Applications

Barbiturates
The b - cyclodextrin induced circular dichroism have been used to assay commercial sodium secobarbital suppositories without a prior purification step. 

Diazapines
A fast dissolving form of benzodiazapines with a high aqueous solubility is desirable for rapid absorption in oral benzodiazapine therapy. Because the dose is only a few mg, cyclodextrin complexation is obvious for the acceleration of the in vivo absorption..The achiral diazapam shows induced circular dichroism in cyclodextrin solutions

Phenothiazines
Complexation -with b-cyclodextrin is effective against the harmolytic, tissue damaging side effect of chloromazine , while the blood level values, and the central nervous system effects remained practically unaltered.

Non-Steroid antiphlogistics
Among the non-steroid antiphlogistic, antipyratic and analgesic drugs anilin-, pyrazolidon-, N-phenylanthranilic, salicylic and phenylacetic acid derivativesmay be complexed with b-cyclodextrin. Indomethacin azapropazone, phenylbutazone, ibuprofen, ibufenac, ketoprofen, flufenamic acid, mefenamic acid, flurbiprofen,pirprofen, fenbufen, fanamates etc., are other examples where the drug dosages can be reduced and bioavailability increased. Also some bitter taste in few cases can be reduced.
The anti- inflammatory activity of the b -cyclodextrin-complexed piroxicam is more than 2 fold better than that of the free drug [27a]. Pirprofen complexed with cyclodextrin reduces the irritating sensation in the throat and increases its solubility in water and also makes it more stable.

Steroids
The release of betamethasone from the ointment is considerably improved by b-and g-cyclodextrin .The blood level of medroxyprogasterone acetatein in a b-cyclodextrin complex is improved. Corticosteroid-17 a-monoesters are unstable and may undergo an acyl-group migration to the corresponding 21-monoesters. The half life of betamethosone-17-valerate, which is available in various formulations for topical applications in some extemporaneously diluted ointments, is only few hours. It rearranges to the much less active 21-valerate. Complexation with Cyclodextrin improves the bioavailability of all the above considerably.
Fluoromethalone-b-cyclodextrin complex along with boric acid, borax and benzalkonium chloride increases the stability of the eye-drop.Spironolactone is a steroidal aldosterone antagonist that has been widely used in the treatment of essential hypertension, edematous states, and primary hyperaldosteronism. Because of its low solubility in water,
the bio-availability and dissolution rate increases manifold in a b-cyclodextrin complex. Prednisolone is a potent, therapeutically important synthetic corticosteroid mainly used for its anti-inflammatory activity in a wide spectrum of diseases. Its cyclodextrin complex increases the solubility/bioavailability. Bufadianolide derivatives show increased stability, and are less toxic when complexed with b-cyclodextrin. From a cholic acid- b-cyclodextrin- complex, injectable solutions can be prepared. The enhanced percutaneous absorption of cyclodextrin-complexed steroids can be utilised in the preparation of pressure sensitive adhesive tapes. Administering steroids (sex hormones) complexed by hydroxypropyl- b- cyclodextrin- as sublingual tablets, the bio - availability can be considerably enhanced.

Other central nervous system drugs
Femoxetine HCL, a selective seroton in uptake inhibitor with anti depressent properties, possesses a very bitter taste. This is eliminated to a very great extent by its complexation with cyclodextrin. The stability of ¦2 -otetrahydrocannabinol is strongly improved by b-cyclodextrin complexation. The stability of the anticholinergic propanthaline bromide can be improved with cyclodextrins. Phenytoin is an antiepileptic drug which, on account of its poor solubility, results in incomplete, and unpredictable absorption. Its solubility and bioavailability can be considerably improved by b-cyclodextrin .The chloral hydrate b-cyclodextrin complex has been suggested as an analgesic sedative Stability and solubility of dantrolene, Na, a muscle relaxant, may be improved by b- cyclodextrin-complexation, making possible the preparation of parenteral formulations. Solubility may be enhanced, and the bitter taste reduced, by complexing the antiepileptic Ca-hopantenate with b-cyclodextrin.

Cardiac glycosides
The oral bio-availability of Bufadienolide e.g. resibufogenin, bufatrienolide e.g. proscillaridin homo-oxacardenolide and the digitalis e.g. digoxin cyclodextrin complexes, can be considerably increased. Digoxin and its derivatives form very stable complexes with b-and -g cyclodextrin.The presence of cyclodextrin protects digoxin against acidic hydrolysis.

Organic nitrates
Organic nitrates are important drugs, particularly in treating or preventing angina pectoris. These compounds, e,g. nitroglycerin, are dangerous explosives and of limited stability even in a highly diluted form. In b-cyclodextrin complexed form, e.g, nitroglycerin content of the complex is 15.6%, they are entirely blast proof and cannot be detonated even with an initiator The b-cyclodextrin complexes of isosorbide-dinitrate isosorbide-5- mononitrate and triethonolamine trinitrate have been reported. The preparation of an isosorbide-dinitrate b-cyclodextrin complexes is also a purification process the isosorbide-dinitrate b-cyclodextrin complexes can be isolated from the reaction mixture, whilst the more hydrophylic byproducts remain in solution.

Anti diabetics
The enhanced bio- availability suggests the possibility of administration of smaller doses of Acetohaxamide b-cyclodextrin complexed drug.
Cyclodextrins and the cyclodextrin-producing CTG-enzyme may be used as components of blood sugar reducing compositions an unusual utilisation of cyclodextrin is represented by the preparation of moranoline derivatives. The CTG-enzyme splits the cyclodextrin ring, and in presence of moranoline,HCL produces glycosylated moranoline derivatives. The product, a maltohexo-, hepto- or octaosyl chain containing moranoline,may be useful in the control of blood sugar increase.

Anti lipemics
Cyclodextrin complexation of the blood cholesterol lowering agent, clofibrate,which is an oily liquid, significantly improves the Volatility, photosensitivity and bitter taste. The dissolution rate and adsorption of the hypolypemic HCG-497 (= N,N-dimethyl-2-chloro-5-[3-methyl-2-phenylamino-]-4-thiazolin-4-yl-phenyl sulphonomide) are enhanced by complexing with b-cyclodextrin.The bioavailability of b-cyclodextrin complexed p-hexadecylaminobenzoic acid may be slightly better than that of the free drug . The blood cholesterol lowering safflower oil, extracted from Carthamus tinctorius, hasbeen stabilised by b-cyclodextrin. Because hardly digestible saccharides reduce fat absorption, cyclodextrins were suggested as antilipemic components of the meal. Elcosapentnenoic acid or docosahaxaenoic acid, contained naturally in liver oil and the body oil of blue fish such as sardines, mackerel etc., have the ability to reduce the cholesterol level in human serum. The fish and also the isolated fish oil have a specific odour that some people cannot tolerate. Moreover these highly unsaturated fatty acids are very sensitive to air oxidation. The consumption of b-cyclodextrin complexes of these fatty acids is recommended, the unsaturated fatty acid content is 9-12% by weight

Vasodilators
Bencyclane, an anticonvulsent and vasodilator drug used clinically for improvement of syndromes accompanying the obstruction of brain blood flow, is intolerably bitter and unstable at acidic pH. Cinnarizine, an agent for increasing cerebral blood flow, has very low water solubility. Its 1:2 b-cyclodextrin complex, (cinnarizine content l4.1%), is very stable The enhancement of solubility of a new cerebral vasodilator, vinpocetine (Cavinton) was improved by spraying-drying its aqueous b-cyclodextrin solution. The dissolution rate of the vasodilator suloctidil may be increased and its bitter taste was totally eliminated by complexing it with b-cyclodextrin. Complexation improves the wettability, dissolution rate, stability and bioavailability of the drug Fendiline. The ubiquinone-10 (ubidecarenone, coenzyme Q 10) is a cardiotonic agent for treatment of angina pactoris. Its stability and solubility is improved by cyclodextrin complexation

Blood anticoagulants, interferon
Interaction between coumarin anti coagulants, and cyclodextrins or dimer coumarin derivatives (dicoumarol) complex of b-cyclodextrin improves the stability and oral bioavailability. The blood platelet aggulatination inhibiting effect of acylated indol derivatives can be used in oral preparation after improving its dispersibility and absorption by b-cyclodextrin-complexation. For carbostyril derivatives a-cyclodextrin was found to be the most appropriate complexing agent. Utilisation of cyclodextrins may be recommended in the production and stabilisation of interferons.

Antitumour agents
Various aromatic aldehydes are found to be effective antitumour agents. All of them are rather sensitive to light and atmospheric oxygen, therefore protection by cyclodextrin complexation will result in better formulation properties, and minimise the unfavourable side effects in the digestive tract.
A salicylaldehyde-b-cyclodextrin complex and Benzaldehyde b-cyclodextrin complex, the preparation of cyclodextrin complexes of 3.4- dihydroxybenzaldoxime, 1.2-Dimethyl-4-formyl-cyclohexane, diethylamino-methyl-benzaldehyde derivatives, benzaldehyde benzo/dialdehydoximes, 3-tiophen-carboxaldehyde various acetal-derivatives of benzaldehyde, and diethyl- aminoacrolein derivatives diethyl-carbamoil-are some examples. A b-cyclodextrin complex of the anti tumour 1.3-bis (2-chloroethyl)-1-nitrosourea retards the decomposition.
Cyclodextrin complexed 5-fluorouracil and its derivatives are promising antitumour agents For example cormoful (1-hexyl- carbamoil-5-fluorouracil, HCFU), one of the masked compounds of 5-fluoro-uracil, has been widely used in the treatment of cercinomas of breast and gastrointestinal tract. Its low solubility and chemical instability in water have however limited the dosage and delivery design
The antitumour all trans-3, 7, 11, 15-tetramethyl-2, 4,6, 10, 14-hexadecapenta- eonic acid can also be protected against oxidation by cyclodextrin complexation. Sulphate esters of 6-deoxy- or 5-carboxy-a-cyclodextrin are shown to have complement inhibiting activity. An immunsuppresive drug could be developed from such derivatives. Antibiotics stabilisation of crystal structure at thiamphenicol reduction of local irritating effect of tiamulin reduction of toxicity of polyether-type antibiotics (e.g. monensin) , enhancement of solubility and stability of chloramphenicol, colistin , AM-715 [ 152 ] (a new antibiotic), etc. Are some such benefits derived from cyclodextrin complexation.. Streptomycin was found to be more effective as a plant-protecting agent after complexing with cyclodextrin. Ampicillin is incompletely absorbed, and the unabsorbed drug within the lower part of the gastrointestinal tract can alter the microbial flora. This
May lead to diarrhae, and a total, and rapidly absorbed formulation is therefore required. Methicillin is liable to rapid hydrolysis in the stomach, which restricts its oral administration. In the presence of b-cyclodextrin the solubility, and bioavailability is improved for both drugs, and their acid hydrolysis is strongly reduced Lankacidin group antibiotics, lankacidins A,C, lankacidinol, lankacyclinol, and their derivatives, are produced by different microorganisms. They are potent drugs, mainly against swine dysentry, but also possess anti tumour activity. Adding cyclodextrin to the fermentation broth, the yield is strongly enhanced (see in 6.3). Its solubility is enhanced about 15 fold in b- and g-cyclodextrin solutions, an injectible suspension of the b-complex is effective in intramuscular treatment of swine against dysentery .In water polyene antibiotics, Amphotericin, Nystatin etc., cannot form true solutions, only micelles. Chemical modification increases the solubility but diminishes their antifungal activity.

Antimicrobial agents
Improvement of the pharmaceutical properties of both organic (e.g. sulphon-amides and metronidazole), and inorganic (e.g. silver ions and iodine), antibacterial agents has been attained by complexing them with cyclodextrins. Metronidazole benzoate is a prodrug of metronidazole, and because of its poor solubility in water, its tasteless benzoate ester is used clinically in the form of oral aqueous suspensions. Inclusion complexation with b-cyclodextrin will depress this phase transition, and consequently increase the physical stability of aqueous suspensions of metronidazole benzoate.Complexation with b-cyclodextrin with increase the physical stability of aqueous metronidazole benzoate suspensions, furthermore it protects the drug against photochemical degradation. The dissolution rate of the alkyl-paraben complex may be enhanced manifold. and the volatility of the phenylalkyl alcohols strongly reduced. Derivatives of 6-deoxy-6-amino-b-cyclodextrin show strong antimicrobial activity against some gram negative bacteria such as Escherichia, Shigella and Pseudomones species. Iodine is a useful antiseptic agent; its cyclodextrin complexes were tasted in various preparations. A gargle composition, containing an iodine b-cyclodextrin complex, may be an adequate bactericide for the buccal cavity. An inclusion complex of silver nitrate ethanolamine and b-cyclodextrin has a greater bactericidal activity then a sulphadiozine-silver complex. The bactericidal squalene is effectively protected against oxidation by b-cyclodextrin complexation . The b-cyclodextrin complexes of a-halo- cinnamaldehydes and hinokitiol may also be useful.

Veterinary anthelmitics
Tetrachloroethyline forms a stable crystalline complex. The solubility of rafoxanide is practically zero, however in a b-cyclodextrin complexed form it can be measured by UV photometry.

Gastrointestinal, liver function and respiratory system drugs.
The hydrochloride of 2-benzoylcarbonyl-phenyl-trans-4-guanidinomethyl cyclohaxane-carboxylate monohydrate (TKGO1) may reduce gastric secretion, and stress induced ulcerogenity. Because of its poor solubility no dose dependent effects were obtained. Its 1:1 b-cyclodextrin complex [TA 903] may result in correct dose dependent responses.The complexed drug was shown to be about as effective a cytoprotective agent in treating ulcer as cimatidine or cetraxate. The unpleasant odour and the hydrolysis of antiulcer gefarnat have been suppressed by complexing with b-cyclodextrin. The throat irritating effect of the liver enzyme production enhancing pyxorin was successfully eliminated by converting the oily liquid into a mirocrystalline solid b-cyclodextrin complex. Both disulfiram and tetramethy disulfiram,used in the treatment of alcoholics, have a poor solubility. Complexing with b-cyclodextrin increases the solubility manifold. In this way the bioavailability problems of this drug can apparently be solved. The solubility of the antitussive dextromethorphan.HBr in a b-cyclodextrin complexed form (1:1) is about twice that of the free drug . Menthol, camphor, and eucalyptus oil containing inhalant formulation with b-cyclodextrin are other examples.

Diuretics
Furosemide and hydrochlorothiazide complexed with b-cyclodextrin increases poor solubility and the low dissolution rate of both drugs .The light induced decomposition of furosemide was also strongly reduce

Vitamins
Only fat-soluble vitamins or their derivatives form stable, crystalline complexes with cyclodextrins. Interactions with water-soluble vitamins have been observed, e.g. with vitamin B1 or B6. The branlike odour of added vitamin B1, can be eliminated with b-cyclodextrin.
The bioavailability, solubility and dissolution of Vitamin D*-b-cyclodextrin complex is enhanced considerably. The stabilising effect of b-cyclodextrin complexation with ergocalciferol in Tablets is quite pronounced. Another extensively studied fat-soluble vitamin is the minadione, Vitamin K3. A considerable improvement of its poor solubility by complexation is possible. Vitamin A, its alcohol, acetate and palmitate,were the first examples of vitamin stabilisatian with cyclodextrin The complex is recommended as a food additive . Ratinoids, bound covalently to dextrin were solubilised by cyclodextrins.

Prostaglandins
Prostaglandins are endogeneous cell hormones which are active at extremely low dose levels. Being unsaturated hydroxy fatty acid derivatives, they have poor water solubility and are rather unstable. The majority of these compounds are low melting crystals, or viscous oils, and difficult to prepare as homogeneous dilutions without considerable degradation [ 96 ]. For cyclodextrin complexation they are ideal model substances. The first cyclodextrin containing drug on the market was the PROSTARMONE tablet, that contained 0.5mg OGE2 + 6mg b-cyclodextrin (for induction of labour). The second one was the PGE1- a-cyclodextrin complex (PROSTAVASIN),
containing 20mg PGE1 + 646.7mg a-cyclodextrin

Natural extracts
The stabilisation of ezulene derivatives mainly guaiazulene, and the complete chamomile oil ("blue oil") with cyclodextrins, and the spectral and pharmacological properties of these complexes may be possible.
The stabilised spice extracts, such as odourless onion and garlic oil cyclodextrin complexes may be prepared. They are recomended for the treatment of high blood pressure, rteriosclerosis etc.The isolated allicin , one of the antibacterial ingradients of garlic can also be stabilised with cyclodextrin. The solubility and light stability of the natural glycosides rutin , and phloridzin have been improved with cyclodextrins.