this was a compound called which we're developing. So the foundation effect, everything was put into this paper which was published. And if you look at the list here, they're from both. Inter designer database systems are typically used for instance synchronization. So you want to conceive and around the same time and what the biggest farm management is for synchronization is quite normal practice using as active as silicon as a device component. So these are some of the devices which are being used to deliver almost to animals to synchronize these stuff. Implants is again a big one. Your implants containing these hormonal products, that's a normal practice again, which is done to wise from six months to 10 minutes. Tropical dosage forms Dustin powder semi solids water. Which is basically topically applied liquid formulation of sheep and cattle. So if you have to treat 1000 sheep on a farm, So what you do is you push them through a channel, it's sort of pathway where you have a channel on the top which keeps on shower coming from top of a light diluted solution and then force animals to walk through that area. So all animals get shower of their antibacter. With the composite. So that's that's what it's like dipping, which is very common in big bumps. OK, there's a question here. Can we get to do the device after it has released all the drug? It varies from system to system. In some cases you can get rid of the device and some you cannot. The difficulty is to keep the system in animal body for a long. of time, so. This requirement here they want for any device to provide deposit under release for four months. The device has to be animal body at least up to this point up to three months. End of three months, if the device gets removed then obviously you will not be able to achieve four months. So in order to solve this problem, if you use something like this which let's say there was 1 tablet for these every three months, every month this device has to be physically present in the system. And with animals, it's not a big issue if the device is left in the body, the big animals, they can handle it quite well. So this is a technology which is used in animals to keep the drug in the system. Again, we cannot use this approach in human, but in animals it can be used. And it is used. OK. The registration quality, safety of the document products in Australia, ABBMA, which is a different agency, it's not in Australia. PC does not control human products. It's a separate agency, but they have their own regulation. They have their own GMP which is very similar to human products. In USUS Department of Agriculture leads to LEXIS responsible pharma products. So US is. Australia in terms of how they control animal products in US Food and Drug administration controls food, cosmetics, drugs for human as well as animals controls on human products. They don't control cosmetics and TV also does not control when animal products in Australia don't ask me why, I don't know the answer to that question, but that's how they. That is different how these things are. Always. And then there have been attempts to harmonize requirements in different regions around the world, which is done through this international group called VICH. There's a human equivalent of it which is called ICH, International Conference on Harmonization, where the US, Japan and Europe, they have been trying to harmonize requirements. So if a company is manufacturing a productivity, if you want to supply to different parts of the world, you follow similar regulations. Without VICH or ICH, each country will ask for different requirements. One may say we want to be 30°, one may say we want to be done at 40. And that can make a big difference in all of the product, how you carry out your research and all of that. So that's a lot of efforts being made around the world to harmonize requirements. OK. To summarize, where dosage forms are similar to human products in terms of pharmaceutical science principles, application of available technologies, these also require patient centric approach, student development, They offer greater opportunities for innovation, commercialization, time and resources required for development of such products are less compared to human products and key difference between.