|Details of Our Technologies
Gastrointestinal mucoadhesive patch system
||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, because the dilution and spreading of absorption
enhancer in the GI tract reduce the enhancing effect of the absorption
enhancer. Professor Kanji Takada (Kyoto Pharmaceutical University, Department
of Pharmacokinetics) 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. In 2018, revised version of GI-MAPS was innovated
to increase the absorption rate of drugs from GI-MAPS..In In
|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. To realize this concept,
GI-MAPS is composed of four portionts, (1) water insoluble base layer,
(2) drug+absorption enhancer carrying layer, (3) adhesive layer and (4)
surface layer. In the case of old type GI-MAPS, adhesive layer was overlayd
on drug carrying layer. As a result, absorption rate of drug from GI-MAPS
was slow, because the gel-forming polymer used to make adhesive layer prevents
the diffusion rate of drug through the surface layer.
In the new type GI-MAPS, adhesive layer is separated from drug carrying
layer and faster absorption rate of drug from GI-MAPS is obtained.
|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-MAPS 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.
The preffered target of new GI-MAPS is an anti-diabetic drug GLP-1 receptor
agonist. Phase III study on semaglutide tablet has been completed by NovoNordisc
where Eligen technology by Emisphere Inc. is used. Eligen technology gives
tablet formulated with 4 mg semaglutide and 300 mg absorption enhancer,
SNAC. Eligen technology has an absorption enhancing effect on semaglutide.
However, new GI-MAPS technology has advantage to Eligen technology, because
it maximumly elucidates the absorption enhancing effect by adhering to
GI tract, forming closed space and maitaining both drug and enhancer within
the same space. Higher BA is obtained.
|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
|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. New type GI-MAPS
is produced by a tableting machine. Production speed is higher and cost
is cheeper than old type GI-MAPS.
|BBioavailability (BA) of peptide/protein drugs
||BA in ratss
||BA in dogs
|interferon (IFN) alfa
||7.8 % (compared to sc injection)
** device method: GI-MAPS mimetic device was fixed onto the jejunum mucosa
Copyright BioSerenTach Inc, 2009