| 1. Introduction |
The technology, which improves the bioavailability (BA) of poorly absorbable
drugs from the gastrointestinal (GI) tract, has been recognized as an important
strategic tool to optimize oral drug therapy and to improve the patient
compliance. Protein/peptide drugs are the representative low BA drugs.
To elucidate the pharmacological activity of protein/peptide drugs, two
barriers, ie. hydrolysis in the GI tract and low membrane permeability,
must be conquered. Oral administration destroys all physiological activity
of the protein/peptide drugs and explains why typical oral BA of protein/peptide
drugs are usually less than 1-2 %. To improve the oral BA of protein/peptide
drugs, some technologies such as absorption enhancers and enzyme inhibitors
and enteric coated formulations, have been challenged. However, no technology
has been launched yet. Recent studies have indicated that the dilution
and spreading of absorption enhancer in GI tract reduce the enhancing effect
of the absorption promoter. Professor Kanji Takada (Kyoto Pharmaceutical
University, Department of Pharmacokinetics) has invented an novel DDS technology
to improve the BA of protein/peptide drugs. This technology is based on
the patch formulation, which creates a closed space on the target site
of GI mucosa by adhering to the mucosal membrane. |
| 2. Concept of GI-MAPS |
The concept of GI-MAPS is (1) to protect drug from the hydrolysis by the
digestive enzymes and (2) to obtain high concentration gradient of drug
and absorption enhancer between the intestinal mucosal surface by adhering
to the target site of the intestine and enterocytes. |
| 3. Function of GI-MAPS |
After oral administration of gelatin capsule containing GI-MAPS, drugs
in the formulation are protected from the gastric juice in the stomach
by enteric film on the adhesive layer (adhesion site-controlling layer)
and protection layer.
When GI-MAPSis transferred to the small intestine, the adhesion site-controlling
layer of GI-MAPSTM is dissolved at the target site of the small intestine, and GI-MAPS adhere
to the intestinal mucosal membrane
As the result of adhesion, the drug carrying layer of GI-MAPS existing
between protecting layer and adhesive layer forms a closed space. Drugs
in the closed space are protected from the attack of the digestive enzymes
in the intestinal lumen.
Dissolution of drug in the drug carrying layer forms the high concentration
gradient of drug between the GI-MAPS and the enterocytes, and consequently
formulated drug can be efficiently absorbed.
In addition, when an absorption enhancer
is formulated with a drug in
the drug carrying
layer, the concentration of
absorption enhancer
as well as drug in this closed
space reaches
to high level. Under this condition,
optimal
absorption enhancing effect
can be obtained.
|
| 4. Proof of the concept of GI-MAPS |
Abdominal incision was performed in dogs whose duodenum GI-MAPS containing
desmopressin was adhered with an adhesive polymer. After application, blood
samples were obtained and plasma drug concentrations were measured by a
LC/MS method. By comparing to the iv data, the BA of desmopressin from
GI-MAPS was 46%, though the BA from co-administration with absorption enhancer
was 10 %.G-CSF (125 microgram) loaded GI-MAPS was orally administered to
beagle dogs. Total white blood cell (WBC) count in the systemic circulation
after administration significantly increased. In contrast, WBC after oral
administration of G-CSF solution did not significantly change from the
pre-dose level. The pharmacological availability of G-CSF from GI-MAPS
was 23% as compared to the intravenous administration of the same dose
of G-CSF. |
| 5. Adhering of GI-MAPS to the intestinal mucosa |
At 1, 2, 3, 4, 5 and 6 hr after administration of GI-MAPS into the rat
duodenum, the rats were sacrificed. The whole small intestine from pyloric
sphincter to the ileo-cecal junction of each rat was divided into five
portions (#l-#5) and the remaining GI-MAPS in the GI tract was visually
detected. GI-MAPS adhered to section #2 and retained there for approximately
2 hr. |
6. Human study of GI-MAPS containing caffeine as a model drug
|
To study the GI transit characteristics of
GI-MAPS, 50 mg of caffeine was formulated
in GI-MAPS and was administered to human
volunteers. After ingestion, saliva samples
were collected consecutively for 12 hr and
salivary caffeine excretion rates were measured
by a HPLC assay method. As a control, enteric
capsule containing 50 mg of caffeine was
used. High salivary caffeine excretion rates
were observed for 8 hours. |
7. Large scale production
|
Professor Takada has codeveloped a GI-MAPS producing machine with Toray Engineering Co. Ltd., in 2008. With this machine,
micron size GI-MAPS can be produced under GMP condition. |
8. Examples
|
BBioavailability (BA) of peptide/protein drugs
| Peptide/protein |
BA in ratss |
BA in dogs |
| erythropoietin (EPO) |
12.1 % |
- |
| interferon (IFN) alfa |
7.8 % (compared to sc injection) |
- |
| salmon calcitonin |
6.2 % |
- |
| desmopressin |
- |
46 %* |
** device method: GI-MAPS mimetic device was fixed onto the jejunum mucosa
|
