Microspheres as Controlled-Release Systems for ... - ACS Publications

Chapter 15

Microspheres as Controlled-Release Systems for Parenteral and Nasal Administration 1

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S. S. Davis , L. Ilium , D. Burgess , J. Ratcliffe , and S. N. Mills 1

Department of Pharmacy, University of Nottingham, Nottingham NG7 2RD, United Kingdom Department of Pharmaceutics, Royal Danish School of Pharmacy, 2 Universitetsparken, 2100 Copenhagen, Denmark

Downloaded by CORNELL UNIV on July 22, 2016 | http://pubs.acs.org Publication Date: September 4, 1987 | doi: 10.1021/bk-1987-0348.ch015

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Microspheres made from natural and synthetic polymers can be used as drug delivery systems for administration by injection, ie intravenous, intramuscular and intraarticular or by the nasal route. The microspheres reach their site of action by exploitation of some suitable passive mechanism (entrapment in capillary beds or uptake by macrophages) or by a direct application into the relevant body compartment. Systems intended for use in man need to be biocompatible and biodegradable if given via the parenteral route. Possible materials include albumin, modified starch and synthetic polymers such as polylactic acid and polycyanoacrylates. A variety of microsphere systems have been investigated in vitro and in vivo and attempts have been made to overcome two major limitations of microsphere systems, namely poor entrapment (payload characteristics) and premature release (burst effect). Sustained release systems have been achieved by appropriate use of crosslinking, heat denaturation, macromolecular carriers or chemical modification. In vivo experiments exploiting the technique of gamma scintigraphy are described. In recent years there has been considerable interest i n the use of colloidal c a r r i e r s , to include microspheres, as a means of d e l i v e r i n g drugs (1-3). A wide variety of systems has been proposed and examined (Table I) and the applications have included not only controlled release formulations but also systems intended for the s p e c i f i c delivery of drugs to target s i t e s . In t h i s respect microsphere systems have been employed i n similar ways to liposomes and emulsions (sometimes termed l i p i d microspheres). Microspheres based upon mixtures of p o l y l a c t i d e and polyglycolide are now finding interesting applications f o r the delivery of the products of biotechnology (namely peptides and proteins). In v i t r o 0097-6156/87/0348-0201$06.00/0 © 1987 American Chemical Society

Lee and Good; Controlled-Release Technology ACS Symposium Series; American Chemical Society: Washington, DC, 1987.

CONTROLLED-RELEASE TECHNOLOGY

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TABLE I. Microsphere systems f o r drug delivery Albumin Starch Gelatin Ethylcellulose P o l y ( D L - l a c t i c acid) Poly(D,L-lactide-co-glycolide) Polyhydroxybutyrate Polyalkylcyanoacrylate


f

and i n vivo evaluations of microsphere systems containing LHRH and vasopressin analogues have been described (4). Detailed reviews on the use of microspheres f o r drug delivery can be found i n recent publications (1-3). This paper w i l l describe j o i n t work conducted i n Nottingham and Copenhagen on the design and evaluation of microsphere systems that w i l l have applications as controlled release systems for delivering drugs intravenously, intramuscularly, into knee joints ( i n t r a a r t i c u l a r l y ) and l o c a l l y into the nasal cavity. The microspheres have been prepared from natural materials such as albumin or synthetic polymers. Depending upon t h e i r application the p a r t i c l e s have ranged i n size from 40 micron to less than 1 micron diameter. In a l l instances the p a r t i c l e s have comprised a homogeneous matrix rather than microencapsulated systems. The requirements f o r a drug delivery system based upon a c o l l o i d a l p a r t i c l e are easy to l i s t but often are much more d i f f i c u l t to achieve both i n v i t r o as well as i n vivo (Table I I ) . TABLE I I . Requirements Must Must Must Must Must Must

f o r microsphere drug delivery systems

accumulate at required s i t e release drug at appropriate rate be stable i n v i t r o be non-toxic be biodegradable and biocompatible be non-immunogenic

In our own experience the major l i m i t a t i o n s i n using microspheres as controlled release systems have been the b i o l o g i c a l a c c e p t a b i l i t y of the p a r t i c l e s , the payload of drug that can be incorporated into the microsphere and poorly defined release characteristics. The l a s t l i m i t a t i o n i s probably the most severe in that i t has been found extremely d i f f i c u l t to provide well defined release c h a r a c t e r i s t i c s of drugs from microspheres over long time periods because of biodégradation and the interaction of tissue components with the microspheres themselves or the tissue space into which they are delivered. In addition, studies with albumin-based systems have been plagued with the so-called "burst e f f e c t " problem where a large portion of the dose i s released rapidly (5). These limitations and methods by which they can be overcome w i l l be discussed i n r e l a t i o n to the d i f f e r e n t routes of administration.


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Microspheres as Controlled-Release Systems


Parenteral administration of microspheres Intravenous delivery. Microspheres have often been used f o r the purposes of drug delivery and targeting following parenteral administration. Small microspheres (less than 7 micron) administered intravenously normally w i l l be removed rapidly and efficiently by the c e l l s of the reticuloendothelial system, p a r t i c u l a r l y the Kupffer c e l l s i n the l i v e r . In theory t h i s presents a p o s s i b i l i t y f o r d i r e c t i n g drugs to t h i s organ and, i f the p a r t i c l e s were slowly degraded, also to provide some form of controlled release e f f e c t . However, uptake of p a r t i c l e s by macrophages can have undesirable consequences. For example suppression of the reticuloendothelial system by overloading with microspheres may be disadvantageous to c l i n i c a l practice and, i n addition, the microspheres may give r i s e to immunogenic e f f e c t s . Recently, an interesting contribution by Artursson et a l (6), on the use of polyacryl starch microspheres f o r the delivery of proteins, has described how starch microspheres themselves were non-immunogenic but when they contained a protein (bovine serum albumin) an immune response was found, not only f o r the protein but also f o r the microspheres. Indeed i t was reported that the starch microspheres were a potent adjuvant to the immune response. These immune reactions and the associated release of b i o l o g i c a l response modifiers by macrophages i s known to be dependent upon physical and chemical properties of the p a r t i c l e s , i n particular their biodegradability. Leaving aside the problems a f f e c t i n g the interaction of microspheres with the reticuloendothelial system, one simple application of microspheres f o r delivery t o the vascular compartment i s t h e i r d i r e c t i o n to the lungs. If microspheres are reasonably large i n size (more than about 10 micron) they w i l l be retained after intravenous administration by a simple process of mechanical entrapment i n the c a p i l l a r y beds of the lungs. This process has been employed f o r many years i n diagnostic imaging (7^ · The same process has been used f o r drug delivery and examples of possible c l i n i c a l applications have included the treatment of respiratory disease (emphysema) and f o r cancer chemotherapy (Q). Biodegradable albumin microspheres have been shown to lodge within the c a p i l l a r y networks of the lungs and then, by a process of biodégradation and d i f f u s i o n , to release the incorporated agent (9). In t h i s respect Willmott and others (9) have reported problems with the above mentioned burst e f f e c t where most of an incorporated anticancer agent (adriamycin) was released soon a f t e r administration, although the remaining small proportion of the dose did achieve a limited controlled release e f f e c t . The rapid and e f f i c i e n t uptake of p a r t i c l e s into organ s i t e s (eg l i v e r and lungs) following intravenous administration can be measured i n animal models using the non-invasive technique of gamma scintigraphy. The combined graph and scintiscan shown i n Figure 1 was obtained using rabbits f o r the administration of ion-exchange microspheres (based upon DEAE-cellulose) into which the model material rose bengal (labeled with iodine-131) had been incorporated through an ion-exchange mechanism. The release of the marker (model drug) from these microspheres was followed using the same non-invasive technique and the release p r o f i l e s f o r free and


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microsphere bound rose bengal are shown i n Figure 2 (10). Other methods of c o n t r o l l i n g the release of the drug could be employed such as covalently binding the drug to the microsphere or attaching the drug to a macromolecule inside the microsphere (macromolecular prodrug design). An important question concerns the tissue concentrations that can be achieved i n delivery by the physical entrapment method. Whether a given dose of microspheres w i l l provide a s u f f i c i e n t l y high l e v e l of drug at the s i t e of action w i l l depend upon the a c t i v i t y of the agent, the loading capacity and release c h a r a c t e r i s t i c s of the microsphere system and the number of c a p i l l a r y beds that can be blocked without causing undue hazard to the patient. These questions have been addressed i n d e t a i l i n the f i e l d of radiodiagnostic imaging where albumin microspheres are used for lung scanning purposes (11). In a related form of application, biodegradable starch microspheres (Spherex) have been administered i n t r a a r t e r i a l l y adjacent to the organs of interest as a way of providing a temporary embolism. In t h i s way a drug substance can be held within a given tissue region for a period of time defined by the biodegradability of the system (12). Albumin microspheres for intramuscular and intraarticular administration. In theory a wide variety of materials exists for the design of controlled release dosage forms for the administration to man, but only a small number of these w i l l be acceptable to regulatory authorities unless detailed and costly t o x i c o l o g i c a l investigations are carried out (13). Recently, we have studied a number of d i f f e r e n t microsphere materials f o r use as c a r r i e r s for steroids with reference to i n t r a a r t i c u l a r therapy (14). The objective was to design a system, administered to the patient approximately once a month, that would provide controlled release of steroid within the knee j o i n t . Albumin, g e l a t i n , polylactide and polycyanoacrylate were examined as potential microsphere materials by h i s t o l o g i c a l tests and studies on t h e i r interaction with macrophages. On the basis of these biocompatibility investigations, albumin was selected as being the best material. The polycyanoacrylates appeared to cause quite severe tissue responses. Albumin microspheres for IM and I - a r t i c u l a r administration have been prepared using two d i f f e r e n t methods; heat s t a b i l i z a t i o n and crosslinking with glutaraldehyde. A scheme f o r the preparation of such microsphere systems i s shown i n Figure 3. Both methods of preparing the albumin microspheres have t h e i r advantages and disadvantages and detailed discussions on the r e l a t i v e merits of d i f f e r e n t methodologies have been given by Sokolosky, Goldberg and t h e i r colleagues (15,16). We have found that crosslinking with glutaraldehyde provided albumin microspheres that were r i g i d and resistant to swelling i n aqueous environments. However, a corresponding change i n release c h a r a c t e r i s t i c s was observed. The release rate of a marker material (labeled prednisolone) increased with increase i n the amount of glutaraldehyde added i n the crossl i n k i n g process. Thus, the microspheres became more r i g i d but also more porous with increasing amounts of glutaraldehyde and crosslinking i t s e l f i s not an e f f e c t i v e mechanism i n reducing the d i f f u s i o n of the low molecular weight material. In comparison heat


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100r

Time (min)

F i g u r e 1. The uptake o f ion-exchange m i c r o s p h e r e s i n t h e lung r e g i o n .

(40-120 urn)

IOOIT

70

1

' • Lung - microspheres and Rose Bengal

• Lungs-free Rose Bengal

I 0

I 1

I 2

I 3

I 4

I 5

I 6

I 7

1

8

Time (days)

F i g u r e 2. The r e l e a s e o f i o d i n e - 1 3 1 the l u n g r e g i o n o f t h e r a b b i t .

labeled

rose

bengal


from


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s t a b i l i z a t i o n was found t o be a much more e f f e c t i v e way of reducing the release of steroids (Figure 4 ) but such a technique i s limited to compounds that are i n s e n s i t i v e to elevated temperatures. Possible ways of reducing the release of low molecular weight materials from microspheres are now being examined. These include the coating of microspheres with an additional layer of polymeric material (eg albumin i t s e l f or a complex coacervate phase) and the attachment of the drug to a high molecular weight carrier (macromolecular prodrug) (eg albumin, dextran) i n order to reduce the rate of d i f f u s i o n . This p r i n c i p l e has been exploited by Yoshioka et a l (Γ7) who incorporated mitomycin C covalently bound to dextran into g e l a t i n microspheres and found a highly reduced release rate of mitomycin C compared to the incorporation of the free drug into the microspheres. While a range of macromolecular c a r r i e r s i s available and can be evaluated i n v i t r o , t h e i r a c c e p t a b i l i t y and biodégradation i n vivo need to be followed closely. Albumin microspheres, s t a b i l i z e d by the glutaraldehyde and heat s t a b i l i z a t i o n methods, have been administered intramuscularly to rabbits and evaluated using the technique of gamma scintigraphy as well as measurement of blood levels (18). Table III shows data obtained after the intramuscular administration of albumin microspheres crosslinked with glutaraldehyde and containing 131-1 labeled rose bengal and the influence of crosslinking on the release of the material. The addition of 5% glutaraldehyde gave r i s e to a s i g n i f i c a n t delay i n the release of the marker from the i n j e c t i o n s i t e as compared to free material. The mechanism of delayed release i s believed t o be a combination of d i f f u s i o n from the microsphere and quite rapid biodégradation of the microsphere material. Measurement of the l i v e r uptake of rose bengal by gamma scintigraphy showed c l e a r l y the change i n the k i n e t i c pattern of release of t h i s material from the s i t e of i n j e c t i o n when incorporated into microspheres. The peak i n l i v e r uptake that occurred between 1 and 2 days a f t e r administration was found t o be reduced more than 50%. The appearance of triamcinolone (labelled with tritium) i n the blood of rabbits following intramuscular adminstration has been evaluated f o r microsphere systems prepared using the heat denaturation method (Figure 5). A c h a r a c t e r i s t i c change i n the release c h a r a c t e r i s t i c s of the drug was achieved. The i n t r a a r t i c u l a r administration of microspheres represents a d i s t i n c t c l i n i c a l opportunity provided that a controlled release of an administered agent can be achieved over a period of weeks, thereby reducing the frequency of quite painful injections into joints. One strategy using microsphere systems i s to arrange f o r t h e i r uptake from the synovial cavity into the synovium through a process of phagocytosis by l o c a l macrophages. The controlled release microsphere residing within the macrophage (lysosomal compartment) should then degrade slowly releasing the drug i n order to control inflammation. R a t c l i f f e (19) has demonstrated that the c r i t i c a l size f o r uptake of p a r t i c l e s by macrophages i s i n the region of 6-9 micron diameter and studies on the d i s t r i b u t i o n of a radiolabel following i n t r a a r t i c u l a r administration of microspheres have indicated that the majority of the dose was located i n the synovium. The biodégradation of the albumin microspheres


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HIGHLY PURE • LIVE QIL

AQUEOUS ALBUMIN SOLUTION WITH ADDED DRUG


WATER-IN-OIL EMULSION Mixed in bet fled cell

ADD GLUTARALDEHYDE ( 1 - 5 " , venous times)

CHEMICALLY STABILIZED MICROSPHERES

HEAT ( 1 0 0 - 1 6 0 ° C)

HEAT STABILIZED MICROSPHERES

Figure 3. The preparation of albumin microspheres.

30 Time (hrs)

The i n v i t r o release of prednisolone from heat Figure 4. s t a b i lLi i z e d albumin microspheres (isotonic buffer, pH 7, 37°C) - effect 3C of heating time a t 160°C; • no heating; Ο 3h; • 6h; Δ12h; • 24h.


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TABLE I I I . Intramuscular administration of albumin microspheres containing 131-iodine labeled rose bengal to rabbits (mean + sem) (n = 3)


System

Injection site activity at 3d (% i n i t i a l dose)

Whole body a c t i v i t y at 3d (% i n i t i a l dose)

Peak l i v e r a c t i v i t y (% i n i t i a l dose)

Aqueous solution

2.5 + 1.2

16.0 ± 2.5

10.6 ± 1.2

Microspheres cross-linked by 1% glutaraldehyde

5.5 ± 1.3

28.5 + 5.2

7.2 +.0.66

Microspheres cross-linked by 5% glutara1dehyde

19.8 ± 1.6

60.0 + 2.0

5.1 ± 0.4

ioo%-

0

50

100 Tim« (hrs)

150

200

Figure 5. The release of t r i t i a t e d triamcinolone from an intramuscular s i t e . • heat s t a b i l i z e d albumin microspheres - 12h at 150°C, t release i n v i t r o = l h V heat s t a b i l i z e d albumin microspheres - 40h at 150°C, 50% * i= 9.2h # suspension t

r

e

l

e

a

s

e

n

v

t

r

o


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themselves has been measured by studying the fate of microspheres (prepared using albumin labeled with iodine-131) and comparing activity-time p r o f i l e s for microsphere systems (t = 3d) with free sodium iodide as the control system < t = l(J mins). The same microsphere systems were used to deliver a model compound (iodine-131 rose bengal). A clear difference between the control system (rose bengal solution) and the microsphere encapsulated system was observed (Figure 6). Interestingly, i n these experiments the release of the rose bengal from the a r t h r i t i c j o i n t was slower than from the normal j o i n t . This i s believed to be due to the interaction of rose bengal with a higher l e v e l of protein present i n the inflamed t i s s u e . While a delay i n the release of a drug has been achieved using a microsphere system, the release of the marker (as well as steroids) i s s t i l l too rapid for any c l i n i c a l application and alternative methods f o r delaying the d i f f u s i o n of the drug from the matrix of the microsphere are being investigated. Larger heat s t a b i l i z e d microspheres (23 micron diameter) containing triamcinolone also provide a controlled release e f f e c t (Figure 7). However, as with the glutaraldehyde system the release i s delayed over a period of days rather than the desired period of weeks.


5 Q %

Nasal administration. Apart from parenteral administration, controlled release dosage forms based upon the microsphere concept should have application to other routes of administration. Microspheres i n the form of p e l l e t s have been used to d e l i v e r drugs to the gastrointestinal t r a c t and other examples include the administration of microspheres to the eye and t o p i c a l l y to the lungs. In recent studies Ilium (20^) has employed microspheres as possible controlled release formulations for nasal application. Such studies have relevance to the delivery of novel macromolecular compounds such as peptides and proteins. The nasal application of drugs i s an area of growing i n t e r e s t (21) and a number of publications has shown that simple molecules as well as more complex species (eg c a l c i t o n i n , i n s u l i n etc) can be well absorbed by this route, either d i r e c t l y or i n the presence of so-called absorption enhancers. One problem with such materials could be too rapid clearance of the delivery system from the nasal cavity through the e f f i c i e n t action of the mucociliary system. For t h i s reason Ilium has considered the use of microsphere systems. The e f f i c i e n t trapping of a microsphere system i n the nose will be very dependent upon the size and the surface characteristics (such as the bioadhesive properties) of the microspheres. Suggestions have been made i n the l i t e r a t u r e (20) that p a r t i c l e s larger than 10-15 micron should be suitable for t h i s purpose as they w i l l deposit within the nasal cavity a f t e r application and not find t h e i r way into the lungs. Studies have been conducted i n human volunteers using a variety of microsphere systems with good bioadhesive properties employing the technique of gamma scintigraphy (20 ). The microspheres were labeled with a technetium complex and powder and solution forms were used as controls. Representative data for the clearance of the microspheres from the nasal cavity are shown i n Table IV.



210


Time (days)

Figure 6. Clearance of iodine-131 rose bengal from normal and a r t h r i t i c rabbit knee joints • rose bengal solution - normal j o i n t Ο rose bengal solution - a r t h r i t i c j o i n t • rose bengal i n glutaraldehyde cross-linked microspheres - normal joint • rose bengal i n cross-linked albumin microspheres a r t h r i t i c joint



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0

211


50

100 Tim« (hrs)

150

200

Figure 7. Intraarticular administration of tritiated triamcinolone • Suspension • Heat s t a b i l i z e d albumin microspheres, 12h at 150 C, t release i n v i t r o = l h V Heat s t a b i l i z e d albumin microspheres, 40h at 150 C, t__. release i n v i t r o = 9.2h o

o


212


TABLE IV. Retention of 99m-technetium-labeled nasal cavity i n human subjects (n = 6) System

i n the

% of t o t a l a c t i v i t y a f t e r 180 min

Solution Powder Albumin microspheres Starch microspheres DEAE-Sephadex microspheres


formulations

19.9 17.0 44.0 49.6 63.3

The microspheres based upon starch and DEAE-Sephadex were e f f e c t i v e in delaying nasal mucociliary clearance. Albumin was l e s s e f f e c t i v e than these two but more e f f e c t i v e than the control powder and solution dosage forms. For the Sephadex system, more than 60% of the r a d i o a c t i v i t y i s retained within the nose at 3 hours. Other experiments are now underway to determine whether starch, albumin and Sephadex microspheres may have u t i l i t y as controlled release systems for d e l i v e r i n g a variety of agents v i a the nasal route. Not only could the drug be incorporated into such a system but absorption enhancers could also be delivered i n t h i s way. The retention of the drug plus the enhancing agent on the nasal mucosa for extended periods of time could well lead to improved b i o a v a i l a b i l i t y of complex species such as peptides and proteins. Conclusions Microspheres made from various biodegradable materials have potential as controlled release systems f o r parenteral and f o r nasal administration. Microspheres prepared i n suitable sizes can be loaded with a variety of drugs and the drug can be released at a controlled rate at the desired s i t e i n the body. Sustained release systems can be obtained by modifying the method of microsphere preparation or by modifying the drug (eg prodrug or macromolecular prodrug design).

Literature Cited 1.

Davis, S.S.; Illum, L.; McVie, J.G.; Tomlinson, E., Eds; "Microspheres and Drug Therapy"; Elsevier: Amsterdam, 1984.

2.

Widder, K.J.; Senyei, A.E.; Sears, B. J. Pharm. Sci. 1982, 71, 379-387.

3.

Morimoto, Y.; Fujimoto, S. CRC Crit. Rev. Therapeutic Carriers 1985, 2, 19-63.

4.

Sanders, L.H.; Kent, J.S; McRae, G.I.; Vickery, B.H.; Tice, T.R.; Lewis, D.H. J. Pharm. Sci. 1984, 73, 1294-7.

5.

Tomlinson, E. J. Controlled Release 1985, 2, 385-91.



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6.

Artursson, P.; Martensson, I.L.; Sjoholm, I. J. Pharm. Sci. 1986, 75, 697-701.

7.

Davis, S.S.; Frier, M.; Illum, L. In "Polymeric Nanoparticles and Microspheres"; Guiot, P.; Couvreur, P., Eds.; CRC Press: Boca Raton, 1986, pp.175-197.

8.

Davis, S.S.; Hunneyball, I.M.; Illum, L.; Ratcliffe, J.H.; Smith, A.; Wilson, C.G. Drugs Expl. Clin. Res. 1985, 9, 63340.

9.

Willmott, N.; Kamel, H.M.H.; Cummings, J . ; Stuart, J.F.P.; Florence, A.T. In "Microspheres and Drug Therapy"; Davis, S.S.; Illum, L.; McVie, J.G.; Tomlinson, E., Eds.; Elsevier: Amsterdam, 1984, pp.205-215.

10.

Illum, L.; Davis, S.S. J. Pharm. Pharmacol. 1982, 34 Suppl., 89P.

213

11. Davis, M.Α.; Taube, R.A. J. Nucl. Med. 1976, 19, 1209-13. 12. Russel, G.F. Pharm. Int. 1983, 4, 260-3. 13. Tomlinson, E. Int. J. Pharm. Technol. Prod. Manuf. 1983, 4, 49-57. 14. Ratcliffe, J.H.; Hunneyball, I.M.; Smith, Α.; Wilson, C.G.; Davis, S.S. J. Pharm. Pharmac. 1984, 36, 431-6. 15.

Sokolowski, T.D.; Royer, G.P. In "Microspheres and Drug Therapy", Davis, S.S.; Illum, L.; McVie, J.G.; Tomlinson, Ε., Eds.; Elsevier: Amsterdam, 1984, pp.295-307.

16. Longo, W.E.; Iwata, H.; Lindheimer, T.Α.; Goldberg, E.P. J. Pharm. Sci. 1982, 71, 1323-8. 17. Yoshioka, T.; Hashida, M.; Muranishi, Α.; Sezaki, H. Int. J. Pharm. 1981, 8, 13141. 18. Mills, S.N. Ph.D. Thesis, University of Nottingham, 1983. 19. Ratcliffe, J.H. Ph.D. Thesis, University of Nottingham, 1984. 20. Illum, L. In "Drug Delivery Systems for Peptides and Proteins"; Davis, S.S., Illum, L. and Tomlinson, Ε., Eds.; Plenum: New York, 1986, in press. 21. Chien, Y.W., Ed. "Transnasal Systemic Medications: Fundamentals, Developmental Concepts and Biomedical Assessments", Elsevier: New York, 1985. RECEIVED October 10, 1986


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