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Dear all,
I am working on a nanoformulation and its pharmacokinetic evaluation in wistar rats.
I want to estimate drug ,released from the nanoformulation in in vivo samples so that i can compare this formulation to marketed product which is availble as conventional formulation.
One assumption is that nanoformulation, when given orally, is absorbed through gastric intestine as particulate form (coated with suitable polymer) through lymphoidal tissues and once it reached in to the systemic circulation,it will be released slowly.
My doubt is that if i am analysing rat samples, i will be analysing both nanocarrier trapped drug as well as released drug from nanoformulation. But on the other hand reference formulation (marketed formulation) will have only API in its plasma samples.In order to establish correlation between my formulation and marketed formulation i have to subtract nano-entrapped drug from released drug.
So is there any method available to separate nanoparticles present in blood from released drug.
Eagerly waiting for your expert comment
Regards,
Rahul Vats
BITS-Pilani, Hyderabad Campus,
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Dear Rahul Vats
What is the objective to to establish a correlation between your nanoformulation and marketed formulation?. In my opinion it is enough to show that the drug from your formulation releases slowly and effect of this formulation on the pharmacokinetic parameters (Area under the curve, Cmax, Tmax, Ka, etc) as compared to the commercial formulation.
Dr. Nadeem Irfan Bukhari
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The following message was posted to: PharmPK
Dear Rahul,
For liposomal drug product, we typically develop a method to separate intact liposome from the plasma and then measure the drug conc in filtrate (filtered plasma) which represents released (if you will available) drug. Depending on the size of the particles that you are dealing with this strategy may work for you.
Rostam
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If you are running an LC-MS method then the nanoparticles should elute at a different retention time, also if the drug is in nanoparticle form in the mass spec the m/z will be different and therefore a further degree of separation is achieved.
The problem you describe is if the sample processing disrupts the nanoparticles and releases free drug, so you need to ensure this doesn't happen.
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Dear Rahul,
The suitable method of analysis can solve this problem. If you are using HPLC or more suitable way to use LC-MS, released drug will give peak at specific time the coated particle will not give the peak at same retention time or using LC-MS in SIM or MRM mode only released drug will furnish particular ions at specified retention time. The method should be validated for the analysis of drug and for its interference from coated form.
Dr Zafar
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Dear rahul,
generally nanonoformulation is use for targeting different organ(targeted drug delivery system). if your formulation is also desire for targeting there is no meaning to see plasma drug concentration in spite of that you have to check how much amount of drug reaching to the organ you are targeting. so you have to remove there organ and check for amount of drug accumulating over there. if your nano is just to increase solubility or bioavaibility then you have to check free plasma drug concentration in rat not drug entrapped in the nanoformulation to compare with marketed product.
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The following message was posted to: PharmPK
Dear Rahul,
You may need to provide more information like which polymer was used to prepare polymeric nano-particles, what was the dose of the drug and loading and how confident you are that drug nano-formulation has crossed intact via lymphatics and to what extent?.
The area of lymphatic uptake of polymeric nano-particles is investigated by Nasir Hussain and Florence (School of Pharmacy, London) along with other researchers worldwide, where in majority polystyrene nanoaprticles labeled with some marker, were investigated for their potential tog et absorbed intact in circulation. This could be highly useful for site-specific targeting (more for antigen presentation) as once in circulation, they may undergo either phagolysosomal through MHC II pathway or may extravasate (if <100 nm) and be in circulation for long time. However, I am not sure that for a high dose drug, to what extent, this is possible. Moreover, I am also not sure how you could have ensured your nano-formualtion remained as "nano" within the harsh environment of git through the course of its residence.
The amount that in fact may get through lymphatics could be so small that it will hardly impact on the outcome of your study (unless the administration is by IV route). Even if some fraction reaches to circulation intact as nano-particles or nano-formulation, you can analyse the same blood sample twice, once "as is" and the other time, after processing your sample with a suitable solvent to solubilize the polymer. Needless to say, that you may need to establish a sensitive analytical method and also need to ensure that this process do not lead to variability in results. Or else, you can make placebo nano-formulation labeled with marker (fluorescence or radio-labeled) and check if you get any traces in plasma in your experimental set up.
Hope this will help.
regards
--
Vaibhav Sihorkar, Ph.D.
Head [Pharmaceutical Development], Aurigene Discovery Technologies Limited
vaibhav_s.-at-.aurigene.com
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Hello
I do not thing that you need to have a different methods for analyzing the samples of nano and conventional formulation. Sensitive method is need for the same , irrespective of the source of the samples. You can not exactly quantify the nano formulation released drug in the plasma, in fact it tell us only the total exposure. So you could compare the exposure between nano and conventional formulations to derive the conclusion.
Any comments are welcome.
Thank you
Best wishes
A.Karthik
Research scholar
MCOPS
Manipal .
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Dear All,
Thanks for your precious expert comments.
I would like to inform you about the drug and nanoformulation requirement. Drug is having poor pharmacokinetics (poor bioavailability) due to very high first pass metabolism, poor solubility and nonspecific target.It is an antiviral drug and its target site (enzyme) is intracellular and target cells are monocytes and macrophages (MPS cells) ..Conventional drug is already in the market with an effective dose of 150 mg for adult human.
To improve bioavailability (by increasing solubility,reducing first pass metabolism) and for targeted drug delivery i decided to go with nanoformulation as Nano has got unique advantages to deliver the drug at target site and also increases the solubility,mean retention time, reduces the first pass metabolism (in turn it increases the bioavailability)
As i know comparator (marketed drug ) drug,once dosed orally, gives concentration which remains above MEC (minimum effective concentration) for 12 hrs.I also have to keep this fact in the mind while preparing nanoformulation equivalent to effective dose of conventional formulation.Therefore i have to compare nanofree pharmacokinetics with conventional drug pharmacokintic. Thats why this separation of nanoformulation from blood is required.
I am still not sure that free drug and nanotrapped drug will have different retention time and molecular weights and will not convert trap to free.
I have gone through so many papers which conclude that oral delivery of nanoformulation is possible but challenging also. I have not decided about the polymer yet.Can anybody suggest me some polymers that is suitable for the formulation? Regards,
Rahul Vats
BITS-Pilani, Hyderabad Campus,
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The following message was posted to: PharmPK
Dear Rahul,
There are a few conceptual sections in your work plan, which may need more discussions scientifically. Specially the following paragraph.
To improve bioavailability (by increasing solubility, reducing first pass metabolism) and for targeted drug delivery, I decided to go with nano-formulation as "Nano" has got unique advantages to deliver the drug at target site (comments: MOSTLY IF NOT ALL, IF IT IS GIVEN BY PARENTERAL ROUTE DUE TO PHAGOLYSOSMAL UPTAKE OR EXTRAVASATION, AS THE CASE MAY BE, SO THIS DOES NOT APPLY HERE AS FOR THAT TOO HAPPEN THE NANO-FORMUALTION HAS TO BE ABSROBED INTACT) and also increases the solubility (comments: ITS DISSOLUTION RATE AND NOT SOLUBILITY THAT IS ENHANCED BY A NANO-FORMUALTION), mean retention time (comments: UNLESS NANOPARTICLES REACHED INTACT IN BLOOD STREAM BY ORAL ROUTE, THIS IS NOT POSSIBLE), reduces the first pass metabolism (comments: IT IS DIFFICULT TO CONCLUDE AS NANOAPRTICLES MAY ALSO UNDERGO PHAGOCYTIC UPTAE, EVEN IF IT OCCCURS, IT WILL ONLY TAKE PLACE IF NANOPARTICLES REACHED INTACT IN BLOOD STREAM BY ORAL ROUTE).
So the whole premise of your work plan resides on the assumption that nano-formulation will reach intact in circulation, which needs to be proven first before you proceed ahead with this approach.
regards
--
Vaibhav Sihorkar, Ph.D.
Head [Pharmaceutical Development] I Aurigene Discovery Technologies Limited
vaibhav_s.-at-.aurigene.com
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Hello
I do not think that you need to have a different methods for analyzing the samples of nano and conventional formulation. Sensitive method is need for the same , irrespective of the source of the samples. You can not exactly quantify the nano formulation released drug in the plasma, in fact it tell us only the total exposure. So you could compare the exposure between nano and conventional formulations to derive the conclusion.
Any comments are welcome.
Thank you
Best wishes
A.Karthik
Research scholar
MCOPS
Manipal .
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