U.S. patent application number 17/255680 was filed with the patent office on 2021-09-02 for pharmaceutical formulation with improved solubility and bioavailability.
The applicant listed for this patent is BIOINICIA, S.L., Consejo Superior de Investigaciones Cientificas (CSIC), ZF POLPHARMA S.A.. Invention is credited to David GALAN NEVADO, Julia HRAKOVSKY, Jose Maria LAGARON CABELLO, Cristina PRIETO LOPEZ, Jose Manuel VALLE BAZ.
Application Number | 20210267898 17/255680 |
Document ID | / |
Family ID | 1000005648535 |
Filed Date | 2021-09-02 |
United States Patent
Application |
20210267898 |
Kind Code |
A1 |
LAGARON CABELLO; Jose Maria ;
et al. |
September 2, 2021 |
Pharmaceutical Formulation with Improved Solubility and
Bioavailability
Abstract
The present invention relates to a pharmaceutical formulation
comprising at least one active pharmaceutical ingredient (API)
having low aqueous solubility or a pharmaceutically acceptable salt
thereof in the form of particles of a size between 1 and 800 nm,
wherein said particles are encapsulated within a large
microparticle of a size between 1 and 100 .mu.m formed by a matrix
comprising at least an excipient. Therefore, the API is entrapped
or encapsulated in the microparticles of excipients. This
pharmaceutical formulation contains the pharmaceutical active
ingredient having improved solubility and subsequently
supra-bioavailability.
Inventors: |
LAGARON CABELLO; Jose Maria;
(Valencia, ES) ; PRIETO LOPEZ; Cristina; (Lugo,
ES) ; VALLE BAZ; Jose Manuel; (Castellon de la Plana,
ES) ; GALAN NEVADO; David; (Malaga, ES) ;
HRAKOVSKY; Julia; (Gdynia, PL) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Consejo Superior de Investigaciones Cientificas (CSIC)
BIOINICIA, S.L.
ZF POLPHARMA S.A. |
Madrid
Valencia
Starogard Gdanski |
|
ES
ES
PL |
|
|
Family ID: |
1000005648535 |
Appl. No.: |
17/255680 |
Filed: |
June 28, 2019 |
PCT Filed: |
June 28, 2019 |
PCT NO: |
PCT/EP2019/067342 |
371 Date: |
December 23, 2020 |
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
B82Y 30/00 20130101;
A61K 45/06 20130101; A61K 9/1611 20130101; B82Y 40/00 20130101;
B82Y 5/00 20130101; A61K 9/146 20130101; A61K 9/1652 20130101; A61K
9/1694 20130101 |
International
Class: |
A61K 9/14 20060101
A61K009/14; A61K 9/16 20060101 A61K009/16; A61K 45/06 20060101
A61K045/06 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 29, 2018 |
EP |
18382484.6 |
Claims
1. A pharmaceutical formulation characterized in that it comprises:
at least one active pharmaceutical ingredient (API) having low
aqueous solubility or a pharmaceutically acceptable salt thereof in
the form of particles of a size between 1 and 800 nm, wherein said
particles are encapsulated within a large microparticle of a size
between 1 and 100 .mu.m formed by a matrix comprising at least an
excipient, wherein the active pharmaceutical ingredient having low
aqueous solubility is selected from the group of Biopharmaceutical
Classification System classes II and IV.
2. A pharmaceutical formulation, according to claim 2, wherein the
active pharmaceutical ingredient is selected form the list
comprising: abiraterone, albendazole, axitinib, atovaquone,
acetazolamide, atorvastatin calcium, amphotericin, aceclofenac,
betamethasone, candesartan cilexetil, carbamazepine, carisoprodol,
cefixime, ceritinib, crizotinib, celecoxib, cephalexin,
clopidogrel, cefuroxime axetil, danazole, dapsone, diclofenac,
dronabinol, etodolac, etoposide, ezetimib, fenofibrate, felodipine,
furosemide, griseofulvin, irbesartan, itrconazole, ibufrofen,
valsartan, ritonavir, paclitaxel, nilotinib, omega 3
polyunsaturated fatty acids, simvastatin, lamotrigine,
lansoprazole, ketoconazole, troglitazone, nimesulide, loratadine,
probucol, ubiquinone, ketoprofen, tinidazole, mesalamine,
metaxalone, loperamide, methylphenidate, methylprednisolone,
mycophenolate, nabumetone, nelfinavir mesylate, pioglotazone HCl,
piroxicam, rifabutin, rifampin, risperidone, ritonavir, tadalafil,
tacrolimus, telmisartan, vitamin D, vardenafil, triamcinolone
acetonide, ofloxacin, nevirapine. or combinations thereof.
3. A pharmaceutical formulation, according to claim 1 or 2
comprises at least one active pharmaceutical ingredient having low
aqueous solubility or a pharmaceutically acceptable salt thereof in
the form of particles of a size between 1 and 500 nm, wherein said
particles are encapsulated within a large microparticle of a size
between 1 and 20 .mu.m formed by a matrix comprising at least an
excipient.
4. A pharmaceutical formulation, according to any of claims 1 to 4
wherein each microparticle encapsulating the API or a
pharmaceutically acceptable salt thereof comprises between 20-85%
by weight of the API or a pharmaceutically acceptable salt thereof
and between 15-80% by weight of one or more excipients.
5. A pharmaceutical formulation, according to any of claims 1 to 4,
comprising: a) 10-85% by weight of microparticles encapsulating the
API or a pharmaceutically acceptable salt thereof; b) 15-90% by
weight of additional excipients.
6. A pharmaceutical formulation, according to any of claims 1 to 5,
wherein the excipients are selected from diluents, binders,
lubricants, disintegrants, glidants, surfactants, thickeners or
combinations thereof.
7. A pharmaceutical formulation, according to claim 6, wherein the
excipients comprise at least one disintegrant selected from
natural, modified or pregelatinized starch, crospovidone,
croscarmellose sodium, sodium starch glycolate, low-substituted
hydroxypropyl cellulose, effervescent disintegrating systems or any
combination thereof.
8. A pharmaceutical formulation, according to any of claims 6 to 7,
wherein the excipients comprise at least one binder selected from:
starch, pregelatinized starch, polyvinyl pyrrolidone, copovidone,
cellulose derivatives, such as hydroxypropylmethyl cellulose,
hydroxypropyl cellulose and carboxymethyl cellulose or any
combination thereof.
9. A pharmaceutical formulation, according to any of claims 6 to 8,
wherein the excipients comprise at least one diluent selected from:
starch, microcrystalline cellulose, lactose, xylitol, mannitol,
maltose, polyols, fructose, guar gum, sorbitol, magnesium
hydroxide, dicalcium phosphate or any combination thereof.
10. A pharmaceutical formulation, according to any of claims 6 to
9, wherein the excipients comprise at least one lubricant selected
from: magnesium stearate, calcium stearate, stearic acid, talc,
sodium stearyl fumarate or any combination thereof.
11. A pharmaceutical formulation, according to any of claims 6 to
10, wherein excipients comprise at least one glidant selected from:
colloidal silica, silica gel, precipitated silica, talc or any
combination thereof.
12. A method to prepare sub-micron particles between 1 and 800 nm
of at least one active pharmaceutical ingredient or pharmaceutical
acceptable salt thereof encapsulated into microparticles between 1
and 100 .mu.m comprising excipients, characterized in that it is
carried out in a facility comprising: an injection unit, which is
preferably a nebuliser or an electronebuliser, a drying unit, which
is arranged after the injection unit, and a collection unit,
arranged after the drying unit. The method comprises the following
stages: a) preparing of an emulsion comprising: at least one active
pharmaceutical ingredient or pharmaceutically acceptable salt
thereof to be encapsulated, one or more excipients; at least two
non-miscible or partially miscible solvents or two miscible
solvents that by solubilizing the API or the excipients become
non-miscible or partially miscible, b) forming droplets from the
solution obtained in stage (a) in the presence of an injection gas
flow; c) drying the droplets obtained in stage (b) in the drying
unit at a controlled temperature to obtain microparticles; and d)
collecting the microparticles obtained in stage (c) by means of the
collection unit.
13. A method according to claim 12 wherein the excipient used in
stage a) comprises a surfactant to stabilize the emulsion.
14. A method according to any of claims 12 to 13 wherein the
solvents used in step a) are selected from the list comprising:
water, alcohol, toluene, ethyl acetate, methylene chloride,
chloroform, dimethyl sulfoxide, dimethyl formamide,
tetrahydrofuran, deep eutectic solvents, natural deep eutectic
solvents and combinations thereof.
15. The method, according to any of claims 12 to 14 wherein stage
c) is carried out at a temperature between 1 and 45.degree. C.
16. The method, according to any of claims 12 to 15, wherein the
stage b) of forming droplets is carried out by applying a voltage
of between 0.1 kV and 500 kV to the solution and injection gas flow
at the outlet of the injection unit.
Description
[0001] The invention relates to pharmaceutical formulations wherein
one or more active pharmaceutical ingredient (API) is present in a
sub-micron form to influence the solubility and bioavailability of
the drug.
BACKGROUND ART
[0002] Most of the recent discovered pharmaceuticals present poor
water solubility, leading to their low effective concentration in
biofluids and poor bioavailability. Different strategies were
developed to overcome this challenge, such as size reduction,
modification of crystallinity, chemical alteration, solubilization
in surfactant micelles or the use of pharmaceutical carriers such
as polymeric micro- and nanoparticles, liposomes, solid-lipid
particles, niosomes and others. Pharmaceutical carriers demonstrate
a broad variety of useful properties such as longevity,
targetability, intracellular penetration, reduced drug doses, which
result in increased patient comfort and compliance (K.
Margulis-Goshen, S. Magdassi, Nanomedicine: Nanotechnology,
Biology, and Medicine 5 (2009) 274-281; V. P. Torchilin, Adv. Drug
Deliv. Rev. 58 (2006) 1532-1555).
[0003] A large number of processes exist for obtaining
pharmaceutical carriers (N. V. N. Jyothy et al. J. Microencapsul.
27 (2010) 187-197; C. E. Mora-Huertas et al. Int. J. Pharm. 385
(2010) 113-142). The selection of a particular technique depends on
the physicochemical properties of the core, the coating used, the
type of particle desired, as well as the production scale and
costs. Most of the conventional techniques to produce
pharmaceutical ingredients have difficulty in controlling particle
size. The emulsion-based technologies allow obtaining particles in
the sub-micron scale with narrow size distribution and high
retention of the bioactive compound. Emulsion-based processes
include emulsion polymerization, emulsion evaporation, emulsion
extraction, solvent diffusion, nanoprecipitation (U.S. Pat. No.
5,049,322) or supercritical fluid extraction of emulsions
(US2004071781A1). These processes present several drawbacks such as
presence of undesirable materials in the final product (residual
monomers or organic solvents), production of liquid suspensions,
slow extraction rate or difficulty to scale-up the process.
[0004] The spray drying technique has been widely used in the
preparation of pharmaceutical powders, most often proposed as a
dehydration process, but has been also used to encapsulate drugs
(R. C. R. Beck et al. Recent Pat. Drug Deliv. Formul. 6 (2012)
195-208). U. Selvaraj and G. L. Messing prepared crystallites of
naproxen of 35 nm inside a matrix of ethyl cellulose, with a
microparticle size of 400 .mu.m by spray drying (WO9713503-1997).
However, the spray drying technique involves evaporation of the
solvent using hot air. The high temperatures employed for such
processing can sometimes degrade thermally labile drugs and
excipients, produce large particles with broad distribution of
particles sizes, impair resolubilization and can be prone to
explosion if organic or alcoholic solvents are used in which low
availability drugs need be dissolved.
[0005] Additionally, the recovery and handling of sub-micron
particles present several technical difficulties for industry
(ISO/TR 12885:2008).
[0006] Thus, due to the above-mentioned limitations of the prior
art processing methods, the present invention proposes a
methodology that overcomes the cited limitations by producing free
flowing microparticles of excipients containing highly dispersed
and distributed sub-micron size particles of low bioavailability
drugs using a high throughput installation that works at room or
near room temperature and that combines high voltage and
nebulizing. These microparticles can then be processed using
conventional technologies existing in the pharma industry to lead
to pharmaceutical preparations that can be commercialized.
SUMMARY OF THE INVENTION
[0007] The present invention relates to pharmaceutical formulations
in which at least one active pharmaceutical ingredient (API) is
used in a sub-micron form. The bioavailability of an API can be
influenced by numerous factors, including, for example, the
physical form and particle size of the API in a pharmaceutical
formulation, the type of excipients present in the pharmaceutical
formulation together with the API, as well as the method by which
the pharmaceutical formulation is prepared.
[0008] A first aspect of the present invention related to a
pharmaceutical formulation comprising:
[0009] at least one active pharmaceutical ingredient (API) having
low aqueous solubility or a pharmaceutically acceptable salt
thereof in the form of particles of size between 1 and 800 nm,
wherein said particles are encapsulated within a large
microparticle of a size between 1 and 100 .mu.m formed by a matrix
comprising at least an excipient.
[0010] The active pharmaceutical ingredient (API) or
pharmaceutically acceptable salt thereof is encapsulated
(entrapped), highly dispersed and distributed into the particles
formed by the excipients (or comprising excipients). Therefore,
each particle made of excipients is a matrix where each sub-micron
particles of the API or pharmaceutically acceptable salt thereof is
separated out from the others by the excipient.
[0011] In a preferred embodiment, the microparticles formed by a
matrix comprising at least an excipient have a size between 1 and
40 .mu.m, more preferably between 1 and 20 .mu.m.
[0012] In a preferred embodiment, the particles of the API or a
pharmaceutically acceptable salt thereof have a size between 1 and
600 nm, more preferably between 1 and 500 nm and even more
preferably between 50 and 500 nm.
[0013] The active pharmaceutical ingredient (API) having low
aqueous solubility is an API that belongs to Biopharmaceutical
Classification System (BCS) Class II and IV. Biopharmaceutical
Classification System is an experimental model that measures
permeability and solubility under prescribed conditions, developed
by Amidon et al. Pharm. Res. 12 (1995) 413-420.
[0014] According to the BCS, drug substances are classified into
four classes based solely on their solubility and intestinal
permeability: Class I: High Solubility, High Permeability; Class
II: Low Solubility, High Permeability; Class III: High Solubility,
Low Permeability and Class IV: Low Solubility, Low
Permeability.
[0015] Some examples of BCS Class II and IV APIs (also called
pharmaceutical drugs) are: abiraterone, albendazole, axitinib,
atovaquone, acetazolamide, atorvastatin calcium, amphotericin,
aceclofenac, betamethasone, candesartan cilexetil, carbamazepine,
carisoprodol, cefixime, ceritinib, crizotinib, celecoxib,
cephalexin, clopidogrel, cefuroxime axetil, danazole, dapsone,
diclofenac, dronabinol, etodolac, etoposide, ezetimib, fenofibrate,
felodipine, furosemide, griseofulvin, irbesartan, itrconazole,
ibufrofen, valsartan, ritonavir, paclitaxel, nilotinib, omega 3
polyunsaturated fatty acids, simvastatin, lamotrigine,
lansoprazole, ketoconazole, troglitazone, nimesulide, loratadine,
probucol, ubiquinone, ketoprofen, tinidazole, mesalamine,
metaxalone, loperamide, methylphenidate, methylprednisolone,
mycophenolate, nabumetone, nelfinavir mesylate, pioglotazone HCl,
piroxicam, rifabutin, rifampin, risperidone, ritonavir, tadalafil,
tacrolimus, telmisartan, vitamin D, vardenafil, triamcinolone
acetonide, ofloxacin, nevirapine etc. or combinations thereof.
[0016] The omega-3 polyunsaturated fatty acids (PUFAs) can be, for
example, .alpha.-linolenic acid (ALA, C18:3 n-3), eicosapentaenoic
acid (EPA, C20:5n-3), and docosahexaenoic acid (DHA, C22:6 n-3),
either in its ethyl ester form (EE) or triglyceride form (TG).
[0017] The low soluble drugs (APIs) are problematic for effective
drug delivery in many cases, characterized by inter and intra
subject variability and significant food effect. These obstacles
can be overcome by usage of sub-micron particle size of the API
providing, this way, better solubility and bioavailability. The
encapsulation of the sub-micron API particles into microparticles
allows, as a main role, to facilitate the formulation of
pharmaceutical preparations containing sub-micron size APIs. In
addition, this encapsulation process can also provide masking of
undesirable organoleptic properties, avoid adverse effects,
increase shelf-life and provide easier handling. The dosage forms
and compositions of the present invention improve patient
compliance by reducing dosage, which can potentially lead to less
adverse effects, as well as food effect and variability
reduction.
[0018] The sub-micron size particles of the API or a
pharmaceutically acceptable salt thereof are highly dispersed and
distributed within the matrix comprising at least an excipient.
Therefore, the particles of the API are separated from each other
by the material of the matrix, so that the particles of the API do
not form agglomerates and hence can increase solubility and
bioavailability.
[0019] In a preferred embodiment, the microparticles of a size
between 1 and 100 .mu.m consist essentially of or consist of at
least an excipient encapsulating the API.
[0020] Preferably, the excipients are polymers having a molecular
weight greater than the molecular weight of the active
pharmaceutical ingredient or the pharmaceutically acceptable salt
thereof.
[0021] In a preferred embodiment, the excipients that form the
matrix of the microparticles are selected from diluents, binders,
lubricants, disintegrants, glidants, surfactans, thickeners or
combinations thereof.
[0022] Combinations of different APIs may be included in the
formulation, including combinations in which not all of the APIs
have low solubility and not all of the APIs have sub-micronized
particle size (between 1 and 800 nm). When the formulation includes
several APIs, at least one of them is in sub-micron ranged size and
has low aqueous solubility.
[0023] A preferred embodiment of the present invention provides a
pharmaceutical formulation comprising, consisting essentially of,
or consisting of at least a low soluble API or a pharmaceutically
acceptable salt thereof in a sub-micron ranged size between 1-500
nm, encapsulated, highly dispersed and distributed into larger
microparticles between 1-20 .mu.m comprising one or more
excipients.
[0024] The microparticles containing the API (also referred as to
large particles of a size between 1 and 100 .mu.m encapsulating the
API or a pharmaceutically acceptable salt thereof) are used to
prepare pharmaceutical formulations in any form typically used by
the pharma industry. More specifically, the pharmaceutical
preparation may be in the form of a tablet, granulate, powder,
capsule, thin films, patches or liquid preparation. For that, the
microparticles containing the API or a pharmaceutically acceptable
salt thereof are combined or mixed with additional excipients to
form tablet, granulate, powder, capsule, thin films, patches or
liquid preparation etc.
[0025] This additional excipients that are used to prepare the
pharmaceutical formulation of the present invention in any form
typically used by the pharmaceutical industry form are preferably
selected from diluents, binders, lubricants, disintegrants,
glidants, surfactans, thickeners or combinations thereof.
Therefore, the additional excipients of the pharmaceutical
composition can be the same as the excipients forming the matrix of
the microparticules encapsulating the API.
[0026] In a preferred embodiment, each microparticle encapsulating
the API or a pharmaceutically acceptable salt thereof in the
pharmaceutical formulation comprises: [0027] a) 20-85% by weight of
the API or a pharmaceutically acceptable salt thereof; [0028] b)
15-80% by weight of excipients.
[0029] In a more preferred embodiment, each microparticle
encapsulating the API or a pharmaceutically acceptable salt thereof
in the pharmaceutical formulation comprises, consists essentially
of or consists of: [0030] a) 20-85% by weight of the API or a
pharmaceutically acceptable salt thereof; [0031] b) 0-30% by weight
of diluent; [0032] c) 0-3% by weight of glidant; [0033] d) 0-80% by
weight of binder; [0034] e) 0-10% by weight of surfactant; [0035]
f) 0-12% by weight of disintegrant; [0036] g) 0.4-2.5% by weight of
lubricant.
[0037] with the proviso that the sum of the components is the 100%
by weight of the particle.
[0038] In a preferred embodiment, each microparticle encapsulating
the API comprises, consists essentially of or consists of: [0039]
a) 20-85% by weight of Valsartan or Abiraterone Acetate or a
pharmaceutically acceptable salt thereof; [0040] b) 0-30% by weight
microcrystalline cellulose; [0041] c) 0-3% by weight colloidal
silicon dioxide; [0042] d) 0-50% by weight hydroxypropyl
methylcellulose; [0043] e) 0-3% by weight sodium lauryl sulfate
[0044] f) 0.4-2.5% by weight magnesium stearate.
[0045] with the proviso that the sum of the components is the 100%
by weight of the particle.
[0046] In a preferred embodiment, the pharmaceutical formulation
comprises: [0047] a) 10-85% by weight of microparticles
encapsulating the API or a pharmaceutically acceptable salt
thereof; [0048] b) 15-90% by weight of additional excipients.
[0049] In a more preferred embodiment, the pharmaceutical
formulation comprises, consists essentially of or consists of:
[0050] a) 10-85% by weight of microparticles containing the API or
a pharmaceutically acceptable salt thereof; [0051] b) 10-85% by
weight of additional diluent; [0052] c) 0-3% by weight of
additional glidant; [0053] d) 0-10% by weight of additional binder;
[0054] e) 0-10% by weight of additional surfactant; [0055] f) 0-12%
by weight of additional disintegrant; [0056] e) 0.5-3% by weight of
additional lubricant.
[0057] with the proviso that the sum of the components is the 100%
by weight of the pharmaceutical formulation.
[0058] The microparticles (microparticle of a size between 1 and
100 .mu.m encapsulating the API or a pharmaceutically acceptable
salt thereof) that the pharmaceutical formulation comprises are
preferably obtained by the method for the industrial encapsulation
of an active pharmaceutical ingredient or pharmaceutically
acceptable salt thereof described in the second aspect of the
invention.
[0059] The term "excipient" refers to a pharmaceutically acceptable
ingredient that is commonly used in the pharmaceutical industry.
Examples of categories of excipients include, but are not limited
to, binders, disintegrants, lubricants, glidants, stabilizers,
surfactants, fillers (diluents), thickeners. One of ordinary skill
in the art may select one or more of the aforementioned excipients
with respect to the particular desired properties.
[0060] Examples of disintegrants include, but are not limited to,
natural, modified or pregelatinized starch, crospovidone,
croscarmellose sodium, sodium starch glycolate, low-substituted
hydroxypropyl cellulose, effervescent disintegrating systems and
any combination thereof.
[0061] Examples of suitable binders include, but are not limited
to, starch, pregelatinized starch, polyvinyl pyrrolidone (PVP),
copovidone, cellulose derivatives, such as hydroxypropylmethyl
cellulose (HPMC), hydroxypropyl cellulose (HPC), carboxymethyl
cellulose (CMC) and their salts and or any combination thereof.
[0062] Examples of suitable diluents include, but are not limited
to, starch, microcrystalline cellulose, cellulose, lactose,
sucrose, xylitol, mannitol, dextrins, maltose, polyols, fructose,
guar gum, sorbitol, magnesium hydroxide, dicalcium phosphate and
any combinations thereof.
[0063] Examples of the lubricant include, but are not limited to,
magnesium stearate, calcium stearate, stearic acid, talc, sodium
stearyl fumarate and any combination thereof.
[0064] Examples of glidant include, but not limited to, colloidal
silica, silica gel, precipitated silica, and any combinations
thereof.
[0065] Surfactants include non-ionic, anionic and cationic
surfactants. Examples of surfactants include, but not limited to,
sorbitan esters and polysorbates (Span.TM., Tween.TM., TEGO.TM.),
poloxamer, sodium lauryl sulfate, Meglumin, poly(vinyl
pyrrolidone), polyglycerol, polyricinoleate, poly(vinyl alcohol),
Pickering emulsifiers and block copolymers.
[0066] The term "encapsulated" in the present invention, when
referring to the API, means that the API is within the particle
(matrix) made of or comprising excipients or it is entrapped or
embedded highly dispersed and distributed in the particle made of
or comprising excipients.
[0067] As used herein, the term "particle size" refers to the
diameter of a spherical particles (particles are preferably
spherical) or refers to equivalent diameter of a non-spherical
particle. "Equivalent diameter" refers to the maximum dimension of
a non-spherical particle. Particle size measurements are commonly
performed using scanning electron microscopy, transmission electron
microscopy, optical microscopy or light scattering.
[0068] The term "consisting essentially of as used herein is
intended to denote a formulation comprising the components as
specified as well as other components in trace amounts wherein the
presence of the other components does not change the essential
characteristics of the specified subject matter.
[0069] A second aspect of the present invention relates a method
for the industrial encapsulation of an active pharmaceutical
ingredient or pharmaceutically acceptable salt thereof.
[0070] The method to prepare sub-micron particles (1 and 800 nm) of
at least one active pharmaceutical ingredient or pharmaceutical
acceptable salt thereof encapsulated into microparticles (1 and 100
.mu.m) comprising excipients, is characterized in that it is
carried out in a facility comprising: [0071] an injection unit,
which is preferably a nebuliser or an electronebuliser, [0072] a
drying unit, which is arranged after the injection unit, and [0073]
a collection unit, arranged after the drying unit.
[0074] The method comprises the following stages:
[0075] a) preparing an emulsion comprising: [0076] at least one
active pharmaceutical ingredient (API) or pharmaceutically
acceptable salt thereof to be encapsulated, [0077] one or more
excipients [0078] at least two non-miscible, partially miscible
solvents or two miscible solvents that by solubilizing the API or
the excipients become non-miscible or partially miscible;
[0079] b) forming droplets from the emulsion obtained in stage (a)
in the presence of an injection gas flow;
[0080] c) drying the droplets obtained in stage (b) in the drying
unit at a controlled temperature to obtain microparticles; and
[0081] d) collecting the microparticles obtained in stage (c) by
means of the collection unit.
[0082] The solvents can be polar or non-polar. The non-polar
solvents (e.g. organic or oil-based) are immiscible, partially
miscible or miscible with the polar solvent, with the condition
that miscible solvents become immiscible or partially miscible due
to the presence of the API or the excipients. Preferred solvents
for use in the invention include, for example, water, alcohol
(preferably ethanol or isopropanol), toluene, ethyl acetate,
acetone, methylene chloride, chloroform, dimethyl sulfoxide (DMSO),
dimethyl formamide (DMF), tetrahydrofuran (THF), deep eutectic
solvents, natural deep eutectic solvents, other organic and
inorganic solvents, and combinations thereof selected on the basis
of their chemical inertness and sufficient solubility
power/dispersability for the solute.
[0083] A variety of emulsions types are suitable for use with the
present invention. For example, oil-in-water (O/W), water-in-oil
(W/O), water-in-oil-in-water (W/O/W), oil-in-water-in-oil (O/W/O),
oil-in-oil (O/O), and Pickering emulsions.
[0084] The term "Pickering emulsion" refers to an emulsion that is
stabilized by solid particles (for example hydroxyapatite, silica,
clay, magnetic nanoparticles) which adsorb onto the interface
between the two phases.
[0085] The size of the droplets (emulsion micelles) obtained in
step a) can depend upon the agitation speed or the degree of
homogenization of the emulsifier and the concentration or solvent
or the solutes. Generally, a higher degree of homogenization,
higher concentrations tend to produce smaller droplets or micelles.
The emulsifier is preferably a dispersator, ultrasonic horn,
microfluidizer, static mixer, colloid mill, fluid energy mill,
turbine mixer, or a spontaneous emulsification technique.
[0086] Preferably, the stage c) is carried out at temperature
between 1-45.degree. C.
[0087] In a preferred embodiment of the invention, the excipient
used in stage a) comprises a surfactant. The surfactant is useful
to extend the stability of the emulsion. They are also very used to
avoid agglomerations of the particles of the API.
[0088] In a preferred embodiment of the invention, the stage b) of
forming droplets is carried out by applying a voltage of between
0.1 kV and 500 kV to the emulsion and injection gas flow at the
outlet of the injection unit. More preferably, stage b) of forming
droplets is carried out by applying a voltage of between 5 kV and
15 kV to the emulsion and injection gas flow at the outlet of the
injection unit.
[0089] In a preferred embodiment of the invention, the stage b) of
forming droplets is carried out by applying a voltage in
alternating current.
[0090] This method allows obtaining an active pharmaceutical
ingredient (API) or pharmaceutically acceptable salt thereof in a
sub-micron particle form encapsulated within microparticles
comprising excipients.
[0091] The resulting blend of the API entrapped into the
microparticles with additional excipients is being used for the
final dosage form manufactured by any of the conventional
pharmaceutical processes. These processes may comprise direct
compression, dry granulation, wet granulation process or
others.
[0092] The proposed formulations may be dry-granulated or
wet-granulated, or the blends (blends formed microparticles
encapsulating the API and additional excipients) may be directly
compressed into tablets, filled into capsules or sachets.
[0093] For pharmaceuticals, the type of processing utilized often
depends upon the properties of the drug, the chosen excipients, and
the dosage form, e.g., particle size, blending compatibility,
density, and flowability.
[0094] In one embodiment, the invention encompasses a method of
making tablets or capsules by wet granulation comprising: providing
a mixture of encapsulated API (microparticules encapsulating the
API), at least one diluent, binder, and granulation liquid;
blending the mixture to obtain a wet granulate; drying the wet
granulate to obtain a dried granulate; and milling the dried
granulate. The method may further comprise combining the dried
granules with one or more additional excipients, adding at least
one lubricant. The resulting granules may be subsequently
encapsulated into capsules, compressed into tablets, or filled into
sachets to form solid or liquid oral dosage forms. The tablets may
further be coated.
[0095] There are economic advantages in the dry compression of
formulations over wet granulation, because the dry compression
requires less equipment, lower power consumption, less time, and
less labour. Also, dry compression avoids the use of organic
solvents during the preparation of the formulations.
[0096] An additional method of the finished product manufacturing
is a dry granulation process. This method of making a formulation
comprises providing a mixture of encapsulated API, at least one
diluent, binder, disintegrant; blending the mixture to obtain a
homogeneous mixture; optionally adding at least one lubricant to
the homogeneous mixture; and dry compressing the homogeneous
mixture into the formulation. The formulation can be in the shape
of a tablet, a slug, or a compact. The method may further comprise
milling the slug or compact into a granulate, adding at least one
lubricant to the milled granulate, and compressing the milled
granulate into tablets, encapsulating into capsules, or filling
into sachets to form solid or liquid oral dosage forms.
[0097] The alternative method of making the tablets or capsules is
by direct compression of dry formulations into tablets or filling
into capsule or sachets. The dry compression, however, is generally
limited to those circumstances in which the active ingredient has
physical characteristics suitable for forming pharmaceutically
acceptable tablets. These physical characteristics include, but are
not limited to, good flowing properties and compressibility. The
encapsulated API made by the invention, would be suitable for the
direct compression or direct filling process, other manufacturing
processes can be applicable for such encapsulated API as well.
[0098] Regarding the encapsulation facility, preferably it
comprises at least: [0099] one injection unit having at least:
[0100] one inlet for an emulsion; [0101] one inlet for injection
gas; and [0102] one outlet for droplets through which sprayed
droplets of emulsion are released, [0103] one drying unit arranged
after the injection unit and comprising at least: [0104] one inlet
for drying gas; [0105] one inlet for droplets; [0106] one
longitudinal receptacle through which the droplets with the drying
gas move until the solvent of the droplets evaporates, forming
microparticles; and [0107] at least one outlet for microparticles
and drying gas through which the microparticles and drying gas that
drags the evaporated solvent with it are released from the
receptacle; [0108] one collection unit arranged after the drying
unit, which is configured to separate the microparticles generated
from the drying gas.
[0109] The facility enables industrial amounts of microcapsules of
maintaining or increasing protection (protection of the API inside
the microcapsule), provided by other low-production techniques,
such as electrospraying and flow focusing.
[0110] The injection unit comprises an injector, at the inlet of
which an emulsion comprising the API (or a pharmaceutically
acceptable salt thereof) to be encapsulated, the encapsulating
material (excipients), solvents and necessary additives (e.g.
typically surfactants, thickeners or Pickering emulsifiers) is
introduced. Throughout the specification, when reference is made to
the emulsion (mixture of immiscible liquids) to be injected.
[0111] The injection unit projects droplets whose size can be
focused or controlled more efficiently through the application of
an electric field at the injector outlet (in this exemplary
embodiment, the injection unit can be an electronebuliser). To this
end, in one exemplary embodiment, the injection unit comprises an
electrode, typically circular, which is arranged at the injector
outlet.
[0112] In the case in which the injection unit comprises an
electric field at the injector outlet, the emulsion is electrically
charged during spraying upon penetrating said electric field which
is generated by applying high voltage, both in alternating current
(AC) and direct current (DC). Adding the electric field enables
better control over the size and monodispersity of the sizes of the
droplets generated in the injector unit. Since APIs are going to be
encapsulated and hot air is not going to be applied for drying, the
droplets generated must be very small in order to reduce subsequent
drying times.
[0113] In this facility hot air is not applied at the injector
outlet of the injection unit. Therefore, better stability and
protection results are achieved in terms of encapsulation of APIs.
It is a continuous process that is executed in a single step under
controlled, typically room temperature conditions.
[0114] The injection unit comprises a nebuliser-, sprayer- or
aerosol-type injector, including pneumatic devices, piezoelectric
devices, ultrasonic devices, vibratory devices, etc. In an
embodiment of the present invention, the injection unit comprises a
pneumatic nebuliser of the type comprising an inlet for a liquid
emulsion and two inlets for injection gas. In this exemplary
embodiment, the injection unit comprises two inlets for injection
gas, of which one inlet for injection gas is arranged coaxially to
the emulsion inlet and an additional inlet for injection gas is
arranged with a certain degree of inclination to the emulsion
inlet.
[0115] That is, one of the inlets for injection gas is arranged
such that the injection gas flow is projected in a coaxial
direction to the emulsion flow, as in any nebuliser, and the other
inlet is arranged such that the injection gas flow is projected at
a certain angle with respect to the emulsion flow, impacting
against the liquid jet flow. This enables greater reduction in drop
size. In this case, the facility may be used with a gas flow that
can be air, nitrogen or other gas and mixtures thereof. For
example, an inert gas would be used to work in a protective
atmosphere or when using a flammable solvent.
[0116] As described, the injection unit projects droplets whose
size depends on the type of injector, specifically in the preferred
case in which the injection unit comprises a nebuliser such as that
described, the size depends on the flow rate of a emulsion current,
on the flow rate of an injection gas current and on the properties
of the emulsion, mainly surface tension, conductivity and
viscosity.
[0117] Additionally, the present invention proposes the use of an
external electric field for greater control of the size of the
droplets and their monodispersity. For this objective in one
exemplary embodiment, the injection unit comprises an electrode,
typically circular, arranged right at the injector outlet. The
liquid, during spraying, is electrically charged upon penetrating
said electrode, which is working at high voltage, both in direct
and alternating current.
[0118] In the drying unit, the droplets formed in the injection
unit are dried at a controlled temperature. During the movement of
the droplets through the drying unit, the solvent of the emulsion
with which the microcapsules have been formed evaporates. After
circulating completely through the drying unit, the solvent
evaporates completely, giving rise to the desired microcapsules
which are subsequently collected by the collection unit. It should
be noted that the unit can dry and encapsulate at a controlled
temperature, typically at ambient or sub-ambient temperature,
without the need to apply heat at a high temperature to vaporise
the solvent. In the case in which an API at ambient temperature is
used, the facility and method make it possible to work at
sub-ambient temperature, such as for example 5.degree. C.
[0119] The drying unit comprises a receptacle. The injection unit
and a drying gas inlet are at one end of said receptacle. The
collection unit is at the opposite end. The drying gas is
introduced in the drying unit at a controlled temperature. The
drying gas may be air, nitrogen or other gas and mixtures
thereof.
[0120] The arrangement of the drying unit with respect to the
injection unit may be both coaxial thereto and at any angle of
inclination therebetween. The present invention preferably proposes
a coaxial arrangement. The drying gas is introduced in the drying
unit at a controlled temperature, typically at ambient temperature.
Since the drying gas is introduced in the drying unit in a certain
direction, it drags the droplets generated in the injection unit
with it. As it circulates through the drying unit, the solvent in
the droplets evaporates, thereby giving rise to the desired
microcapsules.
[0121] The geometry of the drying device a priori may be any which
allows an adequate residence time for drying the drops. An optimum
geometry would be a cylinder with a variable circular
cross-section, with an increasing cross-section from the inlet to
the outlet. This enables greater dragging in the area in which the
drops are largest and this allows longer residence time for a
certain length.
[0122] In another exemplary embodiment, the facility comprises a
drying unit comprising a secondary inlet, arranged perpendicularly
to its longitudinal axis. These drying units comprise a sleeve and
a secondary gas flow. This secondary gas flow is injected in a
direction perpendicular to the surface of the drying unit through
holes or pores arranged on the surface of the drying unit. This
makes it possible to reduce loss of material from adhesion to the
walls of the drying unit. The secondary gas may be air, nitrogen or
other gas and mixtures thereof.
[0123] The drying gas flow must be sufficient to remove all the
solvent injected from the injection unit.
[0124] That is, if, for example, air from outside the facility is
used as the drying gas and the method is being carried out on a
rainy day, with a high degree of humidity, the amount of drying gas
required to evaporate a fixed solvent volume will be greater than
if the method is carried out on a dry day (since the outside air
will have a lower relative humidity).
[0125] Likewise, a smaller drying unit cross-section size is
selected, which generally has a cylindrical configuration, when
wanting to achieve greater dragging and collection of
microparticles. This is because if the drying gas flow rate is
maintained and the drying unit cross-section is decreased, the
dragging speed through the inside of said drying unit
increases.
[0126] Furthermore, it should be noted that higher gas speeds
(obtained, for example, by decreasing the size of the cross-section
of the drying unit as explained previously) give rise to shorter
residence times and, therefore, shorter drying times. This could
make it difficult to dry larger microparticles.
[0127] Therefore, the facility is designed so as to have a specific
compromise emulsion in which dragging speed and residence time for
each emulsion are optimised. The facility will be designed
maintaining compromise dimensions to optimise dragging speed and
drying time in accordance with the emulsion used for encapsulation.
Drying time is also called residence time, since it relates to the
time during which the droplets remain in the drying unit.
[0128] The design of the drying unit depends on the solvent used
and on the API to be encapsulated, since both factors strongly
influence the size of the drop generated by the injection unit and
the evaporation kinetics thereof. The optimum drying unit diameters
and lengths that enable optimum speeds and residence times for, for
example, a facility with a manufacturing yield of approximately 1
kg/h of dry or encapsulated product typically range, but are not
limited to, between 2 and 200 cm in diameter and between 20 cm and
20 m in length, respectively. Larger industrial facilities may use
foreseeably greater diameters and lengths.
[0129] The proposed facility is therefore optimal for industrial
use due to its high yield and makes it possible to carry out the
method for obtaining microcapsules of APIs continuously and in a
single step.
[0130] With the aim of controlling the evaporation of the solvent
more efficiently, the facility, more specifically the drying unit,
may operate at different pressures, even in a vacuum.
[0131] The collection unit enables the efficient separation of the
microcapsules generated from the drying gas. The collection unit
may comprise at least one cyclonic separation, centrifugal
separation or filtration device, with or without electrostatic
charge. The collection unit is preferably a cartridge filter
collector or a cyclonic collector. In one exemplary embodiment, the
collection unit comprises a cyclone collector and a cartridge
filter arranged in series. This makes it possible to collect large
microparticles in the cyclone collector and smaller microparticles
in the cartridge filter collector.
[0132] In the case of using a flammable solvent, inert gases,
typically nitrogen, will preferably be used, and the facility in
which the method is carried out must be manufactured from
ATEX-classified materials and units, comprising venting and
suppression devices.
[0133] In the case that the device is used to obtain a dry product
or aseptic encapsulation, the injection gas and drying gas must be
filtered, typically making them pass through a HEPA H14 filter or
similar, or sterilised, typically by means of exposure to
ultraviolet light, ethylene oxide, radiation, etc., or a
combination thereof. In this case, both the preparation of the
emulsion and handling of the collected product are carried out in a
clean room sterile facility or similar.
[0134] Likewise, in a preferred embodiment, the collection unit
comprises a solvent condensing device, arranged at the drying gas
outlet, downstream from the collection unit. In another exemplary
embodiment, the drying gas collected at said drying gas outlet is
recirculated to resupply the injection unit and/or drying unit.
Typically, the recovery of the solvent or the closed-loop resupply
thereof is of special interest when the solvent or drying gas used
is expensive or for security or sterility reasons. The facility may
also include a device for pre-drying the incoming gas to facilitate
drying of the droplets or the closed-loop recirculation thereof.
This case is a preferred embodiment when the drying gas is ambient
air.
[0135] In summary, the present invention provides a pharmaceutical
formulation containing pharmaceutical active ingredient having
improved solubility and supra-bioavailability. In such the case, a
lower dosage strength can be administrated.
[0136] The sub-micron size particles of a non-water soluble drug
(API) can be obtained in a solid form free of agglomeration that
can be later on used to obtain the finished product, in which by
virtue of the small size of the drug particles within the product,
better bioavailablility can be achieved.
[0137] Unless otherwise defined, all technical and scientific terms
used herein have the same meaning as commonly understood by one of
ordinary skilled in the art to which this invention belongs.
Methods and materials similar or equivalent to those described
herein can be used in the practice of the present invention.
Throughout the description and claims the word "comprise" and its
variations are not intended to exclude other technical features,
additives, components, or steps. Additional objects, advantages and
features of the invention will become apparent to those skilled in
the art upon examination of the description or may be learned by
practice of the invention. The following examples and figures are
provided by way of illustration and are not intended to be limiting
of the present invention.
FIGURES
[0138] FIG. 1. 1a. Shows an exemplary embodiment of the facility
for industrial encapsulation of an API (or pharmaceutically
acceptable salt thereof) wherein the injection unit (1), drying
unit (2) and collection unit (3) can be seen. 1b. Shows another
exemplary embodiment of the facility for industrial encapsulation
of an API (or pharmaceutically acceptable salt thereof) comprising
an electric circuit (9) arranged at the droplet outlet (14) of the
injection unit (1).
[0139] FIG. 2. Shows the SEM images of HPMC-valsartan
microparticles obtained by the electro-nebulizer in example 1.
[0140] FIG. 3: Shows the TEM images of valsartan particles obtained
by the electro-nebulizer, after dissolving the polymer in cold
water in example 1.
[0141] FIG. 4. Shows the SEM images of HPMC-valsartan
microparticles obtained by the electro-nebulizer in example 2.
[0142] FIG. 5. Shows the TEM images of valsartan particles obtained
by the electro-nebulizer, after dissolving the polymer in cold
water in example 2.
[0143] FIG. 6. Shows the SEM images of HPMC-valsartan
microparticles obtained by the electro-nebulizer in example 3.
[0144] FIG. 7. Shows TEM images of valsartan particles obtained by
the electro-nebulizer, after dissolving the polymer in cold
deionized water in example 3.
[0145] FIG. 8. Shows SEM images of HPMC-valsartan microparticles
obtained by the electro-nebulizer in example 4.
[0146] FIG. 9. Shows TEM images of valsartan particles obtained by
the electro-nebulizer, after dissolving the polymer in cold
deionized water in example 4.
EXAMPLES
[0147] As shown in FIG. 1, the facility for carrying out the method
of encapsulation of an API comprises at least: [0148] one injection
unit (1) comprising at least one injector with at least one inlet
for a emulsion (6) (which already includes valsartan to be
encapsulated, the encapsulating material in the case that it is
used for an encapsulation process, a solvent and necessary
additives), an inlet for the injection gas (8) and an outlet for
droplets (14) for the emulsion that exits sprayed in droplets;
[0149] one drying unit (2) arranged after the injection unit (1)
and comprising at least one drying gas inlet (7) and an inlet for
the droplets (11) that exit the injection unit (1); and comprising
a longitudinal receptacle (12) which preferably has a cylindrical
configuration, and which is arranged with its longitudinal
direction horizontal and which has sufficient length to allow the
evaporation of all the solvent of the droplets; and has a
microparticles and drying gas outlet (13) through which
microparticles pass (which are the droplets without the solvent,
which has evaporated during its circulation through the drying
unit); [0150] one collection unit (3) arranged after the drying
unit, which is configured to separate the microparticles generated
from the drying gas (it drags the solvent which has evaporated in
the drying unit) and comprises an outlet for said generated
microparticles (4) and an outlet for the drying gas (5).
[0151] In one exemplary embodiment of the invention, the collection
unit further comprises a solvent condensing device (10), arranged
at the drying gas outlet (5), downstream from the collection unit
(3). In another exemplary embodiment, the facility may comprise a
drying gas recirculation device that makes it possible to redirect
the drying gas towards the injection unit (1) and/or the drying
unit (2).
[0152] In one exemplary embodiment, the injector of the injection
unit is a nebuliser consisting of a sprayer such as that described
above. The injection gas flow rate, in one exemplary embodiment, is
between 1 and 500 L/min. The flow rate of the injected liquid,
which is in the form of emulsion, ranges preferably between 1 ml/h
and 50 L/h.
[0153] In one exemplary embodiment, the facility additionally
comprises a high-voltage electric circuit (9) at the outlet of the
injection unit (1). The voltage used in the circuit depends on the
flow rate of the injected emulsion and ranges between 100 V and 500
kV. The effect achieved is that of charging the emulsion, focusing
the droplet beam and collaborating in the formation of the
droplets, improving control over the size thereof. It also
influences the monodispersity of the droplets, since it generates a
more homogeneous size distribution. A high monodispersity may be
essential to the final product, since it enables greater
homogeneity in the protection or release of the API that has been
encapsulated and, therefore, greater control over the encapsulation
process.
[0154] In one exemplary embodiment, the drying gas flow rate ranges
between 10 and 100,000 m.sup.3/h.
[0155] To this end, in these cases the facility may additionally
comprise a device for pre-drying the drying gas in order for said
drying gas introduced in said unit to be drier, thereby increasing
the yield of the facility. In those cases where ethanol,
isopropanol and other non-aqueous solutions are used drying is
easier because the drying gas, typically air, does not include a
solvent. Therefore, the drying gas is free from ethanol and,
therefore, does not affect the speed of evaporation of the ethanol
in the drying unit.
[0156] In order to control the evaporation of the solvent in the
facility more efficiently, the drying unit further comprises, in
one exemplary embodiment, a pressure control device that makes it
possible to work at different pressures, even in a vacuum.
[0157] Preferably, the facility is designed to obtain a
microparticle size ranging between 1 and 50 .mu.m in diameter. For
typical drying flow rates between 10 and 100,000 m.sup.3/h, the
optimum diameters and lengths of the drying unit range between 20
and 200 cm in diameter and between 20 cm and 20 m in length. In an
exemplary embodiment detailed below, the drying unit comprises a
cylindrical receptacle 60 cm in diameter and 2 m in length with
cone-shaped inlets and outlets.
Example 1
[0158] HPMC-Valsartan Microparticles (Percentage of API in the
Particle is of 30% by Weight)
[0159] In this example, the production of hydroxypropyl methyl
cellulose or hypromellose (HPMC) microparticles containing
sub-micron sized valsartan particles is described, using the
electro-nebulizer technique, with a percentage of API in the
particle of 30% by weight.
[0160] Emulsion Preparation:
[0161] In this case, an oil in water (O/W) emulsion was used, with
a ratio organic phase: aqueous phase of 30:70. In a first step, the
aqueous phase of the emulsion is prepared. The polymer (HMPC) is
dissolved in cold deionized water with a concentration of 20 mg/mL.
10 mg/mL of TEGO (TEGO.RTM. SML sorbitan fatty acid ester) is added
to this mixture. The organic phase of the emulsion consisted of 30
mg/mL of valsartan in chloroform. The organic phase is slowly added
over the aqueous phase and stirred in the ultraturrax for 5 min at
17,000 rpm, followed by 1 min of ultrasounds to achieve a
homogeneous size distribution of the micelles of the emulsion.
During the stirring, the emulsion is maintained in a cold bath to
prevent emulsion temperature from rising.
[0162] Electro-Nebulizer Process:
[0163] Once the emulsion has been obtained, it is immediately used
to generate microparticles by the electro-nebulizer technology. The
emulsion is introduced in the drying chamber by means of the
injection equipment at a flowrate of 10 mL/min. This injection
equipment has an electro-nebulizer to generate an aerosol of the
emulsion and, thus, guarantees an adequate evaporation of the
solvent. This electro-nebulizer operates with a compressed air flow
rate of 10 L/min and a voltage of 10 kV. The aerosol drops are
dried by means of 85 m.sup.3/h of process air, in co-current mode,
and at room temperature. The dried microparticles are collected on
a cyclone.
[0164] Particle Characterization:
[0165] The morphology of the microparticles obtained is studied by
SEM. The HPMC-valsartan microparticles have a medium size of 4.1
.mu.m (.+-.2.0). They are shown in FIG. 2.
[0166] In order to observe the morphology of the drug inside the
HPMC microparticle, the polymer (HMPC) was dissolved in cold
deionized water and the morphology of the drug is studied by
Transmission Electron Microscopy (TEM). The drug exhibits a
submicron size needle shape, shown in FIG. 3.
[0167] The obtained encapsulated Valsartan particles are being used
for the finished product manufacturing by usage of conventional
pharmaceutical techniques.
Example 2
[0168] HPMC-Valsartan Microparticles (Percentage of API in the
Particle is of 63% by Weight)
[0169] In this example, the encapsulation of valsartan in HPMC is
described, using the electro-nebulizer technique, with a percentage
of API in the particle of 63% by weight.
[0170] Emulsion Preparation:
[0171] An oil in water (0/W) emulsion was used, with a ratio
organic phase: aqueous phase of 30:70. In a first step, the aqueous
phase of the emulsion is prepared. The polymer is dissolved in cold
deionized water with a concentration of 20 mg/mL. 10 mg/mL of TEGO
(TEGO.RTM. SML sorbitan fatty acid ester) is dissolved in this
mixture. The organic phase of the emulsion consisted of 120 mg/mL
of valsartan in ethanol 85%. The organic phase is slowly added over
the aqueous phase and stirred in the ultraturrax for 5 min at
17,000 rpm, followed by 1 min of ultrasounds to achieve a
homogeneous size distribution of the micelles of the emulsion.
During the stirring, the emulsion is maintained in a cold bath to
prevent emulsion temperature from rising.
[0172] Electro-Nebulizer Process:
[0173] Once the emulsion has been obtained, it is immediately used
to generate microparticles by the electro-nebulizer method. The
emulsion is introduced in the drying chamber by means of the
injection equipment at a flowrate of 10 mL/min. This injection
equipment has an electro-nebulizer to generate an aerosol of the
emulsion and, thus, guarantee an adequate evaporation of the
solvent. This electro-nebulizer operates with a compressed air
flowrate of 10 L/min and a voltage of 10 kV. The aerosol drops are
dried by means of 85 m.sup.3/h of process air in co-current mode at
room temperature. The dried microparticles are collected on a
cyclone.
[0174] Particle Characterization:
[0175] The morphology of the microparticles obtained is studied by
SEM. The HPMC-valsartan microparticles are spheres with a medium
size of 5.0 .mu.m (.+-.4.1). They are shown in FIG. 4.
[0176] In order to observe the morphology of the drug inside the
HPMC microparticle, the polymer was dissolved in cold deionized
water and the morphology of the drug is observed by TEM. The drug
exhibits a submicron size needle shape which is shown in FIG.
5.
[0177] The obtained encapsulated Valsartan particles are being used
for the finished product manufacturing by usage of conventional
pharmaceutical techniques. The final pharmaceutical formulations is
in the form of a tablet, granulate, powder, capsule or other.
[0178] Example of a Pharmaceutical Composition: [0179] a)
encapsulated valsartan 111 mg (microparticles of HPMC encapsulating
valsartan) [0180] b) microcrystalline cellulose 40 mg [0181] c)
colloidal silicon dioxide 4 mg [0182] d) sodium lauryl sulfate 1 mg
[0183] e) magnesium stearate 1.6 mg [0184] f) Opadry.RTM. White 5
mg
[0185] A mixture was made of encapsulated valsartan,
microcrystalline cellulose, colloidal silicon dioxide, sodium
lauryl sulfate with the above-mentioned quantities. The mixture was
blended for 20 minutes. Magnesium stearate was sieved and added to
the blended mixture and blended for an additional 5 minutes.
Thereafter, the mixture was compressed into tablets using a Fette
tableting press to have a suitable hardness and a friability of
less than 1.0%. The tablet cores were coated with ready to use
coating mixture Opadry.
Example 3
[0186] HPMC-Valsartan Microparticles (Percentage of API in the
Particle is of 82% by Weight)
[0187] In this example, the encapsulation of valsartan in HPMC is
described, using the electro-nebulizer, with a percentage of API in
the particle of 82% by weight.
[0188] Emulsion Preparation:
[0189] In this case, an oil in water emulsion (O/W) was used, with
a ratio organic phase: aqueous phase is of 30:70. In a first step,
the aqueous phase of the emulsion is prepared. The polymer with a
concentration of 10 mg/mL was dissolved in cold deionized water. 1
mg/mL of TEGO (TEGO.RTM. SML sorbitan fatty acid ester) is
dissolved in this mixture. The organic phase of the emulsion
consisted of 120 mg/mL of valsartan in ethanol 85%. The organic
phase is slowly added over the aqueous phase and stirred in the
ultraturrax for 5 min at 17,000 rpm, followed by 1 min of
ultrasounds to achieve a homogeneous size distribution of the
micelles of the emulsion. During the stirring the emulsion is
maintained in a cold bath, to prevent emulsion temperature from
rising.
[0190] Electro-Nebulizer Process:
[0191] Once the emulsion has been obtained, it is immediately used
to generate microparticles by the electro-nebulizer method. The
emulsion is introduced in the drying chamber by means of the
injection equipment at a flow rate of 10 mL/min. This injection
equipment has an electro-nebulizer to generate an aerosol of the
emulsion and, thus, guarantee an adequate evaporation of the
solvent. This electro-nebulizer operates with a compressed air flow
rate of 10 L/min and a voltage of 10 kV. The aerosol drops are
dried by means of 85 m.sup.3/h of process air in co-current mode at
room temperature. The dried microparticles are collected on a
cyclone.
[0192] Particle Characterization:
[0193] The morphology of the microparticles obtained is studied by
SEM. The HPMC-valsartan microparticles are spheres with a medium
size of 6.1 .mu.m (.+-.3.3). They are shown in FIG. 6.
[0194] In order to observe the morphology of the drug inside the
HPMC microparticle, the polymer was dissolved in cold deionized
water and the morphology of the drug is observed by TEM. The drug
shows a submicron size needle shape, which is shown in FIG. 7.
[0195] The obtained encapsulated Valsartan particles are being used
for the finished product manufacturing by usage of conventional
pharmaceutical techniques.
Example 4
[0196] HPMC-Valsartan Microparticles (Percentage of API in the
Particle is of 71% by Weight)
[0197] In this example, the encapsulation of valsartan in HPMC is
described, using the electro-nebulizer, with a percentage of API in
the particle of 71% by weight.
[0198] Emulsion Preparation: In this case, an oil in water emulsion
(O/W) was used, with a ratio organic phase: aqueous phase of 30:70.
In a first step, the aqueous phase of the emulsion is prepared. The
polymer with a concentration of 20 mg/mL was dissolved in cold
deionized water. 1 mg/mL of TEGO (TEGO.RTM. SML sorbitan fatty acid
ester) is dissolved in this mixture. The organic phase of the
emulsion consisted of 120 mg/mL of valsartan in ethanol 85%. The
organic phase is slowly added over the aqueous phase and stirred in
the ultraturrax for 5 min at 17,000 rpm, followed by 1 min of
ultrasounds to achieve a homogeneous size distribution of the
micelles of the emulsion. During the stirring, the emulsion is
maintained in a cold bath to prevent emulsion temperature from
rising.
[0199] Electro-Nebulizer Process:
[0200] Once the emulsion has been obtained, it is immediately used
to generate microparticles by the electro-nebulizer. The emulsion
is introduced in the drying chamber by means of the injection
equipment at a flowrate of 10 mL/min. This injection equipment has
an electro-nebulizer to generate an aerosol of the emulsion and,
thus, guarantees an adequate evaporation of the solvent. This
electro-nebulizer operates with a compressed air flowrate of 10
L/min and a voltage of 10 kV. The drops of the aerosol are dried by
means of 85 m.sup.3/h of process air, in co-current mode, and at
room temperature. The dried microparticles are collected on a
cyclone.
[0201] Particle Characterization:
[0202] The morphology of the microparticles obtained is studied by
SEM. The HPMC-valsartan microparticles are spheres with a medium
size of 6.1 .mu.m (.+-.3.3). They are shown in FIG. 8.
[0203] In order to observe the morphology of the drug inside the
particles inside the HPMC microparticle, the polymer was dissolved
in cold deionized water and the morphology of the drug is observed
by TEM. The drug exhibits a submicron size needle shape, which is
shown in FIG. 9.
[0204] The obtained encapsulated Valsartan particles are being used
for the finished product manufacturing by usage of conventional
pharmaceutical techniques.
Example 5
[0205] HPMC-Abiraterone Acetate Microparticles (Percentage of API
in the Particle is of 63% by Weight)
[0206] In this example, the encapsulation of abiraterone acetate in
HPMC is described, using the electro-nebulizer, with a percentage
of API in the particle of 63% by weight.
[0207] Emulsion Preparation:
[0208] An oil in water (O/W) emulsion was used, with a ratio
organic phase: aqueous phase of 30:70. In a first step, the aqueous
phase of the emulsion is prepared. The polymer is dissolved in cold
deionized water with a concentration of 20 mg/mL. 10 mg/mL of TEGO
(TEGO.RTM. SML sorbitan fatty acid ester) is dissolved in this
mixture. The organic phase of the emulsion consisted of 120 mg/mL
of abiraterone acetate in ethanol 85%. The organic phase is slowly
added over the aqueous phase and stirred in the ultraturrax for 5
min at 17,000 rpm, followed by 1 min of ultrasounds to achieve a
homogeneous size distribution of the micelles of the emulsion.
During the stirring, the emulsion is maintained in a cold bath to
prevent emulsion temperature from rising.
[0209] Electro-Nebulizer Process:
[0210] Once the emulsion has been obtained, it is immediately used
to generate microparticles by the electro-nebulizer. The emulsion
is introduced in the drying chamber by means of the injection
equipment at a flowrate of 10 mL/min. This injection equipment has
an electro-nebulizer to generate an aerosol of the emulsion and,
thus, guarantees an adequate evaporation of the solvent. This
electro-nebulizer operates with a compressed air flowrate of 10
L/min and a voltage of 10 kV. The drops of the aerosol are dried by
means of 85 m.sup.3/h of process air, in co-current mode, and at
room temperature. The dried microparticles are collected on a
cyclone.
[0211] Finished Product:
[0212] The tablet was formulated as one swallowable dosage form
which is bio-equivalent to two 500 mg tablets of Zytiga.RTM.
reference product or four 250 mg tablets of Zytiga.RTM.. The
smaller strengths might be produced by using the proportional
formulation for abiraterone acetate tablets made by the technology
described in the present invention.
* * * * *