Pharmaceutical Development - Science topic

Hi Raju,

I know this is after a quite long time but would it be possible to share your GC method to determine white petrolatum, this would be very helpful. You can directly share your method copy/article to sathish.tanneru@gmail.com.

I appreciate your assistance in advance.

thank you

Sathish

How the calculate optamic products as per ICH guideline because of optamic products dose is very low and impurity calculate as per ICH is very high

I would recommended to use the LC-MS/MS, UPLC-MS, HPLC and amino acid analyzer apparatuses for detecting the amino acids compounds.Of course, you should to consider your research fund/budget.

Drug development professional skilled in study design, protocol writing, monitoring, presentation and investigator relationships. Adept in team work, mentoring, liaising with investigators, auditing, site visits and study overview.

Assist the clinical team in the preparation, handling, distribution, filing and archiving of clinical documents and reports. # Preparing clinical SOPs and Administer clinical trial records according to Good clinical practices. # Contact person between the contract laboratory, study team and study site. # Provide general logistical support for clinical trials such as creating and taking minutes of meetings. #Conduct clinical trial monitoring and assist in source data verification. #Designing essential documents and data collection logs and forms. # Training the site staff to trial specific GCP and GDP. # Maintain Trial master files (TMF) #Conducting Scientific literature search. # Assist in the prepare the dossier for SAEs and trial related communication with regulatory submission. # Perform any other function assigned by organization.

Biomarker is the Early biological signal. Actually it is something New or Chang in the protein which act as marker. According to the such protein signal we can design drug molecules .Biomarker is helpful to New drug development.

Zeta potential can be improved by varying the stabilizer concentration, or by surface modification with cationic agents.

Interesting question

Mohammed Hafiz Alshafie Ahmed Mohammed

Dear sir,

for paracetamol tablet you need 2.5-3.5% moisture in granules and optimized granules fine ratio. if higher % of fines present in blend, tablet will fail in friability test.

in paracetamol tablets optimal LOD is 2.5-3.5%, when we take batch with starch and pvp k-30 paste. if you take gelatin and starch as a binder then optimal LOD will change from 2-3%.

Would you please inform me, how should prepare AOM for IP injection to mice?

We should dilute it in dH2O?

How much should prepare the final volume for IP injection?

Dear Mr. Roa,

Please explain how to calculate the thickness for capsule shape tablet.

What if the tablet is capsule shape?

Which side we need to consider for estimating tablet thickness?

Thank You.

Hey, even if it's probably not that relevant anymore - you could try sucralose as sweetener. Works pretty well!

Regards,

Niklas

Uniformity of Dispersion test is generally meant for *Dispersible Tablets*, which are uncoated or film-coated tablets intended to be dispersed in water before administration giving a homogeneous dispersion.

In *Uniformity of Dispersion test*, 2 Tablets are placed in 100 ml of water & stirred gently until completely dispersed. A *smooth dispersion* should be obtained which should be passed through 22# (710 microns).

Here smooth dispersion (less than 750 micron) is must *to promote acceptable mouth feel without producing any type of grittiness in the oral cavity* which may compromise patient acceptance compliance.

Moreover, as the PSD of dispersed particle reduced, it will be readily available for absorption through mucosa.

(In *other types of IR Tablets*, Disintegration test is generally performed to ensure only disintegration of tablets into granules through 10# (2000um=2mm)

Because these tablets are meant to be swallowed with water which will be directly reach into stomach where it is meant to be disintegrated & dissolved.)

Thank you to All.........

Hello all

I am also trying to make pellets of Famciclovir 250mg. Its an orodispersible formulation in which the pellets should dissolve in Stomach. The total weight of the tablet should not be more than 800mg. Can anyone suggest what are the extrusion aids and binder combinations for this product.

ICH basically provides a common set of guidance documents for submission of dossiers to ICH member countries. It harmonizes the process, as earlier each country had its own set of regulations and formats for dossier submission in order to achieve marketing authorisation in the respective country. ICH tries to bring these countries on the same page to make the filing process smooth.

For gastro retentive preferable medium is acetate buffer pH 1.2 or 0.1 N HCl as gastro retentive we assume to be used in the empty stomach conditions. Volume of dissolution medium you can select on the basis of drug content of your formulation means the concentration of drug in each collected sample should be sufficient enough for the detection thorough your analytical method. Secondly, we should try to correlate with the empty stomach conditions (specially volume). 

you can try to get blood via caudal vein, no cannulation, less wound infection. as for me,end of the test, the liver and kidneys function are normal. i think use same animal model for in vivo and in vitro PK is possible .

Hi Vipul,

Besides checking Pharmacopeia protocols, find the attached pdfs, where you will get all the details of simulated gastric, intestinal, colonic fluid types, volume, conditions etc. 

Doesn't really matter as long as the form you are using is pure (normally >99%) and bio-available. Either grade is fine the drug is the drug obviously for certain methods like HPLC contaminants may be a problem. The main thing is  will it go into solution in your culture medium at the concentration you want to use it, which may dictate whether you but a base or salt form of the drug. In genrral you want to minimise the need or amounts of adding organic solvents to your media (EtOH, DMSO, DMF).

I do not see how carrs would be a preservative. They are added as texturizers. In other words to either make a gel or modify the flow of the products.

But isn't aloe already a viscous product?

Regarding carrs safety . . . The battle is still going on. Industry claims carrs are safe to ingest and a bunch of others claim it is not.

Lipopolysaccharides, endotoxin containing fragments and mutagenase fragments.

Levofloxacin is a weakly acidic drug with carboxylic acid moiety. pKa value = 6.24 and as per handerson hasselbalch equation drug will not shows ionization in any pH below 6.24 thus drug will be completely insoluble in gastric fluid (stomach). Drug will be soluble only if the pH of the medium increases above 6.24. So, ideal for colon delivery.

But for this drug matrix formulation will also be much better as compared to enteric coating since drug is itself not soluble in acidic pH and as coating increase cost of formulation then you should go for matrix of levofloxacin using Eudragit as retarding polymer which do not shows any disintegration in stomach. One more important is permeability of drug which is very less and for this addition of some lipid particles is necessary.

Hi,

Have a look at the following literature:

(68)Ga-labeled peptides in tumor imaging. - NCBI

by HR Maecke - ‎2005 - ‎Cited by 327 - ‎Related articles

Among these, (68)Ga deserves special attention, because it is available from an ... Animals; Clinical Trials as Topic; Drug Delivery Systems/methods*; Gallium ...

****************

Development of Drugs and Technology for Radiation Theragnosis ...

by HJ Jeong - ‎2016 - ‎Cited by 3 - ‎Related articles

Many nanodrug delivery systems, including liposome, use this strategy for the passive ... For the targeted drug delivery of albumin to the liver or a hepatocellular ..... [6]: V. Prasad, R.P. BaumBiodistribution of the Ga-68 labeled somatostatin ...

****************

Chelator free gallium-68 radiolabelling of silica coated iron oxide ...

by BP Burke - ‎2015 - ‎Cited by 10 - ‎Related articles

Aug 13, 2015 - 68Ga (t1/2 = 68 min) is an attractive radioisotope for PET due to ... NRs radiolabelled with gallium-68 for PET/MR multimodal imaging ... based systems have deprotonated carboxylic acid groups at pH 7. ..... C. Sun, J. S. H. Lee and M. Zhang, Adv. Drug Delivery Rev., 2008, 60, 1252 CrossRef CAS PubMed .

Respected Sir, Please try to make co crystal with di-carboxylic acids in different ratio. I think, as per suggestion of Prof. Mayank Joshi 1:1 or 2:1 ratio will work. 

you can use lower mw PLGA or PGA itself. Vit E TPGS used in previous paper also work. Not sure about your main intention as PLG is hydrophobic by nature to slow release esp. as MP unless size reduction, too many articles on this aspect. 

FYI: European Medicines Agency publishes the agendas and minutes of committee meetings. See e.g.

I agree with Riaz. Such compounds (macrocycles, antibiotics, etc) may be actively transported for which there are no reliable in silico models of sufficient size and chemical diverstity.

And my final advice is for you: only tablets and ampoules for parenteral use that have a clear manufacturer's declaration, date of manufacture, expiry date of drug, dosage and dosage form, description of undesirable effects of drug action, Prescribes the law of each state individually is ok!

Drugs that do not have it from the black market and can not be given to patients because it is contrary to the common practice and laws regulating that area!

This is a  general question and as mentioned before there is no easy answer. The answer would depend on several aspects. For example is this an academic exercise or a drug discovery project? Second how many compounds are we talking about? Third what are you going to use the data for? Also when you say lypophilic compounds, there is a wide range of lipophilicity. As a general rule, again talking about oral absorption to narrow the discussion down, two factor, in general, that influence oral absorption. First is permeability and second is solubility. Usually compounds with log P of 1-3 has better permeabilty although there are some exceptions. There are software that can usually predict these two parameters fairly well. But you have to do some studies on a few compounds to confirm the prediction. Now bioavailabilty is a composite of oral absorption and first pass effect. The compound could be well absorbed but shows poor oral bioavailabily. You can get an idea about first pass by determining the metabolic stability using in vitro system such as liver microsomes or hepatocytes, although IV clearance in animal is the best estimate of first pass effect. I would suggest that the compounds that shows the best permeability and solubility and low metabolic stability can be tested in a PO/IV study in animals (usually rats or mice). When you do the PO study it will be best to dose it as a solution to avoid compromising bioavailability because of low solubility. There are many relatively safe vehicles you can use to solubilize  hydrophobic compounds (Gad et al., International Journal of Toxicology 2016). One of them I used a lot is 20% aqueous hydroxypropyl beta cyclodextrin for both IV and oral administration..Hopefully this will help

Good question and I must say I am not sure.  For openers, some form of clinical trial data that say that (Q1) and (Q2) have been explored (say in the original NDA or supplements) over sufficient ranges to make it clear that efficacy and /or safety were not affected over wide range.  Say, clinical trials were conducted and the efficacy and safety were shown to be functions of log of dose and the proposed formulation differs by only 10% in concentration.  That would certainly be enough to get a waiver.  

Could be that similar data, showing that log dose was shown in animal experiments would be sufficient evidence (using biomarkers of pharmacological activity) if it the drug is well known from a mechanism of action point of view.

Both clinical (and or animal) data would need to be shown for the active mouthy as well as all of the other inactive components of the new formation.

gets harder from there.

Thanks Dr Gilles Dollo for the detailed answer. I have applied zero order, first order, Higuchi's model, Hixson Crowell's model and korsmeyer peppas models on my data however, release was best fitted into korsmeyer peppas model because of the high R value but the reviewer asked me  that why you applied Hixson crowell model on sustained release system as it is only for microspheres, thats why i asked here to reconfirm it because I have seen in many papers on sustained release Hixson crowell's model is applied.

Hi Shilpa,

Apart from dissolution, lipolysis studies can give you a good piece of information about which formulation would performe better in vivo. I leave you link below:

Assessment of novel oral lipid-based formulations of amphotericin B using an in vitro lipolysis model.

Try to gradually test with somewhat lower temperatures than those you mention, and I think we should have less hygroscopic bonding material is then spray it with HSO at the nozzle gun!

You can isolate nuclear proteins by first isolating the nuclei only (separating nuclei from cytosol) and then extract the nuclear protein with buffer containing high concentration of salt (NaCl or KCl up to 1 M). You need to know the chemical nature of your drug as well, to know if or how the binding of you drug can be/is affected by the component of buffer you are using.

Normally, in all these cases the main point is about the drug dissolution in the simulated GIT media. Basically, pH, ionic strength, and surfactant presence are the composition variables. Time of residence and motility simulation are the other parameters under consideration. Colonic drug release implies pH near to 8.0 at 37 °C.

I was just having a peruse through some DMPK related questions and looked at this out of interest......I know it's a while since the question was posted but just in case it helps.......I'm no expert on enzyme kenetics but I'm not so sure you actually have an issue here, if the Km for drug A is lower than drug B would you not expect the IC of the inhibitor to be higher?  The binding of drug A occurs with higher afinity than B and therefore (without knowledge of 'K off' assuming an equal rate of transport for A and B)  would require an increased level of inhibitor to reduce transport by half in comparison to B.

Dear Shanker,

Dissolution and broadly speaking any release testing have one of two purposes namely (a) to provide information on the in-vivo behaviour/performance or (b) as a quality control method to provide information on the impact of changes in the formula and/or manufacturing process (on purpose or accidental) on the product release kinetics.

In your particular case I’m not sure you have a problem with the release medium. Most probably it will reside somewhere in the sample preparation and/or analytical determination (just a guess). You state that increasing the dialysis pore size increases the release. I'm afraid that's not so! The release does not depends on the dialysis membrane. What changes is your perception of the release, most probably because you are quantifying also the nanocapsules that are able to cross the dialysis membrane together with the free drug.

If you are only concerned in getting the drug dissolved after 5 hours, all you just need to use a medium in which the drug is soluble! Maybe methanol or dichloromethane can do the job.

However I guess it’s not what you want and that was the reason for my previous questions. Try to figure out the reason why you are getting a low (I’m just guessing) release. Unfortunately, based on the available info, I can’t suggest any dissolution/release medium other than increasing the SLS amount (you may go up to 2% with proper, sound and solid justification). Try 0.5% or 1% and check if there are any changes (there are however drawbacks -some of them severe - in using surfactants in dissolution media).

Regards, Luis

yes

I am already studying effect of diffrent plant extracts in psoriasis. Would be interested for inteacting & may be collaborative work in due course.

Hello,

First I would go to the website of the DSC manufacturer and look up how to process your data after the experiment (hopefully using their software). This will be best since it would involve the same software you used to obtain your data and you would not need to convert your data back and forth. From a first glance you need to do two major things (assuming you have not already done them):

1) Display your data in the same way. Have the same tranisitions (like crystallization peaks) pointing in the same direction on all graphs. This does not seem to be the case and it causes lots of confusion. I also normalize my heat flow (y-axis) by the mass of the sample so the integrals can be directly compared in terms of crystallinity, etc.

2) You should do a baseline subtraction. This could be as simple as running an empty sample pan and subtracting that data from what you have. This will flatten your baseline and hopefully remove any odd stuff NOT caused by your samples.

In addition, I would search if anyone has done DSC on your pure drug so you can see what the result should look like and compare it to yours. Hopefully this would put you in a better position to analyze your data. Good Luck.

 Dear Ahmed,

Try using HPMC K15M. I've used this before to develop Aceclofenac 200 mg SR tablets and follow the dissolution profile as per Diclofenac ER Tablets USP.

Regards,

Abhishek

Dear wu Wenbo,

Would it be possible to attach a file containing the chemical structures and IC50 of the studied compounds?

Thanks,

Rafik

It would probably dissolve in strong polar aprotic solvents such as DMSO, DMF, NMP...

It is soluble in protic solvent ethanol also..

When the polymer is subjected to water, it will swell due to the molecule's hydrophilic pendant group but it will not be dissolved.

Dear Mohammad,

The half maximal inhibitory concentration (IC50) is a measure of the effectiveness of a substance in inhibiting a specific biological or biochemical function.

This quantitative measure indicates how much of a particular drug or other substance (inhibitor) is needed to inhibit a given biological process (or component of a process, i.e. an enzyme, cell, cell receptor or microorganism) by half. The values are typically expressed as molar concentration

It is commonly used as a measure of antagonist drug potency in pharmacological research. According to the FDA, IC50 represents the concentration of a drug that is required for 50% inhibition in vitro.[1] It is comparable to an EC50 for agonist drugs. EC50 also represents the plasma concentration required for obtaining 50% of a maximum effect in vivo.

The IC50 of a drug can be determined by constructing a dose-response curve and examining the effect of different concentrations of antagonist on reversing agonist activity. IC50 values can be calculated for a given antagonist by determining the concentration needed to inhibit half of the maximum biological response of the agonist.[2] IC50 values can be used to compare the potency of two antagonists.

The term half maximal effective concentration (EC50) refers to the concentration of a drug, antibody or toxicant which induces a response halfway between the baseline and maximum after a specified exposure time.[1] It is commonly used as a measure of drug's potency.

The EC50 of a graded dose response curve therefore represents the concentration of a compound where 50% of its maximal effect is observed.[2] The EC50 of a quantal dose response curve represents the concentration of a compound where 50% of the population exhibit a response,[3] after a specified exposure duration.

It is also related to IC50 which is a measure of a compound's inhibition (50% inhibition). For competition binding assays and functional antagonist assays IC50 is the most common summary measure of the dose-response curve. For agonist/stimulator assays the most common summary measure is the EC50.[4] Sometimes it is also expressed as pEC50 = - LOG(EC50) (with EC50 in M/l).

A small change in ligand concentration typically result in rapid changes in response in the biological system, following a sigmoidal function.The inflection point at which the increase in response with increasing ligand concentration begins to slow is the EC50. Which can be mathematically determined by derivation of the best-fit line. While relying on a graph for estimation is more convenient, this typical method yields less accurate results and less precise.

 Given that folic acid is cheap and likely innocuous, it may be worth a trial figuring out whether is helps. The mentioned study may be point to depart from, but I advise to be careful: (1) it is a small, unblinded trial, (2) in neurology, there was a lot of homocysteine, MTHFR, and folic acid substitution addressed in huge trial called VITATOPS, which failed to demonstrate any effect of supplementation despite some studies and pathophysiological ideas supporting supplementation. Maybe a placebo effect as well, which would seem ok to me if it helps...

For intestinal infection, survival was assayed as previously described (Blow et al., 2005). Briefly, 30 male flies were divided evenly between three vials either containing a cellulose acetate plug saturated with 2 ml of LB broth supplemented with streptomycin alone or containing a 1:10 dilution of an overnight culture of V. cholerae that had reached early stationary phase. Viable flies were counted at least once in 24 h. For septic injury, 20 flies were pricked in the dorsal thorax with a 29-gauge needle dipped in a solution containing early stationary-phase bacteria diluted to an OD600 of 0.05 in fresh LB media. Flies were maintained in vials containing a cellulose acetate plug saturated with 5% sucrose in phosphate-buffered saline (PBS). Flies were inoculated in the evening, and the numbers of viable flies were recorded hourly during the following day. Survival curves were constructed for both intestinal and systemic infections, and log-rank tests were used to determine statistical significance. Reproducibility of all survival data was confirmed in at least three independent experiments.

Thank you Dr. Rafik for your reply, 

in pharmaceutical manufacture we have to make sure that all the raw materials comply to specifications as stated in the official pharmacopeial monograph before incorporating it in a product ( GMP & local regulations requirement ) In this case we can't do this as the DL is not stated, and when tested according to the monograph, it will fail in the optical rotation and melting point tests !.

I think that the purity of the DL differs also being synthesized in different method than the L isomer. Note that the optical rotation is required by the BP, USP, Japanese pharmacopeias & the Hand book of pharm excipients

When a decision is to be taken, Do you think that the DL consignment should be rejected or used ?

thanking you sir @ Alok Nahata

The test will depend crucially on your hypothesis to be tested.

Dear Srinivas,

You may conduct a one step reduction of the oxime to furnish the corresponding amine as shown below:

A Mild Single-Step Reduction of Oximes to Amines

Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry

Volume 18, Issue 8, 1988

A mild and convenient procedure has been developed for the reduction of oximes to amines in a single step involving treatment of the oxime with TiCl3 in the presence of NaBH3 CN. This method is especially useful for those substrates in which the intermediate imine is readily hydrolyzed.

Hoping this will be helpful,

Rafik

Did you gave same dose for IV/IM/Sc?

Bioavailability more than 1 (more than 100%) is a common phenomena, not only in i.p. and Sc but also in oral administration. F greater than 1 is relative to i.v. administration and assuming that in any of the routes compared, Clearance does not change. This is a big assumption and many a times rate of elimination is controlled by rate of absorption. Thats what happens in im/ip/Sc. or sustained release dosages.

During regular NCE research it has been observed that with same vehicle when, an NCE was administered i.v. and orally, Fwas greater than 1.

This can be due to many reason.

Detailed investigation can be done as in following paper published in two parts. These papers are must read.

1. xenobiotica, april 2004, vol. 34, no. 4, 353-366

Apparent absolute oral bioavailability in excess of 100% for a vitronectin receptor antagonist (SB-265123) in rat. I. Investigation of potential experimental and mechanistic explanations

K. W. WARD*, L. M. AZZARANO, C. A. EVANS and B. R. SMITH

Preclinical Drug Discovery, Cardiovascular & Urogenital Center of Excellence in Drug

Discovery, GlaxoSmithKline, King of Prussia, PA 19406, USA

2. xenobiotica, april 2004, vol. 34, no. 4, 367-377

Apparent absolute oral bioavailability in excess of 100% for a vitronectin receptor antagonist (SB-265123) in rat. II. Studies implicating transporter-mediated intestinal secretion

Eudragit RSPO is neither soluble nor biodegradable. You can use Eudragit S 100, 12.5, Eudragit or FS 30D for colon targeting. They all dissolve above pH 7.

The FDA is suggesting to you that you need to know enough about the release mechanism of your active to guarantee that your chosen dissolution test is selective at discriminating variations in the manufacturing process that lead to dosage forms with different release profiles in vitro. Said test should be (at least) as sensitive at discriminating differences as would an in vivo release profile (what the FDA is really interested in making sure you control; but it's prohibitively expensive to test this in routine manufacturing!); usually this is easy to achieve if the release is controlled by disintegration of the dosage form to any substantial degree. In vivo the turbulent mixing in the stomach aids the release of active, whereas in vitro the dosage form may form a wetted layer which releases drug slowly through the matrix, and the stirring of the (paddles) may not be sufficient to cause this layer to fall off. If different tablets, to take an example, have even slight differences in the wetting and disintegration speed of that layer, the in vitro profiles may differ considerably, whereas the in vivo absorption profiles of the two may be quite similar. That's what the FDA is interested in; you could present either another dissolution test with different turbulence, or other equivalent types of observations --e.g., a dissolution vs. disintegration study across manufacturing ranges, with reasoned analysis of the results, or a coupled dissolution + proton NMR 3-D scan on tablets (to visualize water intrusion during dissolution). The rigor with which you pursue this point would depend on the type of dosage form you have -- unusual forms might require more testing.

In USP, 10 # size is to pass all type pf granules or particle even big size as of 1.5 to 2 mm size  like sprinkle granules and coated beads etc. Disintegrating apparatus is having some big size mesh to avoid blockage too because it does not effect on DT time.

I'm not a specialist in the field of your question but think that the paper, "Methods for in vitro evaluating antimicrobial activity: A review," in the link below might be useful for you:

For protonation: you wouldn't expect a basic molecule to maintain separate neutral and protonated states in a protic solvent (with methanol)? The spot would migrate per the average protonation proportion, relative to the separate neutral and protonated species. Only specially constructed protonatable species would be able to show main spots, connected to some degree by a streak -- very-hindered-rotation tautomers, for example. Agree related compounds likely. TEA is useful in any event to decrease tailing on silica - you don't necessarily need to pretreat the plate, just add a bit to the eluent. Seeing spots connected by a bridge doesn't necessarily mean that the different species were present in the spotting solution -- they might also be reacting during the chromatography (try running them on a different phase plate to check this, say reverse vs. normal phase).

Dear Anaide Bonjour,

A lack of entrepreneurial behavior has often been highlighted as a contributor to the decline in the research and development (R&D) productivity of the pharmaceutical industry. Academic pharmaceutical science research is expanding further from the University setting to encompass the for-profit private company setting, such as pharmaceutical companies. This parallels the NIH momentum to include multiple funding opportunities for University and private company collaboration. It has been recognized that the non-profit and for-profit combination research model can accelerate the commercialization of pharmaceutical products, and therefore more efficiently improve human health. Entrepreneurial activities require unique considerations in the University environment, but can be modeled after the commercialization expansion of the academic healthcare enterprise. The commercialization of the healthcare enterprise can provide a good model to mimic, as far as oversight and support for entrepreneurial activities. The challenges and rewards of the academic entrepreneurial lifestyle appeal to many faculty members, and this opportunity can be integrated and monitored in the University environment. Universities and entrepreneurs benefit in many ways from a well-designed economic development initiative, and this initiative helps to not only stimulate the economy, but accelerate development of products to improve human health.

For more on this topic, please see the publications contained in the following links:

Hoping this will be helpful,

Rafik

What I do when having many different samples is to add diluted samples to an inert 96 well plate (made of polypropylene, which does not bind proteins to a significant degree) in the same distribution that they will have in the ELISA plate (but in a volume slightly larger than the one I will use for ELISA). Once all the samples are there, it is vey easy and quick to transfer the desired volume (i.e. 50 microliters) from each well to the equivalent well of the ELISA plate with a multichannel pipette to avoid huge delays between the first and the last samples.

Dear Chukwuebuka Egbuna, 

The following links provide you with the required SOPs:

Hoping this will be helpful,

rafik

Dear Tadesse Fikre Teferra,

My experience through 30 years teaching and research would go with natural antioxidants. It is Eco friendly products, however, what  these  bio-molecules chemical state? see if you looked at the nutritional value of an orange has vitamin C, precursors of vitamin A plus more than 150 phytochemicals that may protect form heart disease and some types of cancer. On the other hand,  vitamin C is available in a tablet with unbalanced chemical state usually in reduced form that not always safe. However, the chemical state of vitamin C from an orange have the the state of a chemical balanced in redox and reduced state plus more than 150 phytochemicals.

Also see what victor Herbert said about that:

Based on twenty years of research, The Vitamin Pushers addresses every aspect of this lucrative business and exposes its widespread misinformation campaign. The authors reveal how many health-food companies make false claims about products or services, promote unscientific nutrition practices through the media, show little or no regard for the rules of scientific testing and evidence, and often skirt the law in their schemes for making quick profits while eluding government watchdog agencies. Drs. Barrett and Herbert counter the phony assertions of health-food hucksters with reliable, scientifically based nutrition information, and they suggest how the consumer can avoid "getting quacked." They also include five useful appendices on balancing your diet, evaluating claims made for more than sixty supplements and food products, and much more. The Vitamin Pushers is a much-needed expose of a nationwide scam, which will definitely save you money and might even save your life. 

 Best regards

Aly

hi ..

some time problem in case using same name or its founded in researchgate and you need some change in title(of your work) and then write  different title(within researchgate) then it will be ok to upload your work  please try this ,,,

regards...

Tavşan dili üst yüzey alanı :)

Dear Seran,

Please read the following text. The direct answer to your question is the example marked with bold line.

First, remember the structure and function of a virus. Once attached to its specific target cell, it injects its DNA (or RNA) into the host cell. Once inside the 'infected' cell, this viral DNA (or RNA) replicates itself as well as using the existing machinery within the 'infected' cell to make more viral proteins. It then assembles itself and can now leave this cell to infect other cells. Second, remember the structure and workings of DNA (or RNA). All the DNA strand consists of are 5-carbon deoxyribose (or ribose) sugars linked together by phosphate groups. Additionally, each 5-carbon sugar has one of four possible bases attached: A, G, C, or T. So in order to elongate a strand of DNA (or RNA), the cell simply links the 'sugar-base-phosphate' unit onto the existing 'sugar-base-phosphate' units already linked together forming the strand of DNA. We oversimplify this by saying that the DNA strand grows by adding additional bases. For example, our simplified explanation says that the DNA strand grows by adding an "A", or "G", or "C", or "T" base, one at a time. Remember that this "A", or "G" or "C" or "T" is the 'sugar-base-phosphate' unit with the base being either A, G, C, or T. Thirdly, this is an oversimplified but essentially accurate explanation of how several antiviral drugs work. The antiviral drug will be incorporated into the growing DNA (or RNA) strand as if it were another 'sugar-base-phosphate' unit. Once this drug is incorporated into the growing DNA strand, no other 'sugar-base-phosphate' units can be attached, and so any further grows stops. Hence, terminating the growth of viral DNA within the infected cell.

As an example, let's discuss acyclovir as an antiviral drug for herpes simplex infection. Acyclovir is an analog of 2-deoxyguanosine ("G"). The acyclovir is in fact modified by enzymes made only by the virus so that the acyclovir can now be incorporated into the growing viral DNA strand instead of the "G". Once incorporated, any further elongation stops because unlike "G" that should be there, the acyclovir cannot attach any further nucleoties (acyclovir cannot attach any further "A"'s, or "G"'s, or "C"'s, or "T"'s). A herpes simplex virus attaches to a susceptible host cell (seen on the right), fusing its envelope with the cell membrane, and releasing naked capsids that deliver viral DNA into the nucleus of the host cell, where it initiates the synthesis of viral DNA. Acyclovir molecules entering the cell are converted to acyclovir monophosphate by virus induced thymidine kinase enzyme. Host-cell enzymes add two more phosphates to form acyclovir triphosphate, which is transported to the nucleus. Shown in red is the cleavage of phosphate from the acyclovir triphosphate by the herpes simplex's own enzymes, the herpes simplex's DNA polymerase enzyme incorporates the acyclovir monophosphate into the growing DNA strand as if it were 2-deoxyguanosine monophosphate (a "G" base). Further elongation of the chain is impossible because acyclovir monophosphate lacks the attachment point necessary for the insertion of any additional nucleotides.

I. The acyclovir (as do other antiviral drugs) is mistakenly incorportated into the growing DNA strand. The enzymes adding in "A"'s, or "G"'s, or "C"'s, or "T"'s recognize acyclovir as a "G" and add it in.

II. The acyclovir does not have the proper structure to add any additional "A"'s, or "G"'s, or "C"'s, or "T"'s to it, and so the DNA strand cannot continue to elongate or grow. Once the acyclovir is incorporated, any further growth of viral DNA is terminated.

For more information, please use the following links:

Hoping this will be helpful,

Rafik

Dear Joshua,

check this: https://www.ebi.ac.uk/chembl/

Good luck!

Thank you so much!

Dear Trisha Bansal,

Yes. It can be done.

Understand the distribution potential of your compound using our plasma protein binding assay.

Plasma protein binding is one of Cyprotex's in vitro ADME screening services. Cyprotex deliver consistent, high quality data with cost-efficiency that comes from a highly automated approach.

The extent of binding to plasma influences the way in which a drug distributes into tissues in the body.

Etensive plasma protein binding also limits the amount of free compound available to access sites of action in the cell, and metabolism and elimination may be slower.

Equilibrium dialysis is the most widely accepted method for assessing plasma protein binding as non specific binding effects are minimised compared with other methods such as ultrafiltration.

Cyprotex's Plasma Protein Binding assay is performed using an equilibrium dialysis method and delivers a value of fraction of compound unbound to proteins (fu).

There is a choice of three methods for assessing plasma protein binding using three different percentages of plasma to provide flexibility depending on budget and compound characteristics.

Equilibrium dialysis is the preferred method to determine the free drug fraction, because it is less susceptible to experimental artifacts.

Kariv I, Cao H and Oldenburg KR. (2001) J Pharm Sci 90(5); 580-587

For the protocol details, please use the following link:

Hoping this will be helpful,

Rafik

Use Pro Lipo Neo (Lecithin derived) to prepare hydrophylic API Liposomal.

Please see its brochure

The particles aggregate over the time. We have used Span 80 and Solutol but aggregation was seen after a day. Viscosity agent can be tried next...thank you

Dear Claudia,

The following publication entitled " Challenges and Opportunities in The Encapsulation of Liquid and Semi-Solid Formulations into Capsules for Oral Administration " fully covers the answer to your intersting and important question. Please note that this publication contains some figures for illustrating the method:

The encapsulation of liquids and semi-solids provides solutions for convenient delivery through improved oral absorption of poorly water-soluble drugs. In addition, low dose (content uniformity), highly potent (containment), low melting point drugs, those with a critical stability profile and those for which a delayed release is required are candidates for liquid or semi-solid formulations. Both hard and soft capsules can be considered and in each case the capsule wall may

comprise gelatin or some other suitable polymer such as hypromellose. The choice of a hard or soft capsule will depend primarily on the components of the formulation which provides the best absorption characteristics as well as on the physical characteristics, such as the viscosity of the formulation and the temperature at which the product needs to be filled. Numerous excipients are available for formulation of lipid-based systems and their compatibilities with hard gelatin capsules have been tested. The availability of new enhanced manufacturing equipment has brought new opportunities for liquid-filled hard capsules.

Filling and sealing technologies for hard capsules, provides the formulator with the flexibility of developing formulations in-house from small scale, as required for Phase I studies, up to production.

To view the full publication, please use the following link:

Hoping this will be helpful,

Rafik

Thank you very much Juan! I guess a similar strategy can be used when assessing and comparing efficacy and EC50s or ED50s for different drugs, even if we have drug combinations. Most of what I have read about pertains to dose-response curves and probit analysis in Finney's textbook (1971).  

-David

Dear Rishabh,

The following publications describe methods for drug release from vaginal suppositories:

1-J Drug Target. 2003 Apr;11(3):177-85.

In-vitro evaluation and vaginal absorption of metronidazole suppositories in rabbits.

Ozyazici M1, Turgut EH, Taner MS, Köseoglu K, Ertan G.

Author information

 

Abstract

Vaginal suppository formulations of metronidazole were prepared using six different bases as Witepsol H15, Cremao, Ovucire WL2944, Ovucire WL3264, PEG 1500, PEG 6000. Three different dissolution methods were used to evaluate the in vitro drug release from the suppositories. The diffusion studies were performed through synthetic (cellophane) and natural membrane (rabbit vagina), but the drug did not show good permeation characteristics from natural membrane. Ovucire WL3264 suppositories of metronidazole labeled with 99mTc (Tecnetium-99m) were used for the vaginal absorption and biodistribution studies in the rabbits. Scintigraphic images were collected after vaginal administration of the labeled suppositories using SPECT gamma fitted with a low energy, high-resolution parallel hole collimator. The labeled drug showed high biodistribution in urine beside vaginal site. The results of this study suggested that the Ovucire WL3264 suppository of metronidazole prepared for vaginal infections could also be effective in the urinary infections.

2-METRONIDAZOLE BIOADHESIVE VAGINAL SUPPOSITORIES: FORMULATION, IN VITRO AND

IN VIVO EVALUATION

Research Article

HAIDY ABASS*1, RABAB KAMEL2, AHMED ABDELBARY3

1Department of Pharmaceutical Technology, Faculty of Pharmacy, German University in Cairo, El tagamoo El Khames Main Entrance Cairo,

Egypt, 2Department of Pharmaceutical Technology, National Research Center, Dokki, Cairo, Egypt, 3Department of pharmaceutics and

Industrial Pharmacy ,Faculty of Pharmacy ,Cairo University, Kasr El -Aini St., 11562, Cairo, Egypt. Email:haidy_miu2002@yahoo.com

Received: 29 Aug 2011, Revised and Accepted: 26 Nov 2011

ABSTRACT

Drug administration via mucosal membranes, including the vaginal, has the advantage of by passing the hepatogastrointestinal first pass metabolism associated with oral administration. Metronidazole suppositories were prepared using different suppository bases viz., water soluble bases ( PEGs and gelatin ) emulsion and fatty bases. The physicochemical properties of most of the prepared MTZ suppositories comply with the pharmacopoeial limits and passed the quality control tests. In general, water soluble suppository bases gave higher release than did the emulsion in citrate buffer pH 4. PEG base (F14), gelatin base (Fl8) and emulsion base (F23) gave the highest drug release and selected for further investigation. The release of MTZ from polyethylene glycol bases followed, first and Higuchi order release model, while gelatin and emulsion obeyed first model.

The tested suppository showed enhancement of drug absorption from tested suppository and the One way ANOVA analysis for AUC(0-∞) showed that the P value is 0.0502, considered not significant. The microbiological results showed that the bioadhesive formulae that released the concentration of 0.25 mg/ml of the drug and sustained this concentration for 120 min can be effective on C. albicans moreover bioavailability study was performed on flagyl ® vaginal suppository (market product) and the prepared pluronic127 –cp934 bioadhesive vaginal gel ,eight female rabbits were randomly divided into two groups, each containing four rabbits the results showed that the tested formulae did not exhibit enhancement in bioavailability in comparison to the market product which mean lower side effects and localized effect inside the vagina. 

3-Comparative bone uptake study of alendronate sodium from vaginal suppositories prepared with polyethylene glycol and massa estarinum bases

INTRODUCTION Bisphosphonates are used in the management of various disorders affecting the skeleton, includ- ing osteoporosis, metastatic bone disease and Pa- get’s disease of bone. Bisphosphonates are selec- tively uptake at active bone sites, suppressed the osteoblast and osteoclast mediated bone resorp- tion (1-4). Alendronate sodium (ALD) is a second generation amino bisphosphonates that selec- tively inhibits osteoclast-mediated bone resorp- tion, increases bone mineral density and reduces the incidence of vertebral, hip and other fractures (5-7). Like all bisphosphonates, ALD is poorly ab- sorbed from the gastrointestinal tract, with an oral bioavailability of around 0.9–1.8% (8). Its ab- sorption is markedly reduced by food (9). In recent years, there is a challenge for novel drug delivery systems to achieve improved bio- availability and safety. Various researchers have described new formulations to treat bone dis- ease with minimal side effects and high efficien- cy. Because of the poor gastrointestinal absorp- tion several administration routes have been at- tempted to enhance the bioavailability of bis- phosphonates like intravenous, subcutaneous and intramuscular injections (10-13). Also Asikoglu et al. have demonstrated rectal ab- sorption of ALD (14). The unique properties like rich blood supply and the large surface area makes vagina an important area for systemic drug delivery (15). The advan- ABSTRACT: The aim of this study was to compare the bone uptake of alendronate sodium (ALD) from vaginal suppositories prepared with massa estarinum AB (ME) and polyethylene glycol 1500 (PEG) bases. For this purpose, ALD was radiolabeled with 99mTecnetium Pertech- netate (99mTc) by direct method. Radiochemical purity and stability of 99mTc-ALD was per- formed with chromatographic studies. 99mTc-ALD containing suppositories were prepared with ME and PEG bases. Physical properties of suppositories were evaluated. The physico- chemical diffusion study was carried out to compare the release of ALD from different sup- pository bases. The bone uptake of 99mTc-ALD was observed by gamma scintigraphy stud- ies. 99mTc-ALD containing suppositories were administrated to rabbits via vaginal route. The scintigraphic images were obtained with a gamma camera at different time intervals up to 240 minutes. According to our studies, radiochemical purity of 99mTc-ALD was observed more than 95% up to 6 hours. At 240 minutes of physicochemical diffusion studies, released ALD has 0.620 ± 0.091 mm and 10.465 ± 0.651 mm diameter zone from ME and PEG base suppositories respectively. According to the gamma scintigraphy studies, although no bone uptake observed after ME suppositories application, rabbit’s bones were clearly visible after PEG suppositories applied. The results of physicochemical diffusion and gamma scintigra- phy studies were found compatible in each other. KEY WORDS: Alendronate sodium, bone uptake, vaginal suppository, massa estarinum, polyethylene glycol Comparative bone uptake study of alendronate sodium from vaginal suppositories prepared with polyethylene glycol and massa estarinum base

4- Formulation and in vitro study of antibacterial vaginal suppositories

ARTICLE in PHARMACEUTICA ACTA HELVETIAE 69(3):141-8 · JANUARY 1995 

Vaginal suppositories frequently used in gynaecological therapy were studied. Several antibacterial pharmacons are used for the topical treatment of vaginitis of various origins. In view of the fact that the liberation of the given active substance and the subsequent therapeutic effect may be improved or inhibited by the vehicle, our aim was to find the optimal suppository base for vaginal suppositories containing sulfadimidine, chloramphenicol and gentamicin sulfate by means of in vitro experiments. On the basis of breaking hardness, disintegration time and spreading properties the French Suppocire NA product, and compositions of macrogols with lower molecular weight proved to be the best lipophilic and hydrophilic bases, respectively. Among the lipophilic bases the in vitro drug liberation of Suppocire NA was significantly better (P < 0.05) than the other lipophilic bases. This vehicle is recommended for the topical treatment of vaginitis, as these suppositories have the further advantage that they can easily be produced on a magistral, galenical or industrial scale as well.

Hoping this will be helpful,

Rafik

Thanks to all

Dry in vacuum at lower temp below 30 degrees .

The best for a laboratory is Asset-Backing Method:

Since the valuation is made on the basis of the assets of the company, it is known as Asset-Basis or Asset- Backing Method. At the same time, the shares are valued on the basis of real internal value of the assets of the company and that is why the method is also termed Intrinsic Value Method or Real Value Basis Method.

This method may be made either:

(i) On a going/continuing concern basis; and

(ii) Break-up value basis.

In the case of former, the utility of the assets is to be considered for the purpose of arriving at the value of the assets, but, in the case of the latter, the realizable value of the assets is to be taken. Under this method, value of the net assets of the company is to be determined first.

Thereafter, the net assets are to be divided by the number of shares in order to rind out the value of each share. At the same time, value of goodwill (at its market value), investment (non-trading assets) are to be added to net assets. Similarly, if there are any preference shares, those are also to be deducted with their arrear dividends from the net assets.

However, this following step should carefully be followed while calculating Net Assets or the Funds Available for Equity Shareholders:

(a) Ascertain the total market value of fixed assets and current assets;

(b) Compute the value of goodwill (as per the required method);

(c) Ascertain the total market value of non-trading assets (like investment) which are to be added;

(d) All fictitious assets (viz, Preliminary Expenses, Discount on issue of Shares/Debentures, Debit-Balance of P&L A/c etc.) must be excluded;

(e) Deduct the total amount of Current Liabilities, Amount of Debentures with arrear interest,” if any, Preference Share Capital with arrear dividend, if any.

(f) The balance left is called the Net Assets or Funds Available for Equity Shareholders.

for beta blockers you need to do a functional assay

the easiest assay would be measuring cyclic AMP levels in recombinant cells expressing either the b1 or b2 receptor. perform a concentration-response curve to isoprenaline (general beta agonist) in the presence of different concentrations of your beta blocker...you then get schild plots to get estimates of affinity, and these values can help you determine b1 vs b2 specificity

if you dont have these cells, you can do organ bath experiments in tissue high in b1 (heart) or b2 (trachea) as was done in the 1970s to seperate b1 vs b2 receptors. 

radioligand binding will tell you if your drug binds to the receptor, it wont tell you the function of the drug ie. agonist or antagonist.

dont do immuno staining as the antibodies for b1 and b2 receptors are not specific, and the result wont tell you if the drug is an agonist or antagonist

ONLY FUNCTIONAL EXPTS CAN TELL YOU THIS

Hello Celia,

There is tow methods mathematical  and graphical one. The graphical is as follows: you have to use several groups of animals (mice or rats for example) divided into a control batch receiving only the vehicle (water f eg) and the test batches receiving increasing doses of the drug. each batch receives a single dose. The ratio between tow successive doses must be between [1.2-1.5] (ie: Cn = cn+1 x [1.2-1.5]).

we determine the percentage of the effect corresponding to each dose, draw the dose-response curve: percentage of the response versus the log of the concentration [% response = f (logC)], then EC50 determined graphically, it corresponds to the 50% response.

the presence of antagonist dose may increase the EC50, that is to say the dose-response curve is shifted to the right (50% response is the same but EC50 is greater)

Good luck

ELISA?

Dear Hocine,

it depends on the therapeutic drug class. for Eg  for antiretroviral drug interactions, http://www.hiv-druginteractions.org/ is excellent and I think it can very well meet your expectations.

The exact method will depend on the drug and nanoparticle formulation but there is a method that may be used for polymeric nanoparticles:

To measure drug release from nanoparticles, nanoparticles should be lyophilized, weighed, and resuspended in buffer (I used two different PBS/0.1% Tween-80 buffers, one at pH 7.4 and one at pH 6.5, but you can use whatever buffer is suitable for your drug/nanoparticle preparation) and then incubate in a 37 °C water bath. At various time points (I measured between 15 min and ten days) an aliquot of eluted drug medium should be removed for quantification; this volume must replaced with fresh buffer to prevent sink conditions. Drug release can be quantified by measuring the absorbance of the release media using a plate reader or HPLC, this value, of course, will be unique to the drug you are using. As a control you should also measure blank nanoparticles (with no drug) and make suitable standard curves for your drug concentration in buffer.

Please see the two attached papers of mine for methods and if you have any other questions please let me know.

Read full-text

Source

Article: Pharmacokinetics and biodistribution of lonidamine/paclitaxel loaded, EGFR-targeted nanoparticles in an orthotopic animal model of multi-drug resistant breast cancer

Lara Milane · Zhen-feng Duan · Mansoor Amiji

[Show abstract]

Full-text · Article · Aug 2011 · Nanomedicine: nanotechnology, biology, and medicine

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How do I measure a drug release profile for a drug encapsulated in a nanoparticle? - ResearchGate. Available from: https://www.researchgate.net/post/How_do_I_measure_a_drug_release_profile_for_a_drug_encapsulated_in_a_nanoparticle [accessed Feb 24, 2016].

As Rafik rightly mentioned is correct.

-Cost to Develop New Pharmaceutical Drug Now Exceeds $2.5B

A benchmark report estimates that the cost of bringing a drug to market has more than doubled in the past 10 years.

But, the which required to bring a new bio pharmaceutical drug is also to be considered.

Hi. suggest you start with the attached files. best wishes.