Insuline micronized tablets
Mohammed Mahmoud Shawky Kassab,molecular biologist and specialist of phramacology and toxicology,faculty of pharmacy Cairo university
Abstract
Insulin is essential for the treatment of Diabetes mellitus.Insulin subcutaneous injection has many side effects such as pain at the site of injection and microbial contamination.Insulin is degraded by proteolytic enzymes.Micronization process like Jet or bead milling was used to make micronized particles of insulin less than 50 micron which resulted in more drug solubility and better absorption through biological and physiological membranes of human body.
The 2 Insulin subunits were composed of D amino acids which were not affected by proteoltytic enzymes.Bioadhesive drug such as polyacrylic acid was added to the film coated micronized insulin tablets.It prolonged the retention time of the drug in GIT.This resulted in better bioavailbility of the drug.In our study also, micronized Insulin sublingual tablets were designed which were able to avoid the first pass effect and showed better bioavailability.The test insulin was tested on animal models and compared with standard subcutaneous insulin for efficacy.The test insulin was approximately 80-90% efficacious as the standard one.
Introduction
I-pancreatic hormones
The endocrine portion of the pancreas islets of langerhans consists of different cells that secrete differsnt peptide hormones:
1- Insulin from beta cells
2- Glucagon from alpha cells
3- Somatostatin from sigma cells which locally regulates insulin and glucagon secretion and pancreatic polypeptide .(1)
II-insulin
Insulin is a small protein, with a molecular weight of about 6000 Daltons. It is composed of two chains held together by disulfide bonds. Pharmacological actions of insulin
Insulin has anabolic actions,it favors glucose uptake and storage by many tissues as well as protein production by increasing uptake of amino acids by cells and by increasing ribosomal activity.(2)
Insulin Delivery Systems
1
The standard mode of insulin therapy is subcutaneous injection using conventional disposable needles and syringes.
Disadvantages of insulin injection
1-Pain
2-Lipodystrophy at the injection site.
3-Nerve damage
4-Thermolabile
5-microbial contamination during injection(3)
These drawbacks could be overcome by using new oral delivery systems containing stable modified insulin designed by peptidomimetics which improved physicochemical characters of insulin.
Methodology
1. Chemical synthesis of two insulin subunits using D-amino acids which are synthesized chemically and are not affected by proteolytic enzymes in the gastrointestinal tract(GIT).
2. Linking the the two subunits of insulin together through disulfide bonds by incorporation of L-cysteine residues adjacent to each other in polypeptide molecules.
3. Micronization process like jet or bead milling was applied to make micronized particles of insulin less than 50 micron which resulted in more drug solubility and better absorption through biological membranes of human body, then formulation of oral micronized insulin film coated tablets which contain:
A. Bioadhesive drug such as polyacrylic acid to localize the therapeutic drug delivery in GIT along its sustained release and as a consequence,increases the retention time of insulin in GIT, prolongs the duration of action of insulin and minimizes its side effects due to non specific targeting.This also,allows maximum absorption of the drug with improving the bioavailbility and the efficacy of insulin.
B. Protease inhibitor such as Bowman-Birk soybean extract which inhibits trypsin and chymotrypsin proteolytic enzymes.
4- formulation of sublingual tablets of micronized insulin to avoid the first pass effect and the degradation in GIT.
5- Screening and bioassay of test insulin via doing rabbit glucose method and mouse convulsion method using two and two dose assay technique. Results and discussion
The test micronized insulin in both drug delivery systems which include film coated tablets and sublingual tablets was approximately80- 90% effective and efficacious as the standard drug.
1.Film coated micronized insulin tablets:
2
For screening and bioassay of insulin film coated micronized tablets containing graded doses of insulin from 1 to 10 mg which is physically stable with protease inhibitor and bioadhesive additives,we found after applying that the lowest effective dose which reduced normal rabbit blood glucose from 0.1% to .044% was 2.8 mg of insulin .For bioassay only of film coated micronized tablets containing graded doses of
insulin ,the mouse convulsion method using 2 and 2 dose assay was applied on fasting mice for 24 hours .It showed that 75% of mice suffered from convulsion due to the hypoglycemic effect of insulin starting from dose 2.6 mg of insulin in comparison to 1.5 mg of gliclazide as standard hypoglycemic drug .In both experiments the hypoglycemic effect was shown after2- 3 hours and the duration of action of insulin was 4-6 hours.This suggested that chemically synthesized insulin of D- amino acids improved its physicochemical properties.Film coated micronized insulin tablets using peptidomimetics could overcome a lot of the disadvantages of subcutaneous insulin injection.
2. sublingual insulin tablets:
For screening and bioassay of sublingual micronized insulin tablets containing graded doses of insulin from 1 to 10 mg which is physically stable,it was found that the lowest effective dose which reduced normal rabbit blood glucose from 0.1% to .041% was 2.7 mg of insulin .For bioassay only of sublingual micronized insulin tablets containing graded doses of insulin ,the mouse convulsion method using 2 and 2 dose assay was applied on fasting mice for 24 hours .It showed that 75% of mice suffered from convulsion due to the hypoglycemic effect of insulin starting from dose 2.3 mg of insulin in comparison to 1.5 mg of gliclazide as standard hypoglycemic drug .In both experiments the hypoglycemic effect was shown after2- 3 hours and the duration of action of insulin was 4-6 hours.This suggested that chemically synthesized insulin of D- amino acids in sublingual drug delivery system improved its physicochemical properties.This could overcome many of the drawbacks of subcutaneous injection of insulin.
Conclusion
Our study was a promising approach to solve many of the side effects of subcutaneous insulin injection route such as pain,nerve damage,microbial contamination and lipodystrophy at the injection site. In the fututre,We recommend that studying new approaches to improve physicochemical properities of insulin using genetic engineering to improve efficacy and minimize the side effects of the drug.
References
3
1-Parveen Kumar(2017).Kumarm,Clarks clinical medicine.Ninth edition,Elsevier Edinburgh London.
2-Caroline S,Zeind Michael G(2018).Applied therapeutics,the clinical use of drugs.Eleventh edition,Wolters Kluwer, London
3-Parveen Kumar(2017).Kumarm,Clarks clinical medicine.Ninth edition,Elsevier Edinburgh London.
