Back to the Top
The following message was posted to: PharmPK
Dear Sir,
I need some information or discussion about the drug development
process.
We have a lead candidate compound which is small molecule, MW ~ 300.
It has an excellenct effect profile in vivo animal model, minimal
effective dose is around 0.05 mg/kg. Although its excellent effect
profile, water solubility is extremly low. Permeability is low, and
bioavailability is also relatively low. So, when we try to do an
animal study, we have some practical problem associated with low
solubility. When we evaluate its competitiveness in efficacy,
toxicity, it has good score.
We have some question, how important the solubility is for further
development, do we need go further structure optimize to enhance the
solubility, or develop an optimal vehicle formulation for preclinical
study...
Any strategic, scientific discussions are welcome.
e-mail : Allosophy.aaa.hanmail.net
Back to the Top
The following message was posted to: PharmPK
Solubility is a major hurdle in the development for compounds despite
they are pharmacologically active. It is a problem influencing the
bioavailability if the drug is for oral administration. However, the
issue can be addressed with a couple of pharmaceutical approaches, such
as lipidization, use of colloidal particulate delivery systems, use of
penetration enhancers, lymphatic targeting, etc.
Nadeem
Back to the Top
The following message was posted to: PharmPK
>De: "Halloren"
>[...]Although its excellent effect
>profile, water solubility is extremly low. Permeability is low, and
>bioavailability is also relatively low. So, when we try to do an
>animal study, we have some practical problem associated with low
>solubility. When we evaluate its competitiveness in efficacy,
>toxicity, it has good score.
could you give examples of what kind of problem you identified in
animal studies that could be associated with low solubility?
Efficacy/toxicity score has to be taken with a great care in the case
of insoluble compounds. I would suggest that you really solve the
solubility and formulation issue before using data of such studies.
>We have some question, how important the solubility is for further
>development, do we need go further structure optimize to enhance the
>solubility, or develop an optimal vehicle formulation for preclinical
>study...
All these points are very dependent on the kind of studies you would
like to perform.
The formulation strategy for preclinical studies is key if you want
to ensure the relevance of your data. For instance you say that
efficay/toxicity is a good score. But is this data relating to plasma
concentrations or to amounts of drugs dosed po?
>Any strategic, scientific discussions are welcome.
I think that it could be very valuable to have more information to
discuss all these points : water solubility value of your drug? how
was osed the drug in the different preclinical studies? what kind of
formulation was used? How were paramters calculated to determine
whether your drug is active / non toxic? etc.
....
As a formulation scientist that focussed on formulation issues in
preclinical studies at Sanofi-Aventis, Parke-Davis and Pfizer I could
certainly help.
Please feel free to contact me at the following email address :
fdoc.-a-.acriter-consulting.com
Looking forward to reading you,
Frederic DOC
ACRITER - drug discovery consulting
www.acriter-consulting.com
Back to the Top
The following message was posted to: PharmPK
>De: "Nadeem Irfan Bukhari"
>Solubility is a major hurdle in the development for compounds despite
>they are pharmacologically active. It is a problem influencing the
>bioavailability if the drug is for oral administration.
I fully agree that solubility is a parameter that can influence
bioavailability if the drug is dosed po. The trouble is that if
solubilization varies, absorption varies and pharmacological response
may vary too. This is the reason why solubility may be taken into
account.
>However, the
>issue can be addressed with a couple of pharmaceutical approaches,
such
>as lipidization, use of colloidal particulate delivery systems, use of
>penetration enhancers, lymphatic targeting, etc.
As a formulation scientist I would suggest to get a better
understanding of the impact of solubility of this drug on preclinical
data before anticipating some work on such delivery systems. Those
approches you tell us about are not be the "first-intention answer"
to the present problem. Drug targeting delivery systems may only be
used for very specific applications because of the complexity to
design such a formulation.
Even if one can propose some further formulation development I would
first recommend to analyse the situation in depth. I am quite
convinced that there is a lot to do before spending time and
resources for the design of such a formulation.
Best regards,
Frederic Doc
Back to the Top
dear all
i would like to suggest that try to increase the solubility of the
molecule by using various methods like preparing salt form or complex
formulation or additives .if both solubility and permeability is low
the molecule maynot become a good lead.
i hope this will helps for you.
Back to the Top
The following message was posted to: PharmPK
Dear Colleague,
To improve the solubility of a highly lipophylic compounds by the
application of cyclodextrins is a common and widely discussed approach
in the preclinical development phase of NCEs. Freely water soluble
formulation of even rock like drugs can be obtained, by using the
appropriate cyclodextrin type and applying different, non conventional
solubilization technics. Let me to mention some example from my
practice, like terfenadine, glibenclamide, ketoconazole, paclitaxel,
docetaxel, e.t.c.
As a co-founder of Cyclolab, Cyclodextrin R&D Laboratory, Budapest,
(www.cyclolab.hu) I can offer our help to overcome solubility
problems by the application of cyclodextrins.
Best regards, Maria Vikmon
Back to the Top
The following message was posted to: PharmPK
Solubility is . . . what?
When you say your compound has low solubility, how was this
determined? Poor
in vitro solubility does not always mean poor in vivo solubility.
If your solubility measurement was in pure water at 25C, or in a
phosphate
buffer at 25C or 37C, you might want to consider measuring solubility in
SGF, FASSIF and FESSIF at 37C - the results could be quite different.
Is your compound neutral or ionizable? Do you know the pKa(s)?
If your compound is a base that has high solubility in stomach at low
pH,
you might get lucky and find that you get complete dissolution in
stomach.
Some such drugs will then remain in a supersaturated state for a long
time
(sometimes hours), so that precipitation might not be an issue. On
the other
hand, even with precipitation in the small intestine, if the
precipitation
is as very small particles, then dissolution can occur more quickly
(than
large particles) as drug is absorbed ("sink" effect). Thus, a salt
formulation that dissolves quickly in stomach could be a strategy for
achieving micronization in small intestine (as precipitate).
Best regards,
Walt
Walt Woltosz
Chairman & CEO
Simulations Plus, Inc. (AMEX: SLP)
42505 10th Street West
Lancaster, CA 93534-7059
U.S.A.
http://www.simulations-plus.com
Phone: (661) 723-7723
FAX: (661) 723-5524
E-mail: walt.at.simulations-plus.com
Back to the Top
I appreciate discussion pointts of Dr Walt.
In case if you have in vivo solubility problem, then i would
recomend to use hydroxypropyl cyclodextrins..
Samiulla
Back to the Top
The following message was posted to: PharmPK
>De: "d.s samiulla"
>I appreciate discussion pointts of Dr Walt.
>In case if you have in vivo solubility problem, then i would
>recomend to use hydroxypropyl cyclodextrins..
I am concerned by such a strategy for po dosing. I would like to
point out that the use of cyclodextrins for oral dosage forms leads
to variations in drug absorption and bioavailability. Drug-
cyclodextrin complexs are not easily absorbed from the GI tract. Drug
molecules have to be free in GI fluids to be absorbed and
bioavailable. So if your complex does not free the molecule easily
you can at least delay the absorption ...or decrease it.
Does it make sense?
Regards,
Frederic Doc
Back to the Top
The following message was posted to: PharmPK
Dear Maria,
as a specialist of cyclodextrins would you share your view regarding
the use of cyclodextrins for oral dosage forms.
I would not recommend it but I tend to see that some people do. Could
you give your point of view about this ?
Thanks
Frederic Doc
Back to the Top
I would like to add an interesting dimension to the ongoing
discussions. Of course options include probably in increasing order
of acceptability at earlier stages of drug development like pH
manipulation (role of pKa), salt/prodrug forming potential,
micronization/nanosuspension approach, supersaturation and anti-
nucleation approach or solubilization approaches (HP beta CD,
surfactants, co-solvents alone or in combination).
However, before going further, a formulation scientist should be
clear that increased exposure is well correlated with proportional
increase in therapeutic efficacy as sometimes (larget Vd, log P>6.0),
the wide tissue distribution may dictate the overall effect.
The use of in silico precdictiopn tools may add value if the
quantitiy of the compound is not much worth trying various options. I
think various in silico prediction tools may provide atleast an
insight about the druggability of the molecule and assist in
evaluating whether the absorption issues are dissolution rate
limited, solubility-limited or permeability limited. All these
activities may run in parallel to provide a better understanding
about the molecule and help developing a proper formulation strategy.
Moreover, solubility in water does not add any value for a
formulation scientist. Studies like pH solubility profile, phase
solubility in various acceptable solvents and solubility in bio-
relevent media generally lay down some pivotal information, based
upon which a rationale formulation strategy can be devised.
Thanks and regards,
Vaibhav
Vaibhav Sihorkar, Ph.D
Senior Scientist
Formulation Research Department
Disocvery Research
Dr. Reddy's Laboratories Ltd.
Hyderabad 500 049, India
Back to the Top
The following message was posted to: PharmPK
Dear Frederic,
Unfortunately I could not share your opinion on the oral (non)
availability of a cyclodextrin complexed drug. Practical utility of
cyclodextrin complexation approach is reflected on the growing number
of drug formulations beeing on the market since years. Literature data
suggests that drug release from cyclodextrin complexes is rapid and
quantitative in most cases. Complexed drug release are fully discussed
in the review paper of Valentino J. Stella et al: Mechanism of drug
release from cyclodextrin complexes, published in: Advanced Drug
Delivery Reviews, 36(1999) p3-16.
The solubility/dissolution enhancement of poorly water soluble drugs by
complexation generally translate to an improved bioavailability, an
increase in cmax and decrease of tmax is charachteristic, owing to the
quick dissolution of the complex.
In aqueous solution, the complex association-dissociation is continuous
with lifetime of milliseconds or less. The binding constant of the
complex
is an important parameter, fortunately it is in the range of several
hundreds/thousands order of magnitude.
After parenteral administration, the main driving force for
dissociation of
weakly to moderately bound drugs appears to be the simple dilution.
For strongly bound drugs, contribution of competitive inclusion by
endogenous materials, drug uptake, cyclodextrin elimination may also
be important.
(There is an example for extremely strong complex binding with great
practical significance. Sugammadex, (ORG 25969) a modified gamma-
CD derivative specifically designed for the complexation of rocuronium
bromide, hence to offer a new concept to reverse rocuronium induced
neuromuscular blockade.)
Only uncomplexed (dissociated) drug can permeate across the
membranes.
Because of the nature of complexation equilibria, free drug fraction
will
be always present for absorption. Free drug concentration available for
absorption depends on the value of the association constant. CD-s
taken in high excess can shift the equilibrium towards complexation.
Using CD-s in the necessary smallest amount is advised. It seems, that
the obtainable higher dissolved drug concentration can overcome to
the negative effect caused by complex-binding, so ensuring higher free
drug concentration to be absorbed. It can be demonstrated by
comparative membrane permeation tests, applying membrane with cut-
off lower than the MW of CDs.
Preparation method for CD complexed formulations with high guest
loading depends on the nature of the guest. Some examples for non
conventional complex formation: in case of certain base type drugs,
combining salt formation with
complexation, i.e. CD and acid are used simultaneously in a
predetermined appropriate molar ratio, an unprecedented synergetic
solubility can be attained.
Solubilization of acidic type drugs by pH alteration in presence of
cyclodextrin results in well soluble salts at physiologically
acceptable pH
values.
I hope my explanation could be accepted, and you also tend to
change your opinion on the oral application of CD complexed
formulations.
Let me know if you have any specific question,
Best regards, Maria Vikmon
Back to the Top
The reason why cyclodextrins have not gain momentum in oral
administration according to my personal view is more to do with
difficulties in formulating high dose drugs with cyclodextrins for
oral use. In majority of the cases, such high (sometimes in "g" for
one dose) amount of cyclodextrins needs to be delivered in an
acceptable dosage form/delivery system leading to complexities and
increased cost and over and above safety issues for a chronic dosing.
This may not necessarily be the case with low dose drugs. However, in
any case, the concerns of impact of binding constant are genuine (as
Frederic pointed out and I agree to that) and it needs to be
demonstrated that such formulations translate in to better exposure
(and demonstrates a reasonable dose linearty) and address dissolution
rate- or solubility-limited oral absorption issues and hence a case
by case basis descretion is desired.
Recently efforts like optimization of complexation process with multi-
component system to help reduce the cyclodextrin quantitiy within
permissible limits and further improve efficiency in terms of
dissolution and bioavailability, have become much rationalized. I
have been part of investigations using ternary components to enhance
complexation efficiency and published some interesting results (one
of such publications can be reviewed, Basavaraj et al., 2006,
Pharmaceutically Development and Technology, 11, 443-451). The
addition of a ternary component increases the initial solubility (So)
of the API and in turn increases complexation efficiency contrary to
earlier postulates that more lipophilic the drug, more it will get
complexed with cyclodextrin. Complexation efficiency is a function of
initial solubility and binding consant and hence novel ternary
components are being judiciously identified so that initial
solubility can be improved while maintaining binding constant low to
moderate. Ternary or multi-component system may possibly involve
various weak and strong interactions within their network. These
events may also be thermodynamically more favored.
We may see a change in scientific fraternity with extravascular and
oral uses of such speciality excipients considering more and more
poorly druggable candidates being explored at NCE stage.
regards,
Vaibhav
Back to the Top
The following message was posted to: PharmPK
As dextran enthusiasts, perhaps you or someone else, can help me:
I am have continuing trouble with the chromatographic analysis of
dextran/drugs, particularly with baseline upsets when doing SEC.
These seem to be associated with elution of the total included
portion, and the totally excluded portion. With RI detection, these
upsets can result in large negative-going peaks. This is minimized
with UV detection, when it is possible; but the baseline upsets are
still present.
Any other thoughts?
Thanks in advance,
Frank
Frank Bales, Ph.D.
frankbales.-at-.msn.com
Back to the Top
The following message was posted to: PharmPK
Frank,
Do you have the facility to try an evaporative light scattering
detector? We have tried it with PEG (an envelope around 20kDa) with some
success. ESA (esainc.com) have just brought our an updated version of
this detector (corona charged aerosol detector), I have not tried it but
they may be willing to run some samples for you to see.
Hope this help!
Phil
PharmPK Discussion List Archive Index page
Copyright 1995-2010 David W. A. Bourne (david@boomer.org)