Production of peptides as generic drugs: a patent landscape of octreotide

ABSTRACT

Introduction: New low-cost strategies and enhancement of the already described methods to manufacture peptide molecules on an industrial scale are highly requested, particularly for peptides such as octreotide, which, along with goserelin and leuprolide, dominate the global peptide market. A number of patents related to the production of octreotide can be found, concerning both solution and solid-phase synthesis. Thus, there is a need to revise the existing synthetic approaches in order to organize them in a more comprehensible way.

Area covered: The octreotide patent landscape could help improvement of the methods for manufacturing of octreotide in industrial scale, leading to the appearance of innovative approaches.

Expert opinion: The pharmaceutical value of octreotide can be seen from its high market percentage among other peptide drugs. The complex chemical structure of octreotide represents the main challenge for its industrial production. Two synthetic steps are crucial in the preparation of octreotide: (i) threoninol attachment or on resin formation working in solid-phase and (ii) disulphide bond formation to achieve cyclic structure. Analysis of various patents filed to date allows us to see the trend in simplification of the synthetic approaches from the labor intensive syntheses in solution to the more versatile and rapid solid-phase methods.

KEYWORDS:

• Octreotide
• somatotropin release-inhibiting factor (SRIF)
• peptides manufacturing
• solution and solid-phase methods

Article highlights

• Thanks to a continue upgrading on peptide sciences (synthetic chemistry, solid support materials, purification technology, and biological drug delivery strategies) there are more than 60 FDA-approved peptide medicines on the market.

• Among the analogs of SRIF, octreotide remains the most widely used in clinical practice.

• Octreotide contains several structural features that contribute to a nontrivial synthesis.

• A number of disclosures related to the production of octreotide and its analogs can be found in the literature, and different methods of solution and solid-phase synthesis are often overlapping.

• The methods for octreotide synthesis suitable in bench scale often are not convenient for industrial production due to (i) the possibility of scale-up of the synthesis, (ii) the cost of raw materials, and (iii) time consumption.

• Despite the large number of approaches proposed for the large scale, the search and development of new cost-competitive and economically reasonable strategies for the synthesis of octreotide in industrial scale remain highly requested.

• We summarize various patents filed to date, in order to highlight the main trends and directions in which the synthetic strategies have been developed.

• This analysis could help further improvement of the methods for the manufacturing of octreotide in industrial scale and lead to the appearance of innovative approaches.

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Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.