CA1122077A

CA1122077A - Low temperature preparation of polymer microspheres

Info

Publication number: CA1122077A
Application number: CA000309884A
Authority: CA
Inventors: Jones W. Fong
Original assignee: Sandoz AG
Current assignee: Sandoz AG
Priority date: 1977-08-25
Filing date: 1978-08-23
Publication date: 1982-04-20
Also published as: IE781708L; BE869915A; ATA612478A; IE47255B1; AU3923678A; FR2400950B1; PH15447A; DE2836044A1; FI782501A; CH644768A5; IT1098111B; ZA784855B; NZ188232A; IT7826961A0; GB2003108A; SE7808759L; ES472800A1; AU522215B2; CH649217A5; FI64899C

Abstract

IMPROVEMENTS IN OR RELATING TO ORGANIC COMPOUNDS

Abstract of the Disclosure Microspheres of core material and polymer are produced by adding a phase separation agent to a medium comprising a solution of the polymer and a solution or dispersion of the core material at a temperature of -40 to -100°C. Preferably the core material is a drug and the polymer is biodegradable.
The low temperature phase separation step prevents uncon-trolled agglomeration of the microspheres.

Description

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~ ~ Ca~e 600-6792 IMPROVEMENTS IN OR RELATING TO ORGANIC CO~POUNDS

This invention relates to microspheres comprising - a pol~meric material and a solid core material, which are prepared by phase separation tech,.iques~

By the term "microspheres" is included both microcapsules, which consist of a particle of core material which is coated by an outer layer of polymeric material, and microprills which are homogeneous mixtures of a core material and a polymer. The term "microspheres" also includes both the indivldual microcapsules or microprills and approximately spherical aggregates consisting of a number of microcapsules or microprills~ Microspheres have diameters in the range 1-500 microns, more usually 20-200 microns.
It is known to obtain microcapsules by phase separation techniques in which the core material of the desired particle size is dispersed ln a continuous phase comprising a solution of the polymeric coating material, and the polymeric material is deposited on the core material by gradual precipitation of~the polymer, for example by addition of an incompatible polymer or a non-, : :

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~ZZ~7 ~ 2 - 600-6792 solvent for the polymeric material, or by cooling a hot solution to room temperature. Such processes commonly give rise to uncontrollable aggregation of the encapsul-ated particles, and do not provide a satisfactory pro-cedure for obtaining discrete, spherical, microspheresof polymer and core material by phase separation which would be suitable in a broad range of applications.

It has now been found that these problems may be overcome by carrying~out phase separation at low _emperatures, i.e. from -40 to -100C.

Accordingly, the present invention provides a ~ process for the production of microspheres comprising a -~ polymer and a core materialcharacterised by the step of addin~
a phase separation agent to a medium comprising a solution of~the polymer and a dispersion or solution of the core material -~:
at a temperature of -40 to -100C.

~;; In order to produce microcapsules, the polymer `~ is dissolved in a solvent in which the core material is insoluble, microparticles of the core material are dls-persed in the polymer solution, and a~e separation agent is added to the system at a temperature of -40 to -100C
~; ~ to precipitate the polymer and coat the core material particles.
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In order to produce microprills, the polymer and core material are dissolved in a common~ solvent, and a - ' -,, - .
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l~ZO'77 ~ 3 - 600-67g2 phase separation agent is added to the solutlon at a tem-perature of -40 to -100C to precipitate particles consisting of a homogeneous mixture of polymer and core material.
It will be appreciated that it is not cri.tical at what stage of the process the temperature of the system is lowered to -40 to -100C, so long as phas~ separation -takes place within this temperature ranye.

The core material of the microspheres prepared by the process of this invention may be agricultural agents such as insecticides, fungicides, herbicides, ~odenticides, pesticides, fertilisers, virus particles for crop protection and the like; cosmetic agents such as deodorants, fragrances and the like; food additives such as flavours, oils, fats and the Like; and pharmaceu-15-- ticai agents, e.g. drugs. Microspheres comprising drugs as core materials may be useful as long-acting retard forms for oral or parenteral adminlstration. Pharmaceutical agents, e.g. drugsJ~are especially~preferred core materials and the invention wlll be further described using drugs as~
core materials.
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The ter~ "phase separation a~ent" include~ both non-solvents for the polymer and the core material and polymeric materials which are incompatible with the coating , polymer and the core material. When the phase separation agent~
is an incompatible polymer, then a non-solvent must also be added simultaneously or subseguently in order to harden the ~ ' ' :

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surface of the microspheres and prevent undue agglomeration.
The addition of the non-solvent, when used as a hardener, will also be at the process temperature of from -40 to -100C.
The term "non-solvent" in the subsequent description will be 5 applied both to non-solvents used as phase separation agents and to non-solvents used as hardeners where the phase separation agent is an incompatible polymer.
In the preferred embodiments of the invention, the phase separation agent is a non-solvent and no incompatible - 10 polymer is used.
~ he formation of microcapsules according to this invention is based on polymer phase separation phenomena.
When a phase separation agent is initially added to a polymer .
solution in which solid drug particles are dispersed, the 15 polymer which ~eparates is initially in a liquid phase and is deposited as a ooatlng on the dispersed drug particles.
~ Subsequent addition of non-solvent causes the coating to~
~;~ harden as a capsule~walL completely surrounding the drug particle. By varying the-process conditions, the coated drug 20 particles may remaln as indlvidual capsules or agglomerate ::
in a controlled manner to form larger aggregates of micro-~capsules. Undesirable massive agglomeration occurs when adhesion and coalescence of the encapsulated particles develcp precipitously beyond control. The present low temperature 25 process renders the microspheres sufficiently firm to a~oid~
undesired agglomeration.

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The homogeneous microprills according to this invention are also formed by phase sepaxation phenomena. When a phase separation agent for both the polymer and the drug is added to a homogeneous solution of polymer and drug, both the polymer and the drug separate out together to form homogeneous microprills. Depending on the process con-ditions, they may remain as individual spheres or be allowed to agglomerate in a controlled manner to form ; larger homogeneous microprills.

Depending on the end use of the product, it may be desirable to prepare aggregate microspheres larger than the individual microspheres. For example r for con-trolled release of drug suitable for parenteral admini-stration, the size of the microspheres should be large enough to provide adequate duration of release yet small enough to not restrict passage through the standard syringe needles employed. Thus, the preferred size would be about 150 microns for a No. 20 gauge needle.

For other applications it may be desirable to 20-allow controlled agglomeration to form microspheres larger , or smaller than 150 microns.

The temperature range for the process of this invention is from about -40 to -100C, preferably -40 to -75C, more preferably -50 to -70C. The upper temperature ., ' , Z~77 - 6 - 600~6792 limit is dictated by the necessity to avoid massive agglom-eration. In general, operating at a lower temperature would provide more margin against this undesired agglomer-ation. The lower temperat~res are limited by the freezing 5 point of the solvent, non-solvent or mixture of the two which are utilised.

Natural and synthetic polymers may be used in the process of this invention for the preparation of micro-spheres. For example, the polymers may include cellulosic 10 polymers, polyvinyl acetate, polyvinyl alcohol, polyvinyl chloride, natural and synthetic rubbers, polyacrylates, and polystyrene. When the microspheres of this invention are intended for injectable pharmaceutical applicatlons, bio-degradable polymers such as polylactio acid, polyglycolic 15 acid, polyhydroxybutyric acid and the like and copolymers thereof may be utilised. The polymer should of course be compatible with the core material~to be used. ~
Multiply encapsulated microcapsules may be prepared by the low temperature phase separation process of this invention by utllising preformed microcapsules or~
microprills, dispersed in a polymer solutlon, as the core materiaI. In certain cases it may be necessary to lower the temperature of the polymer solutlon to -40 to ~100C~
prior to the introduction of the preformed microspheres to avoid dissolving the preformed microspheres in the polymer solution. This concept is especially useful for :: ~ : : :
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~Z~77 reducing the init~al release rate, and therefore increas-ing the duration of release, by depositing an e~tra layer of polymer as a barrier on preformed microspheres. This technique can be extended to create multilayered micro-spheres.

Multiple encapsulation can also be used to pro-duce new microcapsules formed by phase-separation of a polymer solution containing a dispersion of one or more kinds of preformed microspheres with or without one or more free drugs in particulate form. For example, two or more drugs can be microencapsulated separately, either because of incompatibility or lack of a common microencapsulation procedure suitable for all the component drugs. These preformed microcapsules may then be mixed together and dispersed in a polymer solution for a subsequent micro-encapsulation to produce new microcapsules containing the previously encapsulated drug particles. Such compartment-alised rni_rocapsules o~fer an advantage over a physical~
mixture in that uniformity is maintained by avoiding any ; - 20 uneven settling of the components upon storage.

Another application for compartmentalised micro-capsules would be to segregate one or more reactants for ; subsequent reaction upon demand. Release for reaction may be effected by pressure rupture, passage of time, exposure to wate~, air, light, heat or other triggering mechanlsm.

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, ' -, ~ 8 ~ 600-6792 For the preparation of microcapsules~ the solvent selected must dissolve the polymer but not the dispersed core material, e.g. drug particles. This requirement is more easily met at low temperatures since drug solubility 5 is usually decreased at lower temperature. For the prep-aration of homogeneous micraprills, the solvent must dissolve both polymer and drug substance at the very low temperature.
For either microcapsules or microprills, the solvent should be relatively volatile, inert to both polymer and drug, 10 having a freezing point sufficiently below the required operating temperature and also be miscible with the non~
. solvent at that low temperature.

Mixtures of solvents may be used where appropriate, for example to depress the freezing point of a~preferred `~ 15 solvent to enable operation at a temperature below its normal freezing point. Another example~is the ~situation - where the dru~ to be encapsulated has~some sclubility in the ;;~
solvent of choice for the polymer; here a second solvent may be added in quantity sufficient to minimise ~he scl~
ubility of the drug wl~thout significantl~ affecting the~
solubiIity of the polymer. By contrast, when it is desired to form microprills, and a single common solvent for drug and for pol~ner cannot be found, then a mixed solvent~
system may be suitable~as a common solvent.

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~ 9 - 600-67~2 For example, where the polymer is a biodegradable polymer such as polylactlc acid, polyglycolic acid and copolymers of these, suitable solvents include toluene, xylene, chloroform, methylene chloride, acetone, ethyl 5 acetate, tetrahydrofuran, dioxane, hexafluoroisopropanol, - and mixtures thereof.
The non-solvent used, whether in the phase separation step or in a subsequent hardening step, must be a non solvent for both the polymer and the drug, at least at the operating lQ temperature Additionally, the non-solvent should be relatively volatile or easily removed by washing with another volatile non-solvent, chemically inert to both polymer and drug, have a freezing point sufficiently below the required ; 15 operatiny temperature and also be mlscible with the solvent at that low temperature.

Although both non-polar and polar non-solvents -may be used, polar non-solvents are~preferred. Examples of non-polar non-solvents include the alkane hydrocarbons .
(e.g., hexane, heptane, cyclohexane). Examples of polar ; non-solvents include water, alcohols (e.g., isopropanol, ; isobutyl alcohol), ethers, polyhydric alcohols (e.g., 1,2-glycols such as propylene glycol; 1,3-glycols such as trimethylene glycol; trihydric alcohols such as glycerol) and ethers and esters of the polyhydric alcohols. Poly-hydric alcohols are especially preferred as the non-solvent ~, -' . , - . . .

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- 10 - 600-67~2 for producing aggregated microspheres of larger diameters.
Other non-solvents which may be used are the fluorocarbons (e.g., Freon 11, Freon-113 from DuPont).

The non-solvent neecl not be limited to a single component system and mixed non-solvent s~stems may be used, for example, to depress the freezing point of a non-solvent to allow operation at a very low temperature. Another example is where the drug substance has some solubility in the preferred non-solvent for the polymer. Sufficient amount of another non-solvent may be added to minimise drug solubility, e.g., the addition of a non-polar non-solvent iike heptane to reduce solubilit~ of a drug in isopropanol. A co-non-solvent may also be used to maintain miscibility between the preferred non-solvent and the preferred solvent.
Where the phase se~aration agent is an incom-patible pGlymer, the polymeric phase separation agent must be incompatible both ~ith the coating pol~ and with ~e oore materialt and miscible with the solvent. Preferably, the ~
polymeric phase separation agent should be miscible with the : . :
non-solvent used in the hardening step, so that the ~on~

solvent will remove traces of the polymeric phase separatLon : : : : .
agent from the microspheres.

Among the polymeric phase separation agents which may be used are polybutadiene, polydimethylsiloxane and the like.

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60~-67~2 The following Examples illustrate the invention.

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EXAMPLE 1:
A solution of 1.0 g poly(D,L-lactic acid) polymer (intrinsic viscosity of 2.32 in hexafl~oroisopropanol at 25C) in 50 ml of toluene was cooled to about -65~C in a dry ice-isopropanol bath. Micronised Mellaril~ pamoate (trademark of Sandoz for thioridazine) (0.5 g) was dispersed in the polymer solution with stirring at 160 rpm. Isopropanol ~150 ml) was added dropwise to the dispersion at the rate of one hour for the first 50 ml and 0.5 hour for the remaining 100 ml. The dry ice bath was removed and the microcapsules were allowed to settle before decanting the supernatant. The product was washed twice with heptane, dried and weighed 1.15 g (77% yield).
Microscopic examination (210X) showed that the product was ` 15 in the form of spherical microcapsules with a diameter of ; about 25-50 microns.

EXAMPLE 2:
The procedure of Example 1 was followed except that 150 ml of isobutyl alcohol (2-methyl-1-propanol) was used `: ~
in place of isopropano~l as non-solvent. This was followed by the addition of 50 ml heptane in ten minutes to facilitate the capsule wall hardening process. The yield was 1.37 9 (91~) of spherical microcapsules with a diameter of 20-30 microns.

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- 13 - 60~-6792 EX~IPLE 3:
The procedure of Example 1 was followed except that 150 ml of 50:50 (v/v) n-propanol/isopropanol was added in place of isopropanol, at the rate of 40 minutes for the first 50 ml and 35 minutes for the remaining 100 ml.
This was followed by the addition of 50 ml heptane. The yield was 1.42 g (95%) of spherical microcapsules with a diameter of 20-40 microns.

EXAMPLE 4:
The procedure of Example 1 was followed except that 150 ml of heptane was used instead of isopropanol, and the dispersion was then allowed to warm up to room temperature over four hours with constant stirring. The product weighed 1.22 g (81% yield). Aggregated micro-spheres of 50-200 micron size were obtained.

EXAMPLE 5:
The procedure of Example 1 was followed except that 150 ml of 15:~5 (v/v) heptane/isopropanol was used instead of isopropanol. The yield was 1.1 g (73~) of spherical microcapsules with a diameter of 25-35 microns.
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EXAMPLE 6:
Somewhat larger microcapsules were prepared when propylene glycol/isopropanol was used as the non-solvent.

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'' ' ' : --A solution of 1.0 g poly(D,L-lactic acid) polymer (intrin-sic viscosity of 2.32 in hexafluoroisopropanol at 25C) in S0 ml toluene was cooled to -50C (slightly warmer temperature was used to avoid freezing the propylene glycol, f.p. -59) in a dry ice-isopropanol bath.
Micronised ~ellaril pamoate (0.5 g) was dispersed in the polymer solution with stirring at 160 rpm. A solution (100 ml) of 33:67 (v/v) propylene glycol/isopropanol was added dropwise to the dispersion at the rate of one hour for-the first 50 ml and 20 minutes for the remaining 50 ml.
This was followed by the addition of 50 ml heptane in 10 minutes. The dry ice bath was removed and the microcap--sules were allowed to settle before~decanting the super-natant. The product was washed once with 1:1 (v/v) heptane/isopropanol, twice with isopropan~l then twice with heptane. After a brief air-drying, mlcroscopic examin-ation showed that the product was well-formed, spherical microcapsules with a diameter of 50-150 but mostly 100-125 microns. However,~after drying in the vacuum oven at 50-60C for four hours, the capsules decreased to about 50 to 75 microns and became crenated. The d.ried product weighed 1.16 g (77% yield) and contained 14.4% Mellaril pamoate.

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' ~' - lS - 600-~792 EXP~PLE 7:
A homogeneous solution of 1.0 g poly(D,L-lactic acid) polymer and 0.5 ~ ~ellariî pamoate in 50 ml of 1:1 (v/v) toluene/chloroform was cooled to -65C with stirr$ng at 160 rpm. The addition of toluene allowed operation at -65 without freezing the chloroform (f.p. -63C).

Isopropanol (150 ml) was added dropwise at the rate of 1.5 hours for the first 100 ml and 0.5 hours for the remaining 50 ml. The product was washed twice with heptane, dried and weighed 1.4 g (93% yield). Microscopic examination showed that the resultant homogeneous micro-prills were 20-50 microns in diameter.
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EXAMPLE 8:
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Larger mlcroprills were prepated when propylene glycol/isopropanol was used as the non-solvent. A homogen-eous solution of 1.0 g polytD,L-lactic acid) polymer and ;
0.5 g Mellaril pamoate in 50 ml chloroform was cooled to ~ - -50C with stirring at 160 rpm. A solution (100 mI) of ; 35:65 (v/v) propylene glycol/isopropanol was added dropwise to above solution at the rate of 70 minutes for the first 50 ,~ 20 ml and 20 minutes for the remaining 50 ml. This was follow~
by the addition of 50 ml heptane in 15 minutes.

AEter decanting the supernatant, the product was washed once with 1:1 (v/v) heptane/isopropanol, twice with isopropanol then twice with heptane. Upon drying, it . .

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~ZZ~77 weighed 1.44 g (96~ yield). Microscopic examination showed that the resultant homogeneous microprills were 100-125 microns in diameter. The product was found to contain 15.1~ weight Mellaril pamoate.

5 EXAMPLE 9:
A solution of 0.22 g poly(DjL-lactic acid) polymer in 50 ml t~luene was cooled to about -65C in a dry ice-isopropanol bath. Microcapsules (0.75 g, about 35 microns, previously prepared as in Example 1 to contain 33~ Mellaril 10 pamoate) were dispersed in the polymer solution with stirring at 160 rpm. Isopropanol (150 ml) was added dropwise to the dispersion and the rest of the procedure of Example 1 was followed. The yield was 0.73 g (75~). Careful microscopic examination (210X) showed a thin, transparent wall of poly-(D,L-lactic acid) polymer surrounding each microcapsule.
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EXAMPLE 10:
The data in this Example showed that the micro-encapsulated drug Mellaril pamoate has slower release rate than the non-encapsulated Mellaril pamoate. Furthermore, 20 the double-encapsulated Mellaril pamoate microcapsules (25-.
;~ 40 microns) showed significantly reduced initial release rate compared to the single-encapsulated microcapsules (50-200 microns). The reason for the shorter release duration~
o~ the double-encapsulated material is due to its smaller size.

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~2~77 ~ Release Non- Single- Double-Encapsulated E~capsulated Drug Encapsulated Drug Hour Dru~ Example 4 Example 9 ; 72 -- 100 --Procedure A sample containing the equivalent of 4.0 mg 15 Mellaril pamoate was placed in a dissolution flask contain-ing 1000 ml of p~ 7~4, 0.2M phosphate buffer. The mixture was maintained at 37C with stirring at 500 rpm. Aliquots were withdrawn at various time points and the absorbance was measured at 224 nm with an ultraviolet spectrophotometer.
20 The percent drug released was based on the maximum absorb-ance measured for each sample.

EXAMPLE 11:
A solution of 0.25 poly(D,L-lactic acid) polymer in 50 ml toluene was cooled to -65C in a dry ice-isopropanol 25 bath. Microprills prepared as in Example 8 containing 16%
Mellarll pamoate were dispersed in the polymer solution with :

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stirring at 160 rpm. The procedure o~ Example 1 was followed except that 100 ml of 20:80 (v~v) heptane/isoprop-anol followed by 50 ml of heptane was used instead of iso-propanol. The yield was 0.89 g (89~) of double-encapsulated microprills of 100-150 microns diameter and containing I0.8 Mellaril pamoate.

EXA~I~LE 12:
A dispersion of 0.6 g bromocriptine (~andoz, Inc.) in ~ solution of 1.4 g poly(D,L-lactic acid) polymer in 10 55 ml of toluene was stirred at 140 rpm with cooling to -70C in a dry ice-isopropanol ~ath. The procedure of Example 1 was followed except that 100 ml of 25:75 (v/v) heptane/isopropanol followed by 50 ml of heptane was used instead of isopropanol. The yield was 1.71 g (86%) of spherical microcapsules of 15-40 microns diameter.
Microscopic examination under polarized light of the mlcro-capsules immersed in oil showed that the microcapsules contained drug particles whose iridescence was visible through the capsule wall.

EXAMPLE 13:
A dispersion of 1.0 g pindolol (Sandoz, Inc.)~
(well-pulverized withm~rtar and pestle) in a solution of 1.0 g poly (D,L-lactic acid) polymer in 100 ml of toluene was stirred at 150 rpm with cooling to -70C in a dry ice-Z~

isopropanol bath. The procedure of Example 1 was followed except that 50 ml of 5:95 (v/v) heptane/isopropanol followed by 50 ml of heptane was used instead of isopropanol. The yield was 1,82 g (91~) of spherical microcapsules of 50~75 microns diameter. Microscopic examination under polarized light of the microcapsules immersed in oil showed that the microcapsules contained drug particles whose iridescence was visible through the capsule wall.

EXA~IPLE 14:
A dispersion of 1.0 g dihydroergotamine mesylate `~
(Sandoz, Inc.) (well-pulverized with mortar and pestle) in a solution of 1.0 g poly (D,L-lactic acid) polymer in 100 ml of toluene was stirred at 140 rpm with cooling to -70C in - a dry ice-isopropanol bath. The procedure of Example l was followed except that 100 ml of isopropanol followed by 100 ml of heptane was used instead of isopropanol alone. The~
yield was 1.98 g (99%) of spherical microcapsules of 75-150 microns diameter. Mlcroscopic examination under polarized light of the microcapsules immersed in oil showed that the microcapsules contained drug particles whose iridescence was visible through the capsule wall.

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Claims

CLAIMS:

1. A process for the production of microspheres comprising a polymer and a core material characterised by the step of adding a phase separation agent to a medium comprising a solution of the polymer and a dispersion or solution of the core material 2t a temperature of -40 to -100°C.

2. A process for the production of microcapsules comprising a coating of polymer around a solld particle of core material, characterised by the step of adding a phase separation agent to a medium comprising a dis-persion of microparticles of the core material in a solution of the polymer at a temperature of -40 to -100°C.

3. A process for the production of microprills comprising a homogeneous mixture of a polymer and a core material characterlsed by the step of adding a phase separation agent to a common solution of the polymer and the core material at a temperature of -40 to -100°C.

4. A process according to Claim 1 in which the core material comprises a drug.

5. A process according to Claim 1 in which the core material comprises preformed mlcrospheres.

6. A process according to Claim 4 in which the polymer is a biodegradable polymer.

7. A process according to Clalm 6 in which the polymer is polylactic acid, polyglycolic acid, poly-hydroxybutyric acid or copolymers thereof.

8. A process according to Claim 1 in which the phase separation agent is a non-solvent for the polymer and the core material.

9. A process according to Claim 8 in which the phase separation agent is a polar non-solvent.

10. A process according to Claim 9 in which aggregated microspheres are produced by the use of a polyhydric alcohol as a polar non-solvent.

11. A process according to Claim 8 in which the phase separation agent is a mixture of polar and non-polar non-solvent.

12. A process according to Claim 1 in which the phase separation agent is added at a temperature of from -40 to -75°C.

13. A process according to Claim 12 in which the phase separation agent is added at a temperature of from -50 to -70°C.