Cyclodextrin (CDs)

Cyclodextrin (CDs) is a kind of cylco-Oligosaccaride. It is also the most steady  and popular molecule microcapsule materials in recent time, It is natural and made from natural starch.   The conformation of the glucose units in the cyclodextrin places the hydrophilic hydroxyl groups at the top and bottom of the three dimensional ring and the hydrophobic glycosidic groups on the interior.So the outer side of bucket keeps strong hydrophile characteristics, the inner side of bucket keeps hydrophobic characteristics. Just because of the unique bucket’s hydrophilic characteristics of outter side and hydrophobe charaacteristics of inner side, it can entrap many kinds of guest moleculesin their internal, particularly to entrap oil form substance and form inclusion complexes.  If the guest substance included by cyclodextrin to form inclusion complexes, the stability and solubility  increase obviously ,  and volatility reduced a lot. Depending on it’s unique characteristc, CD is widely applied in the fields of pharmaceuticals industry, food industry, cosmetics industry and  household chemicals,light industry,agricultures etc.  

I   Hydroxypropyl-Betacyclodextrin　（HP-BCD）

Hydroxypropyl beta-cyclodextrin (HP-BCD) is produced from beta-cyclodextrin (BCD) by addition of propylene oxide to some of the hydroxyl groups of BCD. This modification results in greater solubility of HP-BCD and its complexes compared to BCD. Therefore, HPBCD is used in applications where the solubility of BCD is not sufficiently high and in applications where faster dissolution rates are needed. Other benefits obtained by complexation with the basic BCD, such as protection against chemical degradation and volatilisation are retained by the HP-BCD. HPBCD, in dry form or in solution, is applied in a wide variety of compounds in diverse applications such as pharmaceutical, personal care/cosmetics, diagnostics, chemical processing and many more.

Description

• Chemical Structure

Hydroxypropyl beta-cyclodextrin (HP-BCD) (CAS 94035-02-6) is a partially substituted poly (hydroxypropyl) ether of beta cyclodextrin (BCD). The empirical formula is:

(C₄₂H_70-nO₃₅) (C₃H₇O)_n

It contains not less than 10.0% and not more than 45.0% hydroxypropoxy (-OCH₂CHOHCH₃) groups. The structure is shown below where R represents either hydrogen or a hydroxypropoxy group.

where R= CH₂CHOHCH₃) or H

The basic closed circular structure of BCD is maintained in HP-BCD.   The glycosidic oxygen forming the bond between the adjacent glucose monomers and the hydrogen atoms lining the cavity of the cyclodextrin impart an electron density and hydrophobic character to the cavity. Organic compounds interact with the walls of the cavity to form inclusion complexes. The hydroxyl groups and the hydroxypropyl groups are on the exterior of the molecule and interact with water to provide the increased aqueous solubility of the HP-BCD and the complexes made with the HP-BCD.

Degree of substitution

The hydroxypropyl groups are randomly substituted onto the hydroxyl groups of the cyclodextrin and the amount of substitution is reported as average Degree of Substitution (DS) or number of hydroxypropyl groups per cyclodextrin and is the preferred manner of describing the substitution. An alternative measurement is Molar Substitution (MS) or the average number of substitutions per anhydro glucose unit in the ring of the cylcodextrin. Molar substitution is used with polymers whose molecular weight is not determined or contains a mixture of polymers of different degrees of polymerisation.

Substitution occurs randomly with respect to which hydroxyl groups and which glucose units are modified. There is a distribution around the average degree of substitution of the number of hydroxypropyl groups per cyclodextrin, with some molecules having more than the average and some less than the average degree of substitution. The result is a mixture of many molecular species with respect to the number and location of substitutions around the ring of the cyclodextrin. The reaction to produce HP-BCD is highly controllable and repeatable, so the product is consistent from batch to batch.

Substitution can have an effect on the binding of guests to the HP-BCD. At low degrees of substitution, binding is very similar to that of the unmodified beta-cyclodextrin. Increasing substitution can lead to weaker binding of the guest due to steric hindrance. The effect is dependent upon the particular guest. It is even possible to obtain increased binding as a result of an increase in surface area to which the guest can bind. With most guests, these differences in binding at different degrees of substitution are small, if detectable at all.

Applications

• Improving the solubility of drugs.Insoluble drugs including Chinese herbal medicines might be turned into injections by the derivatives of cyclodextrins.

• Improving the bioavailability of drugs.For example,effectively control release oral dosing of injection of 5-fuorocarbamidopyrimidine might be prepared with an improved bioavailability,which might bring in a decreasing of the dosage but an increasing of the curative effect.On the other hand,an injection could be worked on the patients who haven't any go-aheadism.

• Adjusting or controlling the releasing of the drugs.For example,lasting effective dosings of VA,VE,VD,VK,testosterone and progesterone etc might be made with an improved stability.

• Decreasing the toxicities of the drugs.For example,to decrease the haemocylolysis of the drugs.The stimulating to eyes or nasal cavities of the related drugs cold also be decreased.

• Improving the stabilities of the drugs.For example,to prevent the volatilization,sublimation,oxidation decomposition etc.

• Concealing or rectifying the badness odor of testing.

• Improving the synthesis effects as well as qualities of the drugs by chiral selective catalysis of cyclodextrin derivatives.It is very important for a chiral structure in drugs.

• Constructing stational chiral phases for the separation of isomers of drugs.

• Exploring molecular probes for examining differentiation of gene etc.

• Looking for new drugs or new coordination materials by more proper modifications of cyclodextrions.

• The recent work shows that HP beta CD etc could also accelerate the permeable absorption of the drugs of Testosterne etc.

• Cyclodextrin derivatives not only could play an important role in drugs and related field,but also could play an important role in cosmetics,foods and spices etc based on the structures of cyclodextrin derivatives.

Hydroxypropyl Beta Cyclodextrin  (HP-BCD)  Properties:

HP-BCD retains the properties of β-CD on the whole. But HP-BCD still has some different properties, for example:

1、HP-BCD is in normal temperature water-soluble is very high, about over 50%, so it can't crystalize in alcohol.

2、The selectivity of held matter of HP-BCD is different from β-CD, it probably is changed for some matter holding molecular proportion.

3、HP-BCD neither is resolved and metabolized nor accumulate on the whole, HP-BCD is taked orally that the majority excrete to outside the body with the excretion, the majority will be excrete to outside the body with the urine if the medicine is not absorbed by bowels.

4、HP-BCD can promote held matter to release quickly in organism.  

5、The suerface activation and haemolysis activation of HP-BCD are low than B-CD or other derivative,the usage is more safety.  

HP-BCD contains above-mentioned pioperties, therefore it suffers the extensive concern in the medicine field more and more. In order to strengthen people understanding the application aspect of HP-BCD, and below illustrate with example:

1、In the aspect of increasing water-soluble of insoluble medicine. For example, Dihydroartemisinin and Artemether are all insoluble in water. After holding by HP it's solubility can reach to the standard of Injection power. The solubility of Digoxinum which in the 50% HP solution increases from 0.07mg/ml to 68mg/ml.

2、In the aspect of increasing medicinal stability. For example, after  estradiol is hold by HP-BCD, taking it in room temperature, its degradable half-life extends from 1.2 years to 4 years.

3、In the aspect of dropping medicinal harmful side effect. For example, We can use HP-BCD to make the injection, and then make intramuscular injection, this way can make the absorption of living thing for medicine to obviously increase, and alleviate the harm for stomach and intestines or muscle.

4、In strengthening medicine bioavailability  ratio respect.

5、In the safety of HP-BCD respect. According to systermatic subacute and chronic toxicity research certificate, HP-BCD neither leads to disease nor leads to death for samll mouse. After the rabbit is intravenous injection, HP-BCD is run off from the blood at once, and it will be excrete to outside the body with the urine, continuous injection hasn't bad symptoms too. For mouse and monkeys intravenous inject 200mg/kg of HP-BCD, it will hasn't clinical influence. The dosage of oral taken or intravenous injection HP-BCD is 15g/kg or 10g/kg respectively, it doesn't lead to death for monkeys, too. Human beings' clinical research makes known to oral taken, intravenous infusion, intravenous injection, nasal cavity, under the tongue and eyes for HP-BCD, doesn't show bad reaction and irritant for eyes and muscle. Thus it can be proved that HP-BCD is very safety for living thing.

It will be safe absolutely if accords to following method to use HP-BCD:

The applicative method and dosage of HP-BCD for human body:

1、Intravenous infusion Total weight of application: 30g Method of application: 5% continuous uses 4 days

2、Intravenous injection Total weight of application: 3g Dosage: 150mg/kg Method of application: 5% continuous uses 4 days

3、Oral taken (percent) Total weight of application: 0.2g/kg Dosage: 0.2mg/kg Method of application: pill

4、Nasal cavity Total weight of application: 600mg/day Dosage: 40mg/day Method of application: 10% aqueous solution

5、Oral cavity under the tough Total weight of application: 120mg/kg Dosage: 120mg/kg Method of application: pill

6、Skin Method of application: 45% aqueous solution

HP-BCD hemolysis actived and surface actived is low, it isn't irritant for skin and muscle, even if the consistency of HP-BCD get 100mg/ml, to inject for muscle,it is irritant, too. In these aspect, HP-BCD is better than other solutizers.

To sum up HP-BCD is the best medicine carrier certainly in the present.

Applications    

　 The application directions of Hydroxypropyl-beta-cyclodextrin:

Hydroxypropyl-beta-cycoldextrin is abbreviated to HP-BCD or HPB,it is hydrogen atom which is in the remains of glucose in β-CD 2-, 3- and 6-hydroxl, is replaced hydroxypropyl-oxygen by HP.

HP-BCD, as β-CD, to many other chemical compounds, not only has fine holding action, which develop dissolubility of held matter, also has the advantages of high water-soluble, improvement the release speed of held medicine in the organism and high biological stability . HP-BCD not only getting to safety properties is wide-ranging but also is a medicine subsidiary material what it hasn't harmful side effects 　 　

 HP-BCD Caution:  

1、HP-BCD is easy dissolved in water oneself. In room temperature, solubility＞50g/100ml, even to get over 80g/100ml. When its consistency is ＜40%, it flows very well, not sticking. After medicine and HP-BCD form compound matter, medical consistency of raise and HP-BCD of consistency of raise are linear relationship.

2、When HP-BCD or HP-BCD of medical compound matter was made aqueous solution, produced a volume expansion obviously, their volume expansion are about 1ml/g below low consistency (＜50% w/v). When the consistency ＞20% (w/v), the volume expansion is about 0.7ml/g.

3、HP-BCD is soluble in methanol and ethanol, this situation for raising medical holding provided extensive chance. Usually HP-BCD and medical holding is in a ratio (w/w) of 10-20 to 1 (their ratio can enlarge 30-40 to 1 under some situation), using above-mentioned the technology of raising solubility, HP-BCD of dosage reduced 7-8 to 1 obviously (or 20-30 to 1).

4、HP-BCD aqueous solution is steady for high pressure sterilization temperature and pressure of influence, and 45% (w/v) of HP-BCD aqueous solution can be filtrated by 0.2μ of filter to kill germs below low temperature.

5、HP-BCD is idea medicine that it conquers to universally existent questions in biology products.

In the aspect of HP-BCD increasing medical stability, raising the medicine (can't soluble in water) of solubility, reducing medical irritability for people, raising medical biology utilization ratio as so on, it will bring about important effect. So HP-BCD has a vast range of prospects of development.

　 The commonly used method for HP-BCD holding medicine (or other matter): 　 　

1、Ingredient

a) If the holding matter is water-soluble matter, you will can according fixed proportion to be soluble  in water.

b) If the holding matter isn't water-soluble matter, you will can solubilize holding matter in ethanol、methanol or soluble solvent for holding matter. In addition, when HP-BCD solubilizes in water or alcohol, according to fixed proportion to solubilize each other or mix.

2、Promoting the method of holding reaction (the following handling method, you'd better adjust the temperature higher, it's gradually getting low temperature in the course of the handling.)

a) Taking above-mentioned mixed solution, to stir high speed in room temperature or low temperature.

b) Given above-mentioned condition to treat by ultrasonic wave.

c) Given above-mentioned to grind by milling .

d) Using above-mentioned high pressure (or low pressure) starch.

3、Holding compound matter of drying

The specimens which are after holding and handling can adopt, reduce pressure to dry beside then shatter.

4、Holding compound matter of examination

You can adopt fluorescent light spectrum law to test holding matter how to form normal number, in addition, you can also adopt NMR law to analyze HP-BCD for certain matter of holding information.

5、Holding matter of releasing and picking up.

a) Under the normal situation, holding compound matter is basic steady. In water solution, it usual isn't released by insoluble holding matter in water. But there are some holding matter are fit for HP-α-CD or HP-γ-CD, their stable constants are lower after they and HP-BCD formal holding compound matter, so if they are taken in aqueous solution for long time, holding matter is released of its own accord from HP-BCD, too, and it will form some sediment in water.

b) When holding compound matter is in water solution, it makes holding water-soluble matter enlarge released speed and released measure with the temperature of going up, under the suitable condition making released matter consistency and holding matter consistency  by HP-BCD get to balance.

c) Holding compound matter can be extract again and again by some organic solvent (it will be best solvent which is HP-BCD can't be dissolve.) the method can make holding matter to be extract.

All kind of above-mentioned holding principle, holding compound matter of character, just for HP-BCD reference. You can choose different handling methods to different quality of matter. Even if the same handling method, they still get different holding effect possibly for handling temperature, solution consistency, long or short handling times, handling intensity.

We hope that the users can according to holding matter of quality to choose suit handling method and holding condition, so that it make to get the best holding effect. If you need to help for usage technology, our company of technology department will assist to solve with all our strength. 　 　

II  Alpha+Beta+Gama Mixed cyclodextrin (K50)

     The usage of mixed cylcodextrin is similar to other cyclodextrin, it and mainly can be applicated into food industry, and solves the problem of requiring part of alpha-cyclodextrin. and keeps better water solubility problem of betacylcodextrin.

III 　Betacyclodextrin ( BCD), or Betadex  

Beta-cyclodextrin is a non-reducing cyclic　saccharide　consisting of seven α-1,4-linked D-glucopyranosyl units. Theproduct is manufactured by the action of the enzyme cycloglycosyltransferase　(CGTase) obtained from Bacillus circulans,
Paenibacillus macerans or recombinant Bacillus licheniformis　strain SJ1608 on partially hydrolysed starch.other name is Betadex, or chemical name is Cycloheptaamylose.