`
`a
`
`PZ-WISSENSCHAFT
`
`Thorsteinn Loftsson!, Marcus E. Brewster?”, Hartmut Derendorf* and Nicholas Bodor*
`
`2-Hydroxypropyl-6-cyclodextrin: Properties and Usage
`in Pharmaceutical Formulations
`
`wD
`
`how
`
`Departmentof Pharmacy, University of Iceland, IS-101 Reykjavik, Iceland
`Center for Drug Design and Delivery, College of Pharmacy, J. Hillis Miller Health Center, Box J-497, University of Florida, Gainesville,
`FL 32610-0497, USA
`Pharmatec, Inc., P.O. Box 730, Alachua, FL 32615 USA
`Departmentof Pharmaceutics, College of Pharmacy, J, Hillis Miller Health Center, Box J-494, University of Florida, Gainesville,
`FL 32610-0494, USA
`
`
`
`
`
`
` water soluble cyclodextrin-drug complexes have been investi-
`
`The solubility of drugs is an important factor with respect to
`drug administration and drug delivery. Many physical and
`chemical approaches have beén used to improve the solubil-
`ity of poorly water-soluble compounds, Recently various _
`watcr soluble cyelodextrin-drug complexes have been inves-
`tigated and shownto bean attractive alternativeto existing
`methods. Howéver, a serious drawback in their therapeutic
`use
`is
`their
`toxicity.
`2-Hydroxypropyl-fB-cyclodextrin
`(HPBCD) has been shown to lack these toxic side effects. It
`has been used to increase the solubility of a variety of drugs
`dramatically. An overviewis given overthe effectsof HPBCD
`on drug solubility and drug stability. Some examples of
`applications in animal and humanstudies are reviewed.
`
`2-Hydroxypropyl!-f-cyclodextrin (HPBCD): Eigenschaften
`und Verwendung in pharmazeutischen Zubereitungen
`
`Die Léslichkeit von Arzneistoffen ist ein wichtiger Faktor in
`bezug auf dic Arzncimittelanwendung und Bioverfiigbar-
`keit. Es gibt eine Vielzahl physikalischer und chemischer
`Ansitze zur Verbesserung der Léslichkeit schlecht wasser-
`léslicher Substanzen. In denletzten Jahren ist gezeigt wor-
`den, daB der Einsatz von Cyclodextrin-Derivaten eine
`attraktive Alternative zu diesen Methoden darstellt. Aller-
`dings ist die Anwendung einiger dieser Derivate als Arznei-
`stoffvehikel hiufig mit erheblicher Toxizitét verbunden.
`Versuche mit 2-Hydroxypropyl-8-cyclodextrin (HPACD)
`haben dagegen keine Toxizitat nachweisen kénnen. Diese
`Substanz kann die Wasserldstichkeit schwer léslicher Ver-
`bindungensignifikant erhdhen, Der vorlicgende Artikel gibt
`einen Uberblick tiber den BinfluB von HPBCD auf die
`Loslichkeit und Stabilitat einer Vielzahl von Arzneistoffen,
`Einige Beispicle von tierexperimentellen und klinischen
`Anwendungen von HPBCD-Komplexen werdenvorgestellt,
`
` a
`
`Keywords: 2-Hydroxypropyl-B-cyclodextrin, drugs,
`solubility, stability, toxicity, review
`
`Oo
`
`Introduction
`
`Formulation of pharmaceutical dosage forms is frequently
`hampered by poor aqueoussolubility of the drugs which again
`can severelylimit their therapeutical application. Also, slow
`dissolution of a solid state drug formulation andside effects of
`some drugs are the results of their poor aqueoussolubility.
`
`Increasing the drug solubility through appropriate formulation
`can, thus, lead to increased therapeutic efficiency of the drug.
`Various methods have been used to increase the solubility of
`drugs, such as the use of organic solvents, emulsions, liposomes
`and micells, adjustments of pH and the dielectric constant of
`the solvent system, chemical modifications, and complexation
`of the drugs with appropriate inorganic or organic complexing
`agent. Unfortunatcly all of the above mentioned techniques
`have their limitations and pharmaceutical formulators are
`constantly searching for new methods to increasethe solubility
`of drugs and ways to improve the old ones. Recently various
`
`Pharm. Zig. Wiss., Nr. 1+ 4. 4136, Jahrgang 1991
`
`gated and shownto be anattractive alternative to the existing
`methods,
`
`Cyclodextrins were first isolated by Villiers in 1891 as digests of
`Bacillus amylobacter on potato starch (1), but the foundations
`of the cyclodextrin chemistry were laid down by Schardinger in
`the period 1903~1911 (2,3) and many of the older literature
`refers to cyclodextrins as Schardinger’s dextrins, Cyclodex-
`trins are formed by enzymatic cyclizationof starch. Until 1970,
`only small amounts of cyclodextrins could be produced in the
`laboratory and the high production cost prevented the usage of
`cyclodextrins in the pharmaceutical industry. In recent years,
`dramatic improvements in the cyclodextrin production and
`purification have been achieved and the cyclodextrins have
`become cheaper, This has made industrial applications of
`cyclodextrins possible,
`
`Cyclodextrins and their Derivates
`
`Cyclodextrins are cyclic oligosaccharides with hydroxyl groups
`on the outersurface anda void cavity in the center. Their outer
`surface is hydrophilic, and therefore they are usually soluble in
`5
`
`Hopewell EX1077
`Hopewell v. Merck
`IPR2023-00480
`
`Hopewell EX1077
`Hopewell v. Merck
`IPR2023-00480
`
`1
`
`

`

`PZ-WISSENSCHAFT
`
`
`
`
`
`CH,OHyA
`HOH soxolfom
`
`/ \ ae GH,OH
`Ho
`=O
`,
`HO
`
`0
`ofan HO
`
`0 tig
`fox
`
`9”
`
`oO
`
`OH
`
`HOCH;
`
`/\
`
`°
`
`HOCH
`
`CH,OH
`
`.
`
`:
`
`CH,OH
`
`sn
`
`OH
`HO
`oO
`
`Se edCH,OH
`GH,OH
`°
`
`04
`
`CH,OH
`
`CH,OH
`
`Table 1: Structure and Physical Properties of Various Cyclodextrins® 9:
`
`
`
`
`
`
`
`
`Gamma(y)
`Beta (B)
`| Alpha (a)
`
`eenie
`972
`1135
`1297
`Molecular weight
`6
`7
`8
`Glucose monomers
`05
`0.6
`0.8
`internal cavity diameter (nm)
`14.5
`1.85
`23,3
`Water solubility (g/100 mL, 25 °C)
`7”
`7h
`T
`Surface tension (mN/m)
`255-260
`255-265
`240-245
`Melting range (°C)
`10.2
`13~15
`8-18
`Waterofcrystallization (%)
`6
`11
`17
`Molecules of waterin cavity
`
`.
`
`:
`
`” Modified from References (4) and (5)
`
`water, but the cavity has lipophilic character. The most com-
`mon cyclodextrins are a-cyclodextrin, B-cyclodextrin and y-
`cyclodextrin, consisting of 6, 7and 8 a-1,4-linked glucoseunits,
`respectively (Table 1}. The numberof these units determines
`the size of the cavity. Cyclodextrins are capable of forming
`inclusion complexes with a wide variety of hydrophobic drug
`molecules by taking up a whole molecule, or some partof it,
`intothe cavity. The stability of the complex formed depends on
`howwell the guest molecule fits into the cyclodextrin cavity (6,
`7, 8,9).
`
`Unfortunately, the cyclodextrin which is he most useful for
`incorporating a number of drugs, §-cyclodextrin,
`is poorly
`water soluble (only 1.85 g/L00 ml) compared with o- and y-
`cyclodextrin (14.5 and 23.3 9/100 ml, respectively). This low
`solubility of B-cyclodextrin is believed to be associated with
`strong intermolecular hydrogen bonding in the cyclodextrin
`crystal. Alkylation (methyl- and ethyl-B-cyclodextrin) or
`hydroxyalkylation (hydroxypropy!-B-cyclodextrin and hydro-
`xyethyl-6-cyclodextrin) of the hydroxyl groups or substitution
`of the primary hydroxyl groups by saccharides (glucosyl-p-
`cyclodextrin and maltosyl-}-cyclodextrin) of the cyclic oligo-
`mer disrupts this hydrogen bonding which destabilizes the
`crystal lattice (10). In addition, these manipulations cantrans-.
`form the crystalline material
`into amorphous mixtures of
`isomeric cyclodextrins (11). The amorphous nature of modi-
`fied B-cyclodextrin as well as the derivation contribute to
`increasing the aqueous solubility of the preparations. The
`_B-cyclodextrin derivatives,
`including 2-hydroxypropyl-B-
`‘eyclodextrin (HPBCD), have been shown to possess similar
`solubilizing and stabilizing effects on drugs in aqucous solu-
`tions as the parent B-cyclodextrin (12, 13).
`
`6
`
`HPBCDis obtained bytrealinga base-solubilizedsolution of B-
`cyclodextrin with propylene oxide, The resulting mixture of
`isomers is then purified to give HPBCD of various mean
`degreesofsubstitution (14), The average numberof 2-hydro-
`xypropyl groups substituted on the B-cyclodextrin nucleus is
`determined by the amount of propylene oxide used.
`
`Toxicity Studies
`
`One of he most serious drawbacks in the use of (}-cyclodextrin
`or alkylated B-cyclodextrins such as methyl-B-cyclodextrin is
`their toxicity (11, 15). Systemic administration of B-cyclodex-
`trin-associated with severe nephrosis. This toxicity is appar-
`ently related to the poor water solubility of B-cyclodextrin and
`after i.p. ori.v. administration, the material collects, crystalli-
`zes and precipitates in the kidney. The LDsyof B-cyclodextrin
`is, therefore, unfortunately low, in the range of 300-700 mp/kg
`(i.v. in rats) (7, 15, 16). The toxicity of methylated B-cyclodex-
`tring is related to a distinct physical property namely their
`surface activity. Methylated B-cyclodextrins are relatively
`lipophilic and act to destabilize biologicalmembraneseven at
`low concentration. This property causes methyl-6-cyclodex-
`trin to be hemolytic and also imports a low i.v. LDsy (200 mg/
`kg) (16).
`
`in particular
`and
`The hydroxyalkylated-B-cyclodextrins
`HPBCDlack these untoward biological effects as indicated by
`extensive animal and human testing (17. 18, 19, 20, 21). Animal
`studies using a variety of model systems havefailed to identify
`any significant
`toxicological potential. Intravenous evalua-
`tions have included subacute and subchronic administrationof
`HPBCD to rats and monkeys (200 mg/kg every second day) and
`subchronicadministration to rats and dogs (doses as highas 400
`
`Pharm, Ztg, Wiss,, Nr. 1
`
`+ 4,
`
`/ 136. Jahryang 1991
`
`2
`
`

`

`PZ-WISSENSCHAFT
`
`mg/kg daily) (17). In addition, i.v. doses as large as 10 g/kg were
`shownnot to be acutely Icthal ortoxic to monkeys (17). High
`dose oral administration was. also innocuous.
`In all animal
`testing, there were no significant changes in kidney function
`and HPBCD was readily and completely excreted by renal
`elimination. The mean plasma half-life of HPBCD was 0.9 hrs
`in dogs (19).
`Humanclinical studies on HP8CD have beensimilarly encou-
`raging. This excipient was used in doses as high as 5 g as a
`vehicle for an estrogen derivative with no adverse effects in a
`group (n=10) of post-menopausal women (20), In a separate
`study, a rising dose tolerance paradigm was used to evaluate
`HPBCD (0.5 g to 3.0 g) in two groups (n=8) of healthy
`volunteers (21), There were no adverse effects and no altera-
`tion in any of the renospecific parameters examined,
`In
`humans, HPBCDis cleared from the plasma witha half-life of
`1.4-1.8 hrs ands almosttotally eliminatedby the kidrieys. This
`favorable profile has led several pharmaceutical companiesto
`exploit this potential excipient with several drug combinations
`in advanced clinical tests,-
` *
`
`Effects of HPBCD on Drug Solubility
`Table 2 shows the effects of HPBCD on the aqueous solubility
`~ of a number of drugs possessing different physicochemical
`properties, such as molecular size, lipophilicity, aqueous solu-
`_ bility and chemical structure. The largest solubility enhance-
`“ment appearsto be obtained whenhe drug shows low aqueous
`solubility, ¢.g., norethindrone acetate, HPBCDhaslittle or no
`effect on the aqueous solubility of hydrophilic and water
`soluble drugs, ¢.g., propranolol hydrochloride and_
`tri-
`fluorothymidinc. Also, it appears that only some lipophilic
`part of the drug molecule hasto fil into the lipophilic HPBCD
`cavity and not the entire molecule. Thus, steroids with a flat
`unsaturated and unhindered A-ring, like dexamethasone and
`17$-estradiol, or accessible pheny! or benzylrings, like chlor-
`diazepoxide, generally have good solubility in aqueous
`HPBCDsolutions. Steroids with a hindered A-ring, like ethy-
`nylestradiol 3-methyl ether, and benzodiazepines with hinde-
`red phenyl! or benzyl rings have less solubility, The aqueous
`solubility of the drugs generally showslinear dependency on
`the HPBCD coneéentration and the phase-solubility diagrams
`are of Higuchi’s A,-type (24, 25). Figure 1 shows, for example,
`this linear type of phase-solubility diagrams for six steroids,
`There are, however, examplesof both positive (Ap-type) and
`negative (A,-type) deviations fromlinearity (12, 26).
`
`The enthalpy change for theHPBCD complex formation, like
`for other cyclodextrin complexation, is negative and the free
`energy decreases through the complexation process (12, 26,
`27). Thus, the HPBCD complexes will dissociate when the
`temperature is increased, Since increase in the free energy is
`generally observed when drugsare dissolved in pure water, the
`solubility enhancement is larger at low temperature than at
`high temperature (22).
`
`The solubility enhancement of drugs in water obtained through
`HPBCD complexation has been shownto be very advantage-
`ous in a number of pharmaceutical formulations. For example,
`due to their low aqueous solubility the anti-cancer drugs
`chlorambucil and melphalan have only been marketed as
`tablets. [thas now been shownthat it is possible to formulate
`both chlorambucil and melphalan in an aqueous i.y. solution
`through HPBCD complexation (26). The daily dosage of both
`drugs could be dissolved in !
`io 2 ml of isotonic HPBCD
`
`Pharm, Zig. Wiss., Nr. 1+ 4. / 136, Jabrgung 1991
`
`80
`
`onoa
`
`>oc
`
`20
`
`
`
`
`
`(mg/mL)
`SOLUBILITY
`
`O Ethynylestradiol
`A 176-Estradlot
`@ Naorethindrone acetate
`© Norethindrone
`MB Ethynylestradiol-3-methy!ether
`® D(-}-Norgestrel
`
`0
`
`10
`
`20
`
`30.
`
`40
`
`50
`
`60
`
`2-HPBCD CONCENTRATION (%wiv)
`
`
`
`
`
`Figure 1: Phase-solubility diagrams for various steroids at neutral pH
`and25°C (from Reference 22)
`
`solution. Also, replacing chlorambucil with the solid HPBCD-
`chlorambucil complex in tablets significantly improves the
`dissolution of the drug.
`
`An example in which HPBCD has been shown to be useful in
`obviating the need for water-soluble prodrugs is the case of
`dexamethasone, Dexamethasone is a widely used glucocor-
`ticoid which is used in the treatment of shock, trauma and
`asthma. In many instances, i.v. administration is necessary but
`the poor aqueous solubility of dexamethasone prevents simple
`aqueous formulation, Currently, a water-soluble prodrug of
`the steroid, dexamethasone-21-phosphate sodiumsalt, is used.
`This compound reverts to the parent compound subsequentto
`i.v. dosing but is associated with various unpleasant side effects
`not associated with dexamethasone itself. Administration of a
`HPACD complex of dexamethasone may, therefore, provide
`an advantage over the currently used therapy. Intravenous
`administration of the dexamethasone-HPBCD complex to
`dogsresulted in higher initial plasma levels of dexamethasone
`than those obtained after dexamethasone phosphate dosing.
`The area underthe dexamethasone plasma concentration-time
`curve during the therapeutically important first hour after the
`injection was more than 50% higher than after the administra-
`tion ofan equivalentdose of the phosphate prodrug (Fig. 2). At
`later time points there was no significant difference in the
`pharmacokinetics of dexamethasone generated fromthe pro-
`drug vs. the HPBCD. Althoughthe utilized HPLC-assay does
`not differentiate betweenfree and complexed dexamethasone,
`the administered dose of cyclodextrins of approximately 2g
`should be sufficiently diluted in the blood streamto result in
`rapid complex dissociation (28).
`
`Another application of HPBCD has been to sublingual
`administration of gonodal steroids. Due to their low aqueous
`solubility and a large first-pass effect, oral administration of
`these steroids frequently results in alow and variable bioavaila-
`bility. Pitha has shown that when testostcrone is complexed
`with HPBCD, it
`is readily absorbed from under the tongue
`resulling in rapid increase in plasma levels (29). Similar
`findings were observedforestradiol and progesterone (29).
`
`Many transdermal delivery systems and topical semi-solid
`preparations cause side effects in the skin due to long term
`
`7
`
`3
`
`

`

`
`
`
`
`
`
`
`.
`
`;
`
`|
`
`.
`
`.
`
`,
`
`.
`
`|
`
`11
`3.3
`1.7
`20
`_
`0.3
`0.0L
`05
`0.12
`0.02.
`0.008
`0.05"
`<Q.15
`0.07"
`0.004"
`0.003"
`0,008
`0.00!
`0.28"
`0.01%
`0.3
`0.02°
`30
`0.1
`0.01
`2.1
`0.045
`<0,17
`0.2
`1,25"
`0.005
`0.0002
`0,002
`13
`0.03
`127
`1.1
`0,02
`0.015
`107
`<0.07
`<0.07
`0.001
`0.03"
`0.2°
`0.17°
`0.15"
`<0.21
`0.026
`1.7"
`8.3
`58.4
`0.4"
`
`58
`45
`58
`58
`45 .
`58
`58
`45
`58
`25
`58
`58
`58
`58
`58
`58
`58
`58
`48
`45
`58
`58
`58
`58
`58
`38
`58
`58
`25
`45
`58
`58
`58
`58
`58
`58
`45
`58
`4S
`58
`48
`45
`58
`45
`45
`45
`4S
`58
`SG
`45
`58
`58
`45
`
`:
`
`/
`
`67.0
`13.4,
`3.9
`116.0
`16.8
`30.0
`147.8
`30.1
`10.5
`0.65
`44.3
`7.4
`1.3
`68.0
`40.5
`41,0
`68.2
`13.3
`ALB
`8.0
`9.3
`4,2.
`95.0)
`12.0
`8.3
`21.9.
`10.0
`39.0
`0.2
`10.4
`19.0
`19.5
`4.9
`80.0,
`4.2,
`238.0
`2.4
`9.3
`34.0
`24
`2.6
`0.8
`4.6
`42.0
`2.9
`4,7
`4.4
`10.0
`38.0)
`3.9
`11.0
`72.6
`6.9
`
`‘
`
`.
`
`“
`
`6
`4
`2
`6
`_
`100
`15,000
`60
`90
`33
`5,500
`150
`_—
`1,000
`10,000
`14,000
`8.500
`13,000
`150
`800
`30
`210
`3
`120
`851)
`IQ
`200
`_
`|
`8
`4,000
`97,500
`2,500
`6
`150
`2
`2
`450
`2.300
`1
`ves
`=
`4.600
`1,400
`18
`30
`30
`_
`1500
`2
`1
`I
`15
`
`
`
`Ref.
`
`14
`23
`22
`14
`23
`23
`22
`23
`id
`23
`22
`22
`14
`14
`22
`14
`22
`22
`23
`23
`i4
`14
`14
`23
`22
`23
`22
`i4
`22
`14
`22
`22
`22
`14
`22
`td
`23
`22
`14
`22 '
`1
`14
`22
`14
`23
`23
`23
`14
`I4
`23
`14
`22
`23
`
`
`
`=,
`
`PZ-WISSENSCHAFT
`
`Table 2: Solubility of some drugs in water and aqueous MPBCDsolutions at roomtemperature
`
`Drug
`
`Solubility
`in water
`(mg/ml)
`
`HPBCD
`concent.
`(% wiv)
`
`Solubility in the
`aqueous HPBCD
`solution (mg/ml)
`
`Increase
`in solubility
`(HPBCD/Awater)
`
`,
`
`Acetaminophen
`Acetylsalicylic acid
`Acyclovir (at pH 7.2)
`Apomorphine
`Carbamazepine
`Chiorambucil
`Chlordiazepoxide
`Chiortetracycline
`Chlorthalidone
`Cholecalciferol
`Dexamethasone
`Diazepam
`Dicumarol
`Digoxin
`17B-estradiol
`-
`Estrial
`17a-Ethynylestradiol
`Ethynylestradiol 3-mothy! ether
`Hydrocortisone
`Hydrocortisone acetate
`Hydroflumethiazide
`indomethacin
`Iproniazid phosphate
`Lomustine
`Medazepam(at pH 7.5)
`Melphalan
`Methotrexate (at pH 7.6)
`17-Methyltestosterone
`Nitrofurantoin (at pH 7)
`Nitroglycerin
`Norethindrone
`Norethindrone acetate
`D(-)-Norgestrel
`Ouabain
`Oxazepam
`Oxperolol
`Oxytetracycline
`Phenytoin
`Progesterone
`Propranolol HCT
`Retinal
`All-trans-Retinoic acid
`All-trans-Retinol
`Spironolactone
`Sulfadiazine
`Sulfamerazine
`Sulfamethiazine
`Sulpiride
`Testosterone
`Tetracycline
`Theophylline
`Trifluorothymidine
`Trimethoprim
`
`a
`
`L Literature values
`
`8
`
`Pharm, Ztg. Wiss., Nr.
`
`1
`
`+ 4, / 136. Jahrgang 1094
`
`4
`
`

`

`PZ-WISSENSCHAFT
`
`Effects of HPBCD on Drug Stability
`
`_ Frequently the rate of degradation of a drug within the
`‘inclusion complex is slower than out
`in the solution and
`yaddition of HPACD to.aqueous solution of the drug results in
`increased stability and, thus, longer shelf-life (Table 3). There
`are, however, some examples of cyclodextrin destabilization of
`drugs suchas of prostaglandin E, (37).
`The recent developmentsin biotechnology have made biologi-
`cally active peptides and proteins available in sufficient quan-
`tities to be used as drugs. Many of these peptides and proteins
`/ are very unstable in aqueous solutions and their formulations
`have brought anew challenge to the pharmaceutical scientists.
`\ One of the main problems of injectable protein solutions is the
`| ageregation ofthe proteins and changesin their three-dimen-
`/ sional-structure which’ leads to denaturation and, conse-
`i
`/ quently, deactivation. HPBCD has been shownto stabilize
`aqueous buffer solutions ofinsulin and interleukin-2 (36, 38).
`|
`
`|,
`
`Conclusion
`
`In conclusion, HPBCD is a non-toxie cyclic oligosaccharide
`capable of forming hydrophilic inclusion complexes with a
`large number of lipophilic drugs. The complexation can
`improve the clinical usage of the drugs by increasing their
`aqueous solubility, rate of dissolution and pharmaccutical
`availability. The complexation canalso improvethestability of
`many drugs in aqueous solutions and increase thetr shelf-life.
`HPBCD is a new pharmaceutical excipient with numerous
`potential uses in the pharniaceutical industry,
`
`References
`
`(1) Villiers, A.: Sur la fermentation de la fécule par l’action du
`ferment butyriqué, C.R, Acad. Sci. 772 (1891) 536-538,
`(2). Schardinger, F.: Uberdie Zalassigkeit des Warmhaltens von zum
`Genus bestimmten Nahrungsmittein mittels Warme speichern-
`der Apparatc, sog. Thermophore. Wien. Klin, Wschr., /6 (1903)
`468-474,
`
`
`
`
`
`2 0.0
`Pf?OdePeNaNnonoeRAREREEEEEEEEEPEELS
`SIRs
`TTTOP,-
`NNOS
`WeetePeeee,
`
`ae
`
`TNTAEPPSNyLAAANAS
`NNINCEES
`RAREEEETSSONeeeEe
`
`RARE
`
`<
`
`4¢¢¢42?¢?z
`
`~
`
`VNAREEPLELLaSLEATEe
`
`2
`
`1.5
`
`AUC(0-th) 5
`
`0.5
`
`Phosphate Ester
`HPBCD Compiex
`
`
`
`
`2.0
`
`Dog
`
`Figure 2: Area under the dexamethasone plasma concentration-time
`curve for six different dogs alter intravenous administration
`of 5 mg/kg dexamethasonein formof its phosphate ester or
`HPBCD-complex
`
`occlusion. It is possible that these side effects can be avoided by
`using nonocclusive aqueous vehicle systems. Many lipophilic
`drugs, such as steroid, have very low aqueous solubility and
`cannot be used in aqueous vehicle systems without effective
`solubilization. HPBCD forms water soluble complexes with a
`numberof steroids and aqueous HPBCDsolutions have been
`shown to be effective vehicle systems for the transdermal
`delivery of 17B-estradiol, hydrocortisone and testosterone
`(30). Although the concentration of ihe free drug in the vehicle
`was low, the drug molecules within the complex were in a fast
`equilibrium with the free drug molecules out in the solution
`resulting in an effective delivery of the drug to the skin surface.
`
`Other formulations where HPBCD has been used to increase
`aqueous solubility of drugs include parenteral formulations of
`alfaxalone (31), nimodipine (18), testosterone (32) and of
`chemical delivery systems containing various drugs (33, 34,
`35), Also,HPBCD hasbeenused tosalubilize proteins (36).
`
`Table 3: The effect of HPBCD onthe rate of degradation of some drugs in aqueoussolutions
`
`
`D+HPBCD = D-HPacD
`J
`y
`ke
`Degradation
`products
`
`yk
`
`
`
`
`
`
`k,is the rate constant for the degradation ofthe drug out in the solution, i.e., outside the complex, and k,is the rate constant for the degradation
`
`of the drug within the inclusion complux,.
`
`Drug Ko/ke|Ref.Buffer
`
`
`
`
`
`
`13
`24
`9.7x 1073
`2
`45
`2.6
`Formate
`Acctate
`5.9
`55
`3.0x 107?
`13x 1077
`2.3
`13
`
`Phosphate
`7.0
`55
`6.9X107*
`3.4% 107+
`2.0
`13
`
`
`Nitric acid
`1,3
`60)
`8.6X107+
`5.0x 107?
`17
`26
`Mellvaine buffer
`7.0
`6)
`0,22
`7.5x 1079
`29
`26
`
`
`Sodium hydroxide 11.7|60 0.43 1x07? 39 26
`
`
`
`
`Hydrochloric acid
`Nitric acid
`Mellvaine buffer
`
`1.3
`73
`
`50
`80
`
`1.0x 1077
`9.5x1075
`
`12
`26
`26
`
`Acctylsalicylic acid
`Chiorambuei!
`
`Lomustine
`
`Melphalan
`
`Pharm, Ztg, Wiss. Nr.
`
`| 4. / 136. Jahrgang 1991
`
`9
`
`5
`
`

`

`PZ-WISSENSCHAFT
`
`(is —
`
`(3) Schardinger, F.: Uber thermophile Bacterien aus verschiedenen
`Spcisen und Milch, sowie ber cinige Umsetzungsproducte
`darselben in kohlenhydrathaltigen Nihrlésungen, darunter kry-
`stallisierte Polysaccharide (Dextrine) aus Stirke. Z. Unters.
`Nahr. GenuBm. 6 (1903) 865-880.
`(4) Pagington, J.S.; B-Cyclodextrin: The success of molecular inclu-
`sion, Chem. Brit. (1987) 455-458.
`(5) Uckama, K. and M. Otagiri: Cyclodextrins in drug carrier
`systems, CRC Crit. Rev. Therap. Drug Carrier Systems, 3 (1987)
`1-40.
`(6) Uckama, K.: Pharmaceutical applications of cyclodextrin com-
`plexation, Yakugaku Zasshi. 70/7 (1981) 857-873.
`(7) Szejtli, J.:; Cyclodextrin and their inclusion complexes, Akade-
`mia: Kiado, Budapest, 1982.
`(8) Duchéne, D. (Ed.); Cyclodextrins and their industrial uses,
`Editions de Santé, Paris 1987,
`(9) Huber, O. and J, Szejtli (Eds.): Proceedings of the fourth
`international symposium on cyclodextrins, Kluwer Academic
`Publishers, Dordrecht 1988.
`(10) Duchéne, D. and D, Wouessidjewe: Physicochemical] characteri-
`stics and pharmaccutical uses of cyclodextrin derivatives, partl.,
`Pharm. Tech. /4 (1990) 26-34.
`(iL) Pitha, J. and J. Pitha: Amorphous water-soluble derivatives of
`cyclodextrin: nontoxic dissolution enhancing excipients, J.
`Pharm. Sci, 74 (1985) 987-990.
`(12) Loftsson, T., B. J. Olatsdéttir and H. Fridriksdéttir: Compara- ,
`tive study on inclusion complexation of acctylsalicylic acid,
`cholcalciferol and melphalan with §- and y-cyclodextrin and some
`of their derivatives, Acta Pharm, Nord. 2 (1990) 303-312.
`(13) Loftsson, T. and H. Fridriksdéttir; Degradation of lomustine
`(CCNU)in aqueoussolutions, Int. J. Pharm. (1990) 243-247.
`(14) Pitha, J., J. Milecki, H. Fales, L. Pannell and K. Uckama:
`Hydroxypropyl-B-cyclodexirin: Preparation. and characteriza-
`tion, effects onsolubility of drugs, Int. J. Pharm. 29 (1986) 73-82.
`Frank, D.,J.Gray,and R. Weaver: Cyclodextrin nephrosis in the
`rat, Am. J. Pathol. 63 (1976) 367-382.
`(16) Miller, B.W. and U, Brauns: Solubilization of drugs by modified
`§-cyclodextrins, Int. J. Pharm. 26 (1985) 77-88.
`(17) Brewster, M.B., K.S. Estes and N. Bodor: An intravenous
`toxicity study of 2-hydroxypropyl-B-cyclodextrin, an useful drug
`solubilizer,
`in rats and monkeys,
`Int, J, Pharm. 39 (1990)
`231-243.
`Yoshida, A.,M. Yamamoto, T. ltoh, T.Irie, F. Hirayama and kK.
`UVekama: Utility of 2-hydroxypropyl-B-cyclodextrin in an intra-
`muscularinjectable preparation of nimodipine, Chem, Pharm,
`Bull, 38 (1990) 176-179,
`(19) Monbaliu, J.. L. van Beijsterveldt, W. Meuldermas, S. Szath-
`mary and J. Heykants: Disposition of hydroxypropyl-B-cyclo-
`dextrin in experimental animals, Abstracts, 5th International
`Symposium on Cyclodextrins (1990) 132,
`(20) Howes,J..N, Bodor, M. Brewster, K. Estes and M. Eve: A pilot
`study with PR-63 in postmenopausal volunteers, J. Clin. Pharma-
`col. 28 (1988) 951.
`(21) Seiler, K.. R. DeCoster, W. Junge and H. Huss: Safetyprofile
`and i.v. tolerance of hydroxypropyl-$-cyclodextrin after increa-
`sing single dose, Abstracts, Sth International Symposium on
`Cyclodextrins (1990) 133.
`(22) Loftsson, T, and N. Bodor: Effects of 2-hydroxypropyl-6-cyclo-
`--dextrin on the aqueous solutility of drugs and transdermal
`delivery of 17f-estradiol, Acta Pharm. Nord. / (1989) 185-194.
`(23) Loftsson T, and M.&. Brewster, unpublished results.
`
`(24) Higuchi, T, and K.A. Connors: Phase-solubility techniques, ina
`C.N. Reilly (Ed.), Advancesin analytical chemistry and instru-
`mentation, Interscience, New York 1965 pp. 117-212,
`(25) Repta,A.J.; Altcration of apparent solubility through complexa-
`tion, in SH. Yalkowsky (Ed.), Techniques of solubilization of
`drugs, Marcel Dekker, New York 1981, pp. 135-157.
`(26) Loftsson, T., 8. Bjdrnsdéttir, G. Palsdéitir and N. Bodor: The
`effects of 2-hydroxypropyl-fi-cyclodextrin on the solubility and
`stability of chlorambucil and melphalanin aqueous solution, int,
`J, Pharm. 57 (1989) 63-72.
`
`(8=
`
`-
`
`
`
`
`(31 ws
`
`(27) Clarke. R.J.,J. H. Coates andS.F, Lincoln: Inclusion complexes
`ofthe cyclomalto-oligosaccharids (cyclodextrins), in R.S. Tipson
`and 1D. Horten (Bds.), Advances in carbohydrate chemistry and
`biochemistry, Vol. 46. Academic Press, New York 1988, pp.
`205-249,
`(28) Dictecl, K., K.S. Estes, M.E. Brewster, N.S, Bodor and H.
`Derendorf: The use of 2-hydroxypropyl-f-cyclodextrin as a
`vehicle for intravenous administration of dexamethasone indogs,
`Int. J. Pharm. 59 (1990) 225-230,
`(29) Pitha, J.,S.M. Harman and M.E. Micel: Hydrophilic cyclodex-
`trin derivatives enable effective oral administration of steroidal
`hormones, J. Pharm. Sci. 75 (1986) 165-167.
`(30) Loftsson, T., B. J. Olafsdéttir and N. Bodor: The effects of
`cyclodextrins on transdermal delivery of drugs, Acta Pharm.
`Technol., 37 (1991) in print,
`Brewster, M.E., K.S. Estes and N. Bodor: Development of non-
`surfactant formulation for alfaxalone through th use of chemi-
`cally-modified cyclodextrins, J, Parenter. Sei. Technol, 4.3 (1989)
`262-265,
`:
`(32) Taylor. G.T., J, Weiss and J. Pitha: Testosterone in a cyclodex-'
`trin-containing formulations: Behavioral and physiological
`effects of cpisode-like pulses in rats, Pharm, Res. 6 (1989)
`641-646,
`(33) Brewster, M., K. Estes, T, Loftsson, R. Perchalski, H. Deren-
`dorf, G. Mullersman and N. Bodor: Improved delivery through
`. biological membranes XXXL. Solubilization and stabilization of
`an estradiol chemical delivery system by modified B-cyclodex-
`trins, J. Pharm. Sci. 77 (1988) 981-985.
`Anderson, W.R., J.W. Simpkins, M.E, Brewster and N.S,
`Bodor; Evidence for prolonged suppression of stress-induced
`release of adrenocorticotropic hormoneandcorticosterone with
`a brain-enhanced dexamethason-redox delivery systom, Neuro-
`endochrinology 50 (1989) 9-16,
`(35) Anderson, W.R.,J.W. Simpkins, M.E. Brewster and N. Bodor:
`Brain-enhanced delivery of testosterone using a chemical dell-
`very system complexed with 2-hydrexypropyl-fi-cyclodextrin,
`Drug Des. Deliv. 2 (1988) 287-298.
`(36) Brewster, M.E., J.W. Simpkins, M:S. Hora, W.C, Stern and N,
`Bodor: The potential use of cyclodextrins in parenteral formula-
`tions, J. Parenter. Sei. Technol. 43 (1989) 231-240.
`(37) Yoshida, A., M. Yamamoto, T. ric, F. Hirayama and K,
`Uckama: Some pharmaccutical propertics of 3-hydroxypropyl-
`and 2,3-dihydroxypropyl-f-cyclodextrins and their solubilizing
`and stabilizing abilities, Chem. Pharm, Bull, 37 (1989)
`1059-1063,
`(38) Brewster, M.E., J. W. Simpkins, M.S. Hora and N. Bodor:
`Application of2-hydroxypropyl-fi-cyclodextrin to proteinstabili-
`zation and solubjlization,
`in D, Duchéne (Ed,), Minutes Sth
`International Symposium on Cyclodextrins, Editions de Santé,
`Paris, PP. 440-444,
`
`(34a
`
`Correspondence:
`Prof. Dr. T. Laftsson
`Department of Pharmacy
`University of Iceland
`15-101 Reykjavik
`Iceland
`
`
`
`
`10
`
`Pharm. Ztg. Wiss.. Nr. 1+ 4.4136, Jahrgang 1991
`
`6
`
`