Novel vitamin b12 - biodegradable micro particulate conjugate carrier systems for peroral delivery of drugs, therapeutic peptides/proteins and vaccines

Abstract

The invention relates to a novel complex for oral delivery of drugs, therapeutic protein / peptides and vaccines which are loaded in a Vitamin B2 (VB12) coupled particulate carrier system with spacers in between, the carrier system with spacers having a formula VB12-R' / R''-N wherein, R' or R'' is spacer and / or agents for derivatization of VB12 to provide either NH2 or COOH or SH groups, and N is the micro or nano particle carriers for the delivery of injectable drugs, therapeutic protein / peptides and vaccines.

Description

[0001] This invention relates to a complex for oral delivery of drugs, therapeutic protein / peptides, vaccines, which are loaded in Vitamin B.sub.12 coupled particulate carriers system with spacers in between. Typically, VB.sub.12 acts as ligand for endocytosis through intestine and the particulate systems will act as a cargo protecting the intestinal labile drugs to deliver them to systemic destination and / or to the specific site required.[0002] Although many peptide / proteins, pharmaceuticals and vaccines are currently administered by injection, this method of delivery has a number of disadvantages which has led the scientific community to strive to develop an alternative oral delivery system for these bioactives. The inherent limitations to parenteral delivery include (1) patient compliance (there is a need for repeated injections due to the short half-life of these molecules) (2) discomfort from this form of delivery caused by the need for repeated prolonged dosage regimen (3) hig...

AI Technical Summary

Benefits of technology

0136] Due to the fragility of the protein bioactives encapsulation was carried out through cryopreparation (cold temperature) and carbohydrate (lyophilization and osmotic balance-in emulsion). The typical procedure is out-lined for the PLGA polymer. 500 .mu.l (500 .mu.g) of hepatitis `B` surface antigen or 100-200 .mu.l 100IU insulin containing 80-100 mM trehalose was emulsified in 9-10 ml dichloromethane containing 100 mg PLGA by sonication for 10 seconds at 4-6.degree. C. The primary emulsion temperature was than lowered below the freezing point of inner aqueous phase (dry ice/acetone) and then emulsified

Problems solved by technology

Although many peptide / proteins, pharmaceuticals and vaccines are currently administered by injection, this method of delivery has a number of disadvantages which has led the scientific community to strive to develop an alternative oral delivery system for these bioactives.

The inherent limitations to parenteral delivery include (1) patient compliance (there is a need for repeated injections due to the short half-life of these molecules) (2) discomfort from this form of delivery caused by the need for repeated prolonged dosage regimen (3) highly variable bioavailability both within and between subjects for molecules such as subcutaneous insulin and (4) the non-physiological delivery pattern particularly of subcutaneous injections.

Further, small increases in actual drug delivered due to changes in dosage and / or mode of delivery may cause down-regulation of the desired response to most of these bioactives.

Apart from the problem described, parenteral vaccines are of limited efficacy due to the need for repeated vaccination and due to the fact that they elicit only humoral immunity.

The major delivery barriers common to these routes are (1) poor intrinsic permeability due to large size and hydrophilicity of the bioactive (2) enzymatic degradation in the hostile environment of GIT by lumenal proteases and cellular peptidases, unlike some of the traditional drugs.

1) Degradation of the above bioactives in the harsh environment of intestine and by gut proteases.

2) Their large size and hydrophilicity causes permeability problem across the intestine.

3) The fragility of these bioactives precludes to be formulated as oral dosage forms.

4) And finally their short in-vivo half lives.

However, such successful oral delivery of conjugates cannot be obtained with many other bioactives because of the limited uptake of VB.sub.12 (1 nmol / dose), the loss of bioactivity due to covalent linkage, loss of IF affinity of VB.sub.12 (steric factor) and finally the liability of such conjugates to GIT degradation.

However, the level of transport cannot be extended to other polymeric particulates in general.

Among all these approaches, there was some enhancement of delivery, but major break through of achieving therapeutically relevant dose delivery is not achieved.

1) Protein is not protected from degradation by proteases in gut.

2) All proteins cannot be coupled, as some protein bioactives may loose active molecular confirmation due to its coupling to bulky VB.sub.12 (steric factors).

3) Uptake of VB.sub.12 transport system (1 nano gram g / dose) is not sufficient for proteins which have very short half lives i.e. therapeutically relevant dose cannot be achieved.

However, pharmaceutically relevant oral delivery of many vitamin B12-pharmaceutical conjugates does not occur with many of these bioactives due to the limited uptake capacity of the VB.sub.12 transport system, loss of bioactivity of native protein during conjugation to VB.sub.12, loss of intrinsic factor (IF) affinity of the conjugates and finally due to the liability of the bioactives to GI degradation.

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