Polymeric Delivery Systems - American Chemical Society

Chapter 11

Microcapsules Containing Water-Soluble Cyclodextrin Inclusion Complexes of Water-Insoluble Drugs Thorsteinn Loftsson and Thórdís Kristmundsdófttir

Downloaded by UNIV OF SYDNEY on March 28, 2013 | http://pubs.acs.org Publication Date: March 5, 1993 | doi: 10.1021/bk-1993-0520.ch011

Department of Pharmacy, University of Iceland, Reylyavik IS-101, Iceland

One of the most common practiced microencapsulation in the pharmaceutical industry is to form slow-release oral dosage forms of lipophilic water-insoluble drugs. In general, water-insoluble drugs possess inherent slow– release properties, but in many cases their release rate can be increased by formation of water-soluble drug– cyclodextrin inclusion complexes. Micro-encapsulation of such water-soluble complexes will result in drug-delivery forms with release rates independent of their water solubility. In recent years, microencapsulation has been used successfully in many technological fields. In the pharmaceutical industry microcapsules have for example been used to improve the bioavailability o f drugs, to protect drugs from decomposition, to convert liquids to free-flowing powder, and to mask unfavourable odour and taste (1). However, one of the most c o m m o n usage o f m i c r o e n c a p s u l a t i o n i n the pharmaceutical industry is to form slow-release oral dosage forms and in the literature there are numerous reports o f successful developments o f such dosage forms. M o s t o f the drugs tested so far have a l i p o p h i l i c character. L i p o p h i l i c water-insoluble drugs are rather easily microencapsulated and they possess inherent slow-release properties in the pure form as w e l l as when they are incorporated into polymeric matrices. T h e preparation o f microcapsules c o n t a i n i n g hydrophilic water-soluble drugs is a greater challenge and there are fewer reports on such forms of microcapsules. W e believe in many cases the release rate o f water-insoluble drugs from microcapsules can be better controlled if, water-soluble drug-cyclodextrin inclusion

0097-6156/93/0520-0168$06.50/0 © 1993 American Chemical Society

In Polymeric Delivery Systems; El-Nokaly, M., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1993.

11. LOFTSSON & KRISTMUNDSDOTTIR

Cyclodextrin

Inclusion Complexes

169

complexes of the drugs, rather than the pure drugs themselves are incorporated into the microcapsules. In this chapter we describe a method for p r o d u c i n g microcapsules of h y d r o p h i l i c water-soluble cyclodextrin complexes containing lipophilic water-insoluble drugs.


Cyclodextrins

C y c l o d e x t r i n s f o r m a group o f s t r u c t u r a l l y r e l a t e d cyclic oligosaccharides w i t h a h y d r o p h i l i c outer surface and a rather lipophilic cavity in the center. They are natural products formed by the action of enzymes on starch. V a r i o u s cyclodextrin d e r i v a t i v e s have also been synthesised. F o l l o w i n g is a short review o f cyclodextrins and their properties. For further information excellent reviews have been published in recent years (2-7). H i s t o r y . Cyclodextrins were first isolated from starch degradation products by V i l l i e r s in 1891 (8). The foundations of the cyclodextrin chemistry were laid down by Schardinger in the period 1903 to 1911 (9, 10), and many of the o l d literature refer to cyclodextrins as S c h a r d i n g e r ' s dextrins. C y c l o d e x t r i n s have also been c a l l e d c y c l o a m y l o s e s and c y c l o g l u c a n s . C y c l o d e x t r i n s are formed by enzymatic c y c l i z a t i o n of starch by a group o f a m y l a s e s c a l l e d glycosyltransferases. The enzymes convert partially prehydrolysed starch to a mixture of cyclic and acyclic dextrins from w h i c h the pure homogeneous, crystalline cyclodextrins are isolated. Until 1970, only small amounts of cyclodextrins could be produced in the laboratory and the high production cost prevented the usage of cyclodextrins in industry. The recent biotechnological advancements have resulted in dramatic improvements in the c y c l o d e x t r i n production w h i c h has lowered their production cost (11). T h i s has made i n d u s t r i a l applications of cyclodextrins possible. Since 1960, close to 1000 patents have been filed on both the production of cyclodextrins and their usage. The first patent on the preparation of d r u g - c y c l o d e x t r i n complexes was registered in 1953 (12). C h e m i s t r y of cyclodextrins. The important structural characteristics of the c y c l o d e x t r i n molecules are their c y l i n d r i c a l shape, somewhat hydrophobic central cavity and the h y d r o p h i l i c h y d r o x y l groups on the outer surface. T h e polarity o f the cyclodextrin cavity has been estimated to be similar to that of aqueous alcoholic solution (13). Due to lack of free rotation about the bonds connecting the glucopyranose units, the cyclodextrins are not perfectly cylindrical molecules but to some extent cone shaped. A l l the primary h y d r o x y l groups are located on the narrow side w h i l e a l l the



170

POLYMERIC DELIVERY SYSTEMS

secondary h y d r o x y l groups are located o n the wider side. The most common cyclodextrins are a - c y c l o d e x t r i n (or cyclohexaamylose), β-cyclodextrin (or c y c l o h e p t a a m y l o s e ) and γ-cyclodextrin (or cyclooctaamylose), consisting of 6, 7 or 8 a - 1 , 4 linked glucopyranose units, respectively (Table I). Cyclodextrins are capable of forming inclusion complexes w i t h many molecules by taking up a whole molecule, or some part o f it, into the cavity (5, 6). T h e cyclodextrins become the "host" molecules and the molecules w h i c h go into the cavity the "guest" molecules. N o covalent bonds are formed or broken during the complex formation and i n aqueous solutions the complexes are readily dissociated and free guest molecules are i n a rapid e q u i l i b r i u m w i t h the molecules bound w i t h i n the cyclodextrin cavity. T h e d r i v i n g force for the complex formation is thought to be the release o f enthalpy-rich water from the c y c l o d e x t r i n cavity. T h e water molecules located inside the cavity cannot satisfy their hydrogen bonding potentials and therefore exist i n a higher energy state compared to the water molecules out i n the aqueous c y c l o d e x t r i n solution (3, 13). These enthalpy-rich water molecules are readily replaced by suitable guest molecules less polar than water. T h e size and chemical structure o f the guest molecule are also important. O n l y relatively apolar molecules of appropriate size can go into the cyclodextrin cavity. T o o large or too polar molecules w i l l not form inclusion complexes with cyclodextrins. However, it is often sufficient for complex formation that some apolar part of a molecule fits into the cavity. F o r example, many polypeptides and proteins contain some amino acids carrying hydrophobic aromatic moieties capable of forming inclusion complexes w i t h cyclodextrins (6, 14). T h e size of the cyclodextrin cavity is also very important (Table I). For instance, the α-cyclodextrin cavity is too small for naphthalene and only the γ-cyclodextrin cavity can a c c o m m o d a t e anthracene (5). α-Cyclodextrin can be used for small molecules o r s l i m side chains of larger molecules. β-Cyclodextrin is the most useful for complexation o f average size molecules such as most drugs. γ-Cyclodextrin can be used for complexation o f large molecules such as macrolide antibiotics. Unfortunately, β-cyclodextrin has l o w aqueous solubility (only 1.85 g/100 ml) and causes severe toxic effects upon systemic administration (15, 16). T o improve their physicochemical and biological properties, the m o l e c u l a r structure o f the parent c y c l o d e x t r i n s , i.e. α - , β- and γ-cyclodextrin, have been modified. Branched cyclodextrins can be obtained by reacting a cyclodextrin w i t h glucose or maltose i n the presence of pullulance enzyme [13]. Other c o m m o n c y c l o d e x t r i n derivatives are formed by a l k y l a t i o n (e.g. m e t h y l - and ethyl-βc y c l o d e x t r i n ) o r h y d r o x y a l k y l a t i o n (e.g. h y d r o x y p r o p y l - a n d


11.

Cyclodextrin Inclusion Complexes

LOFTSSON & KRISTMUNDSDOTTIR

Table

I:

The

structure

of

β-cyclodextrin


p r o p e r t i e s o f α - , β-, a n d γ - c y c l o d e x t r i n

and

physical

1

CH2pH Ο

HOCH; Η Ο

γΙ°

Η ί Ο Η

HoVo o~y

HO HOCH '

HO

2

°

Η Ο ^ ^ Η , Ο Η

CHP-.

β-Cyclodextrin

a-Cyclodextrin

β-Cyclodextrin

γ-Cyclodextrin

M o l e c u l a r weight

972

1135

1297

N u m b e r o f g l u c o p y r a n o s e units

6

7

8

Internal c a v i t y diameter ( Â )

4.7-5.3

6.0-6.5

7.5-8.3

A p p r o x . c a v i t y v o l u m e (Â-^)

174

262

472

M o l e c u l e s o f water i n c a v i t y

6

W a t e r s o l u b i l i t y at 25°C (g/100 m l )

14.5 10.2 255-260

11 1.85 13-15 255-265

23.3 8-18 240-245

W a t e r o f crystallization

(%)

M e l t i n g range ( ° C )

171

17

1 M o d i f i e d from references 7 and 13



172


h y d r o x y e t h y l - d e r i v a t i v e s o f α-, β- and γ-cyclodextrin) o f the h y d r o x y l groups (5). These manipulations frequently transform the c r y s t a l l i n e c y c l o d e x t r i n s into amorphous mixtures o f i s o m e r i c c y c l o d e x t r i n derivatives and, thus, the aqueous s o l u b i l i t y of the d e r i v a t i v e s is u s u a l l y m u c h larger than that of the parent cyclodextrin. For example, 2 - h y d r o x y p r o p y l ^ - c y c l o d e x t r i n is obtained by treating a base-solubilized solution of β-cyclodextrin with propylene oxide. The aqueous solubility of 2 - h y d r o x y p r o p y l ^ cyclodextrin is over 60 g/100 ml and it shows virtually no toxic side effects upon parenteral administration (7, 17). B o t h the m o l a r substitution, i.e. the average number of propylene oxide m o l e c u l e s that have reacted with one glucopyranose unit, and the location of the hydroxy propyl groups on the β-cyclodextrin molecule w i l l affect the c o m p l e x a t i o n properties of the 2 - h y d r o x y p r o p y l ^ - c y c l o d e x t r i n molecule (18). V a r i o u s methods have been used to detect f o r m a t i o n o f cyclodextrin inclusion complexes. In the solid state thermal analysis, X - r a y analysis, infrared spectroscopy, rate of dissolution, v a c u u m sublimation and vacuum drying have been used. In aqueous solutions s p e c t r a l c h a n g e s (e.g. NMR, ultraviolet, fluorescence, phosphorescence and c i r c u l a r d i c h r o i s m ) , and the effect of the c y c l o d e x t r i n molecules on the solubility and stability of the guest molecules have been used (19). Solubility and kinetic methods are mainly used for determining stability constants of the c y c l o d e x t r i n inclusion complexes (19, 20). C y c l o d e x t r i n encapsulation of a hydrophobic guest molecule w i l l affect many of its physicochemical properties. In the solid state, the cyclodextrin complexes frequently increase the rate of dissolution of the guest molecule, increase its chemical stability, and reduce its volatility and s u b l i m a t i o n . In aqueous s o l u t i o n s , c y c l o d e x t r i n complexes can both increase the solubility and stability of the guest molecule, as w e l l as reduce its v o l a t i l i t y and absorption into or adsorption on surfaces and membranes. F o r these reasons various industrial applications of cyclodextrins and their derivatives are now being tested. Usage of cyclodextrins in p h a r m a c e u t i c a l formulations.

In

the pharmaceutical industry cyclodextrins are mainly used to increase the aqueous solubility, stability and bioavailability of drugs but they have also been used to convert l i q u i d drugs into macrocrystalline powders, reduce gastro-intestinal irritation, and reduce or eliminate unpleasant taste and smell. F o l l o w i n g are few examples of usage of cyclodextrins in pharmaceutical formulations.



11.



173

C y c l o d e x t r i n s have been used to improve both the solubility and chemical stability o f anticancer drugs. M a n y anticancer drugs owe their pharmacological activity to their instability i n aqueous solution, therefore it is often difficult to introduce these drugs into aqueous formulations. F o r example, the s o l u b i l i t y o f the anticancer drug chlorambucil i n water is only 0.3 mg/ml and its shelf-life i n aqueous buffer solution at p H 7.4 and 25°C is only about 11 minutes. T h e desired intravenous dose would be about 10 m g and to give this dosage one w o u l d have to inject about 35 to 4 0 m l of pure aqueous solution o f the drug w i t h i n 11 minutes from its d i s s o l u t i o n , w h i c h is quite impossible. C h l o r a m b u c i l forms an i n c l u s i o n c o m p l e x w i t h 2hydroxypropyl-p-cyclodextrin. In aqueous isotonic 2-hydroxyp r o p y l - P - c y c l o d e x t r i n solution (approximately 2 3 % w/v) the solubility of chlorambucil is about 17 mg/ml and, thus, 10 m g dose o f the d r u g c o u l d easily be d i s s o l v e d i n one m l o f isotonic 2h y d r o x y p r o p y l - P - c y c l o d e x t r i n solution (21). T h e complexation w i l l also result i n 2- to 3-fold increase in the shelf-life. Cyclodextrins have also been shown to increase the aqueous solubility and/or the s t a b i l i t y o f f o l l o w i n g anticancer d r u g s : D a u n o r u b i c i n ( 2 2 ) , d o x o r u b i c i n (22, 23), estramustine (24), lomustine (25), m e l p h a l a n (21) and tauromustine (Loftsson, T . ; Baldvinsdottir, J . Acta Pharm. Nord., i n press). The non-steroidal anti-inflammatory drugs ( N S A I D s ) are one o f the most commonly used group of drugs in the world. However, most N S A I D s cause some form of gastro-intestinal irritation especially at the high sustained dosages necessary for treatment o f a r t h r i t i s . Several approaches have been tested for reducing or preventing this side effect o f the N S A I D s i n c l u d i n g p r o d r u g formation, m i c r o e n c a p s u l a t i o n , addition o f neutralising excipients and c o prescription o f anti-ulcer agents. A recently tested method f o r reduction o f gastrointestinal irritation is complexation o f N S A I D s with cyclodextrins (26). T h e cyclodextrin complexation o f N S A I D s frequently results i n more rapid absorption o f the N S A I D s after oral administration w h i c h again can reduce the potential for gastric lesions due to shorter time of contact between the N S A I D s and the mucosa. It has for example been shown that gastric tolerance o f piroxicam can be increased by β-cyclodextrin complexation (27). β-Cyclodextrin also increases the chemical stability of acetylsalicylic acid in aqueous solutions (Loftsson, T . , unpublished data). N M R studies o f the c o m p l e x a t i o n o f the acetylsalicylic acid with β-cyclodextrin have shown that during the complex formation the benzene ring of the drug m o l e c u l e goes into the c a v i t y f r o m the w i d e r side o f the βc y c l o d e x t r i n molecule. T h e N M R studies also show that i n the inclusion complex the benzene ring is located well inside the cavity but



174

POLYMERIC DELIVERY

SYSTEMS

the acetyl group is standing out o f the cavity ( F i g . 1). The complexation increases the stability of the drug by protection of the c h e m i c a l l y weak spot, i.e. the ester b o n d , o f the molecule. Cyclodextrins have also been shown to increase the aqueous solubility and/or the stability of following N S A I D s : Diclofenac (28), ibuprofen, indomethacin (28, 29), naproxen (30) and tenoxicam. Steroids as a group consist of relatively large w a t e r - i n s o l u b l e molecules. The molecules are too large to fit completely into the c y c l o d e x t r i n cavity but since only some l i p o p h i l i c part of the molecule, e.g. the Α-ring, has to fit into the cavity many steroids form cyclodextrin inclusion complexes. T h u s , steroids w i t h a flat unsaturated and u n h i n d e r e d Α-ring, l i k e dexamethasone and 17p-estradiol, generally have a good solubility in aqueous 2-hydroxypropyl-p-cyclodextrin solutions. Steroids with a hindered Α-ring, like ethynylestradiol 3-methyl ether, have less solubility (31). Microencapsulation Microencapsulation can be defined as the coating of small particles or droplets of liquids, where the size of microencapsulated particles can range from a fraction of a μπι to several hundred μιτι. The term microcapsule has not only been applied to coated particles or droplets but also to d i s p e r s i o n s i n a s o l i d m a t r i x (32). Microencapsulation makes it possible to alter the properties of the encapsulated product; controlling release characteristics, i m p r o v i n g stability by protecting from the environment and converting liquids into solids (33). Preparation of microcapsules. Microcapsules can be prepared by several processes, each has its advantages and disadvantages, and no one process is suitable for all substances. The choice of a process is dependent upon the intended size of the microencapsulated product, and the p h y s i c o c h e m i c a l properties of both the substance to be encapsulated as w e l l as the coating material. T h e structure of the microcapsule, whether the encapsulated substance is surrounded by a thin coating or is dispersed throughout a polymeric matrix, is also dependent upon the process used. The various microencapsulation techniques are (34): coacervation phase separation; interfacial p o l y m e r i z a t i o n ; solvent e v a p o r a t i o n ; spray d r y i n g and spray congealing; pan coating; multiorifice centrifugal process and air suspension. For a description of the microencapsulation techniques the reader is referred to the many excellent reviews available (3224).



11.



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Figure 1. Schematic drawing of a acetylsalicylic acid β-cyclodextrin inclusion complex in aqueous solution (Loftsson, T . et al, unpublished data).



176


The shape and the morphology of microcapsules depend on the core material, the type of coating material used and the method of microencapsulation. W h e n applying a thin surface coating on drug crystals (e.g. by coacervate phase separation or by air suspension) the shape of the microcapsule w i l l be governed by the crystal shape, whereas w h e n the coating is t h i c k e r or when the method of microencapsulation involves dissolving the core material during the process (e.g. by solvent evaporation), spherical or nearly spherical microcapsules w i l l be obtained. The size and the size distribution of microcapsules is influenced by the method of encapsulation and by the process parameters used. Since the size of the microcapsules affects the release rate of the encapsulated substance, an accurate characterization of the size distribution is important. S i e v i n g and Coulter Counter methods have been used for the size determination of microcapsules (32). Usage of

microencapsulation

in p h a r m a c y .

The

first practical

application of microencapsulation was in the printing industry in the 1950s when it was used in production of carbonless copying paper (1). Microencapsulation has since been used for a variety of applications in many other fields, e.g. in the food, chemical, agriculture, cosmetic and pharmaceutical industries. W i t h i n the pharmaceutical industry microencapsulation has mainly been used for: changing liquids into solids, masking unpleasant taste or odor, protecting drugs from the e n v i r o n m e n t (moisture, o x i d a t i o n ) , m o d i f i c a t i o n o f the d r u g dissolution profile, decreasing the evaporation of volatile substances, preventing incompatibility, improving the p o w d e r flow characteristics and obtaining controlled/sustained release of drugs. In a sustained release formulation, the microcapsules can be presented as powder, capsules or tablets, or they are suspended i n liquid formulations for parenteral use. Microcapsules usually exhibit high mechanical resistance and are able to withstand abrasion and other damage during the manufacturing procedure and subsequent storage. However, there has been some concern that microcapsules might loose their integrity during tableting causing increased release rate of the active ingredient (35, 36). O n the c o n t r a r y , several researchers have demonstrated that in many instances compression of microcapsules results in substantial prolongation of the release of the active ingredient (37-39). One of the determining factors in drug release f r o m tableted m i c r o c a p s u l e s is the structure of the microcapsules, with matrix type microcapsules being more resilient than microcapsules consisting of thinly coated drug crystals. Other determining factors are compression pressure (40, 41), core to w a l l





177

ratio and size distribution (40), the excipients used (39-41), flow characteristics (43) and other manufacturing conditions (37) . One of the first drugs to be microencapsulated was aspirin and other N S A I D s , including indomethacin (44), ibuprofen (45, 46) and naproxen (47). Other examples of microencapsulated drugs are propranolol (48), theophylline (49, 50), isoniazid (51) and potassium chloride (52). Steroids have been encapsulated for prolonged release, especially for the release of contraceptive steroids (53) and parenteral usage o f microencapsulated drugs have s h o w n clear advantages targeted delivery systems and in parenteral sustained drug (54-56). Anticancer drugs w h i c h have rapid clearance and toxic side effects are obviously good candidates for microencapsulation (57, 58). Release mechanism for microencapsulated drugs can be diffusion through the coating material, release through the pores of a matrix or by disruption or erosion of the coating. In many cases an initial "burst effect" is seen, w h i c h is probably caused by dissolution of free drug on or near the surface of the microcapsule (56). The release of drugs from microcapsules usually follow first order kinetics but zero order release kinetics are sometimes obtained (32). Coating

materials

used

for

microencapsulation.

To

a large

extent the polymeric coating material controls the microcapsule properties. The choice of coating material is governed by the purpose of encapsulation. If the aim is to obtain sustained/controlled release, then the coating material should facilitate a sufficient reduction in the dissolution rate of the drug. A considerable variety of polymers have been used for coating in microencapsulation. A prerequisite for the coating material is its good stability, and formation of a continuous f i l m w h i c h adheres to the core. Ethylcellulose is the polymer w h i c h has been most commonly used in the microencapsulation of drugs for oral use. It forms a strong, flexible f i l m stable against both heat and l i g h t , a n d is therefore a most s u i t a b l e c a n d i d a t e for microencapsulation (59, 60). For the microencapsulation of drugs intended for parenteral use (injections or implanting) biodegradable polymers have been used (61). Release from biodegradable polymers is by diffusion through the polymer and by polymer degradation. If the polymer degradation is rapid, then the release of drug could become erratic and it is therefore desirable the polymer is degraded at a considerably slower rate than the drug release (1). A wide range of natural and synthetic biodegradable polymers have been investigated but most attention has been focused o n poly(lactic acid), poly(glycolic) acid and poly(lactide-co-glycolide)



178


(54, 61-63). The properties of poly(lactic acid) depend to a large extent upon whether the polymer is synthesized from the o p t i c a l l y active L-lactic acid or the optically inactive racemic mixture D L - l a c t i c acid. P o l y ( L - l a c t i c acid) is a semicrystalline polymer and p o l y ( D L lactic acid) is amorphous but the crystallinity of poly(lactide-coglycolide) is dependent upon the ratio of the two components, with less than 70 % glycolide resulting in an amorphous polymer (62). T h e release rate of drugs from poly(lactic acid) is affected by the crystallinity of the polymer and its molecular weight. Jalil and N i x o n (64) reported that the molecular weight of poly(L-lactic acid) affected the microcapsule structure, w i t h the high molecular weight p o l y ( L lactic acid) f o r m i n g a more porous structure than low molecular weight p o l y ( L - l a c t i c acid). B o d m e i e r and C h e n (65) found, w h e n w o r k i n g with mixtures of high and low molecular weight p o l y ( D L lactic acid), an increase in the release rate with an increase in the low molecular weight fraction in the mixture. Microencapsulation

of

water-soluble

2-hydroxypropyl-p-

cyclodextrin c o m p l e x e s . W e have tested several methods for preparing microcapsules containing d r u g - c y c l o d e x t r i n complexes, i n c l u d i n g microencapsulation o f the l y o p h i l i s e d d r u g - c y c l o d e x t r i n c o m p l e x . H o w e v e r the most c o n v e n i e n t method for preparing microcapsules containing water-soluble drug-cyclodextrin complexes is the solvent evaporation process. The original (O/W) version o f the solvent evaporation process involves the making of an emulsion where the disperse phase consists of a solution of the coating material and the drug to be encapsulated in an organic solvent (methylene chloride or c h l o r o f o r m ) . T h e s o l u t i o n is e m u l s i f i e d in an aqueous phase containing an emulsifier. The organic solvent is then removed by heating or under v a c u u m whereafter the m i c r o c a p s u l e s can be separated by décantation and filtration. T h e solvent evaporation method of microencapsulation gives microcapsules containing the encapsulated drug dispersed throughout a p o l y m e r i c matrix. T h e particles obtained may present various internal structures depending upon the nature of the components and on the ratio o f drug to coating m a t e r i a l . M o s t l y three p h y s i c a l states are d i s t i n g u i s h a b l e i.e. metastable molecular dispersion, stable molecular dispersion and crystalline dispersion (45). The amount of drug in the microcapsule depends both on the ratio o f drug to coating material and the s o l u b i l i t y of the drug in the processing m e d i u m , i.e. unless the drug is relatively insoluble i n the processing medium a proportion of the drug w i l l be lost f r o m the microcapsules during preparation. Several process parameters (e.g. type and concentration of emulsifier, rate of stirring, ratio of organic



11.



179

phase to aqueous phase) can be adjusted to control the characteristics of the microencapsulated product. The solvent evaporation method of microencapsulation has been used extensively for the preparation of poly(lactic acid) microspheres (66) but it has not been c o m m o n l y used for other coating materials. The solvent evaporation method is particularly suitable for the encapsulation of slightly-soluble materials in a hydrophobic polymer. T h e microencapsulation of water-soluble drugs is not practical using the O/W version of the solvent evaporation technique described above as the drug w o u l d to a great extent be lost to the aqueous phase. Tsai et al. reported using a W/O version of the solvent e v a p o r a t i o n technique where the drug and the coating polymer were dissolved i n acetonitrile and then dispersed in l i q u i d paraffin (67). H u a n g and Ghebre-Sellassie reported the use of ethanol as the dispersed phase (68). T h i s method, using ethanol for the disperse phase, was a p p l i c a b l e for the m i c r o e n c a p s u l a t i o n o f the water-soluble 2 hydroxypropyl-β-cyclodextrin c o m p l e x e s w i t h e t h y l c e l l u l o s e . However when it came to the microencapsulation using poly(DL-lactic acid) the method had to be modified due to the low solubility of the coating polymer in ethanol. B y using methylene chloride as the dispersed phase it was possible to dissolve the poly(DL-lactic acid) but the 2-hydroxypropyl-|îrcyclodextrin complex was suspended in that solution. Preparation

of

microcapsules

The microcapsules containing water-soluble drug-cyclodextrin complexes were prepared by the e m u l s i o n - s o l v e n t evaporation method (69) and f o l l o w i n g is a short description of this method. The coating vessel described in Fig.2 was used. W h e n using ethylcellulose as coating material it was dissolved in ethanol, then diethyl phthalate, cyclodextrin and finally the drug were added and dissolved in the polymeric solution, w h i c h formed the disperse phase of the emulsion (Fig. 2). The exact drug-cyclodextrin ratio depends on how m u c h drug is incorporated into the c y c l o d e x t r i n derivative used in the experiment, and the i n c o r p o r a t i o n was determined f r o m d r u g cyclodextrin phase-solubility diagram obtained in aqueous solutions (31). In our experiments we mainly used hydrocortisone as a sample drug and the c y c l o d e x t r i n d e r i v a t i v e was 2 - h y d r o x y p r o p y l ^ cyclodextrin. W h e n using poly(DL-lactic acid) as coating material the polymer was dissolved in methylene chloride and after suspending the l y o p h i l i z e d d r u g - 2 - h y d r o x y l p r o p y l ^ - c y c l o d e x t r i n c o m p l e x in the solution, it was dispersed in the continuous phase.



180


-GLASS

SI

STIRRER

= 150 TO

800

RPM

THE DISPERSE PHASE (ABOUT 100 ml) ^ ^ , Τ Η Ε

Af

F i g u r e 2. the

Apparatus

emulsion-solvent

for

preparation

evaporation

COATING V E S S E L

THE CONTINUOUS P H A S E (ABOUT 300 ml)

of

microcapsules

method.


by



181

The continuous phase of the emulsion was composed of n-heptane (90 m l ) , paraffin p r e l i q u i d u m P h . E u r . (180 ml) and sorbitan monooleate (2.7 to 8.1 ml). The two phases were m i x e d in the coating vessel and the mixture stirred continuously at a rate of 150800 rpm under ambient conditions until all solvent had evaporated (19-48 h). The microcapsules formed were then filtered, washed with η-heptane, and dried for one hour in a vacuum oven at 55°C.


Release

studies

The release studies were carried out in the U S P X X I I described paddle apparatus for dissolution rate determination. T h e release rate was determined at 37±1°C and 100 rpm by a d d i n g m i c r o c a p s u l e s equivalent to 5 mg of the drug to 500 m l of simulated gastric fluid T S U S P X X I I p H 7.50 (without e n z y m e ) , 1% 2 - h y d r o x y p r o p y l - P c y c l o d e x t r i n or 0 . 0 2 % polysorbate 80 i n simulated gastric f l u i d . Samples (1.5 ml) were withdrawn at various time intervals, filtered through 0.45 m m membrane filters ( M i l l e x - H V ; M i l l i p o r e , U . S . A . ) and analysed by high-performance l i q u i d chromatographic ( H P L C ) methods. Results a n d

discussion

W e have successfully microencapsulated several water-soluble drugc y c l o d e x t r i n c o m p l e x e s by the described method, i n c l u d i n g a 2 - h y d r o x y p r o p y l - a - c y c l o d e x t r i n complex of carboplatin a n d 2 - h y d r o x y p r o p y l - p - c y c l o d e x t r i n complexes of d e x a m e t h a s o n e , 1 7 p - e s t r a d i o l , h y d r o c o r t i s o n e and m e t h y l p r e d n i s o l o n e . The preparation was very simple and the drug-cyclodextrin complex was formed during the evaporation of the disperse phase. The products consisted of regularly shaped spherical microparticles with a smooth surface (Fig. 3). The average drug loading of the microcapsules was determined to be between 2 and 4 % . F i g . 4 shows the effect of a plasticizer, i.e. diethyl phthalate, on the release of hydrocortisone from ethylcellulose microcapsules. The release rate of hydrocortisone from microcapsules consisting only of a hydrocortisone - 2 - h y d r o x y p r o p y l - p - c y c l o d e x t r i n complex and the ethylcellulose polymer is very slow. A b o u t 3 0 % of the drug was released w i t h i n the first 150 m i n . Similar results were obtained w i t h ethylcellulose microcapsules containing a 17p-estradiol 2 - h y d r o x y p r o p y l - p - c y c l o d e x t r i n complex (Fig. 5). A d d i t i o n of a plasticizer significantly increases the release rate and it could in fact be c o n t r o l l e d by the amount of p l a s t i c i z e r added d u r i n g the microcapsule production. A d d i t i o n of plasticizers, w h i c h improves the flexibility of the ethylcellulose polymer chains and also reduces the



182


Figure 3. Scanning electron micrographs of microcapsules containing a hydrocortisone 2-hydroxypropyl-P c y c l o d e x t r i n complex, 170x enlargement. T h e coating material was ethylcellulose.


11.



183


100η

0-+^ 0

1

1

1

50

100

150

π 200

1 250

Time (min) Figure 4. T h e effect of the p o l y m e r - p l a s t i c i z e r (i.e. ethylcellulose - diethyl phthalate) ratio on the release of hydrocortisone from microcapsules containing a hydrocortisone - 2 - h y d r o x y p r o p y l - P - c y c l o d e x t r i n complex: 1:3, Ο ; 1:1, 0 ; 2:1, • ; 3:1, Δ ; 9:1, Ο ; only ethylcellulose, V · The total amount of the polymer and plastizer used was kept constant at 2.00 g per 1.00 g hydrocortisone - 2 - h y d r o x y p r o p y l - P - c y c l o d e x t r i n complex. (Reproduced with permission from ref. 69. C o p y r i g h t 1992 T a y l o r & Francis.)


184



100 π

βο π

Time

(min)

F i g u r e 5. T h e effect o f the p o l y m e r - p l a s t i c i z e r (i.e. e t h y l cellulose - d i e t h y l p h t h a l a t e ) r a t i o o n the r e l e a s e o f 17βe s t r a d i o l f r o m m i c r o c a p s u l e s c o n t a i n i n g a 17p-estradiol - 2h y d r o x y p r o p y l - P - c y c l o - d e x t r i n complex: 1:3, • ; 2:1, • ; 9:1, #; o n l y e t h y l c e l l u l o s e , Ο - T h e t o t a l a m o u n t o f the p o l y m e r a n d p l a s t i c i z e r u s e d was k e p t c o n s t a n t at 2.00 g p e r l.Og 17p-estradiol-2-hydroxypropyl-P-cyclodextrin complex.



11.



185

total amount of polymer in the microcapsules apparently opens up the polymer network w h i c h results in a faster drug release. A l s o , the plasticizer used forms a rather labile inclusion complex with 2 - h y d r o x y p r o p y l - P - c y c l o d e x t r i n and, thus, can accelerate the drug release by competing with the drug for the cyclodextrin cavity. F i g . 6 shows the effect of surfactant, i.e. sorbitan monooleate, on the release of hydrocortisone f r o m polylactic acid m i c r o c a p s u l e s c o n t a i n i n g a hydrocortisone - 2 - h y d r o x y p r o p y l - p - c y c l o d e x t r i n complex. Increasing the amount of surfactant results in more dense polymer network w h i c h results in a slower drug release. F i g . 7 shows the effect of the dissolution medium on the release rate of hydrocortisone from ethylcellulose microcapsules and the results are compared to the dissolution of free (uncoated and uncomplexed) hydrocortisone under the same conditions. The results show that while the dissolution of free hydrocortisone was accelerated by addition of a surfactant or the water-soluble complexing agent a 2 - h y d r o x y p r o p y l - P - c y c l o d e x t r i n c o m p l e x the release rate of hydrocortisone from the microcapsules is virtually unaffected. The dissolution of uncoated hydrocortisone - 2 - h y d r o x y p r o p y l - p - c y c l o d e x t r i n c o m p l e x was almost instantaneous under these same conditions. 40Ί

$30

ΟH

1

0

50

1

1

100

150

Time

—

1

200

1

250

(min)

Figure 6. The effect of amount of surfactant, sorbitan monooleate, added to the continuous phase on the release of hydrocortisone from poly(DL-lactic acid) microcapsules containing a hydrocortisone 2-hydroxypropyl-Pcyclo-dextrin complex. The per cent amount of surfactant in the disperse phase: • , 1%; Δ , 2 % ; Ο , 3 % .



186


50

100

150

200

250

Time (min)

Figure 7. The effect of dissolution medium composition on the release of h y d r o c o r t i s o n e from ethylcellulose microcapsules (polymer-plasticizer ratio 2:1) containing water-soluble hydrocortisone 2-hydroxypropyl-Pcyclodextrin complex and on the dissolution of free (i.e. uncoated and uncomplexed) hydrocortisone. Free hydrocortisone, closed symbols; microcapsules containing hydrocortisone 2-hydroxypropyl-P-cyclodextrin complex, open symbols: Ο and • , 0.02% polysorbate 80 in simulated gastric fluid; Ο and # , 1% 2 - h y d r o x y p r o p y l β-cyclodextrin in simulated gastric fluid; Δ and A > simulated gastric fluid. (Reproduced with permission from ref. 69. Copyright 1992 Taylor & Francis.) Conclusion A hydrophile/lipophile version of the emulsion-solvent evaporation method can be used to prepare microcapsules of water-soluble drug c y c l o d e x t r i n complexes of l i p o p h i l i c water-insoluble drugs. L i p o p h i l i c water-insoluble drugs possess inherent s l o w release properties w h i c h can l i m i t their release rate f r o m slow-release m i c r o c a p s u l e systems. T h e p h y s i c a l characteristics of the microcapsules prepared could result i n better control o f the release rate of this type of drugs, i.e. make the release independent of the aqueous solubility of the drug. Acknowledgement T h i s w o r k was supported by a grant from the Icelandic Science Foundation. Technical support was provided by K . Ingvarsdottir and J . Baldvinsdottir.


11.

LOFTSSON & KRISTMUNDSDÓTTIR

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