Biorelevant Dissolution Media

                                         

Biorelevant Media

How a medicine should be taken is usually explained in the patient information leaflet provided by the manufacturer. Whether a drug is taken before or after a meal can have a big impact on its absorption because food changes the properties of gastrointestinal fluids a lot. Gut fluids in both fasted and fed states are simulated by Biorelevant Media.

Why should I test in Biorelevant Media?

BE studies are pivotal in showing similarity between a pharmaceutically equivalent generic formulation and the reference listed drug in ANDA submission. Different regulatory agencies have different requirements regarding BE studies for immediate release (IR) products. Refer below link more information

https://www.blogger.com/blog/post/edit/2376840283485197087/2192731683837054919

As all of us know, there are few medicines which need to be taken before meal (fasting) and few are after meal (Fed). Whether a drug is taken before or after a meal can have a big impact on its absorption because food changes the properties of gastrointestinal fluids a lot .Therefore, it is obvious to probe the similarity between a pharmaceutically equivalent generic formulation and the reference listed drug in fasting /or fed condition or in both conditions as per the active molecule of interest.

According to European Medicines Agency BE guidance, a BE study should be conducted under fasting conditions as this is considered to be the most sensitive condition to detect a potential difference between formulations. For products that are recommended to be taken with food, the BE study should be conducted only under fed conditions.

In the US FDA guidance, fasting and fed studies might be needed for IR products. Exceptions can be made when the product is recommended to be taken only on an empty stomach. If the product is to be taken only with food, fasting and fed studies are recommended, except when there is safety concern with fasting administration. 

As the bioequivalence needs to be proven in fast and fed condition, further the bioequivalence study to be performed on Human volunteer, therefore there is a demand to understand the comparative invitro dissolution  behavior of generic product & reference product on different GIT fluid/ simulated GIT fluids.

Biorelevant in vitro dissolution testing is useful for qualitative forecasting of formulation and food effects on the dissolution and availability of orally administered drugs.

Biorelevant dissolution medium

Before the development of biorelevant dissolution medium the following steps should be considered

1)         Fluid composition in the GIT

2)         Hydrodynamics in the GIT

3)         API/formulation properties

4)         Prediction of plasma profile

5)         Development of IVIVCs

 

1) Fluid composition of GIT

The features of GI fluid are altered in fasted and fed condition and they affect the dissolution. Several physiochemical and physiological properties of GI fluids such as pH, buffer capacity, bile component concentration and state of aggregation and enzyme activity can greatly influence the drug dissolution process. For simulation of GI fluid the composition of GI fluid plays important role because upon simulating biological environment after a convenient alternative could facilitate routine and experimental in vitro dissolution work. Several physiologically based models for GI transit and absorption have been developed recently

Stomach:

Motility in the stomach and small bowel is organized into two basic motor patterns fasting and fed. Fasting motor pattern is characterized by cyclic repetition of periods of quiescence altering with periods of contractile activity. Fed motor pattern is characterized by irregular but persistant phasic contractile activity. It develops almost immediately after ingestion of food and replaces the fasting pattern at whatever point in the interdigestive cycle the meal is eaten.

Under fasting condition pH of healthy human stomach is acidic, ranging between 1 and 3. Fluid volume in the stomach would initially be around 300ml in fasted state and 500ml or more in the fed state.

Intestine:

Motility of intestine comprises of intraluminal flow, motion of the wall that induce the flow and systems that regulate the wall motions. Fluid volume in small intestine is of 200ml in fasted state and 1L in the fed state. It has been found that the bioavailability of poorly soluble drug can be markedly enhanced by meal intake and its related changes in GI tract physiology such as secretions, digestion processes and motility.

The human intestinal fluid contains bile salts, phospholipids, monoglycerides, free fatty acids and cholesterol. The increased solubility in FeSSIF-V2 can be explained by the formation of solubilizing micelles from bile salts, lecithin, GMO and sodium oleate.

Colon:

Unlike the motility of the stomach and small intestine which is characterized by the cyclic appearance of the migrating motor complex under fasted conditions, colonic motility is rather limited and in progress due to its inaccessibility and regional differences in structure and function.

 

The composition of biorelevant media which are proposed by dissolution scientist in fasted and fed state for stomach, intestine and colon are shown in table from 1-4.

Table 1: Composition of the Media to Simulate Gastric Contents in the Fasted State

Gastric Contents	SGFSLS	SGFTriton	FaSSGF
Sodium lauryl sulfate(%w/v)	0.25/0.05	-	-
Triton X 100 (%w/v)	-	0.1	-
Pepsin (mg/ml)	-	-	0.1
NaTc ( µm)	-	-	80
Lecithin (µm)	-	-	20
NaCl	34.2	34.2	34.2
pH	1.2	1.2	1.6
Surface Tension (mN/m)	33.7	32.0	42.6
Osmolality (mOsml/Kg)	180± 3.6	157.7± 2.9	120.7± 2.5

 

Table 2: Composition of the Media to Simulate Gastric contents in the Fed State

Gastric Contents	Early	Middle	Late
Sodium chloride (mM)	148	237.02	122.6
Acetic acid (mM)	-	17.12	-
Sodium acetate( mM)	-	29.75	-
Ortho-phosphoric acid (mM)	-	-	5.5
Sodium dihydrogen phosphate (mM)	-	-	32
Milk: buffer	1:0	1:1	1:3
Hydrochloric acid/sodium hydroxide	qs pH 6.4	qs pH 5	qs pH 3
pH	6.4	5	3
Osmolality (mOsmol/Kg)	559± 10	400±10	300±10
Buffer capacity (mml/pH)	21.33	25	25

 

Table 3: Composition of the Media to Simulate the Contents of the Small Intestine in the Fasted State

Contents of the Small Intestine	FaSSIF	FaSSIF-V2
Sodium Taurocholate (mM)	3	3
Lecithin (mM)	0.75	0.2
Dibasic sodium phosphate (mM)	28.65	-
Maleic acid (mM)	-	19.12
Sodium hydroxide (mM)	8.7	34.8
Sodium chloride (mM)	105.85	68.62
pH	6.5	6.5
Osmolality (mOsmol/Kg)	270± 10	180± 10
Buffer capacity (mmol/l/pH)	12	10

 

Table 4: Composition of the media to simulate the Contents of the Small Intestine in the Fed State

Contents of the Small Intestine	FeSSIF	Early	Middle	Late	FeSSIF-V2
Sodium Taurocholate (mM)	15	10	7.5	4.5	10
Lecithin (mM)	3.75	3	2	0.5	2
Glyceryl monooleate (mM)	-	6.5	5	1	5
Sodium oleate (mM)	-	40	30	0.8	0.8
Acetic acid	140	-	-	-	-
Maleic acid	-	28.6	44	58.09	55.02
Sodium hydroxide (mM)	101	52.5	65.3	72	81.65
Sodium chloride (mM)	173	145.2	122.8	51	125.5
pH	5.0	6.5	5.8	5.4	5.8
Osmolality (mOsmol/Kg)	635± 10	400± 10	390± 10	240± 10	390± 10
Buffer capacity (mmol/L/pH)	76	25	25	15	25