>> KLEPTOSE^® native and modified cyclodextrins: Multi-functional excipients for molecular encapsulation

To cover the specific needs of the pharmaceutical and cosmetic industry, Roquette has developed a range of KLEPTOSE^® products: β-cyclodextrins, hydroxypropyl β-cyclodextrins and methylated β-cyclodextrins.

Interest in cyclodextrins has sharpened over the past years leading to a strong market demand, and several pharmaceutical and cosmetic products containing β-cyclodextrins or their derivatives have reached the market successfully.

The versatile excipient

Cyclodextrins (CDs), native and modified, have the ability to form inclusion compounds through molecular encapsulation with a wide range of organic molecules. This ability makes the CDs and their derivatives valuable as formulation aids. They are used to increase aqueous solubility of poorly soluble drugs and consequently to avoid the use of organic solvents. Their use is, however, also of great interest for improving physical and chemical stability of drugs (protection against light, oxidation, etc.), for enhancing local tolerance of drugs and for any other applications where inclusion compounds would enable innovative solutions. Medicinal products containing cyclodextrins and their derivatives are world-wide marketed including, among others, oral, parenteral, topical and eye preparations.

Native cyclodextrins

CDs are cyclic oligosaccharides obtained from starch by enzymatic cyclisation using cycloglycosyltransferases. They are composed of α-(1,4) linked glucopyranose subunits. Several unsubstituted or native cyclodextrins exist; the most referenced ones being α-cyclodextrin, β-cyclodextrin and γ-cyclodextrin constituted of 6, 7 or 8 α-(1,4) glucopyranose units respectively. β-cyclodextrin (βCD) is the most accessible and useful one with a significant industrial usage. Roquette’s brand name for βCD is KLEPTOSE^®.

KLEPTOSE^®

The βCD molecule is a torus shaped ring. Due to the spatial distribution of its hydroxyl groups, the βCD molecule has a polar hydrophilic outside and an apolar hydrophobic cavity. As a consequence of this particular structure, βCD is, when in presence of water, able to encapsulate or entrap guest molecules to form the so-called inclusion compounds.

Figure 1: Chemical structure of β-CD

βCD is a crystalline, homogeneous, non-hygroscopic substance with a low aqueous solubility (approx.1.85% at room temperature). It is currently considered to be an essentially non-toxic and non-irritant ingredient, authorized for food applications and used in oral and topical pharmaceutical applications. Due to its nephrotoxicity, βCD is not suitable for parenteral applications.

Modified cyclodextrins

The native CDs can be chemically modified by hydroxyalkylation, alkylation or sulfoalkylation. The principal aim of such modification is to increase the solubility of the parent native cyclodextrins.

The hydroxypropyl betacyclodextrin (HPβCD) has the highest aqueous solubility (65% at 25°C) and combined with its safety profile it represents an ideal profile for pharmaceutical applications. The high aqueous solubility of modified cyclodextrins HPβCD allows extension of the applications as the method of preparation of the inclusion compounds is easier compared to native βCD (in aqueous solution versus in semi-solid state, “kneading method”). Most important is the safety profile of HPβCD: it is a suitable excipient for parenteral applications as well as for oral, topical and ophthalmic applications.

KLEPTOSE^® HPB / KLEPTOSE^® HP

Roquette has developed a range of substituted HPβCD with different degrees of substitution (DS = number of hydroxypropyl groups per molecule of βCD) as described by the Molar Substitution value (MS = average number of hydroxypropyl groups per anhydroglucose unit). KLEPTOSE^® HPβCD derivatives - KLEPTOSE^® HPB and KLEPTOSE^® HP - are suitable for the cosmetic and pharmaceutical industry, including a pyrogen free grade produced under cGMP conditions for parenteral applications.

Figure 2: Advantages of HPβCD for the pharmaceutical industry and patients

KLEPTOSE^® CRYSMEB EXP

The pioneering product, ROQUETTE’s KLEPTOSE^® HPB derivative, has now been successfully marketed and used for several years. KLEPTOSE^® CRYSMEB EXP is a second-generation product (under development at lab scale), which has several advantages including the possibility of increased solubilisation power while maintaining a high biological tolerance.

KLEPTOSE^® CRYSMEB EXP is a mixture of methyl βCD containing on average 4 methyl groups per native βCD molecule (i.e. a typical MS of 0.57). Due to its high aqueous solubility (20% at 20°C), it dissolves easily in water (unlike βCD), and solubility increases with temperature.

As with the KLEPTOSE^® HPB, the KLEPTOSE^® CRYSMEB EXP can be used in pharmaceutical applications with different aims:

• to increase water solubility and rate of dissolution of poorly soluble drug
• to increase the rate of transfer of a drug from solution into tissue without damaging the tissue
• to reduce side effects of active ingredients
• to reduce bitterness or unpleasant odour of some drugs.

KLEPTOSE^® CRYSMEB EXP can also be used in cosmetics for different aims, in particular for solubilisation or stabilization of ingredients.

Early preliminary toxicological information indicates that this methyl βCD shows potential for the development of injectable products and should be further investigated by formal toxicity studies.

Main applications and benefits

There are many potential applications of CDs and their derivatives in the pharmaceutical and cosmetics field. A non exhaustive list of main applications is given hereafter.

Pharmaceutical field:

• Increase poor aqueous solubility of drugs with subsequently increased dissolution rate and hence improved bioavailability
• Increase physical and chemical stability of drugs (increase shelf-life and reduce time to market)
• Enhance local tolerance after topical or oral administration
• Improve organoleptic properties of drugs (taste and/or odour masking)
• Enhance drug delivery to and through biological membranes)
• Prevent drug-drug , drug-excipient interactions and drug-container interaction
• Convert oily/liquid or volatile material into stable/microcrystalline powder
• …

Cosmetics field:

• Fragrance masking or release
• Delivery of specific substances
• Enhancement of UV filter activity
• Reduction of local irritation
• …
   

Table 1 : Key points of the KLEPTOSE^® range :

	KLEPTOSE®	KLEPTOSE®  HPB (medium MS, approx. 0.65)	KLEPTOSE® HP (high MS, approx. 0.85)	KLEPTOSE®  CRYSMEB EXP (Lab scale development for market evaluation)
Generic name	Betacyclodextrin	Hydroxypropyl betacyclodextrin	Hydroxypropyl betacyclodextrin	2-O-methyl betacyclodextrin
Grades	Standard DC (Direct compres-sion) Specific particle size (200F, 10)  And Specific moisture content (7PC)	Oral Parenteral (endotoxin controlled)	Oral Parenteral (endotoxin controlled)	Standard
Applications	Pharmaceutical, Cosmetics and Nutraceutical	Pharmaceutical and Cosmetics	Pharmaceutical and Cosmetics	Pharmaceutical and Cosmetics
Route of administration	Oral and Topical	Oral, Topical and Parenteral	Oral, Topical and Parenteral	Oral Topical and Parenteral (*)
Aqueous solubility	1.85% at room temperature	65% at 25°C	65% at 25°C	20% at 20°C
Complex preparation: common method	Semi-solid phase: kneading or “slurry” method	Liquid phase: in aqueous solution	Liquid phase: in aqueous solution	Liquid phase : in aqueous solution
Monographs	EP, USP, JPE	EP, USP	EP, USP	Roquette’s monograph
DMF	US	US and Canada	US and Canada	-
Food use status	ADI 5 mg/kg body weight	-	-	-
Patent , FTO	NA	Shiseido’s patent in cosmetic applications until 2009.   Worldwide Janssen’s patent in pharmaceutical applications expired in 2004 except in the US until 2019.		Patents secured by Roquette : production and pharmaceutical applications

 (*) Early preliminary toxicological studies tend to show the safety of parenteral use of KLEPTOSE^® CRYSMEB