Narrator - Dr. Abel  00:00
Welcome to HelixTalk, an educational podcast for healthcare students and providers, covering real life clinical pearls, professional pharmacy topics and drug therapy discussions. This podcast is

Narrator - ?  00:12
provided by pharmacists and faculty members at Rosalind Franklin University, College of Pharmacy.

Narrator - Dr. Abel  00:17
This podcast contains general information for educational purposes only. This is not professional advice, and should not be used in lieu of obtaining advice from a qualified health care provider.

Narrator - ?  00:27
And now on to the show.

Dr. Sean Kane  00:31
Welcome to HelixTalk episode 138 I'm your co-host, Dr. Kane, and I'm Dr. Patel, and the title of today's episode is hidden pharmaceutics, the fascinating science behind dosage formulations and Dr. Patel. I'm actually incredibly excited that we have two guests with us today, Dr. Deshmukh and Dr. Ahlschwede, who are pharmaceutics experts at the College of Pharmacy at Rosalind Franklin University. We've pulled them in to kind of give some clinical context to the science behind the pharmaceuticals of products that many of us are already familiar with,

Dr. Khyati Patel  01:04
and I'm super excited that they have decided to join and answer our expert questions. So let's get started. Perfect.

Dr. Sean Kane  01:12
So without further ado, we have four different topics that we're going to jump through. The first one is absolutely fascinating. So it's fentanyl patches. And you know, fentanyl patches have actually been around for really long time. You know, they were released in the early 1990s under the brand name of Duragesic. Fentanyl itself is a really potent synthetic opioid. It's gotten a lot of attention recently because of drug overdoses associated with fentanyl, but many patients take fentanyl patches for therapeutic indications. And this is an important drug in a very unique dosage form as well.

Dr. Khyati Patel  01:47
And with that being said, you know, it goes without saying, this is a schedule to control substances. And you know, obviously there is black box warning for risk for addiction, abuse and misuse. And because it is so potent, like you said, Dr. Kane, it is reserved for somebody who has chronic pain who's been on other opioids, meaning they're opioid tolerant patients. And you know, obviously this is for chronic condition or chronic pain, therefore not to be used as PRN. And so the patch in itself is formulated such it can be worn for 72 hours.

Dr. Sean Kane  02:24
And clearly, I mean, there's a benefit there, that instead of taking an oral medication several times a day, now you're putting something on your skin every three days. So if someone has difficulty swallowing or the pill burden becomes problematic for that patient, this formulation could potentially have an advantage, but of course, there are some disadvantages kinetically. So because it's a patch, it's not going to work as quickly as an oral formulation will, and it takes at least a day to really fully kick in. And also, when you remove the fentanyl patch, it takes about a day for the drug levels to go down, enough that would say that more or less the drug is out of your system.

Dr. Khyati Patel  03:00
And if I'm correct, Dr. Kane, then this is where we bring in our expert. But there used to be like that original formulation, and then later on, it was reformulated. So I'm all about learning what was that original formulation, and why was there a need to reformulate it?

Speaker 1  03:16
Yes, I can answer that. The original formulation in the early 90s, it was formulated as a drug and reservoir system. And what this means is that the fentanyl and alcohol are gelled with a polymer called hydroxyethyl cellulose, and it's loaded into the patch. So the term reservoir just simply means that the drug is in solution, suspension or gel, and then we also have the membrane that controls the flux, flow and rate of the drug from the reservoir to the skin.

Dr. Sean Kane  03:50
So Dr. Ahlschwede, that sounds pretty normal, I guess I'm not terribly familiar with the technology of patches, but you said that that was the original formulation. What was wrong with that formulation? Yeah, so

Speaker 1  04:03
Well, eventually patients learn that they could cut the patch. And if you cut the patch, unfortunately, because the drug is in a solution, suspension or gel, it will cause the contents to leak out all at once, and people were either taking it orally or injecting it. So people were heavily abusing the reservoir system patch

Dr. Khyati Patel  04:28
and Dr. Ahlschwede, the new formulation is now kind of in this adhesive matrix system. Can you, can you explain to our audience, like, what is this matrix patches?

Speaker 1  04:40
Yes, that's correct, and it was reformulated into an adhesive matrix system. And there's two layers, the transparent backing layer, and then the drug, and then the adhesive layer. So what we do is it's the drug is spread like in a polymer, and it's more of an adhesive layer. And one. This allows us to do is it's not liquid based. So technically speaking, if you cut the patch, it's not going to cause like dose jumping. It's not going to cause the fentanyl to leak out. However, that doesn't mean that, because you can theoretically cut the patch, that you should be cutting it, fentanyl has a narrow therapeutic window. So if you cut it and you don't cut it properly to size, that can cause a big problem. Another thing to know is that there's not really many clinical studies supporting cutting patches, and if you cut these patches, it's likely going to damage the adhesive layer, which could cause the fentanyl patch to not work as intended.

Dr. Khyati Patel  05:41
And potentially, you know, if they cut it, it still can be abused. I mean, I've heard stories about people trying to chew on them. I can't imagine the taste or boiling in the water. So there is that potential still possible. But something cool that comes with this matrix system is the patch size that determines the dose. And so you got this fentanyl patches that have the same amount of fentanyl per square centimeter, but your 25 microgram per hour patch is, you know, half the size of that 50 microgram per hour patch. So this is all about like proportion to the surface area. Yeah.

Speaker 2  06:19
So I just wanted to add one more thing to what, Dr. Patel, you just stated that there is this misconception that this new formulation that we have now, the matrix formulation, will eliminate abuse Well, as you rightly noted, people can still chew on it. So I think that's something that healthcare providers pharmacists, when they're talking to patients that they make them very clear that you know, there is a potential for this, and you need to be careful around not trying to do anything else other than using the way it is intended to be used.

Dr. Sean Kane  06:54
And I think what's so fascinating about the story is Hindsight is 2020 right? But in the 1990s apparently it wasn't really thought of that much that these, the original fentanyl patch, would be abused in the way it was that simply taking scissors to it would allow you to have access to the entire three days worth of fentanyl. It's great that we've reformulated it. It's not perfect, but clearly it's better than simply cutting it to allow for abuse of it. So I think that that's fascinating, right? That the formulation has now been reformulated to an abuse deterrent or harder to abuse formulation, which I think makes total sense, given the opioid epidemic that we're dealing with right now.

Dr. Khyati Patel  07:35
And I guess that brings the focus to how we should discard the used patches. You know, even after 72 hours, there is some fentanyl still remain in the patch. And you know, somebody can pick it up from the regular garbage if it's tossed in there. So the really, the disposal recommendation is to fold a patch in half and go ahead and flush it down the toilet, because the fear is that if it's discarded into the regular garbage, kids can pick it up, or pets can go into the trash can and pick it up. And, you know, fentanyl is a very potent opioid, as we established earlier, and FDA doesn't seem to think that a little exposure in the environment is, you know, kind of offsets the potential harm it can bring to unintended users, like the pets or the kids. But there is another pharmaceutical consideration that comes with the patch product, and there's box warning for it too, and that has to do with temperatures. Can you describe that?

Speaker 1  08:35
Dr. Ahlschwede, so whenever the patient is exposed to a higher temperature, whether it be a heating pad, sauna, hot tubs or sunbathing, it can increase the flux, or rate of flow of the drug from the patch to the patient. So it could lead to an increase in concentration of the drug that the patient's receiving. Even a high fever, if the patient has a high fever, for example, a body temperature of 104 can lead to an increase in serum concentration by up to 1/3

Dr. Sean Kane  09:06
what I think is so fascinating about that is one clearly, patients should be aware of that fever period, but you know, if someone has pain, it's not uncommon that they may reach for a heating pad that is certainly going to exceed 104 degrees surface temperature on a patient's body. But then two, it's also something that we need to be aware of, that patients could potentially abuse fentanyl patches by intentionally using external heat to provide a higher flux or higher rate of drug flow through the skin, both its potential for, you know, overdosing by accident, but also misuse as well.

Dr. Khyati Patel  09:41
All in all, I believe patches are amazingly awesome formulations, especially established earlier. It's it's good for people who have poor oral intake, or, you know, pill burden is an issue, especially with a formulation that is put on 72 hours, and obviously 72 hours. But moving on. To one awesome formulation to another. Let's talk about osmotic tablets. You know, these osmotic tablets. From what I recall are these kind of core tablets. There's a core created which has a semi permeable membrane made of, you know, cellulose esters or cellulose acetate, and then the drug is kind of put in there. So. Dr. Deshmukh, can you explain, you know, what kind of layers or formulation that's involved in making osmotic tablets? Absolutely.

Speaker 2  10:32
But before we talk any further. Dr. Kane, thanks for that kind introduction. And I must say that even though you called us experts, we are some one who know a little bit more about these type of dosage forms actually full credit to the people in industry who come up with these novel strategies. Full credit to them. So Dr, Patel, to your point, before we talk about this new dosage form or small tablet, I do want to just tell a little bit of what osmotic pressure is, and osmotic pressure is nothing but pressure that is needed to what we would call a stop in the osmosis process. And what is osmosis? Osmosis is nothing but movement of water from a higher concentration, so water that is in large quantities, to a drier place where there is less than to facilitate that transfer, you need a semi permeable membrane, and also we need solids. So when water moves from one end to the other end, ions and solids move from the dryer end into as a result, you have a net equilibrium where there's no more osmotic pressure. So that's the basic principle that governs osmotic tablets. So coming to this particular dosage form, the dosage form can be divided into a lot of different categories. The key requirement is some kind of a semi permeable membrane that separates the contents on the dryer side versus the wetter side, and that allows the movement, and we will have we, as a result, have a lot of different systems that could be single chamber, where there is just one semi permeable membrane on outside. Content in the inside the water enters, enters into the semi permeable membrane and pushes the contents out. In addition, we have what we call as multi chamber products. And lot of the drugs on the market that Dr. Patel may want to talk about a bit more are based on that principle, where you have osmotic elements, such as salts that could be lactose or even sodium chloride, for that matter, that are placed in a chamber along with the drug that is separated by a semi permeable membrane. The water first enters into that sodium chloride chamber, because sodium chloride is an ion that has an affinity for water, and because that water has entered now, the semi permeable membrane that is present inside that particular tablet causes a push, and this is called a push and pull mechanism causes a push, and that causes the drug that is on the other side of the membrane to be released. How does the drug get released? Generally, the drug gets released through a very precise hole that is drilled into these very advanced usage forms. And because of that hole through a technique, generally using laser, small amounts of drug can slowly start moving up. In a nutshell, this is how most of the osmotic dosage form.

Dr. Sean Kane  13:34
So, Dr. Deshmukh, you mentioned it, but I do think we have to emphasize the coolness of this mechanism. So basically, we have a thing that absorbs water, that pushes drug out of a precision laser drilled tablet orifice or a hole. How neat is it that we're literally using a laser to drill a small precision hole where the drug will then get pushed or leak out in a very controlled fashion? That blows my mind.

Speaker 2  14:01
Yes, absolutely. You can call it sci fi technology.

Dr. Sean Kane  14:05
Absolutely, yes. You know, this is cool. And what's neat about it is that this isn't just like one random drug on the market. There are a variety of drugs on the market that do use this osmotic laser drilled hole technology. Generally, these drugs are going to have shorter half lives, be higher potency or they there's a need for having a long duration of effect for these. So usually these are considered to be extended release dosage forms in some way. So er, XL, CR, things like that.

Speaker 2  14:36
Yes, that's absolutely right. And as I stated earlier, that one of the primary drivers for all these dosage forms is basically to see if we can maintain steady drug concentrations. That's one another important thing that gets missed out is we want to increase patient compliance. We want patients to take their medications on time. Because obviously, with. Long term, it has a lot of therapeutic benefits. Maintaining the right concentrations throughout, avoiding toxic concentrations are concentrations that may not be therapeutically effective, so these types of dosage forms basically help us in achieving that. And I think Dr. Patel, you may have some very specific examples that you may want to share where why maintaining the right dosage form becomes a critical aspect.

Dr. Khyati Patel  15:26
Yeah, absolutely. We have actually quite a few different XL versions of tablets that are made with this technology. First and foremost that comes to mind is Procardia XL, which is the brand name for nicardipine XL, we know Nicardipine is a dihydropyridine calcium channel blocker that's used for hypertension. The issue here is with its IR release formulation, which has a shorter Half Life, ends up, you know, having patient to take this drug three times a day. Another issue is that, you know, the onset of action is pretty rapid, so you have blood pressure dropping too quickly, and then body adjusting to that blood pressure drop and causing, we call it reflex tachycardia. And so technically, in practice, we teach students that you know, don't ever use the IR formulation, but the Excel formulation, which is made using this, you know, osmotic technology that definitely helps to create this lower onset so you don't have that reflex tachycardia. And not only that, it allows for once daily dosing.

Dr. Sean Kane  16:34
You know, a second example is glucotrol XL. This is a form of glipizide. It's a sulfonylurea for type two diabetes. Interestingly, the immediate release the original formulation is given once or twice a day, and the Excel formulation is given once a day. So for that patient that takes it twice a day, they may be able to have it once a day, but there are plenty of patients that just take glipizide once a day and don't need the Excel formulation. So maybe not as clear of a benefit here, probably there's a role of kind of patent extension here, where they're just trying to manage the life cycle of a given product that a manufacturer has to make profit

Dr. Khyati Patel  17:11
just beyond patent extended use of this technology, you know, one that is really therapeutic use that comes to Mind. Another example is for Concerta, methylphenidate. We know Methylphenidate is used for ADHD treatment. It's a stimulant, the IR version of that, which is ritalin, needs to be dosed two to three times per day. You have, you know, kids taking this medication, they're in school, probably the dosing of two to three times a day is a little bit problematic, versus Concerta, which has osmotic as well as immediate released component combined in one tablet, allows for that one's daily regimen. So the immediate release component kind of provides that quick onset with within one hour, and then the osmotic component provides that longer action over five or nine hours. And so, you know, not, not all of them are done with the intent of, you know, extending patents or collecting market share. But some have this innovative release fashion where it allows for convenient dosing.

Speaker 2  18:14
In addition some other features about osmotic derivatives, specifically, is, generally water is the only factor that drives the release of the medications. So if you have food in the stomach, food drug interactions, they are not that critical. Our GI tract has pH that changes as time goes by. Have acidic pH in the stomach and basic in this time. So generally, that doesn't affect the delivery of the drug, because many of the other dosage forms that are controlled and delayed release, pH does become an important component,

Dr. Khyati Patel  18:51
and no wonder. You know, with this sci fi technology and the precision that it acquires, these tablets can be a little bit more expensive than the other er formulations that are out there. But I think one thing that comes to mind, and this, you know, it's great to geek out on these technologies and the the nuances, but when it comes to like telling the patient what to expect when they're getting a medication, one thing that comes to mind is to let them know, hey, when you you know when you're going number two, and you notice, like a skeleton, or like a pill, like structure in the toilet bowl. Don't be scared. It's not that the medication is going through without any effect. It's basically a skeleton, like a ghost tablet that they're seeing in there. So they don't think, like the medication is not really working for them. So that's that's one of usually a counseling point that we want to include for these patients.

Dr. Sean Kane  19:44
So kind of transitioning to our third category, here is Depakote sprinkles. So Depakote is a formulation of valproic acid. It actually comes in three different salt forms, valproic acid, valproate, sodium, and then a combo of both of those called divalproex sodium. They all mean the same thing, and there are different brand names based on the formulation in the salt form. So we have Depakote, Depakene, and Depacon. And then to make matters even more complicated, we have a ton of different dosage formulations of valproic acid. So we have immediate release capsules and solutions, an IV injection, delayed release tablet, a 24 hour extended release tablet that lasts longer than the Dr. tablet. And then what we're talking about are the Dr. sprinkle capsules, which we'll be focusing on a little bit more. And you know, this is really confusing, and some of these are not bio equivalent. Many of these are not bio equivalent. So it is important that, as health care providers, we appreciate that there are a variety of different ways to give valproic acid, both in terms of dosage form and the salt form. In terms of indications, this is commonly used for epilepsy, bipolar disorder and even migraine prophylaxis, among a variety of off label indications. So this is fairly common in clinical practice, and these sprinkles come up quite a bit, right?

Dr. Khyati Patel  21:03
So the sprinkle really refers to these little palettes, bead looking palettes inside the capsule coating that are kind of coated further to prevent that medication from dissolving in the stomach. Because, you know, it's intended to dissolve somewhere else. And Dr. Deshmukh, you know, this is also where your expertise kind of shines. But can you explain exactly, you know, how does the sprinkle inside the capsule work, and where do they get absorbed?

Speaker 2  21:32
Before we go there, I just want to again, re emphasize those three abbreviations we talked about. IR, being immediate release, dr, being delayed release. And sometimes there is a confusion between especially delayed release and extended release. So delayed releases where you have literally, as the word states delaying the release of the whole quantity of whereas when you're talking about extended release, what we're saying is the drug is being released slowly over a period. And Depakote is a classic example where we have medications in all the three categories, and that's where the sprinkle component, specifically is a delayed release component. And specifically, when you talk about the delayed release, the reason why this gets delayed is because this drug on fluoric acid, specifically coated with a certain polymer that is sensitive to pH. So depending on the pH condition in the gut, it changes as as time goes by, from one end to the other in the acidic pH, the polymer does not disintegrate. It stays intact and protects the drug. But as we move into the intestines, small intestines, specifically, the pH is slightly higher, and the drug will eventually disintegrate and release the content, depending on the thickness of the coating. Again, the delayed release properties can be manipulated. Sometimes you may have a very thin coating that causes the drug. Sometimes you may have a thicker coating that will take its own time to get released, and you can, as a result, again, indirectly manipulate the release characteristics of the medication.

Dr. Sean Kane  23:14
And you know, what I think is unique about these is that, you know, the capsule that holds these sprinkles is really not where the magic is. So it's really about these granules or the sprinkles inside the capsule, and that's where that delayed release product is. So for that reason, you can open a capsule and sprinkle the sprinkles, which is how it got its name, onto food applesauce, as long as you don't chew it. So if you chew it, you're really destroying that coating around the granules or the sprinkles. So you can't do that, but you can release it onto food or drink it in the ICU. We could potentially put this in water and then put it through an NG or an OG tube, as long as you're not destroying the sprinkles or crushing the sprinkles. That's where that delayed release magic is happening. And you know, the sprinkles are not unique to Depakote, although that's a common example. There's a ton of other products on the market, just to name a few that use a sprinkle type technology. So there's Singulair packets for asthma, Sustiva (efavirenz) for HIV, Topamax sprinkle capsules for seizures, Celebrex, a variety of other ones that we could go through. Many of these do have this kind of sprinkle based technology where the magic is inside the capsule. You can still swallow the capsules whole, if you want to. But on the inside of the capsule, those beads, if you will, are where that delayed or extended release product lives

Dr. Khyati Patel  24:41
and based on, you know, this delayed release, it does still provide less frequent dosing, you know. So for example, in the case of the Depakote delayed release, you know, it's a B ID with the sprinkled product, versus, you know, tid or Q ID with the immediate release product. So it provides a. Little bit of a benefit. But there's other types of delayed release sprinkle products that actually can be broken. So again, you can't really crush it because they're Dr. coated, but they can be broken. So one example is the Doryx is the brand name that's made with this particular technology. Contains the sprinkles in the in the tablets in itself. So you can, for example, where the scoring is split up the tablet, but you can't really crush it, because you end up crushing those sprinkles that are embedded into the tablet. Another example is Jadenu Sprinkles. These are used for iron overload, as a chelating agent. It comes with sprinkle and in a packet, so their granules are small enough where, you know, you don't really have to chew or anything. You just you can simply swallow them too.

Dr. Sean Kane  25:51
Our fourth and final drug category that we're going to talk about today is amiodarone. So this is a Vaughan-Williams class III antiarrhythmic. It actually works on basically all of the Vaughan-Williams channels. So it's a sodium channel blocker, a calcium channel blocker, a beta blocker, a potassium channel blocker. We use it for atrial and ventricular arrhythmia, so AFib and also ventricular arrhythmias as well. And it's available as an oral formulation, which we're not going to focus on, but the IV formulation as well, which we are going to focus on the brand names for IV, there's actually two different brand names—Nexterone and Cordarone. And what's fascinating about this is that the formulations are different because of the excipients. And because of that, those excipients actually play a role in the clinical effect of the drug, and usually we don't see excipients play that role, aside from maybe a safety concern, which I guess you could argue is present here. But Dr. Ahlschwede, maybe you can tell us a little bit more about the difference in the excipients, or the inactive ingredients between Nexterone and Cordarone, and why that might matter clinically.

Speaker 1  26:57
Yes, so unfortunately, in both scenarios, they all have excipients that have unwanted side effects or possible toxicity. The first one is Nexterone. It contains the cyclodextrin. And cyclodextrin is a unique polymer which has affinity for both hydrophobic and hydrophilic agents. So we use cyclodextrin to help dissolve poorly water soluble drugs, and cyclodextrin can form a complex such that it consists of a hydrophobic cavity that encapsulates this poorly water soluble drug and a hydrophilic surface to be able to interact with the water. And there's a variety of cyclodextrin formulations on the market, there's different types of polymers, like beta cyclodextrin, alpha cyclodextrin, Hydroxypropyl beta cyclodextrin, but in this amiodarone formulation, it uses abbreviated s, B, E, C, D, sulfa butyl ether beta cyclodextrin. And the problem with the s, B, E, C, D, is that it has a risk of renal toxicity.

Dr. Sean Kane  28:07
Dr. Ahlschwede, we probably should have mentioned it, that Nexterone, the product we just talked about, is actually like the second one to the market. So given that it was kind of the newer product in the market, I would assume then the older product Cordarone must have had some issue with it that they were trying to correct by using cyclodextrin in it correct.

Speaker 1  28:27
The original formulation is Cordarone, and that's the micellar formulation, and it has the hydrophobic and hydrophilic components that form the shell or a core like cyclodextrin. It's not a cyclodextrin complex. It doesn't have cyclodextrin in it. It is a mycellular formulation. In order to make that micellar formulation, we have to solubilize the drug using benzyl alcohol, and then we also use what we call twin 80, also known as polysorbate 80, as the surfactant solubilizing agent. The unfortunate thing with these two excipients is that both benzo alcohol and tween 80 can cause hypotension. And just

Dr. Sean Kane  29:11
to highlight that a little bit again, one of the things that's going on here is that now we're giving a cardiovascular medication sometimes to patients that are already hypotensive because of their arrhythmia that they're having. You know one important difference, and we'll get to other differences as well, is that Nexterone, instead of causing hypotension from the tween 80 or the polysorbate 80 and the benzyl alcohol, we're kind of substituting that toxicity for a potential different toxicity related to nephrotoxicity from cyclodextrin accumulation. So I think it's fascinating, and probably something that goes under appreciated on the inpatient side in terms of the difference between these two drugs that you might think are pretty similar, but in actuality or not,

Dr. Khyati Patel  29:55
you know, kind of other concerns that come with these IV amiodarone products are. It, amiodarone, in itself, can leach a plasticizer. It's a phthalate based plasticizer, like DHP, because obviously, you know, we have the IV tubing that's made of PVC. More of the issue is because of the higher concentration of amiodarone, or if the drip IV flow rate is, you know, lower because you're kind of getting more of that reaction happening with the low rates either or products, the Cordarone or the Nexterone, they both have this issue. But with the Cordarone, the polysorbate also further leaches out the DHP from the PVC tubing. So I guess that Cordarone product potentially has more of the issue. And you know, to our audience, DHP, which is a byproduct of DEHP, is known to and thought to cause cancer and other illnesses. So the less DHP, the better it is.

Dr. Sean Kane  31:00
Yeah, and on top of that, you know, there are other considerations that are more logistic considerations. So for example, Nexterone, the one with cyclodextrin, the newer formulation comes as a pre-mixed bag, whereas the Cordarone, the older formulation, between 80 and benzo alcohol, you actually have to make that. There is no pre mixed formulation. And I can tell you, especially in patients with unstable arrhythmias, including ventricular arrhythmias, to be able to have a pre mixed product readily available that doesn't have to be made in an IV hood, that's a huge advantage. So there is definitely a benefit there. The pre mixed bags don't contain PVC and don't contain DEHP, so the leaching issue is less of a concern, but, you know, again, probably a worthy trade off, given that this can last quite a bit longer in a in terms of shelf life, versus a product that is made in an IV hood.

Speaker 1  31:53
Yes, and I just wanted to jump in and say One common question I get from my students is, why would the FDA approve a product that is known to leach out DHP? So the reason for this that we need to keep in mind is that amiodarone is used as a life saving drug. It's used commonly in our emergency room, and there, this is the best therapy that we have. There is no other comparable therapy at the time, which is why the Cordarone was approved with the issue of knowing to leach out DHP.

Dr. Sean Kane  32:30
I think that's a great point, given that there are going to be patients where it's a risk benefit, and there's a clear benefit in an emergency setting in addition to that. So not only is the pre-mixed bag Nexterone of benefit; another advantage is the lack of benzyl alcohol in tween 80, so it's not just a theoretical concern about hypotension. There were actually studies that support this as well. So for example, there was a retrospective study of 160 patients comparing Cordarone the older formulation with the benzyl alcohol in tween 80 versus Nexterone the newer formulation. And basically the difference in blood pressure was about 10% so those that got the older formulation with the benzyl alcohol in tween 80, their map, mean arterial pressures were about 10% lower. Those patients that got the older formulation, 30% of them needed IV fluid boluses for hypotension, versus about 2% with the newer formulation. And also the need for vasopressors to support hypotension was about 4% with the older Cordarone versus 0% with the newer Nexterone. So again, it's fascinating that there are clinical differences between these two formulations because of the inactive ingredients. It's not just amiodarone versus amiodarone. There is a true difference in how a patient may respond to therapy. And again, I think that that's fascinating and something that probably isn't emphasized enough on the inpatient side.

Dr. Khyati Patel  33:59
Yeah, and I think the slight trade off to keep in mind, with the Nexterone, even though it seems to be like a little bit more improved product than the older version that it does contain cyclo dextrin, so knowing that that could be nephrotoxic. But all in all, you know, it seems like Nexterone is kind of winning over here.

Dr. Sean Kane  34:19
So Dr. Al, should I know that you mentioned that there's a variety of different kinds of cyclodextrin on the market, and the SP ECD we've actually covered historically, it's the same Excipient that we've seen in remdesivir, as well as voraconazole. Can you tell us anything about SP ECD versus any of the other cyclodextrins that are on the market?

Speaker 1  34:38
Yes, so SB ECD does offer slightly better solubility than other cyclodextrins when it comes to amiodarone and other medications, but one thing to keep in mind is there's a trade off to this, that SB ECD has a higher risk of nephrotoxicity compared to our other cyclodextrin formulation.

Dr. Sean Kane  35:00
Patients, I think that you know, clinically, this doesn't come up a lot, at least in my practice, for that patient on an IV infusion of amiodarone, but I do think that it could potentially matter for that patient with either big risk factors for acute kidney injury or they have already some degree of renal impairment, perhaps you would be more inclined to switch them to an oral amiodarone sooner, if you knew that they're getting an IV infusion that had the cyclodextrin in it.

Dr. Khyati Patel  35:29
I think we learned about very neat formulations today. And I think my favorite was where fentanyl patches were reformulated from this drug in a reservoir system, which was the older formulation to the new formulation, which is the adhesive matrix system. And this was done to prevent, quote, unquote, leaking of the fentanyl from the patches when they were cut. And this was done to prevent abuse and misuse.

Speaker 2  35:57
Thank you. Dr. Patel, for me, those osmotic tablet systems. I mean, it's just a fascinating system provided by nature, if I may, see a simple process of osmosis can do wonders. And there are many drugs out there, Procardia XL, Glucotrol XL and Concerta that we talked about. And all of them have that push pull mechanism. They have an active layer of a drug. And then there is this second layer, which is an osmotically active layer that pushes the drug out through a very fine sci fi based laser hole, and it allows for the drug to be delivered at a zero rate and maintain constant concentration of the drug in the blood.

Dr. Sean Kane  36:37
Then the third one we talked about was the sprinkle dosage form, where you have these pellets inside of a capsule, like Depakote sprinkles, but there's a variety of other products on the market, and the capsule itself is not doing anything. But the magic is in these pellets that are typically coated in a polymer that allows for a delayed or an extended release formulation. The benefit here is that you can open the capsule, and as long as long as you don't crush those pellets, it maintains its delayed release formulation so it can be put on applesauce or food, as long as it's not chewed or crushed in some way, and it would preserve that delayed or extended release kinetic profile.

Speaker 1  37:14
And lastly, my favorite is the amiodarone IV formulations, and it's my favorite due to the risk of leaching out DEHP, which that risk could be again, modulated by not infusing at a super high concentration and not infusing at a super low rate. And there's two formulations out in the market, the conventional formulation Cordarone, which contains benzyl alcohol in tween 80. Both of these excipients are known to cause hypotension, and the newer formulation, Nexterone, uses cyclodextrin as a solubilizing agent, and it's not associated with hypotension, but it has an increased risk of nephrotoxicity, especially at higher cumulative doses.

Dr. Sean Kane  38:06
Well, Dr. Deshmukh and Dr. Ahlschwede. I want to first thank you for your time and your expertise. This was a fascinating topic, and I hope the audience took away some clinical pearls from the fascinating science behind the dosage forms in terms of the pharmaceutics. For those listeners, if you want to see show notes, I go to HelixTalk.com this is episode 138 where we have some clinical pearls. We're also on Twitter at HelixTalk, where we release some of these clinical pearls over a period of months. So you can kind of get those in your Twitter feed. And we love the five star reviews in iTunes. So keep those coming. And if you have any episodes that you'd like to hear from us, you can contact us, and our contact information is on HelixTalk.com so again, thank you so much. And with that, I'm Dr. Kane

Dr. Khyati Patel  38:47
and I'm Dr. Patel, and once again, thank you, Dr. Deshmukh and Dr. Ahlschwede for joining us today. And to our audience, students, study hard.

Narrator - Dr. Abel  38:56
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Narrator - ?  39:07
suggest an episode or contact us. We're online at HelixTalk.com thank you for listening to this episode of HelixTalk. This is an educational production copyright Rosalind Franklin University of Medicine and Science.