Very low impurity Hydroxypropyl Betacyclodextrin (KLEPTOSE HPB-LB) complying with Chinese Pharmacopoeia from Roquette to Resolve Formulation Challenges

Divya Prabhudesai, M.Pharm and Heeshma Shah, M.Pharm, Ph.D. of Technical Services Department, Signet Excipients, Mumbai, and, and Amit Chivate, M.Pharm, Area Marketing Manager, Roquette India, Mumbai write about acceptable impurity levels of Hydroxypropyl Betacyclodextrin to ensure higher patient compliance and solution to address various formulation and registration challenges

Cyclodextrins (CDs) are cyclic oligosaccharides containing six (α-CD), seven (β-CD), eight (γ-CD) or more α-D-glucopyranoside units linked via 1->4 linkages.(1,2) These are obtained by enzymatic cyclization from starch using enzymes called cycloglycosyl transferases (CGTases). CGTases are usually classified into three subgroups (α-, β-, and γ-CGTases), which yield specific CDs, i.e., α-, β-, or γ-CDs.3 The most commonly used cyclodextrins along with their properties are listed in Table 1:(2,4)

Amongst these, β-cyclodextrin has significant industrial usage due to its adequate cavity size, efficient drug complexation and loading, ease of availability, and relatively lower cost.(5)

Roquette, a global leader in plant-based ingredients for pharmaceutical (polyols, starches and related excipients), nutraceutical and food industries offers betacyclodextrins and modified betacyclodextrins under the brand name KLEPTOSE® for pharmaceutical applications. The most commonly used species for producing β-CD are Paenibacillus macerans, Bacillus circulans, Alkaliphillic bacillus sp. and Bacillus agaradhaerense.3 However, the enzymes used by Roquette for cyclization are produced from Bacillus circulans.1 Both native and modified cyclodextrins have the ability to form inclusion complexes through molecular encapsulation with a wide range of organic molecules. This ability makes them a valuable formulation aid in enhancing the solubility and bioavailability of poorly soluble drugs, to improve the physical and chemical stability (protection against light, oxidation, heat, hydrolysis, etc.), for enhancing local tolerance and for masking bitter taste or odor of certain drugs.(6,7)

Roquette also offers KLEPTOSE® HPB and KLEPTOSE® HP, modified hydroxypropylated betacyclodextrins (HPβCD) having high aqueous solubility (65% at 25⁰C and 80% at 50⁰C) and biological tolerance. These are purified polydisperse products resulting from the controlled reaction of propylene oxide and native betacyclodextrin under base catalysis. HPβCD have reduced haemolytic potential and are also tested for endotoxins, making them suitable not only for oral applications but also for parenteral and topical applications. KLEPTOSE® HPB and KLEPTOSE® HP have molar substitution (MS) of 0.58 – 0.68 and 0.81 – 0.99, respectively which comply to the requirements of USP/NF and Ph. Eur.(8)

Structure and Mechanism of Action of HPβCD
HPβCD molecule has a torus-shaped ring structure with polar hydrophilic exterior and an apolar hydrophobic cavity. This structural feature is due to the spatial distribution of its external hydrophilic properties. Because of this structure, HPβCD encapsulates or entraps guest molecules to form so-called inclusion compounds when in aqueous solution.

The secondary OH groups on C-2 and C-3 are on the opposite edges, which give HPβCD its external hydrophilic properties. The inside of an HPβCD ring is composed of a surface of hydrophobic C-3 and C-5 hydrogens as well as glycosidic ether-like oxygen.6 The chemical structure of HPβCD is shown in Figure 1.

Launch of KLEPTOSE® HPB-LB Parenteral Grade
Roquette has recently added a new grade to the KLEPTOSE portfolio, i.e., KLEPTOSE® HPB-LB. The term LB in its name stands for LOW BETADEX (βCD) content. KLEPTOSE® HPB-LB has tighter specification limits for impurities and stringent molar substitution as depicted in Table 2. It is a multi-compendial product that complies with USP/NF, Ph. Eur. as well as with Chinese Pharmacopoeia (ChP).

KLEPTOSE® HPB-LB will help overcome registration filing challenges of pharmaceutical products in China as well as rest of the world, without the need to develop multiple drug solutions.(9)

The lower level of impurities particularly BETADEX (βCD) (more stringent than the ChP requirement) indicates Roquette’s commitment to patient compliance. This allows the formulators to use higher amounts of KLEPTOSE® HPB-LB in the formulations thus resolving many solubility challenges and regulators to ascertain safety of the patients.

Value added benefits of KLEPTOSE® HPB-LB Parenteral grade are for R&D and Supply Chain:9

Research and Development

• Multi-compendial with compliance to China Pharmacopoeia (ChP), accelerating entry into China and other global markets
• High water solubility, enabling delivery of molecules in small volume parenteral dosage forms
• Low viscosity: 20 cP at 20°C, and use up to 40% HPβCD: ideal for injection, especially subcutaneous
• Endotoxin controlled, making it suitable for parenteral applications
• Encapsulation process versatility

• Encapsulation efficiency for a wide range of molecules for solubility enhancement and stabilization against light and oxidation

• Stability at high temperature allowing terminal steam sterilization
• Stability at hydrolysis over a wide range of pH, enabling formulation of acidic and alkaline actives without affecting their stability 
• Extensive toxicological data, reducing challenges of regulatory filings for various dosage form and routes 

Supply Chain

• Production and quality systems following GMP regulations, thereby ensuring no material rejections
• Fiber-free packaging, with tamper-proof evidence, allowing authenticity of quality
• Enhanced packaging with recyclable materials, thereby displaying commitment towards sustainability 

Conclusion

Roquette is an innovator in the development of cyclodextrins with its KLEPTOSE® range of βCDs and HPβCDs. They provide an extensive toxicological data for this range for various routes of administration, which help in developing safe and efficacious pharmaceutical products.6 The introduction of KLEPTOSE® HPB-LB parenteral grade product to the portfolio is an effort to provide higher patient compliance and solution to address various formulation and registration challenges.

References

1. Technical Brochure of Kleptose: Betacyclodextrins and hydroxypropyl betacyclodextrins. France: Roquette Frères S. A., 2006.
2. Brewster M, et al. Cyclodextrins As Pharmaceutical Solubilizers. Advanced Drug Delivery Reviews 2007; 59(7); 645-666.
3. Arce-Vázquez MB, et al. Integral Use Of Amaranth Starch To Obtain Cyclodextrin Glycosyltransferase, By Bacillus Megaterium, To Produce β-Cyclodextrin. Frontiers in Microbiology 2016; 7; 1-11.
4. Chaplin M. Cyclodextrins. Water Structure and Science 2019.
5. Gidwani B, et al. A Comprehensive Review on Cyclodextrin-Based Carriers for Delivery of Chemotherapeutic Cytotoxic Anticancer Drugs. BioMed Research International 2015; 1-15.
6. Blouet E. A New Multi-Compendia Modified Beta-Cyclodextrin, KLEPTOSE® HPB-LB Parenteral Grade. ONdrugDelivery Magazine 2019; 97; 12-15.
7. Kumar A, et al. The Cyclodextrins: A Review. International Journal of Pharmaceutical Research and Bio-science 2013; 2(2); 291-304.
8. Technical Brochure of Kleptose HP / Kleptose: Multifunctional excipients for molecular encapsulation. France: Roquette Frères S. A., 2007.
9. Technical Brochure of Kleptose HPB LB Parenteral Grade: A multi-compendial excipient for efficient drug delivery. France: Roquette Frères S. A., 2019.