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jag009 ★★★ NJ, 2014-08-22 18:47 (3893 d 23:16 ago) Posting: # 13419 Views: 9,192 |
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Guys and Girls, A question... Suppose you have an IR drug product which is highly soluble but poor in permeability and has a Tmax of 8 hrs. Do you think slowing down the rate of in-vitro release will affect the overall PK? Assume this scenario... Under the same dissolution medium, assuming the reference is releasing no less than 80% at 30 mins, and your product is releasing no less than 80% at 60 mins. What do you think? Thanks John |
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Dr_Dan ★★ Germany, 2014-08-22 21:27 (3893 d 20:36 ago) @ jag009 Posting: # 13421 Views: 7,920 |
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Dear John Highly soluble but poor in permeability => BCS class III drug. In Europe you have to show dissolution in three pH media: 1.2, 4.5 and 6.8. If your drug is highly soluble then the drug should be dissolved completely within 30 minutes in all three media. According to your question this is not the case. Could you please specify which dissolution media you use? With a tmax of 8 h the rate limiting factor will be the absorption, however, it would be useful to know more about the dissolution to make reasonable assumptions for PK. Kind regards Dr_Dan — Kind regards and have a nice day Dr_Dan |
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jag009 ★★★ NJ, 2014-08-25 17:19 (3891 d 00:43 ago) @ Dr_Dan Posting: # 13429 Views: 7,880 |
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Hi Dr. Dan, In Europe it's three medium for IR drug? For FDA they only asked for 1 medium and that's 1.2N HCl as per USP. USP specs listed no less than 75% in 60 mins. We submitted our drug's release spec based on USP spec disso (NLT 75 in 60 mins) and FDA came back with no less than 80% in 30 min. John |
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luvblooms ★★ India, 2014-08-26 08:41 (3890 d 09:22 ago) @ jag009 Posting: # 13431 Views: 7,841 |
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Hey John ❝ Assume this scenario... ❝ Under the same dissolution medium, assuming the reference is releasing no less than 80% at 30 mins, and your product is releasing no less than 80% at 60 mins. What do you think? For highly soluble-low permeable drugs, the rate of drug absorption is limited by permeability which is also governed by gastric emptying time (or availability of drug at the site of absorption) For any highly soluble if drug release >85% in 20-30 min, then only absorption would be mainly controlled by the emptying from the stomach(normal GIT: 10-120 min depending upon the type of phase). In your case where the reference is releasing no less than 80% at 30 mins, and your product is releasing no less than 80% at 60 mins; I would be a bit cautious as it would surely affect the rate of drug availability at the site of absorption and your formulation is some how controlling the rate of release. BTW you mentioned Tmax=8 hrs, is there any lag time or the plasma concentration picks up slowly? If there is a lag of 1-2 hrs, may be the differences would not be that prominent but if there is no T lag, it might affect the absorption (saturation absorption?? Metabolism???) Any information about behaviour in fed condition? How the formulation behaviour in viscous media??? Any disintegration delays?? Try these papers, good read for BCS class III drug a) Tsume, Yasuhiro; Amidon, Gordon L.; The Biowaiver Extension for BCS Class III Drugs: The Effect of Dissolution Rate on the Bioequivalence of BCS Class III Immediate-Release Drugs Predicted by Computer Simulation; Molecular Pharmaceutics; 7, 4, 1235-1243 For simulating Fed condition b) Jelena Parojčić, Dragana Vasiljević, Svetlana Ibrić, Zorica Djurić; Tablet disintegration and drug dissolution in viscous media: Paracetamol IR tablets; International Journal of Pharmaceutics 355 (2008) 93–99 — ~A happy Soul~ |
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jag009 ★★★ NJ, 2014-08-26 19:33 (3889 d 22:30 ago) @ luvblooms Posting: # 13435 Views: 7,744 |
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Hi Bloom, ❝ For highly soluble-low permeable drugs, the rate of drug absorption is limited by permeability which is also governed by gastric emptying time (or availability of drug at the site of absorption). For any highly soluble if drug release >85% in 20-30 min, then only absorption would be mainly controlled by the emptying from the stomach(normal GIT: 10-120 min depending upon the type of phase). Bingo! ❝ In your case where the reference is releasing no less than 80% at 30 mins, and your product is releasing no less than 80% at 60 mins; I would be a bit cautious as it would surely affect the rate of drug availability at the site of absorption and your formulation is some how controlling the rate of release. BTW you mentioned Tmax=8 hrs, is there any lag time or the plasma concentration picks up slowly? No lagtime and both T and R have 7.6 - 8 hr Tmax. My question to the formulators was that if the product leaves the stomach at less than 60 mins, and if you want a spec of >=80 at 60 mins, I see a potential problem of the remaining part of the product not dissolving at post gastric pH, which can affect PK. The knucklehead director wouldn't listen and insisted that there shouldn't be any effect on BE because the Tmax is so long because drug permeability is the rate limiting step in our case. ❝ Any information about behaviour in fed condition? No different. No food effect on Tmax. Thanks John |
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luvblooms ★★ India, 2014-08-28 10:21 (3888 d 07:42 ago) @ jag009 Posting: # 13439 Views: 7,771 |
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Hi John, ❝ My question to the formulators was that if the product leaves the stomach at less than 60 mins, and if you want a spec of >=80 at 60 mins, I see a potential problem of the remaining part of the product not dissolving at post gastric pH, which can affect PK. The knucklehead director wouldn't listen and insisted that there shouldn't be any effect on BE because the Tmax is so long because drug permeability is the rate limiting step in our case. Can understand the frustration. Have to go through same situation almost everyday.  But such is life. If possible try to look at the opening pattern or release profile in the viscous media. It might give you some idea about formulation behavior in fed situation. — ~A happy Soul~ |
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Samaya B ☆ India, 2014-09-01 09:48 (3884 d 08:15 ago) @ luvblooms Posting: # 13444 Views: 7,671 |
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❝ If possible try to look at the opening pattern or release profile in the viscous media. It might give you some idea about formulation behavior in fed situation. Dear luvblooms, What kind of conclusion can be drawn from dissolution / disintegration behaviour of formulation in fed viscous media when there isn't a significant difference between Tmax of T and R? (No lagtime and both T and R have 7.6 - 8 hr Tmax)... Out of curiosity!! Thanks. Regards, Samaya. |
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luvblooms ★★ India, 2014-09-01 16:09 (3884 d 01:54 ago) @ Samaya B Posting: # 13446 Views: 7,584 |
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Dear Samaya ❝ What kind of conclusion can be drawn from dissolution / disintegration behaviour of formulation in fed viscous media when there isn't a significant difference between Tmax of T and R? (No lagtime and both T and R have 7.6 - 8 hr Tmax)... Out of curiosity!! No T lag, means absorption starts from upper part of GIT or there might be a chance of Cmax build-up through hepatic recirculation (Typical example Raloxifene) You can get few ideas as
Try this paper Jelena Parojčić, Dragana Vasiljević, Svetlana Ibrić, Zorica Djurić; Tablet disintegration and drug dissolution in viscous media: Paracetamol IR tablets; International Journal of Pharmaceutics 355 (2008) 93–99 And also check some back refrences. Hope this will give you some food for thought — ~A happy Soul~ |
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Samaya B ☆ India, 2014-09-04 08:54 (3881 d 09:09 ago) @ luvblooms Posting: # 13455 Views: 7,535 |
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Dear luvblooms, Thanks a ton for detailed explanation!!  Regards, Samaya. |
Ing. Helmut Schütz