Silicone-hardened pharmaceutical microcapsules and process of making the same

There is disclosed a process for preparing compositions comprising microcapsules by phase separation microencapsulation wherein the hardening agent employed is a volatile silicone fluid and with the compositions prepared thereby. The use of the volatile silicone fluid as a hardening agent permits the production of microcapsules substantially free of any alkane hardening agent, eliminating potential combustability problems of the prior art processes and toxicity problems of the prior art compositions.

This invention is concerned with a process for preparing compositions 
comprising microencapsulated pharmaceutical agents by phase separation 
microencapsulation, wherein the hardening agent is a volatile silicone 
fluid and with compositions prepared thereby. 
BACKGROUND OF THE INVENTION 
Microcapsules consist of a core material surrounded by a coating or 
encapsulating substance which is normally a polymer. Microcapsules may 
consist of one or more spherical core particles surrounded by a coating, 
or the microencapsulated substance may exist as one or more irregularly 
shaped particles surrounded by a coating which may have spherical form, or 
the exterior of the microcapsules may be irregular in shape. In general, 
microcapsules are produced to provide protection for the core material 
and/or to control the rate of release of the core material to the 
surrounding environment. Also included within the term microcapsule are 
those in which the pharmaceutical agent is present as a solid solution in 
the coating and may be present at one or more points or portions of the 
microcapsule surface. The term microsphere has also been applied to the 
above-named microcapsules. 
As suggested by Beck et al., U.S. Pat. No. 4,585,651, dated Apr. 29, 1986 
which discloses pharmaceutical compositions comprising microparticles of a 
pharmaceutical agent incorporated in a biocompatible and biodegradable 
matrix material, the methods for preparation of microcapsules may be 
classified in three principal types: 
(1) phase separation methods including aqueous and organic phase separation 
processes, melt dispersion and spray drying; 
(2) interfacial reactions including interfacial polymerization, in situ 
polymerization and chemical vapor depositions; and 
(3) physical methods, including fluidized bed spray coating, electrostatic 
coating and physical vapor deposition. 
The distinguishing feature of phase separation microencapsulation is the 
initial production of a new dispersed phase containing the coating 
substance via some physical or chemical change. The dispersed coating 
phase ultimately surrounds and coats the core material which itself is 
also initially dispersed or dissolved in the continuous phase. 
In one preferred type of phase separation, microencapsulation is carried 
out by addition of a non-solvent for the coating polymer and the core 
material to a solution of the coating polymer which contains dispersed or 
dissolved core material. This type of phase separation process comprises 
the following steps. 
(i) A solution of coating material is prepared. 
(ii) The core material is dispersed or dissolved in the coating solution. 
The core material may be solid or liquid and may or may not be soluble in 
the coating solution. The core material may also contain, in addition to 
any pharmaceutical agent, excipients such as antioxidants, preservatives, 
release-modifying agents, and the like. Any or all of the core material 
ingredients may be solid or liquid. 
(iii) While stirring the composition of (ii), a non-solvent for the coating 
material and core material is added. The non-solvent must be miscible with 
or soluble in the coating solvent. Addition of the non-solvent causes the 
coating material to come out of solution in the form of a dispersed liquid 
phase comprising a concentrated solution of the coating polymer in the 
original coating solvent. In the case where the core material is soluble 
in the coating solution, the core material will also be present in the 
coating solution phase. In the case where the core material is not soluble 
in the coating solution, the newly created phase surrounds and coats the 
dispersed core phase. In this instance, a necessary property of the 
coating phase is that it wet the core phase in preference to the 
continuous phase. 
(iv) The dispersion (iii) is added to the hardening solvent. The purpose of 
this solvent is to extract polymer solvent from the coating/core droplets 
formed in step (iii). After hardening, the microcapsules will exist as 
particles suspended in the hardening solvent. The microcapsules may then 
be recovered by filtration or other convenient means. 
Kent et al., European Patent Publication Number EPO-052- 510, published May 
26, 1982, discloses the microencapsulation of water soluble polypeptides 
in biocompatible, biodegradable polymers such as 
poly(lactide-co-glycolide)copolymers, also by a phase separation process 
utilizing an alkane solvent, and specifically exemplifies heptane as a 
hardening solvent. 
The previously used hardening agents including hexane, heptane, cyclohexane 
and other alkane solvents leave substantial amounts of hardening agent 
residues in the microcapsules. Tests have shown that heptane hardened 
microcapsules typically contain 5-15% by weight of heptane. Since 
hardening agents can ultimately be released, low toxicity is of paramount 
importance for hardening agents used to produce microcapsules for 
pharmaceutical applications, and it would be advantageous to provide the 
same. 
In addition, a further drawback in use of hydrocarbon hardening agents of 
the prior art is that they are flammable and therefore require the use of 
explosion-proof facilities for manufacturing microcapsules. 
It has now been discovered that if volatile silicone fluids are used as 
hardening agents, the drawbacks of the prior art are overcome because of 
their very low toxicity and non-flammability characteristics. 
Microcapsules produced by the phase separation microencapsulation process 
are different and better than those of the prior art because the residual 
hardening agent content is very low, e.g., of the order of less than 2-3 
wt %, preferably less than 1-2% and more preferably less than 1%. The 
results obtained herein are surprising because, while the coating material 
solvent is readily removable by vacuum drying, it has heretofore been the 
experience that residual prior art hardening agents, once incorporated 
into microcapsules, are not readily removed by drying because they are, by 
nature, not soluble in the coating material and therefore do not permeate 
through the coating material. 
Volatile silicone fluids are unique because these fluids essentially are 
not incorporated into the microcapsules during the hardening step. 
The improvement in phase separation microencapsulation thus provided by the 
present invention removes a major obstacle which in the past has prevented 
use of this technology to produce a drug delivery system. 
SUMMARY OF THE INVENTION 
In accordance with the present invention, there is provided an improvement 
in a known process for preparing a pharmaceutical composition in 
microcapsule form, said process comprising: 
(a) dispersing a solution containing a pharmaceutical agent in an organic 
solvent containing a biocompatible encapsulating polymer which may also be 
biodegradable; 
(b) adding to the dispersion a non-solvent for the encapsulating polymer 
and pharmaceutical agent; and 
(c) adding the product of step (b) to a hardening solvent to extract said 
organic solvent and produce solid microcapsules of said pharmaceutical 
composition, the improvement comprising using as the hardening solvent a 
volatile fluid. 
Also provided by the invention are compositions of matter comprising a 
microencapsulated core material wherein the microcapsules are prepared by 
phase separation microencapsulation employing a volatile silicone fluid as 
a hardening agent. Such compositions are different from those of the prior 
art because they have a residual hardening agent content of less than 
about 3% by weight, preferably less than 2% by weight and especially 
preferably less than 1% by weight and are substantially free of any alkane 
hardening agents. 
Criteria which core materials must satisfy in order to be microencapsulated 
by the process of this invention are as follows. The core material must 
have low solubility in the coating non-solvent and also low solubility in 
the volatile silicone hardening agent. Low solubility means less than 
about 5% weight/weight; preferably less than about 1% and most preferably 
less than about 0.1%. Also in the case of core materials which are 
microencapsulated as solids or liquids dispersed in the coating solution, 
the concentrated coating solution phase generated upon addition of the 
non-solvent must wet the core phase in preference to the continuous phase. 
In the case of core materials which are soluble in the initial coating 
solution, the core material must partition into the coating phase 
generated upon addition of the coating non-solvent. Thus the class of core 
materials which may be microencapsulated by the process of this invention 
is determined by the physicochemical properties of the core, coating, 
coating solvent and hardening agent. 
Among the pharmaceutical agents which satisfy these criteria in general are 
peptides and proteins. Specific examples of the latter are: atrial 
natriuretic factor, tumor necrosis factor, oxytocin, vasopressin, 
adrenocorticotrophic hormone (ACTH), epidemial growth factor, tryocidins, 
gramicidins, gramicidins, renin, bradykinin, angiotensins, enctorphins, 
enkephalins, calcitonin, salmon calcitonin, secretin, calcitonin gene 
related factor, tissue plasminogen factor, kidney plasminogen factor, 
cholecystokinin, melanocyte inhibiting factor, melanocyte stimulating 
hormone, neuropeptide y, nerve growth factor, muramyl dipeptide, 
thymopoietin, human growth hormone, porcine growth hormone, bovine growth 
hormone, insulin, thyrotropin releasing hormone (TRH), arogastrone, 
pentagastrin, tetragastrin, gastrin, interferons, glucagon, somatostatin, 
prolactin, superoxide dismutose, luteinizing hormone releasing hormone 
(LHRH), H-5-Oxo-Pro-His-Trp-Ser-Tyr-DTrp-Leu-Arg-Pro-GlyNH.sub.2, 
H-5-Oxo-Pro-His-Trp-Ser-Tyr-3-(2 
Napthyl)-D-alanyl-Leu-Arg-Pro-Gly-NH.sub.2, Luteinizing hormone-releasing 
factor (pig), 6-[0-(1,1-dimethylethyl)-D-serine]-10-deglycinamide-, 
2-(aminocarbonyl)hydrazide (9CI), Luteinizing hormone-releasing factor 
(pig), 
6-[0-(1,1-dimethylethyl)-D-serine]-9-(N-ethyl-L-prolinamide)-10-deglycinam 
ide-(9CI), Luteinizing hormone-releasing factor (pig), 
6-D-leucine-9-(N-ethyl-L-prolinamide)-10-deglycinamide-(9CI) and synthetic 
analogs and modifications and pharmacologically active fragments thereof 
and pharmaceutically acceptable salts thereof. 
Other classes of compounds suitable for microencapsulation by this process 
includes: penicillins, beta-lactamase inhibitors, cephalosporine, 
quinolones, aminoglycoside antibiotics (gentamicin, tobramycin, kanamycin, 
amikacin), estradiol, norethisterone, norethindrone, progesterone, 
testosterone, amcinonide, achromycin, tetracyclines (doxycycline, 
minocycline, oxytetracycline, tetracycline, chlortetracycline, 
demeclocycline, methacyline), clindamycin, Vitamin B-12, anesthetics 
(procaine, tetracaine, lidocaine, mepivacaine, etidocaine), mitoxantrone, 
bisantrene, doxorubicin, mitomycin C, bleomycin, vinblastine, vincristine, 
cytosine arabinoside, ARA-AC, actinomycin D, daunomycin, daunomycin 
benzoylhydrazone, nitrogen mustards, 5-azacytidine, calcium leucovorin, 
cis-platinum compounds, 5-fluorouracil, methotrexate, aminopterin, 
maytansine, melphalan, mecaptopurines, methyl CCNU, hexamethylmelamine, 
etoposide, hydroxyurea, levamisole, mitoquazone, misonidazole, 
pentostatin, teniposide, thioquanine, dichloromethotrexate, 
chloprothixene, molindone, loxapine, haloperidol, chlorpromazine, 
triflupromazine, mesoridazine, thioridazine, fluphenazine, perphenazine, 
trifluoperazine, thiothixene, and pharmaceutically acceptable salts of the 
foregoing, hydromorphone, oxymorphone, levorphenol, hydrocodone, 
oxycodone, nalorphine, naloxone, naltrexone, buprenorphine, butorphenol, 
nalbuphine, mepridine, alphaprodine, anileridine, diphenoxylate, fentanyl 
and pharmaceutically acceptable salts of the foregoing. 
The encapsulating polymer may be biodegradable or non-biodegradable as the 
application dictates. The term biodegradable is used herein to mean that 
the polymer degrades when administered to a living organism by hydrolysis 
or as a result of enzymatically catalyzed degradation or by a combination 
of the two. 
Among the encapsulating polymers which can be utilized, there are named: 
polyglycolide, polylactide (L OR DL), poly(glycolide-co-l-lactide), 
poly(glycolide-co-dl-lactide), poly(p-dioxanone), 
poly(glycolide-co-trimethylene carbonate), poly(alkylene diglycolates), 
poly(alkylene succinates), poly(alkylene oxalates), poly(capro-lactone), 
poly( -hydroxybutyric acid), poly(ortho esters), poly(anhydrides), 
poly(amide-esters), poly(alkylene tartrate), poly(alkylene fumarate), 
cellulose based polyurethanes, ethyl cellulose, methyl cellulose, 
hydroxypropyl cellulose, and other cellulose derivatives. 
In addition, blends of the above polymers and other copolymers of the above 
may be used. 
The choice of non-solvent is dictated by the chemical nature of the 
encapsulation polymer and the polymer solvent. The non-solvent must be 
miscible with the polymer solvent and as the name implies, a non-solvent 
for the encapsulating polymer or coating. The non-solvent must have 
greater affinity for the polymer solvent than the encapsulating polymer. 
Typical non-solvents are silicone oils (polydidemethylsiloxane), vegetable 
oils, polyisobutylene, mineral oils, cyclic polydimethylsiloxanes and 
related oils and the like. 
Encapsulating polymer or coating solvents must be miscible with the 
hardening agent which in the process of this invention is a volatile 
silicone fluid. Typically, halogenated organic solvents such as methylene 
chloride and 1,1,2-trichloroethane or other C.sub.1 -C.sub.4 halogenated 
alkanes are employed. 
The volatile silicone fluid is preferably octamethylcyclotetrasiloxane or 
decamethylcyclopentasiloxane or a low molecular weight linear 
polydimethylsiloxane, such as hexamethyldisiloxane. 
DETAILED DESCRIPTION OF THE INVENTION 
The methods and materials used to prepare microencapsulated pharmaceutical 
agents are well known to those skilled in the art as evidenced by the 
above-mentioned patents and publications. 
Merely by way of illustration, biodegradable polymers such as 
poly(glycolide-co-dl-lactide), poly(lactide) and other similar polyester 
type polymers have been used to produce microcapsules containing a number 
of drugs. The solvent used for these polymers is normally methylene 
chloride or other halogenated solvents, such as C.sub.1 -C.sub.4 
halogenated alkanes, e.g., methylene chloride and 1,1,2-trichloroethane. 
Phase inducing substances, i.e., non-solvents, or the so-called 
coacervation agents, are typically silicone oil (polydimethylsiloxane), 
vegetable oils and polyisobutylene, but they can also include mineral 
oils, and other related oils, and the like. The hardening solvents most 
commonly used in the prior art are flammable alkanes such as heptane and 
cyclohexane. 
It is essential in the current invention to use a particular class of 
hardening agents for phase separation microencapsulation induced by the 
addition of a non-solvent for the coating polymer. 
These hardening agents are volatile silicone fluids. 
Suitable volatile silicone fluids are: 
octamethylcyclotetrasiloxane; 
decamethylcyclopentasiloxane; and 
low molecular weight linear polydimethylsiloxanes such as 
hexamethyldisiloxane. 
Preferred agents are octamethylcyclotetrasiloxane and 
decamethylcyclopentasiloxane. These agents are non-flammable (flash points 
of 55.degree. C. and 76.degree. C., respectively). Also, since they are 
pure substances rather than mixtures, they may be easily recovered by 
distillation and recycled. 
Such fluids can be made by procedures known to those skilled in this art; 
and they are all commercially available. 
The microcapsules may range in diameter from about 0.1 to 1000 microns, 
preferably 5 to 200 microns, and especially preferably 10-180 microns, 
depending on the procedure employed. They may be administered to a subject 
by any means or route desired. The amount of pharmaceutical agent used 
will comprise an effective amount greater than a conventional single dose. 
This can be readily determined by those skilled in this art, but, for 
example, if a hormone is used, the amount will comprise up to about 70% by 
weight of the microcapsules, preferably from about 0.01 to about 40% by 
weight of the microcapsules, and especially preferably from 0.1 to 10% by 
weight of the microcapsules. 
While the composition of matter employing the above described hardening 
agents and the process by which the microcapsules are produced are 
generically applicable to a variety of pharmaceutical agents, they are 
specifically applicable to microcapsule formulations containing peptides 
or proteins such as those listed above. 
For example, (D-Trp.sup.6)-LH-RH, a synthetic decapeptide analogue of the 
naturally occurring Luteinizing Hormone Releasing Hormone, used for the 
treatment of hormone related diseases such as hormone-dependent breast, 
prostate and ovarian cancers, endometriosis and precocious puberty. 
One of the main problems with this product is that it must be administered 
parenterally and because it has a short biological half-life daily 
injection is required which is at best inconvenient and has undesirable 
effects. 
Microcapsules prepared with a biodegradable encapsulating polymer according 
to the current invention provide the ideal delivery system for D-Trp.sup.6 
-LH-RH and related or similar drugs. Injected subcutaneously or 
intramuscularly, the polymer portion of the microcapsule will biodegrade 
and bioerode, resulting in the release of the peptide into the body for 
periods ranging from several hours to several months.

DESCRIPTION OF THE PREFERRED EMBODIMENTS 
The following examples illustrate the invention, but are not intended to 
limit the claims in any manner whatsoever. 
EXAMPLE 1 
A 6.0 g portion of poly(glycotide-co-dl-lactide) polymer was added to 300 g 
of methylene chloride and dissolved by stirring at high speed for 24 
hours. A 0.24 g portion of D-Trp.sup.6 -LH-RH.RTM. (84% purity) was added 
to approximately one half of the polymer/methylene chloride solution and 
was dispersed with a homogenizer. 
The drug/polymer/methylene chloride solution together with the remainder of 
the polymer-methylene chloride solution was then added to a vessel 
equipped with a stirrer rotating at 2250 rpm. This mixture was stirred 
until homogeneous and a non-solvent consisting of 218 g of polydimethyl 
siloxane having a viscosity of 350 centistokes was infused into the 
mixture at a rate of 4 ml per minute. The total mixing time was 56 
minutes. 
This mixture was then discharged into 6 gallons of 
octamethylcyclotetrasiloxane and mixed at a speed of 750 rpm. When the 
microspheres were completely discharged into the 
octamethylcyclotetrasiloxane the mixing speed was increased to 1500 rpm. 
The total mixing time was 2.5 hours. 
The hardened microcapsules were collected by passing the mixture through a 
stainless steel collection screen having 5 micron openings. The 
microcapsules were then vacuum dried. 
The above microcapsules were tested to determine the rate of D-Trp.sup.6 
-LH-RH release in vitro by the following procedure: 
The release apparatus consisted of a porous microcapsule container which 
was placed in a culture tube containing a specified amount of the release 
medium, pH 7.4 phosphate buffer. The tube was rotated in a 37.degree. C. 
incubator. Periodically over a period of 45 days the release medium was 
removed, assayed for D-Trp.sup.6 -LH-RH by HPLC, and replaced with fresh 
medium. 
Drug release was observed to occur over a period of forty-five days. 
Residual octamethylcyclotetrasiloxane levels were found to be two to three 
percent by weight. For comparison, heptane hardened microcapsules contain 
5-15% heptane typically. 
EXAMPLE 2 
If the procedure of Example 1 is repeated, substituting 
decamethylcyclopentasiloxane for octamethylcyclotetrasiloxane, 
substantially the same results will be obtained. 
EXAMPLE 3 
If the procedure of Example 1 is repeated, substituting 
hexamethyldisiloxane for octamethylcyclotetrasiloxane, substantially the 
same results will be obtained. 
EXAMPLE 4 
A 50 gram batch of D-Trp.sup.6 -LH-RH microcapsules was produced using the 
following method: 
A 50 gram portion poly(glycolide-co-lactide) having a lactide to glycolide 
rates of approximately 53:47 and an inherent viscosity of about 0.65 dl/g 
(as measured in a 0.5% w/v hexafluoroisopropanol solution at 30.degree. 
C.) copolymer was dissolved into 950 grams methylene chloride by stirring 
overnight. The solution was filtered through a stainless steel screen 
having eight micron openings. 
An amount of 2.0 grams of spray-dried D-Trp.sup.6 -LH-RH was mixed into the 
polymer solution using high shear mixer for about 30 seconds. The 
D-Trp.sup.6 -LH-RH had a mean particle size of approximately 3 microns. 
The drug/copolymer/methylene chloride solution was added to the 
microencapsulation vessel equipped with a stirrer rotating at 300 rpm. A 
non-solvent consisting of 1,000 grams of a polydimethylsiloxane having a 
viscosity of 350 centistokes was infused at 100 grams/min. The total 
mixing time was 12 minutes. This mixture was then discharged into 5 
gallons (18.2 kilos) of octamethylcyclotetrasiloxane and mixed at 750 rpm. 
When the microspheres were completely discharged the mixing speed was 
increased up to 1500 rpm. Total mixing time was 2 hours. 
The hardened microcapsules were then collected by passing the mixture 
through a stainless steel screen with eight micron openings. The 
microcapsules were then vacuum dried. 
EXAMPLE 5 
A six gram batch of cyanocobalamin (Vitamin B.sub.12) microcapsules were 
produced using the following method: 
120 grams of a 5% (w/w) poly(glycolide-co-dl-lactide) polymer solution in 
methylene chloride was filtered through a 0.2 micron millipore membrane 
filter. The polymer had an inherent viscosity of about 0.29 dl/g (as 
measured in a 0.5 w/v hexafluoroisopropanol solution at 30.degree. C.) and 
a lactide to glycolide ratio of about 53:47. 
An amount of 0.24 grams Vitamin B.sub.12 having a mean particle size of 
about 5 microns was added to the 120 grams of filtered 5% solution. The 
B.sub.12 was blended into the polymer solution using a homogenizer for 
about 30 seconds. 
The B.sub.12 solution was added to the microencapsulation vessel equipped 
with a stirrer rotating at 300 rpm. A non-solvent consisting of 
polydimethylsiloxane having a viscosity of 350 centistokes was infused at 
100 grams per minute for one minute to give a total added quantity of 100 
grams. The solution was stirred for an additional two minutes. 
The above suspension was discharged into 4 gallons of 
octamethylcyclotetrasiloxane fluid mixed for 2 hours at a stirrer speed 
increased over time from 750 to 1500 rpm. 
Microcapsules were collected, rinsed with octamethylcyclotetrasiloxane and 
dried under vacuum. The microcapsules ranged in diameter from about 30 to 
120 microns. 
EXAMPLE 6 
A 15 gram batch of minocycline microspheres was produced using the 
following method: 
A 300 gram portion of a 5% poly(glycolide-co-dl-lactide) solution in 
methylene chloride was filtered through a 0.2 micron millipore membrane. 
The polymer had an inherent viscosity of about 0.67 dl/g (as determined in 
a 0.5% (w/v) hexafluoroisopropanol solution at 30.degree. C.) and a 
lactide to glycolide ratio of about 53:47. 
A 6.2 gram portion of micronized minocycline HCL (85.7% pure and having a 
mean particle size of about 3 microns) was added to the 300 grams of 
filtered polymer solution. 
The drug was dispersed in the polymer solution with a homogenizer for about 
1 to 2 minutes. 
The suspension was added to a microencapsulation vessel equipped with a 
stirrer and stirring at 300 rpm. Polydimethylsiloxane having a viscosity 
of 350 centistokes was infused at 100 grams per minute for 3 minutes for a 
total of 300 grams. The mixture was stirred for an additional 2 minutes 
then discharged into 5 gallons of octamethylcyclotetrasiloxane mixing at 
speeds varying from 750 rpm to 1500 rpm for two hours. 
The microcapsules were collected by filtration, rinsed with 
octamethylcyclotetrasiloxane and dried under vacuum. Diameters of these 
microcapsules ranged from about 30 to 120 microns. 
The above-mentioned patents and publications are incorporated herein by 
reference. 
Many variations of this invention will occur to those skilled in this art 
in light of the above, detailed description. For example, instead of 
(D-Trp.sup.6)-LH-RH, a steroid hormone can be used, e.g., norethindrone, 
norethisterone, and the like or other vitamins or antibiotics can be used. 
Instead of silicone oil as a non-solvent, mineral oil or peanut oil can be 
used. All such obvious variations are within the full intended scope of 
the appended claims.