Poly(hydroxybutyrate-hydroxyvalerate) microspheres containing progesterone: preparation, morphology and release properties.

J. MICROENCAPSULATION,

1991, VOL. 8,

NO.

2, 185-202

Poly(hydr0xybutyrate-hydroxyvalerate)microspheres containing progesterone: preparation, morphology and release properties

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N U T A N GANGRADE and JAMES C. PRICE? College of Pharmacy, The University of Georgia, Athens, Georgia 30602 (Received and accepted 6 July 1990) The biodegradable polyesters, poly(hydr0xybutyrate) (PHB) and poly(hydr0xybutyrate-hydroxyvalerate) (PHBV) were investigated for use as sustained delivery carriers of a model drug, progesterone. Spherical microspheres containing the drug were prepared by an emulsion solvent-evaporation method with gelatin as an emulsifier. Methylene chloride as the polymer solvent yielded smoother microspheres than chloroform. The surface texture was also dependent upon the temperature of the preparation and polymer used. Surface crystals were observed when the drug loading was increased beyond 5 per cent w/w. Thermograms of the microspheres did not show an endotherm corresponding to the melting of the drug because the drug dissolved in the melted polymer while heating. The amount of residual solvent in the microspheres (gas chromatographic assay) ranged from 3.4 to 58.4ppm and was dependent on the processing temperature, concentration of the polymer in the solvent and the polymer composition. In uitro release of the drug was slowest from microspheres made from copolymer containing 9 per cent hydroxyvalerate. A Iess porous microsphere matrix was formed by this copolymer.

Introduction During the last two decades there has been considerable interest and progress in the field of parenteral controlled release systems. T o overcome the problem of surgical removal of the delivery system after the drug reservoir has exhausted, biodegradable polymeric carriers have been developed. Biodegradable polymers for controlled delivery of drugs have been reviewed by several authors (Wood 1980, Heller 1984, Holland et al. 1986, Juni and Nakano 1987). Poly(1actic acid) (PLA) and its copolymers with glycolic acid have been extensively investigated. Films (Yolles et al. 1975, Pitt et al. 1979), beads and rods (Schwope et al. 1975, Wise et al. 1978) and microcapsules and microspheres (Beck et al. 1979, Benita et al. 1984, Suzuki and Price 1985) of PLA and related copolymers have been prepared. P L A and most other biodegradable polymers are prepared by chemical synthesis (Kulkarni et al. 1971). A disadvantage of synthetic polymers is that residues of polymerisation additives may be undesirable, especially if the system has to b e administered parenterally (Wood 1980). Recently, a polyester, poly(hydr0xybutyrate) (PHB) and its copolymers with hydroxyvalerate (HV) have been made available by ICI Chemical Industries (Holmes 1985). Their structures are shown in figure 1. These polymers are entirely natural and are obtained from micro-organisms. T h e major bacterial source of PHBV is a gram-negative bacteria, Alcaligenes eutrophus. PHVB polymers are biodegradable and biocompatible

t T o whom correspondence should be addressed. 0265-2048/91 $3.00 0 1991 Taylor & Francis Ltd.

N . Gangrade and J . C . Price

186


r

(4 Figure 1 .

( a ) Structure of PHB homopolymer. ( b ) Structure of PHBV copolymer.

(Korsatko et al. 1983, Korsatko et al. 1984, Akhtar and Pouton 1989a). Only a few investigations concerning parenteral microspheres of PHB have been reported (Bissery et al. 1984,1985, Juni et al. 1986). T h e use of PHBV polymers as carriers of macromolecular peptides has also been discussed (Akhtar and Pouton 1989 a). T h e objective of this study was to evaluate the potential of PHBV polymers as carriers of a low molecular weight model drug, progesterone (M.W.314). Progesterone is not effective orally except in high doses and has a short elimination halflife (t,,2) in humans (Fylling 1970). Progesterone-loaded microspheres were prepared by an emulsion solventevaporation technique. Morphology and release characteristics of the resulting microspheres were studied as a function of formulation and preparative conditions employed to manufacture the microspheres. A disadvantage of the solvent-evaporation technique is that the solvent may not completely evaporate. This residual solvent in the microspheres can be hazardous to health of the patient receiving the dosage form. There have been no reports in the literature on the quantitation of residual organic solvent in PHBV microspheres. I n this study, the amount of residual methylene chloride in the dried PHBV microspheres was determined by using a gas chromatographic assay method.

Experimental Materials T h e following materials were used as received from the supplier without further purification: PHB homopolymer, PHBV copolymer containing 9 mole per cent HV (PHBV9), and PHBV copolymer containing 24mole per cent H V (PHBV24) (ICI Chemical Industries, Wilmington, DE); progesterone, polyvinyl alcohol, and

Progesterone-loaded P H B V microspheres

187


methyl cellulose (Sigma Chemical Co., St. Louis, MO); methylene chloride and chloroform (J. T. Baker, Inc., Phillipsburg, N.J.); 2-propanol and sodium lauryl sulfate (Fisher Scientific Co., St. Louis, MO); Gelatin (P. Leiner & Sons).

Preparation of microspheres Microspheres were prepared by an emulsion solvent-evaporation method at ambient pressure. Typically, the polymer (0.98 to 3.53 g) and progesterone (20 to 360 mg) were dissolved in a water-immiscible organic solvent (20 ml). T h e solution was poured into the aqueous phase (500 ml) containing 0.5 per cent w/v gelatin. T h e resulting emulsion was stirred vigorously for 1 h at 30°C. T h e microspheres were collected by filtration, washed with water and dried at room temperature. T h e dried microspheres were sieved and stored in a dessicator. Drug content analysis Duplicate samples of 5-10 mg of microspheres were weighed and placed in 50 ml volumetric flasks, containing approximately 20 ml of chloroform. Each flask was heated in a water bath at 50°C for 20minutes to dissolve all the microspheres. Solutions were cooled to room temperature, filled to volume with chloroform and analysed spectrophotometrically at 243-4nm. Drug release studies In vitro drug release studies were done using a USP XXI paddle type dissolution apparatus (Hanson Research). An accurately weighed quantity of 50 to 100 mg of microspheres (125-1 77 pm diameter) were placed in the dissolution medium made of 20 parts by volume of 2-propanol in 80 parts water. T h e maximum concentration of the drug in the dissolution medium was always less than 1/20 the solubility. Periodic samples were withdrawn and assayed spectrophotometrically at 248.2 nm. Graphical data points are an average of dissolution samples from six batches. Drug solubility T o determine the solubility of progesterone in the dissolution medium, excess progesterone was placed in contact with the medium. Triplicate samples were shaken for 72 h at 37°C. T h e samples were filtered through a 0.8 micron size filter and the solubility was determined by measuring the concentration of the drug spectrophotometrically after suitable dilution. Scanning electron microscopy The surface morphology of the microspheres was examined by scanning electron microscope (Philips, mode 505). T h e dried microspheres were mounted on metal stubs, coated for 300 seconds (or 50 nm metal thickness) under an argon atmosphere with gold-palladium (Hummer X coater, Anatech Ltd.) and then observed with the

SEM. Differential scanning calorimetry Thermograms of the drug, the polymers and the microspheres were obtained with a Perkin-Elmer differential scanning calorimeter (DSC) (Model 1B) that had been calibrated by the melting transition of indium. T h e samples (15 mg) were sealed in aluminium pans and scanned at a rate of 10"Cmin-'.

N . Gangrade and J . C. Price


188

Gas chromatographic determination of residual solvent T h e amount of residual methylene chloride in the microspheres was determined with a Perkin-Elmer gas chromatograph (GC) (model Sigma 300) equipped with an electron capture detector (ECD) maintained at 360°C. A 10 per cent FFAP on 80100 mesh Chromosorb W packed in a stainless steel column (1/8”i.d. x 6’length) (Alltech) at 75°C was used. T h e temperature of the head space analyser and the injection port were 60°C and 150°C respectively. Argon-methane (95 : 5 mixture) was used as the carrier gas (flow rate: 60 ml min- I ) . T h e sensitivity of the assay was 2.5 ng. Five to 50mg of microsphere samples were used for injection. Results are reported as mean of three determinations.

Results and discussion Microspheres can be prepared by various techniques, for example, coacervation phase separation, spray drying, hot melt method and solvent evaporation. T h e solvent evaporation technique is useful for entrapment of water-insoluble drugs such as contraceptives (Beck et al. 1979) anti-inflammatory agents (Bodmeier and Chen 1989), neuroleptics (Suzuki and Price 1985) and anticancer drugs (Bissery et a / . 1984). Two important factors that need careful consideration while optimizing the process are the emulsifier(s) and the solvent. T h e results obtained with different emulsifiers for the preparation of P H B microspheres using chloroform as the solvent have been given in table 1. Spherical microspheres were obtained with chloroform as solvent and gelatin as the emulsifier. However, the microspheres were very porous and their surface was irregular. When the solvent was changed from chloroform to methylene chloride, the microsphere surfaces were smoother (figures 2 and 3). Bissery et al. (1984) have reported the preparation and evaluation of CCNU-loaded PHB microspheres. I n their method, the polymer solution in chloroform was emulsified in a 0.25 per cent polyvinyl alcohol solution. T h e resulting suspension was stirred in a 1 per cent methyl cellulose solution until the solvent evaporated. They noticed a shrivelled appearance and considerable deviation from sphericity in the resulting microspheres. Pramar et al. (1987) studied the effect of solvent on the microsphere surface. They found that the surface of ethyl cellulose microspheres was irregular with chloroform but smooth with all other solvents tested. Solvent selection in the preparation of poly(D1-lactide) microspheres by the solvent evaporation method has been discussed by Bodmeier and McGinity (1988).

Table 1. Effect of emulsifying agent on microsphere formation.

Emulsifying agent Polyvinyl alcohol (PVA) (Av.M.W. 10 000) Sodium lauryl sulfate (with PVA) Methyl cellulose (3000 cps) Gelatin (Type A, 293 bloom)

Concentration (percentage w/v) 2.5,S.O

0025-1.0 0.25-1‘0

0.5-1.0

Result Microparticles aggregated before hardening. Could not be separated by washing Did not improve the aggregation behavior. Particles were oval to elongated in shape. Discrete and spherical microparticles.


Progesterone-loaded

PHB V microspheres

189

Figure 2.

Scanning electron micrograph of PHBV24 microsphere prepared with a chloroform solution (12 per cent w/v) at 30°C.

Figure 3.

Scanning electron micrograph of a PHBV24 microsphere prepared from methylene chloride solution (12 per cent w/v) at 30°C.


190

N . Gangrade and J . C. Price

Preparative factors such as the temperature of preparation and polymer composition also affect the surface texture of the microspheres. T h e number of visible pores in PHBV24 microspheres prepared with methylene chloride decreased when the temperature of the preparation was increased from 25°C to 40°C (figure 4). T h e surface of PHB microspheres was very rough. Increasing HV content of the copolymer gave smoother microspheres (figures 5 and 6). T h e morphology of the microspheres depends on the crystallinity and the precipitation behaviour of the polymer. PHBV polymers are highly crystalline and, therefore, do not produce very smooth microspheres. PLA is a more amorphous polymer and gives smoother microspheres. There are conflicting reports about the effect of HV content on the crystallinity of the copolymer. According to Holmes (1989, the crystallinity of the copolymer decreases as the HV content increases. T h e supplier’sdata sheet on these polymers shows that the PHB homopolymer is 80 per cent crystalline. T h e degree of crystallinity drops linearly to 40 per cent for the copolymer containing 24 per cent HV. But according to Bluhm et al. (1986) and Akhtar et al. (1988,1989)the degree of crystallinity for PHB and copolymers up to 47 per cent HV is similar. However, the hydroxyvalerate copolymer does have a plasticizing effect and causes a lowering of the m.p. of the copolymer. This effect also seems to be responsible for smoothness of the PHBV24 microspheres compared with PHB microspheres. T h e reproducibility of the microsphere batches prepared under the same conditions was examined with respect to the yield, drug content, and the dissolution profile (table 2). T h e yield was calculated from the ratio of weight of microspheres obtained to the total amount of drug and polymer dissolved in the solvent. Evaporation of the solvent from the droplets in contact with the propeller leads to solid polymer adhering to it. T h e adherence is greater when the evaporation is faster or when a more viscous polymer solution is used. Therefore, relatively lower yields were obtained for PHBV24 microspheres prepared at 40°C and PHBV24 microspheres prepared with an 18 per cent w/v solution. A 12 per cent w/v solution of P H B

Figure 4.



Progesterone-loaded PHB V microspheres

191

Figure 5 .


Figure 6.

Scanning electron micrograph of a PHB microsphere prepared from methylene chloride solution (12 per cent w/v) at 30°C.


192 Table 2.

Reproducibility of yield, drug content and T,, of microspheres prepared under different conditions.

Preparative variable

Yield* (per cent)

Drug content* (per cent w/w)

(min)

43.1 f6.2 71.8 f4 9 8 4 7 f3.5

2.24 f0.24 1.82f0.21 1.93 f0.21

108.0f 10.6 243.0 20.0 6 6 0 f5.7

89.5 f2.1 8 4 7 f 3.5 86.2 f3.1 74.0 f8.3

1.82 f0 2 7 1.93 f 0 2 1 1.77 f0.27 1.96f0 0 9

8 4 0 f7.5 66.0 f5.7 123.0 f9.0 1 545 -t 15-0

89.8 f3,4 908 f4 3 8 4 7 f3.5 85.0f 2.5 65.5 f7.6

1.68 f0 2 4 2.09 f0 4 2 1.93 f0.21 2.46 f0.21 2.27 f0.24

15.6 f3.2 21.0f3.4 66.0 f5.7 2400 f 18.6 191.2 f9.8

8 4 7 f3-5 87.1 f2.8 88.8 f4.3 87.9 f2.7 83.6 f5.0

1.93 f 0 2 1 4 6 8 f0.25 6.80 f0.54 9.46 f0.44 15.5 f0.17

66.0 f5.7 70.5 f5.4 71.0f 3.0 90.4 f8.3 67.5 f5.4

T50X

HV Content of polymer (mole per cent)" 0


9 24 Temperature of preparation ("c)~

25 30 35 40 Concentration of polymer in organic solvent (per cent w/v)E

5 9 12 15 18 Drug loading (per cent w / w ) ~

2 5 7 10 15

*Shown as va1uefS.D. ( n = 6 ) . Polymer concentration = 12 per cent w/v; temperature = 30°C; drug loading = 2 per cent w/w. PHBV24 microspheres; polymer concentration= 12 per cent w/v; drug loading= 2 per cent w/w. 'PHBV24 microspheres; temperature= 30°C; drug loading= 2 per cent w/w. PHBV24 microspheres; temperature = 30°C; polymer concentration = 12 per cent w/v.

was also very viscous and gave lower yield of microspheres (43.1 per cent). Irrespective of the preparative conditions employed, the amount of the drug in the microspheres was more than 80 per cent of the theoretical content. During the formation of microspheres, the solvent diffuses into the aqueous phase and evaporates. As the solvent is removed from the microglobules, the polymer and the drug precipitate at some time in the process. Depending upon the solubility of the drug in the polymer, the drug can be present either in the dissolved state or in the form of particles dispersed in the polymeric matrix. I n the particulate state, the drug can exist in crystalline or amorphous form. At 5 per cent w/w concentration, SEM examination of the microspheres did not show any drug crystals on the surface. Increasing the drug content further resulted in the appearance of surface crystals of progesterone. DSC analysis was done to determine the state of the drug in the PHBV24 microspheres. Progesterone exists in two polymorphic forms -a(m.p. 130°C) and



Figure 7 .

193

Scanning electron micrograph of a microsphere containing 10 per cent w/w of progesterone in PHBV24.

340

360

380

400

420

440

460

TEHPEWI"I'RE ('K)

Figure 8. DSC thermograms of ( a ) a-progesterone, ( b ) /f-progesterone, (c) PHBV24 copolymer, ( d )drug-free PHBV24 microspheres, ( e )PHBV24 microspheres containing 10 per cent w/w progesterone.



194

B(m.p. 12lOC). Both of these show a sharp endotherm in a D S C thermogram (figure 8). T h e melting transition of PHBV24 is shown by a broad peak at 124°C. Thermograms of microspheres containing 10 per cent wlw drug did not show any peak corresponding to the melting transition of progesterone. This was unexpected since drug crystals were visible on the surface of these microspheres (figure 7). T h e absence of an observable melting peak for the drug can be attributed to the fact that drug dissolves in the melted polymer. It would be inappropriate to conclude (from D S C results) that the drug is in dissolved state in the microspheres containing more than 5 per cent wjw drug. Similar observations were made by Bodmeier and Chen (1989) who concluded that indomethacin dissolves in melted ethyl cellulose/poly(ecaprolactone) matrix when the microspheres are scanned on a DSC. Solubilities of progesterone and cholesterol in another polymer, polydimethylsiloxane, have been obtained by using a D S C method (Theeuwes et al. 1974). Figures 9 to 12 show the dissolution profiles of the microspheres. Unencapsulated progesterone dissolved rapidly in the dissolution medium. T h e release of the drug (2 per cent w/w loading) was faster from P H B and PHBV24 microspheres than from PHBV9 microspheres. This seems to be due to difference in porosity of the polymeric matrices formed when the solvent evaporates. At the 9 per cent level, hydroxyvalerate (HV) has an optimum plasticizing effect giving rise to a less porous deposition of the copolymer. At the 24 per cent HV level, plasticization is excessive, leading to softening of the matrix and greater diffusivity of the drug through it. Juni et al. (1 986) have shown the effect of plasticizing additives (a series of fatty acids and their alkyl ester) on the release of aclarubicin from P H B microspheres. Ethyl esters of acids with more than 12 C-atoms in the acyl chain and butyl esters of acids with more than 10 C-atoms in the acyl chain exhibited remarkable acceleration of the drug release. They attributed this to increased channelization provided by the additives. Brophy and Deasy (1986) reported the release characteristics of oral PHBV microspheres containing sulphamethizole. P H B microspheres released the drug

1 .oo

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0.80 0.80

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0--62il A ’

/*’

0-0

0.60

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0.20

0.00

I

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1

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TIME (HRS)

Figure 9. Drug release profiles of PHB (0),PHBV9 ( A ) and PHBV24 ( 0 )microspheres (drug content 2 per cent w/w).

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1 .oo

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'-O0I

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0.00 0

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1

2

TIME (HRS) Figure 10. Drug release profiles of PHBV24 microspheres prepared at various temperatures: 25°C ( 0 )30°C , (A),35°C (U) and 40°C (V).Drug content 2 per cent w/w.

1 .oo

0.80

0.60

0.40

0.20

0.00

Figure 11. Drug release profiles of PHBV24 microspheres containing 2 per cent w/w ( O ) , 5 per cent (A),7 per cent w/w (U), 10 per cent w/w (V)and 15 per cent w/w ( 0 )drug. Pure drug (a).


196

‘A

1 .oo i

0.80


0.60 0.40

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0.00

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Figure 12. Drug release profiles of microspheres prepared with 5 per cent w / v (0), 9 per cent w/v ( A ) , 12 per cent w/v (El), 15 per cent w/v (V), and 18 per cent w/v ( 0 )PHBV24 copolymer in rnethylene chloride. faster than PHBV (17 per cent HV) copolymer microspheres. This was thought to be due to better matrix formation with the more homogeneous and amorphous copolymer. Figures 13 to 15 show scanning electron photomicrographs of internal surfaces of the microspheres. P H B homopolymer forms a matrix that has numerous cavities of fairly large size. PHBV9 and PHBV24 matrices have fewer cavities. Interestingly, PHBV9 microspheres had the fewest cavities. Some of these cavities may extend up to the outer surface of the microspheres forming channels. These channels provide passage for the solvent to enter and dissolve the drug. T h e channels probably are the reason for the lack of difference in the dissolution profiles of PHBV24 microspheres containing different payloads of progesterone (figure 11). T h e influence of temperature of preparation on the dissolution profile of the microspheres is shown in figure 10. T,, increases gradually with the temperature of preparation. T h e number of pores in the microspheres, as seen under the SEM, decreases with an increase in the temperature of preparation. An examination of internal sections of the microspheres prepared at higher temperatures also showed a decrease in the number of cavities. T h e release of the drug from microspheres prepared from 5 and 9 per cent w/v PHBV24 solutions in methylene chloride was as fast as that of the unencapsulated drug (figure 12). These microspheres are very porous and therefore have a high specific surface. This high surface area is exposed to the solvent and causes faster dissolution of the drug. With increasing concentration of the polymer, the microspheres become more compact and have less specific surface; hence, slower dissolution, No swelling was observed in any microspheres after a 12 hour release study. SEM examination of microspheres before and after release studies showed no change in the surface appearance or the diameter of the microspheres. T h e release of the drug from polymeric matrices depends on geometric shape of the device, state of the drug in the matrix, and porosity of the matrix. Higuchi (1963) proposed a mathematical model for the release of solid drugs



197

Figure 13.

Scanning electron micrograph of the internal fracture surface of PHB microsphere.

Figure 14.

Scanning electron micrograph of the internal fracture surface of PHBV9 microsphere.


198


Figure 15. Scanning electron micrograph of the internal fracture surface of PHBV24 microsphere. dispersed in solid spherical matrices. Table 3 lists slopes, intercepts and correlation coefficients of Higuchi plots of the dissolution data obtained in this study. Values of the correlation coefficient suggest that the release profiles of the microspheres can readily be described by the Higuchi model. We have noted earlier that the compactness of the polymeric matrix formed depends on preparative conditions such as temperature of the preparation, the HV content of the polymer, and the concentration of the polymer in the solvent. Gas chromatographic studies revealed that a more compact matrix retained higher amounts of methylene chloride. T h e amount of residual solvent in PHBV24 microspheres increased from 3.7 to 5.8 ppm when the temperature of the preparation was increased from 25 to 40°C (figure 17). T h e effect was more noticeable among PHBV24 microspheres prepared with different concentrations of the polymer in methylene chloride (figure 18). T h e amount of residual methylene chloride at 18 per cent w/v level was almost 300 times that at 5 per cent w/v level. These results are further substantiated by the observation that PHBV9 microspheres retain 30 ppm of methylene chloride compared with PHB and PHBV24 microspheres that retain only 3 4 p p m of methylene chloride (figure 16). Residual solvent in the microspheres can be evaporated by heating the microspheres. No residual methylene chloride was detected in the microspheres heated at 40°C for 30min. Heating may not remove all the solvent from the microspheres if they are very compact or if the solvent is bound strongly b y the polymer. An alternative method to prepare biodegradable microspheres without the use of an organic solvent is the hot-melt technique (Benita et al. 1984, Mathiowitz and Langer 1987, Bodmeier and Chen 1989). In this technique, the drug is dispersed in melted polymer which is then dispersed in an immiscible liquid (usually aqueous) phase maintained at the temperature of the drug-polymer mixture. T h e temperature

Progesterone-loaded PHB V microspheres Table 3.

Slopes, intercepts and correlation coefficients of Higuchi plots+ of the dissolution data.

Preparative variable


199

HV Content of polymer (mole per cent)o 0 9 24 Temperature of preparation ("C)b 25 30 35 40 Concentration of polymer in organic solvent (per cent wjv)' 5 9 12 15 18 Drug loading (per cent w / w ) ~ 2 5 7 10 15

Slopet"

Interceptst*

Correlation coefficient

0.009 k 0.008 0.048 f0.003 0.045 k0.002 -0.054+0.014 0.130 f0'004 - 0.024 f0.01 2

0.988 0.990 0.997

0.071 f0004 0.01 6 f0024 0.130_t0.004 -0'024f0.012 0~060f0002 -0013f0018 0.053 f0.002 - 001 6 k0.014

0.985 0.997 0.993 0.992

0.1 38 f0.067 0.21 1f0.043 0~512f0020 -0.041 f0.021 0.130 f0'004 - 0.024 f0.01 2 0.024 0.001 0002 0.007 0.003 f0.017 0.035 k 0002

0.926 0.997 0.997 0984 0.978

0.130f0~004 -0024+0-012 0.017 f0.014 0.076 f0002 0.018 & 0.01 1 0.064 f-0.002 0020 f001 1 0.086 k 0003 0.025 f0.010 0.062 k 0.003

0.997 0995 0.993 0.996 0.991

+

* 1 - 3F2'3 2F versus T where F = fraction remaining to be released T =time. ?Shown as va1uekS.D. (n=6). Polymer concentration = 12 per cent w/v; temperature = 30°C; drug loading = 2 per cent wjw.

PHBV24 microspheres; polymer concentration = 12 per cent wjv; drug loading = 2 per cent wjw.

'PHBV24 microspheres; temperature= 30°C; drug loading= 2 per cent wjw. PHBV24 microspheres; temperature = 30°C; polymer concentration = 12 per cent wjv.

is then decreased to below the congealing point of the polymer to form solid microspheres. Both the polymer and the drug should be thermostable. Attempts to use this method to prepare PHBV microspheres were unsuccessful for two reasons. First, the m.p. of these polymers is between 120-180°C and could not be lowered by the incorporation of plasticizers such as cottonseed oil, triacetin, tributyrin, and dibutyl and dioctyl esters of sebacic acid. Second, the consistency of the melted polymers was too thick to achieve dispersion into small droplets. In conclusion, microspheres of PHBV polymers containing progesterone were successfully prepared. Morphology and release properties of the microspheres were functions of emulsifier, solvent, polymer composition, preparation temperature and concentration of the polymer solution in the organic solvent. These microspheres could potentially be used for sustained parenteral delivery of the drug. Microspheres of appropriate size can be suspended in a suitable vehicle and injected s.c., i.m. or locally at the site of action.



200

HV Content of polymer (mole %) Figure 16. Amount of residual methylene chloride in PHB, PHBV9 and PHBV24 microspheres.

n

6

E

Q. Q.

W

0)

-0

'E

2

1 25

30

35

40

Temperature of Preparation ("C) Figure 17.

Effect of preparation temperature on the amount of residual methylene chloride in PHBV24 microspheres.


201

n


E n n W

Concentration of PHBV24 in solvent (% w/v) Figure 18. Effect of concentration of the polymer solution used to prepare microspheres on the amount of residual methylene chloride in PHBV24 microspheres.

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Preparation and evaluation of sustained release loxoprofen loaded microspheres.

Preparation and antioxidant properties of selenium nanoparticles-loaded chitosan microspheres.

Eudragit E microspheres containing bacampicillin: preparation by solvent removal methods.

PLGA microspheres for onychomycosis treatment.

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The preparation and release properties of microcapsules [proceedings].

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Polymeric nanoparticles containing diazepam: preparation, optimization, characterization, in-vitro drug release and release kinetic study.

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Cross-linked chitosan microspheres: preparation and evaluation as a matrix for the controlled release of pharmaceuticals.

Characteristics and release profiles of MPEG-PCL-MPEG microspheres containing immunoglobulin G.

Retention and subsequent release of radioactivity from the incineration of wastes containing microspheres.

Alginate Microspheres Containing Temperature Sensitive Liposomes (TSL) for MR-Guided Embolization and Triggered Release of Doxorubicin.

Preparation of lung-targeting, emodin-loaded polylactic acid microspheres and their properties.

Preparation and properties of BSA-loaded microspheres based on multi-(amino acid) copolymer for protein delivery.

Preparation of monodisperse aqueous microspheres containing high concentration of l-ascorbic acid by microchannel emulsification.

Preparation of controlled release anticancer agents. I: 5-Fluorouracil-ethyl cellulose microspheres.

Statistical optimization of controlled release microspheres containing cetirizine hydrochloride as a model for water soluble drugs.

A physicochemical study of the morphology of progesterone-loaded microspheres fabricated from poly(D,L-lactide-co-glycolide).

Preparation of enteric-coated microspheres of Mycoplasma hyopneumoniae vaccine with cellulose acetate phthalate: (II). Effect of temperature and pH on the stability and release behaviour of microspheres.

Preparation of monodisperse ferrite nanocrystals with tunable morphology and magnetic properties.

Preparation and evaluation of Eudragit gels. I: Eudragit organogels containing drugs as rectal sustained-release preparations.