Pharmaceutical Formulation Development Series: Why Aren't Emulsions Sexy?
0 views
Skip to first unread message
Bruce Rehlaender, Ph.D.
May 16, 2013, 1:48:08 PM5/16/13
to publish-the...@googlegroups.com
*****************************************************************
Message delivered directly to members of the group:
publish-the...@googlegroups.com
*****************************************************************
Please consider this free-reprint article written by:
Bruce Rehlaender, Ph.D.
*****************************
IMPORTANT - Publication/Reprint Terms
- You have permission to publish this article electronically in free-only publications such as a website or an ezine as long as the bylines are included.
- You are not allowed to use this article for commercial purposes. The article should only be reprinted in a publicly accessible website and not in a members-only commercial site.
- You are not allowed to post/reprint this article in any sites/publications that contains or supports hate, violence, porn and warez or any indecent and illegal sites/publications.
- You are not allowed to use this article in UCE (Unsolicited Commercial Email) or SPAM. This article MUST be distributed in an opt-in email list only.
- If you distribute this article in an ezine or newsletter, we ask that you send a copy of the newsletter or ezine that contains the article to http://www.isnare.com/eta.php?aid=1840100
- If you post this article in a website/forum/blog, ALL links MUST be set to hyperlinks and we ask that you send a copy of the URL where the article is posted to http://www.isnare.com/eta.php?aid=1840100
- We request that you ask permission from the author if you want to publish this article in print.
The role of iSnare.com is only to distribute this article as part of its Article Distribution feature ( http://www.isnare.com/distribution.php ). iSnare.com does NOT own this article, please respect the author's copyright and this publication/reprint terms. If you do not agree to any of these terms, please do not reprint or publish this article.
*****************************
Article Title: Pharmaceutical Formulation Development Series: Why Aren't Emulsions Sexy?
Author: Bruce Rehlaender, Ph.D.
Word Count: 657
Article URL: http://www.isnare.com/?aid=1840100&ca=Medicines+and+Remedies
Format: 64cpl
Contact The Author: http://www.isnare.com/eta.php?aid=1840100
Easy Publish Tool: http://www.isnare.com/html.php?aid=1840100
*********************** ARTICLE START ***********************
I�ve always had a soft spot for injectable emulsions, probably because, I spent most of the first 8 years of my career formulating insoluble drugs into emulsions for IV administration. But 50 years after the European approval of Intralipid, propofol and clevidipine remain the only two non-nutrient drugs I know of that are formulated as injectable emulsions. In the last few years we have seen a significant uptick in approved cyclodextrin-solubilized products, and the use of anaphylaxis-inducing cremophors and polysorbates persists, but emulsions remain swept in the corner and all but forgotten.
The biggest appeal of injectable emulsions as drug delivery vehicles is that they are composed entirely of stuff that is floating around the bloodstream anyway: triglycerides, phospholipids, water, and a bit of glycerin for tonicity. To the body, the oil droplets look pretty much like chylomicrons, and they are metabolized and cleared as such. Other solubilizers, be they cyclodextrins or PEGylated surfactants, are not things nature intended us to have in our blood, and there are consequences to this, be it the potential for nephrotoxicity with cyclodextrins or the risk of anaphylaxis with the surfactants.
That is not to say that emulsions are squeaky clean. If you give too much too fast you will quite obviously see spikes in serum triglycerides, but, more ominously, increases in liver enzymes can also occur. In practical terms this means that an emulsion formulation might be a good option if it will be administered as a relatively small volume, but if hundreds of milliliters per day are needed, then lipid intake could be a problem. Of course if you need to give that much of another solubilizer, you might avoid the liver toxicity but get hit with something else; it�s tough out there in the world of infusing insoluble molecules.
So what is so unsexy about emulsions? They are hard to make, but so are liposomes, and liposomes are still pretty hot stuff after all these years. But, of course, liposomes can do so much more. They can be used to encapsulate water soluble drugs, can be pegylated to hide them from the big, bad reticulo-endothelial system, can have ligands attached to them to target them to tumors and other bad neighborhods, can be lyophilized, sterile filtered, and so on.
The common wisdom is that emulsions cannot be filtered because the droplets are too large, and they cannot be frozen, let alone lyophilized, lest they fall apart. However, this is not necessarily true, as it is possible with enough phospholipids and with high enough pressure to reduce droplet size to well below the 200 nm limit of a sterilizing filter. Even lyophilization is possible if the formulation and lyo cycle are right.
I suspect that the biggest reason emulsions have had such a disappointing career in the injectable drug delivery business is their high start up cost. Especially in these days of tight-fisted venture capitalists paying for much of early drug development, it is much quicker, easier, and cheaper to pull some hydroxypropyl beta cyclodextrin or polysorbate 80 off the shelf than to develop an emulsion. Once something goes into humans, change is hard, and sometimes when we think �it�s just for Phase 1,� it�s still there when the ink is drying on the NDA.
Formulations made with Cremophor or Polysorbate are as messy as those excipients themselves, but the appeal of cyclodextrins is undeniable, and I tend to use them when I can. However, not every solubilization approach works for every molecule, and there are times (e.g. when treating patients with compromised kidneys) when a cyclodextrin formulation is not appropriate. In times like that I might still want to pull an emulsion out of the pile in the corner, dust it off a bit and try to give it some luster.
Find more articles like this one by searching for "PharmaDirections Formulation Development Blog".
About The Author: Bruce Rehlaender, Ph.D., Principal, Formulation Development at http://www.PharmaDirections.com, a pharmaceutical consulting and project management company specializing in preclinical development, formulation development and regulatory affairs. We design and direct preclinical programs for biotech.
Please use the HTML version of this article at:
http://www.isnare.com/html.php?aid=1840100
*********************** ARTICLE END ***********************
- To distribute your articles go to http://www.isnare.com/distribution.php
- For more free-reprint articles go to http://www.isnare.com
Message delivered directly to members of the group:
publish-the...@googlegroups.com
*****************************************************************
Please consider this free-reprint article written by:
Bruce Rehlaender, Ph.D.
*****************************
IMPORTANT - Publication/Reprint Terms
- You have permission to publish this article electronically in free-only publications such as a website or an ezine as long as the bylines are included.
- You are not allowed to use this article for commercial purposes. The article should only be reprinted in a publicly accessible website and not in a members-only commercial site.
- You are not allowed to post/reprint this article in any sites/publications that contains or supports hate, violence, porn and warez or any indecent and illegal sites/publications.
- You are not allowed to use this article in UCE (Unsolicited Commercial Email) or SPAM. This article MUST be distributed in an opt-in email list only.
- If you distribute this article in an ezine or newsletter, we ask that you send a copy of the newsletter or ezine that contains the article to http://www.isnare.com/eta.php?aid=1840100
- If you post this article in a website/forum/blog, ALL links MUST be set to hyperlinks and we ask that you send a copy of the URL where the article is posted to http://www.isnare.com/eta.php?aid=1840100
- We request that you ask permission from the author if you want to publish this article in print.
The role of iSnare.com is only to distribute this article as part of its Article Distribution feature ( http://www.isnare.com/distribution.php ). iSnare.com does NOT own this article, please respect the author's copyright and this publication/reprint terms. If you do not agree to any of these terms, please do not reprint or publish this article.
*****************************
Article Title: Pharmaceutical Formulation Development Series: Why Aren't Emulsions Sexy?
Author: Bruce Rehlaender, Ph.D.
Word Count: 657
Article URL: http://www.isnare.com/?aid=1840100&ca=Medicines+and+Remedies
Format: 64cpl
Contact The Author: http://www.isnare.com/eta.php?aid=1840100
Easy Publish Tool: http://www.isnare.com/html.php?aid=1840100
*********************** ARTICLE START ***********************
I�ve always had a soft spot for injectable emulsions, probably because, I spent most of the first 8 years of my career formulating insoluble drugs into emulsions for IV administration. But 50 years after the European approval of Intralipid, propofol and clevidipine remain the only two non-nutrient drugs I know of that are formulated as injectable emulsions. In the last few years we have seen a significant uptick in approved cyclodextrin-solubilized products, and the use of anaphylaxis-inducing cremophors and polysorbates persists, but emulsions remain swept in the corner and all but forgotten.
The biggest appeal of injectable emulsions as drug delivery vehicles is that they are composed entirely of stuff that is floating around the bloodstream anyway: triglycerides, phospholipids, water, and a bit of glycerin for tonicity. To the body, the oil droplets look pretty much like chylomicrons, and they are metabolized and cleared as such. Other solubilizers, be they cyclodextrins or PEGylated surfactants, are not things nature intended us to have in our blood, and there are consequences to this, be it the potential for nephrotoxicity with cyclodextrins or the risk of anaphylaxis with the surfactants.
That is not to say that emulsions are squeaky clean. If you give too much too fast you will quite obviously see spikes in serum triglycerides, but, more ominously, increases in liver enzymes can also occur. In practical terms this means that an emulsion formulation might be a good option if it will be administered as a relatively small volume, but if hundreds of milliliters per day are needed, then lipid intake could be a problem. Of course if you need to give that much of another solubilizer, you might avoid the liver toxicity but get hit with something else; it�s tough out there in the world of infusing insoluble molecules.
So what is so unsexy about emulsions? They are hard to make, but so are liposomes, and liposomes are still pretty hot stuff after all these years. But, of course, liposomes can do so much more. They can be used to encapsulate water soluble drugs, can be pegylated to hide them from the big, bad reticulo-endothelial system, can have ligands attached to them to target them to tumors and other bad neighborhods, can be lyophilized, sterile filtered, and so on.
The common wisdom is that emulsions cannot be filtered because the droplets are too large, and they cannot be frozen, let alone lyophilized, lest they fall apart. However, this is not necessarily true, as it is possible with enough phospholipids and with high enough pressure to reduce droplet size to well below the 200 nm limit of a sterilizing filter. Even lyophilization is possible if the formulation and lyo cycle are right.
I suspect that the biggest reason emulsions have had such a disappointing career in the injectable drug delivery business is their high start up cost. Especially in these days of tight-fisted venture capitalists paying for much of early drug development, it is much quicker, easier, and cheaper to pull some hydroxypropyl beta cyclodextrin or polysorbate 80 off the shelf than to develop an emulsion. Once something goes into humans, change is hard, and sometimes when we think �it�s just for Phase 1,� it�s still there when the ink is drying on the NDA.
Formulations made with Cremophor or Polysorbate are as messy as those excipients themselves, but the appeal of cyclodextrins is undeniable, and I tend to use them when I can. However, not every solubilization approach works for every molecule, and there are times (e.g. when treating patients with compromised kidneys) when a cyclodextrin formulation is not appropriate. In times like that I might still want to pull an emulsion out of the pile in the corner, dust it off a bit and try to give it some luster.
Find more articles like this one by searching for "PharmaDirections Formulation Development Blog".
About The Author: Bruce Rehlaender, Ph.D., Principal, Formulation Development at http://www.PharmaDirections.com, a pharmaceutical consulting and project management company specializing in preclinical development, formulation development and regulatory affairs. We design and direct preclinical programs for biotech.
Please use the HTML version of this article at:
http://www.isnare.com/html.php?aid=1840100
*********************** ARTICLE END ***********************
- To distribute your articles go to http://www.isnare.com/distribution.php
- For more free-reprint articles go to http://www.isnare.com
Reply all
Reply to author
Forward
0 new messages