U.S. patent application number 15/155699 was filed with the patent office on 2017-03-30 for dry powder formulation of azole derivative for inhalation.
This patent application is currently assigned to GALEPHAR PHARMACEUTICAL RESEARCH, INC.. The applicant listed for this patent is Karim AMIGHI, Philippe BAUDIER, Arthur DEBOECK, Christophe DURET, Thami SEBTI, Francis VANDERBIST. Invention is credited to Karim AMIGHI, Philippe BAUDIER, Arthur DEBOECK, Christophe DURET, Thami SEBTI, Francis VANDERBIST.
Application Number | 20170087154 15/155699 |
Document ID | / |
Family ID | 47297298 |
Filed Date | 2017-03-30 |
United States Patent
Application |
20170087154 |
Kind Code |
A1 |
DEBOECK; Arthur ; et
al. |
March 30, 2017 |
DRY POWDER FORMULATION OF AZOLE DERIVATIVE FOR INHALATION
Abstract
A spray dried-powder composition for inhalation comprising
particles (X) containing (a) between 5 and 50% by weight of at
least one azole derivative in amorphous state but not in
crystalline structure and (b) at least one matricial agent to the
composition selected from a group consisting of polyol such as
sorbitol, mannitol and xylitol; a monosaccharides such as glucose
and arabinose; disaccharide such as lactose, maltose, saccharose
and dextrose; cholesterol, and any mixture thereof, wherein the
composition provides a dissolution rate of said azole derivative of
at least, 5% within 10 minutes, 10% within 20 minutes and 40%
within 60 minutes when tested in the dissolution apparatus type 2
of the United States Pharmacopoeia at 50 rotation per minute,
37.degree. C. in 900 milliliters of an aqueous dissolution medium
adjusted at pH 1.2 and containing 0.3% of sodium laurylsulfate.
Inventors: |
DEBOECK; Arthur; (Gurabo,
PR) ; VANDERBIST; Francis; (Beersel, BE) ;
BAUDIER; Philippe; (Uccle, BE) ; SEBTI; Thami;
(Braine-le-Comte, BE) ; DURET; Christophe;
(Bouillon, BE) ; AMIGHI; Karim; (Woluwe Saint
Pierre, BE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
DEBOECK; Arthur
VANDERBIST; Francis
BAUDIER; Philippe
SEBTI; Thami
DURET; Christophe
AMIGHI; Karim |
Gurabo
Beersel
Uccle
Braine-le-Comte
Bouillon
Woluwe Saint Pierre |
PR |
US
BE
BE
BE
BE
BE |
|
|
Assignee: |
GALEPHAR PHARMACEUTICAL RESEARCH,
INC.
Humacao
PR
|
Family ID: |
47297298 |
Appl. No.: |
15/155699 |
Filed: |
May 16, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13261916 |
Aug 4, 2014 |
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PCT/EP2012/074785 |
Dec 7, 2012 |
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15155699 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 47/14 20130101;
A61K 47/26 20130101; A61K 9/0075 20130101; A61K 31/496 20130101;
A61K 2300/00 20130101; A61P 31/10 20180101; A61K 9/1694 20130101;
A61K 9/1688 20130101; A61K 47/28 20130101; A61K 9/1682 20130101;
A61K 9/1617 20130101; A61K 9/1623 20130101 |
International
Class: |
A61K 31/496 20060101
A61K031/496; A61K 9/00 20060101 A61K009/00; A61K 9/16 20060101
A61K009/16 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 9, 2011 |
EP |
11192851.1 |
Claims
1. Spray dried particles for inhalation composition comprising: a)
between 5 to 50% by weight of at least one azole compound in an
amorphous state; and b) at least one matricial agent to the
composition selected from the group consisting of polyol including
one of sorbitol, mannitol or xylitol; a monosaccharide including
one of glucose or arabinose; disaccharide including one of lactose,
maltose, saccharose or dextrose; cholesterol, and any mixture
thereof.
2. The particles according to claim 1, wherein the matricial agent
is mannitol or cholesterol.
3. The particles according to claim 1, wherein the weight ratio of
the at least one azole compound/at least one matricial agent is
between 0.5/99.5 and 40/60.
4. The particles according to claim 1 further comprising a
surfactant.
5. The particles according to claim 4 comprising between 0.1 and 5%
by weight of the surfactant.
6. The particles according to claim 4, wherein said surfactant
comprises lecithin, phospholipids derivatives including phosphatic
acids, phosphatidyl choline (saturated and unsaturated),
phoshpatidyl ethanol amine, phosphatidyl glycerol, phosphatidyl
serine, phosphatidyl inositol, dioleoylphosphatidylcholine,
dimyristoyl phosphatidylcholine, dipalmitoylphosphatidylcholine,
distearoyl phosphatidylcholine, diarachidoyl phosphatidylcholine,
dibenoyl phosphatidylcholine, ditricosanoyl phosphatidylcholine,
dilignoceroylphatidylcholine, dimiristoylphosphatidylethanolamine,
dipalmitoyl-phosphatidylethanoalamine,
pipalmitoleoylphasphatidylethanolamine,
distearoyl-phosphatidylethanolamine,
dimyristoylphosphatidylglycerol, dipalmitoylphosphatidyl glycerol,
dipalmitolcoylphosphatidylglycerol and hydrogenated derivates or
modified vitamins comprise .alpha.-tochopherols derivates.
7. The spray dried-powder composition for inhalation comprising
particles (X) according to claim 1, wherein said composition
comprises at least 50% of the matricial agent and provides a
dissolution rate of said azole derivative of at least, 5% within 10
minutes, 10% within 20 minutes and 40% within 60 minutes when
tested in the dissolution apparatus type 2 of the United States
Pharmacopoeia at 50 rotation per minute, 37.degree. C. in 900
milliliters of an aqueous dissolution medium adjusted at pH 1.2 and
containing 0.3% of sodium laurylsulfate.
8. The spray dried-powder composition according to claim 7
providing a Fine Particle Fraction of the azole derivative of at
least 35% of the total nominal dose of the azole in the powder
following the method "preparations for inhalation: assessment of
fines particles" using the Multi-stage Liquid Impinger, Apparatus
C-chapter 2.9.18 of the European Pharmacopoeia.
9. The spray dried-powder composition according to claim 7 further
comprising particles (Y) according to claim 4.
10. The spray dried-powder composition according to claim 9,
wherein the particles (Y) contain between 0.5 and 5% by weight of
the surfactant(s).
11. The spray dried-powder composition according to claim 7 further
comprising particles (Z) containing up to 20% by weight of
nanoparticles of the at least one azole compound in crystalline
structure having a mean size between 0.1 and 1 .mu.m.
12. The spray dried-powder composition according to claim 9
providing a dissolution rate of the at least one azole compound of
5 to 50% within 5 minutes, 10 to 60% within 10 minutes, 15 to 90%
within 20 minutes and 40 to 100% after 60 minutes.
13. The spray dried-powder composition according to claim 7,
wherein the at least one azole compound is selected from the group
consisting of iconazole, fluconazole, itraconazole, posaconazole,
voriconazole, isoconazole, ketoconazole, oxiconazole, bifonazole,
fenticonazole, tioconazole, terconazole, sulconazole, ravuconazole,
econazole, terconazole, and itraconazole and mixtures thereof.
14. A method for preparing spray dried particles comprising the
steps of: a) preparing a liquid composition comprising: i. a liquid
carrier comprising a class 3 solvent according to European
Pharmacopoeia including acetic acid, heptane, acetone, isobutyl
acetate, anisole, isopropyl acetate,1-Butanol, methyl acetate,
2-Butanol, 3-Methyl-1-butanol, Butyl acetate, methylethylketone,
tert-Butylmethyl ether, methylisobutylketone, cumene,
2-Methyl-1-propanol, dimethyl sulfoxide, pentane, ii. ethanol,
1-Pentanol, Ethyl acetate, 1-Propanol, ethyl ether, 2-Propanol,
ethyl formate, propyl acetate, or formic acid, or mixtures thereof,
or the mixture of any of the above with water; iii. at least one
azole compound in solution in said liquid carrier; and iv. at least
one matricial agent in solution in said liquid carrier, wherein the
weight ratio of the at least one azole compound/at least one
matricial agent is between 0.5/99.5 and 40/60, and b) spray drying
the liquid composition thereby producing particles for the dry
powder composition.
15. The method according to claim 14 further comprising the steps
of: c) preparing another liquid composition comprising a liquid
carrier comprising a class 3 solvent or any mixture of two or more
of such solvents with or without water and at least one matricial
agent in solution in said liquid carrier, wherein the liquid
composition further comprises: i. at least one azole compound in
solution in said liquid carrier and at least one surfactant; and/or
ii. nanoparticles of at least one azole compound having a mean size
between 0.1 and 1 .mu.m, and d) spray drying said liquid
composition provided by step (c) thereby producing particles for
the dry powder composition.
16. The method according to claim 15 comprising a step of
physically blending the particles obtained by steps (b) with the
particles obtained by step (d).
17. A liquid composition prepared according to the method of claim
14.
18. The liquid composition according to claim 17 further comprising
at least one surfactant and/or nanoparticles of at least one azole
compound having a mean size between 0.1 and 1 .mu.m.
19. The spray dried-powder composition according to claim 13,
wherein the at least one azole compound is itraconazole.
Description
FIELD OF THE INVENTION
[0001] Aspergillosis refers to the spectrum of pathologies caused
by Aspergillus species which are filamentous fungi more precisely
ascomycetes classified in the form subdivision of the
Deuteromycotina.
[0002] Invasive aspergillosis (IA) is an advance state of
aspergillus colonization after conidia germination and is a
frequent cause of infectious disease related to morbidity and
mortality in immunocompromised (IC) patients. In the past two
decades, the incidence rate of IA infections has dramatically
increased. For example, from the 80s to 1997, the trend in
mortality associated with invasive aspergillosis showed an increase
of 357%. Being an opportunistic disease this can be explained by
the rising number of IC patients nowadays encountered in clinical
practice.
[0003] The principal gateway to this pathogen (80 to 90% of IA) and
are often the starting points of the invasion that can lead to
disseminated state, fatal in more than 90% of cases. The fungus can
disseminate after invasion of the pulmonary tissue through the
blood stream to reach liver, spleen, kidney, brain and other
organs. The invasive state is mainly reach in IC population who
after conidia's inhalation has not enough immune defenses
(principally macrophages) to prevent their germination and
therefore hyphae proliferation (principally neutrophils) through
tissues and blood capillaries in the contamination area.
[0004] Clinical guidelines recommend the use of amphotericin B as
primary treatment of pulmonary invasive aspergillosis. However
amphotericin B is not well tolerated, shows a lot of severe adverse
reactions. Moreover, inhaled amphotericin B was shown to be
ineffective as prophylaxis in patients with prolonged neutropenia
following chemotherapy or autologous bone marrow transplantation.
For those reasons their use is often contraindicated and the first
line therapy, considered as gold standard class, are the azole
derivates (itraconazole, voriconazole, posaconazole, ravuconazole).
Despite those current therapies (oral and intravenous), once the
invasive stage is reached, the mortality rate goes from 50 to 90%
(in regards with population's category and study. For most IC
patients progression can be terrifically fast (e.g. 7-14 days from
onset to death). This high rate of failure can be explained by the
conjuncture of several factors. First of all, invasive pulmonary
aspergillosis difficult to diagnose in the first stage of the
disease and once first manifestations occur advance invasive state
is often already reach. Another important reason of failure is that
existing therapies (oral, intravenous) induce a lot of side effects
and metabolic interactions due to their high systemic exposure
necessary to reach suitable pulmonary concentration. Moreover, due
to the poor water solubility of azole derivates (e.g. <1
.mu.g/ml for itraconazole), oral therapies show high inter and
intra-individual variation in term of bioavailability that can lead
to infra therapeutic concentrations in the lung tissue. Another
important factor is also to take into account in the explanation of
high rate treatment failure. Indeed, for an optimal antifungal
activity, minimum inhibitory concentration (MIC) in pulmonary lung
epithelium and lung tissue has to be maintained. With conventional
therapies (oral, IV) those concentrations may not be reach inside
the fungal lesion despite high systemic concentrations.
[0005] For those reasons pulmonary delivery can be an interesting
alternative for prophylaxis and/or treatment of invasive pulmonary
aspergillosis. By delivering antifungals directly to the lung in
the infection's site, concentration above the MIC90% could be
effectively and directly maintained in the lung tissue while
minimizing systemic exposure therefore side effects and metabolic
interactions. However, to reach that result the poorly water
soluble active ingredient has to be delivered efficiently into the
lung and must be dissolved in-situ as much as possible.
[0006] Over the years, pulmonary drug delivery has extensively been
developed. Interest in this particular route of administration can
be justified by the numerous problems it overcomes and the
advantages it offers in particular situations. Indeed, pulmonary
drug delivery can be effective both for systemic delivery and
localized delivery to treat systemic or lung diseases. This non
invasive route of administration avoids hepatic first-pass effect
which, for example, can lead to active pharmaceutical ingredient
(API) inactivation or formation of toxic metabolites. It has been
demonstrated that pulmonary drug delivery required smaller doses
than by oral route to achieve equivalent pulmonary therapeutic
effects. This can be particularly interesting in the case of
pulmonary infectious diseases treated by inhalation of
anti-infectious drugs (as azole derivates) presenting systemic
sides effects and metabolic interactions. Indeed, pulmonary drug
delivery allows minimizing systemic concentration, thus side
effects, while maintaining effective lung concentration directly to
the site of infection. The administration of the anti-infectious
drug directly to the lung allows minimization of systemic
concentrations therefore drug systemic side effects and metabolic
interactions which are very pronounced with common antifungal
drugs. Those interactions and side effects are often the reason of
treatment failures in the different patient populations.
[0007] There are several approaches to achieve oral inhalation
(pulmonary delivery). Inhaler devices can be classified in three
different types, including liquid nebulizers, pressurized aerosol
metered dose inhalers (pMDIs), and dry powder dispersions devices.
The two formers are losing interest due to their disadvantages that
can be overcome through the use of dry powder inhalers (DPIs). The
majors problems encountered in liquid nebulization are the drug
instability during storage, the relatively long time to achieve
total nebulization, risk of bacterial contamination, high cost, low
efficiency and poor reproducibility. Regarding pMDIs one of the
principal source of administration's procedure failure is the
necessity of synchronization between dose activation and breathing.
For those reasons DPIs are nowadays at the top of the research
interest in the pulmonary delivery field.
[0008] Regarding problems underlying above, the problem to be
solved is to provide patients with antifungal inhaled compositions
that offer a high lung deposition and allow an adequate dissolution
profile of the poorly water soluble active ingredient in-situ,
therefore allowing an optimized efficacy of the drug product.
Additionally, the inhaled compositions should present an acceptable
safety profile, should be stable, should be easy to administer in a
reproducible and precise way. The manufacturing process of said
composition should be short, simple, cheap, ecological, reliable,
and environmentally friendly (no USP class 1 or 2 solvents)
[0009] Firstly, an important characteristic that the formulation
must possess is an improved and optimal in vitro dissolution
profile (compared to the unformulated drug). The manufacturing
process must present the flexibility of controlling the dissolution
rate of the active ingredient to obtain an optimal pharmacokinetic
profile thus providing an optimal therapeutic response. An optimal
pharmacokinetic profile corresponds to a maximization of lung time
residence while minimizing systemic absorption and elimination.
Azole compounds are poorly water-soluble substances (e.g.
solubility of itraconazole pII 7<1 .mu.g/ml) and inhalation of
an insoluble powder can lead to (i) poor tolerance and/or (ii) lack
of efficacy. The low wettability of poorly water soluble active
ingredients can cause irritation and inflammation to the pulmonary
mucosa after inhalation. Wettability of the inhaled particles must
be enhanced. Furthermore, to be effective, antifungal drugs have to
reach after administration (in this case by inhalation) a pulmonary
concentration that is above the MIC of the concerned fungus. It is
commonly recognized that the active form of a drug is the dissolved
state. In other words, the dissolved proportion of the inhaled dose
has to be maintained in the lung epithelium and lung tissue above
the MIC of Aspergillus. Then the dissolution rate of the drug will
directly influence the proportion of the deposited dose that can
play its antifungal activity. As mentioned above, azole compound
are poorly soluble and micronized bulk material present an
extremely poor dissolution rate. Improvement of its dissolution
rate and wettability are here necessary to avoid excessive
elimination of the undissolved fraction of the drug by alveolar
macrophages in the lower airways and mucociliary clearance in the
upper airways. However, acceleration of the dissolution rate of the
active ingredient has preferably to be limited to a certain extend
because a too fast dissolution rate would result in an excessive
absorption of the dissolved fraction to the systemic compartment
and thus possibly to adverse event. A need that the invention must
satisfy is the possibility to modify the dry powder composition to
improve and/or modulate its dissolution rate while keeping good
powder flowability and high dispersibility properties. The
dissolution rate of the active ingredient must be kept in a
determined ranged and it should be possible to make vary the
dissolution profile (greater or less amount of dissolved active
substance at the same time point within the dissolution range) in
order to make vary the in-situ dissolution rate therefore the
therapeutic and side effects.
[0010] Secondly, antifungal azole compound after oral inhalation
has to reach the site of infection. The dry powder should present
an optimized aerodynamic behavior. That means than the dry powder
must reach the potential conidia's deposition site where fungus can
grow and invade peripheral tissue area. Regarding this, it is
obvious that after dose actuation from a dry powder inhaler, a
determinate fraction of the generated particles have to present an
aerodynamic diameter range similar than those of fungal conidia
(between 1.9 and 6 .mu.m) to provide to the lung an appropriated
antifungal dose. The generated particles from an inhaler device in
breath condition must present a high percentage of particles having
an aerodynamic diameter less than 6 .mu.m. This percentage will
directly influence the dose really reaching the lungs. The
aerodynamic behavior of particles is determined by their size and
composition. As described above, the formulation must present an
optimized dissolution profile to obtain an optimal pharmacokinetic
profile in vivo. Once an optimized composition has been developed,
it should be possible to modify its aerodynamic behavior in order
to modulate powder fine particle fraction to reach a suitable dose
deposition that would play correctly its fungal activity (depending
on its dissolution rate profile).
[0011] Thirdly, another primordial point is to take in
consideration. Indeed, after inhalation the dry powder must present
a good safety profile and must be compatible with the lung membrane
to avoid hyper-responsiveness, cough, airway spasticity or
inflammation. Dissolution rate improvement, necessary in this
particular case, often needs the use of specific excipients that
can cause adverse reaction or that are not suitable for pulmonary
administration. Since documentation on the safety profile of
inhaled excipient is quiet limited, to avoid pulmonary toxicity
after inhalation, the use physiologic component, generally
recognized as safe (GRAS) and authorized excipients must be
privileged in pulmonary formulations (for example the U.S. Food and
Drug Administration (FDA database). This is a real limitation
because authorized excipients are quiet limited and mainly
endogenous or derivates of endogenous substances to the lung are
recognized as GRAS excipient. Moreover considering again the safety
profile of the formulation, the manufacturing process should
preferentially avoid the use of the United States Pharmacopeial
Convention (USP) and European Pharmacopoeia class 1 and 2 solvent
due to their high toxicity and low tolerated residual level in
pharmaceutical formulations. From an ecological perspective, the
used of only class 3 solvent and save excipients considerably
reduced pollution and operators hazardous contaminations risks
which are no negligible gains. This also reduces the manufacturing
cost by reducing the resources that must be implemented to avoid
possible contamination of the operators or leaks to the
environment.
[0012] Fourthly, powder for use in dry powder inhaler must display
good flowability, low agglomeration tendency for an easy processing
at industrial scale.
[0013] Finally, the manufacturing process must be simple,
continuous and designed to be realized in one or two step to obtain
the final dry product.
[0014] There is here a need to develop a simple, flexible process
using only GRAS authorized excipient and low toxic potential
solvents to produce a dry powder for inhalation to treat pulmonary
invasive aspergillosis (i) that allows improvement and/or control
of active ingredient's dissolution rate (ii) that allows
modification of the aerodynamic behavior of the particle while
keeping dissolution rate improvement and/or modification (iii)
presenting good flow properties (iv) involving a simple, reliable,
reproducible and relatively cheap manufacturing process.
[0015] This invention allows producing a dry powder with a high
percentage of particles presenting the same aerodynamic diameter
that inhaled conidia. This fraction of particles presents an
improved and/or controlled dissolution profile compared to
unformulated drug. This release profile can be modified by only
using endogenous or GRAS substances and low toxicity potential
solvents. The whole process is a one or two step procedures.
BACKGROUND OF THE INVENTION
[0016] Several approaches to develop a formulation suitable for
pulmonary administration of poorly soluble compound have been
developed. Majority of those inventions disclose a strategy of
process or formulation but none of those satisfied all the needs
described above.
[0017] Regarding problems underlying above, the problem to be
solved is to provide patients with antifungal inhaled compositions
that offer a high lung deposition and at the same time allow an
adequate dissolution profile of the poorly water soluble active
ingredient in-situ, therefore allowing an optimized efficacy of the
drug product. Additionally, the inhaled compositions should present
an acceptable safety profile, should be stable, should be easy to
administer in a reproducible and precise way. The manufacturing
process of said composition should be short, simple, cheap,
ecological, reliable, and environmentally friendly (no USP class 1
or 2 solvents)
[0018] Numerous inventors developed suspensions, nanosuspensions
and solutions of poorly soluble active ingredients suitable for
nebulization (U.S. Pat. No. 6,264,922 B1, German Pat, Pub. No. 101
45 361 A1, PCT International Pub. No. WO 03035031, PCT
international Pub. No. WO 2009/137611 A2). But as previously
mentioned pulmonary administration by nebulization presents
problems and disadvantages such as drug instability, long time to
achieve total dose administration, risk of bacterial contamination,
high cost, low efficiency and poor reproducibility. Moreover these
strategies, due to inherent solubility of drug nanoparticles, do
not allow optimization of drug's dissolution rate.
[0019] PCT International Pub. No. WO 2009/106333 A1 describes a new
nanosuspension of antifungal azole derivates with improved purity
profile. This high purity profile is guaranty by a high quality
production process minimizing contamination of the formulation
which could come from equipments. This assured minimum toxicity
that can be caused by inorganic insoluble impurity.
[0020] Canadian Pub. No. 2014401 A1 relates to pharmaceutical
compositions for treating invasive fungal infections by inhalation.
It describes dry powder for inhalation wherein the micronized
active ingredient is blended with an acceptable carrier. Those
compositions allow deep penetration of the active ingredient to the
lung but do not promote dissolution rate.
[0021] Many other research groups have developed interest in the
development of a drug formulated as a dry powder for inhalation
presenting solubility improvement.
[0022] U.S. Pat. No. 6,645,528 B1 discloses a method of fabrication
of porous drug matrices presenting a faster dissolution rate than
bulk material and no porous drug matrices of the same drug. This
matricial product could be administrated by inhalation as a dry
powder. In the manufacturing procedure, the active ingredient is
dissolved in a volatile solvent to form drug solution. A pore
forming agent is combined to the drug solution to form an emulsion,
suspension or second solution. The volatile solvent and pore
forming agent are then removed (preferably by spray drying) to
yield the porous matrix of drug. The pore forming agent can be a
volatile liquid or a volatile solid preferably a volatile salt that
are immiscible with the volatile solvent. The authors describe that
the use of a pore forming agent was the critical characteristic for
dissolution rate enhancement of the active ingredient. However they
did not mention or demonstrate that by this process in vitro
dissolution rate and aerodynamic behavior of inhaled particles
could be optimized. Moreover no example of in vitro impaction and
dissolution tests specifically designed for dry powder for
inhalation were disclosed. In another aspect, solvent and excipient
used in all examples were not in concordance with toxicity
requirements in the field of pulmonary administration. This concept
of formulation has preferentially been developed to produce
parenteral formulation that needs a re-dispersion step in solution
before administration. U.S. Pat. Appl. Pub. No. 2004/0105821 A1
applied this concept to dry powder for inhalation to produced
sustained release formulation for inhalation and included in the
description an application to antifungal agents such azole
derivates but no examples are provided.
[0023] U.S. Pat. No. 7,521,068 B2 describes formulations and
associated manufacturing procedure for nanoparticulate dispersion
aerosol, dry powder nanoparticulate aerosol formulation, and
propellant based aerosol formulations preparation. The aqueous
dispersion or dry powder describe therein contained insoluble drug
particles (including azole derivates) having a surface modifier on
their surface. In the surfaced modifier are included, organic and
inorganic pharmaceutical excipients. Such excipients include
various polymers, low molecular weight oligomers, natural products
and surfactant.
[0024] The dry powder formulation is obtained by drying an aqueous
nanosuspension. Prior drying, the aqueous dispersion of drug and
surface modifier can contain a dissolved diluent such as
sugars.
[0025] Regarding our particular situation (maximization of lung
residence time while minimizing systemic absorption and
elimination) where dissolution rate is primordial, this invention
presents some disadvantages. Indeed, it was correctly emphasized on
the advantage that size reduction has on dissolution rate
improvement since there is proportionality between the solid API
dissolution rate and its surface area available for dissolution as
described by the Nernst-Brunner/Noyes-Whitney equation. But it is
not possible with this manufacturing process to modify dissolution
rate of the solid nanoparticle present in the formulation. The
dissolution rate of the solid API after inhalation would be
inherent to nanoparticles dissolution rate which can lead to
excessive absorption in the systemic compartment therefore
enhancing the probability adverse reactions, drug-drug and
metabolic interactions which could induce treatment failure.
Nanoparticles dissolution velocity is generally tremendous fast and
this invention do not clearly establish the possibility to delay,
decrease or control dissolution rate of the active ingredient.
Additionally, a surface modifier is necessary for nanosuspension
stabilization and it will result in surface wetting enhancement of
particles and consequently to their dissolution rate. Moreover,
diluents and excipient that can be added prior the drying step of
the aqueous nanosuspension are limited to hydrophilic components
and cannot be hydrophobic due to the aqueous nature of the
described dispersants. Once this diluent will be after inhalation
in contact with the aqueous pulmonary surfactant its dissolution
will be fast and it would not be possible to modify nanoparticles
dissolution rate therefore their systemic absorption leading to an
excessive elimination.
[0026] PCT International Pub. No. WO 2004/060903 A2 discloses
effective lung concentration and residence time specifically for
amphotericin B after inhalation to treat or to give a prophylaxis
against fungal infection. However, recent data indicates that
toxicity related to this formulation type which is a serious
limitation for pulmonary administration that cannot be accepted
(Spickard and Hirschmann, Archives of Internal Medicine 1994,
154(6), 686). Additionally, amphotericin B was shown to be
ineffective as prophylaxis in patients with prolonged neutropenia
following chemotherapy or autologous bone marrow transplantation.
Formulations described therein are lipid complex based formulations
of amphotericin B that can be disadvantageous for the azole
derivates because of their poor solubility. In the description of
the invention azole derivates are included but no examples of this
pharmaceutical class were provided. No specific manufacturing
procedure was underlined to allow optimization of those
concentration and residence time. Lipid/phospholipid based
formulations production methods are described but those process are
specific to amphotericin B (complex formation) and could not be
applied to different compounds such as azole derivates.
[0027] U.S. Pat. Appl. Pub. No. 2007/0287675 A1 describes inhalable
compositions and methods for making such compositions. Compositions
are constituted of one or more respirable aggregates comprising one
or more poorly water soluble active agent. After inhalation those
composition allow to reach a maximum lung concentration of at least
0.25 .mu.g/g that can be kept for a certain period. The inventors
describe a series of methods that can be use to prepare those
respirable aggregates. Those methods comprise Ultra rapid freezing
(U.S. Pat. Appl. Pub. No. 2004/0137070), Spray freezing into liquid
(U.S. Pat. No. 6,862,890), Evaporative precipitation into aqueous
solution (U.S. Pat. No. 6,862,890), control precipitation (U.S.
Pat. Appl. Pub. No. 2003/0049323), High Internal Phase solutions
(U.S. Pat. Nos. 5,539,021 and 5,688,842). They demonstrate in a
comparative example the possibility to provide aggregates with
different in vitro dissolution rate but not with the same
manufacturing process. Their process involves the use of surfactant
in determined proportion. Those proportions are fixed in order to
generate a controlled particle size and no to modulate the
dissolution properties of the drug substance. Neither examples of
impaction tests nor in vitro results specifically designed for dry
powder for inhalation were disclosed. In all examples provided
therein the use of class 1 and 2 solvent, toxic after inhalation,
was required for total solubilization of the itraconazole.
[0028] Solubilisation of drugs in co-solvents or micellar-solutions
is other possibilities to improved and/or modify dissolution rate
of poorly soluble active ingredients. However those kinds of
formulations are also designed to be administrated by nebulization
and not as a dry powder for inhalation. Complexation with
cyclodextrin is another strategy to improve dissolution rate of
poorly soluble substance when formulated as dry powder for
inhalation. However, cyclodextrin have shown after inhalation to
induce inflammatory reaction signs and its safety profile is,
nowadays, not clear enough. Polymeric surfactants such as
co-polymers of polyoxyethylene and polyoxypropylene have been used
in several DPI formulations presenting an improved in vitro
dissolution rate (McConville et al., 2006). Those polymers have
been noted to produce slight alveolitis after 2 weeks of exposure
in inhalation toxicity study Formation of salt forms with enhanced
dissolution profiles and formation of solid dispersion are also
common techniques in formulation field to improve dissolution rate
of poorly soluble substances.
[0029] Another possibility to improve dissolution rate of a drug is
the modification of the physical form of the dry active ingredient.
Both nanonizing dry crystalline particles and formation of
amorphous dry form of the drug induce an improvement of substance's
dissolution rate. However, drying particles generally induce their
aggregation and then a loss of dissolution rate improvement due to
the decrease in the total surface area available to the dissolution
medium. Moreover there is here a need to form particles with a
determinate aerodynamic diameter to reach after inhalation the site
of infection of the Aspergillus colonization site (regarding their
aerodynamic diameter). Dispersing those nanosize crystalline and/or
amorphous particles in acceptable excipient for inhalation is an
interesting approach to form particles with appropriated
aerodynamic diameter and to keep dissolution rate improvement of
generated dry particles once deposited on the pulmonary mucosa. The
nature of the matricial agent should have the properties to enhance
or delayed dissolution rate of the active ingredient (compared to
another formulation). All excipients and solvent in use have to be
physiologically tolerated or recognized as save to minimize
potential toxicity after inhalation or during production and reduce
hazardous environmental contaminations.
[0030] The present invention provides a one or two step procedure
to produce this type of dry powder using only safe and authorized
excipient/solvent. This dry powder presents good flowability. The
produced dry powders present appropriated aerodynamic features
(regarding inhaled conidia) once emitted from a dry powder inhaler
device. The concept of formulation allows improvement and/or
modification/control . . . of the poorly soluble active ingredient
dissolution rate to obtain a formulation that will minimize
systemic absorption while maximizing its residence time in the lung
and hence its efficacy.
SUMMARY OF THE INVENTION
[0031] The subject matter of the present invention is defined in
the appended independent claims. Preferred embodiments are defined
in the dependent claims.
[0032] In a first embodiment, the subject matter of the present
invention is spray-dried particles (X) for a inhalation composition
comprising (a) between 5 and 50% by weight of at least one azole
derivative in amorphous state and (b) at least one matricial agent
to the composition selected from a group consisting of polyol such
as sorbitol, mannitol and xylitol; a monosaccharides such as
glucose and arabinose; disaccharide such as lactose, maltose,
saccharose and dextrose; cholesterol, and any mixture thereof.
Preferably, said matricial agent is mannitol or cholesterol.
Advantageously, the weight ratio of azole derivative(s)/matricial
agent(s) is between 0.5/99.5 and 40/60, preferably between 1/99 and
35/65, more preferably between 10/90 and 35/65. Said azole
derivative do not comprise a compound of the group consisting of
omeprazole, esomeprazole, lansoprazole, pantoprazole and
rabeprazole.
[0033] In particular, said particles further comprise a surfactant
and preferably comprise between 0.1 and 5% by weight of the
surfactant. Advantageously, said surfactant is selected from
lecithin, phospholipids derivatives such as phosphatic acids,
phosphatidyl choline (saturated and unsaturated), phoshpatidyl
ethanol amine, phosphatidyl glycerol, phosphatidyl serine,
phosphatidyl inositol, dioleoylphosphatidylcholine, dimyristoyl
phosphatidylcholine, dipalmitoylphosphatidylcholine, distearoyl
phosphatidylcholine, diarachidoyl phosphatidylcholine, dibenoyl
phosphatidylcholine, ditricosanoyl phosphatidylcholine,
dilignoceroylphatidylcholine, dimiristoylphosphatidylethanolamine,
dipalmitoyl-phosphatidylethanoalamine,
pipalmitoleoylphasphatidylethanolamine,
distearoyl-phosphatidylethanolamine,
dimyristoylphosphatidylglycerol, dipalmitoylphosphatidyl glycerol,
dipalmitolcoylphosphatidylglycerol and more preferentially
hydrogenated derivates or modified vitamins comprise
.alpha.-tochopherols derivates.
[0034] The subject matter of the present invention is also a spray
dried-powder composition for inhalation comprising the particles
(X), wherein said composition comprises at least 50% of the
matricial agent and provides a dissolution rate of said azole
derivative of at least, 5% within 10 minutes, 10% within 20 minutes
and 40% within 60 minutes when tested in the dissolution apparatus
type 2 of the United States Pharmacopoeia at 50 rotation per
minute, 37.degree. C. in 900 milliliters of an aqueous dissolution
medium adjusted at pH 1.2 and containing 0.3% of sodium
laurylsulfate. Said composition preferably provides a Fine Particle
Fraction of the azole derivative of at least 35% of the total
nominal dose of the azole in the powder following the method
"preparations for inhalation: assessment of fines particles" using
the Multi-stage Liquid Impinger, Apparatus C-chapter 2.9.18 of the
European Pharmacopoeia.
[0035] Advantageously, said composition further comprises another
type of particles (Y) which contain (a) between 5 and 50% by weight
of at least one azole derivative in amorphous state (b) at least
one matricial agent, and (c) a surfactant Said particles (Y)
preferably contain between 0.5 and 5% by weight of the
surfactant(s).
[0036] Advantageously, said composition further comprises another
type of particles (Z) which further contain up to 20% by weight of
nanoparticles of the azole derivative in crystalline structure
having a mean size between 0.1 and 1 .mu.m.
[0037] In particular, said composition provides a dissolution rate
of the azole derivative of 5 to 50% within 5 minutes, 10 to 60%
within 10 minutes, 15 to 90% within 20 minutes and 40 to 100% after
60 minutes.
[0038] Preferably, the azole derivative(s) is selected from
miconazole, fluconazole, itraconazole, posaconazole, voriconazole,
isoconazole, ketoconazole, oxiconazole, bifonazole, fenticonazole,
tioconazole, terconazole, sulconazole, ravuconazole, econazole,
terconazole, preferably, itraconazole.
[0039] The subject matter of the present invention is also a method
for preparing said spray dried particles and composition which
comprises the following steps of: [0040] a) preparing a liquid
composition comprising: [0041] i. a liquid carrier selected from a
class 3 solvent according to European Pharmacopoeia such as acetic
acid, heptane, acetone, isobutyl acetate, anisole, isopropyl
acetate,1-Butanol, methyl acetate, 2-Butanol, 3-Methyl-1-butanol,
Butyl acetate, methylethylketone, tert-Butylmethyl ether,
methylisobutylketone, cumene, 2-Methyl-1-propanol, dimethyl
sulfoxide, pentane, ethanol, 1-Pentanol, Ethyl acetate, 1-Propanol,
ethyl ether, 2-Propanol, ethyl formate, propyl acetate, formic
acid, or the mixture thereof, or the mixture of such solvent with
water; [0042] ii. at least one azole derivative in solution in said
liquid carrier; and [0043] iii. at least one matricial agent in
solution in said liquid carrier, [0044] wherein the weight ratio of
azole derivative(s)/matricial agent(s) is between 0.5/99.5 and
40/60, preferably between 1/99 and 35/65, more preferably between
10/90 and 35/65, [0045] b) spray drying the liquid composition for
producing particles for the dry powder composition.
[0046] Preferably, said method further comprises the steps of:
[0047] c) preparing another liquid composition comprising a liquid
carrier selected from a class 3 solvent or any mixture of two or
more solvents with or without water and at least one matricial
agent in solution in said liquid carrier, wherein the liquid
composition further comprises: [0048] i. at least one azole
derivative in solution in said liquid carrier and at least one
surfactant; and/or [0049] ii. nanoparticles of at least one azole
derivative having a mean size between 0.1 and 1 .mu.m, [0050] d)
spray drying said liquid composition provided by step (c) for
producing particles for the dry powder composition; and [0051] e)
physically blending the particles obtained by steps (b) and
(d).
[0052] The subject matter of the present invention is also a liquid
composition comprising: [0053] i. a liquid carrier selected from a
class 3 solvent according to European Pharmacopoeia such as acetic
acid, heptane, acetone, isobutyl acetate, anisole, isopropyl
acetate,1-Butanol, methyl acetate, 2-Butanol, 3-Methyl-1-butanol,
Butyl acetate, methylethylketone, tert-Butylmethyl ether,
methylisobutylketone, cumene, 2-Methyl-1-propanol, dimethyl
sulfoxide, pentane, ethanol, 1-Pentanol, Ethyl acetate, 1-Propanol,
ethyl ether, 2-Propanol, ethyl formate, propyl acetate, formic
acid, or the mixture thereof, or the mixture of such solvent with
water; [0054] ii. at least one azole derivative in solution in said
liquid carrier; and [0055] iii at least one matricial agent in
solution in said liquid carrier, [0056] wherein the weight ratio of
azole derivative(s)/matricial agent(s) is between 0.5/99.5 and
40/60, preferably between 1/99 and 35/65, more preferably between
10/90 and 35/65.
[0057] Preferably, said liquid composition further comprises at
least one surfactant and/or nanoparticles of at least one azole
derivative having a mean size between 0.1 and 1 .mu.m.
BRIEF DESCRIPTION OF THE FIGURES
[0058] FIG. 1 is the MDSC heating curves of spray dried
itraconazole.
[0059] FIG. 2 is in vitro dissolution profile of micronized
crystalline bulk itraconazole, pure amorphous itraconazole and a
spray dried powder formulation according to the present invention
(example 1B) comprising hydrophilic matricial and itraconazole.
[0060] FIG. 3 is in vitro deposition patterns (mean.+-.S.D, n=3) of
spray dried powder formulations according to the present invention
(examples 2A to 2D) determined with an MsLI from the Axhaler.RTM.
device. Results are exposed as percentage of itraconazole
(expressed in function of the nominal dose) recovered from the
device and each part of the impactor (throat, stage 1, 2, 3, 4 and
the filter). The following conditions were used: 100 ml/min, 2.4 s.
Three No. 3 HPMC capsules filled with a quantity of formulation
corresponding to 2.5 mg of itraconazole were used per test.
[0061] FIG. 4 is in vitro dissolution profile of bulk crystalline
itraconazole and the spray dried formulations according to present
invention (examples 2A to 2D).
[0062] FIG. 5 is the SEM photographs of spray dried powder
formulations according to the present invention (examples 3A to 3E)
and a spray dried itraconazole (example 3F) at magnification
.times.1000.
[0063] FIG. 6 is the MDSC heating curves of spray dried powder
formulations according to the present invention (examples 3A to
3E), spray dried itraconazole (example 3F) and spray dried
mannitol.
[0064] FIG. 7 is in vitro deposition patterns (mean.+-.S.D, n=3) of
spray dried powder formulations according to the present invention
(examples 3A to 3E) determined with an MsLI from the Axhaler.RTM.
device. Results are exposed as percentage of itraconazole
(expressed in function of the nominal dose) recovered from the
device and each part of the impactor (throat, stage 1, 2, 3, 4 and
the filter). The following conditions were used: 100 ml/min, 2.4 s.
Three No. 3 HPMC capsules filled with a quantity of formulation
corresponding to 2.5 mg of itraconazole were used per test.
[0065] FIG. 8 is in vitro dissolution profile of micronized
crystalline bulk itraconazole, spray dried amorphous itraconazole
(example 3F) and spray dried powder formulations according to the
present invention (examples 3A to 3E).
[0066] FIG. 9 is in vitro dissolution profile of spray dried powder
formulations according to the present invention (examples 3A to 3E)
with Curve A defining the dissolution rate of 5% within 10 minutes,
10% within 20 minutes and 40% within 60 minutes.
[0067] FIG. 10 is in vitro dissolution profile of spray dried
powder formulations according to the present invention (examples 3A
to 3E) with Curves B and B' defining the dissolution rate of 5%
within 5 minutes, 10% within 10 minutes, 15% within 20 minutes and
40% within 60 minutes, and the one of 50% within 5 minutes, 60%
within 10 minutes, 90% within 20 minutes and 100% within 60
minutes, respectively.
[0068] FIG. 11 is in vitro dissolution profile of micronized
crystalline bulk itraconazole and a spray dried powder formulation
according to the present invention comprising Itraconazole,
cholesterol and phospholipon (example 4).
[0069] FIG. 12 is in vitro dissolution profile of micronized
crystalline bulk itraconazole and spray dried powder formulations
comprising itraconazole and mannitol according to the present
invention, i.e., particles not containing crystalline nanoparticles
of itraconazole (example 5A) and particles containing crystalline
nanoparticles of itraconazole (example 5B).
DESCRIPTION OF THE INVENTION
[0070] This invention is related to a dry powder formulation for
inhalation of azole derivatives with the proviso that said azole
derivative is not a compound of the group consisting of the family
of omeprazole, esomeprazole, lansoprazole, pantoprazole and
rabeprazole and a process to provide it.
[0071] Azole derivatives can be selected from the group consisting
of miconazole, fluconazole, itraconazole, posaconazole,
voriconazole, isoconazole, ketoconazole, oxiconazole, bifonazole,
fenticonazole, tioconazole, terconazole, sulconazole, ravuconazole,
econazole, terconazole.
[0072] The dry powder of the invention can present high
dispersibility capabilities to maximize, after inhalation from an
inhaler device, the proportion of particles presenting an
appropriated aerodynamic diameter range.
[0073] Appropriated aerodynamic range refers to aerodynamic
diameter that presents inhaled conidia. Generated particles from an
inhaler device in breath conditions must present the same
aerodynamic range that inhaled aspergillus conidia (1.9-6 .mu.m) to
reach potential infections sites for an optimal treatment targeting
and effectiveness.
[0074] Advantageously, the dry powder composition is based on the
use of exclusively physiological component excipients, safe,
generally recognized as save (GRAS) excipients, FDA authorized
excipients for inhalation therapy to guaranty a good safety profile
after inhalation and to be compatible with the lung membrane to
avoid hyper-responsiveness, cough, airway spasticity or
inflammation.
[0075] The manufacturing process requires one or two step(s) to
obtain the final dry product and all techniques used are made for
an easy scaling up to industrial batch size production. The dry
powder in itself is designed to possess enhanced flow properties
for an easy processing at industrial scale.
[0076] The dry powder is specifically designed for oral inhalation
to treat or give prophylaxis against pulmonary invasive
aspergillosis. The azole derivatives are in form that allows that
dissolution rate can be improved at different extent and/or
modified by varying the composition of the dry powder. The
improvement can be controlled by modifying the dry powder
composition and/or the active pharmaceutical ingredient (API)
physical state or by combining prior administration different
embodiments of the invention.
[0077] This is advantageous because the modification of dissolution
rate can overcome in Vivo clearance and absorption mechanisms that
lead to decreasing drug proportion in the site of infection.
[0078] The dry powder is constituted of matricial microparticles.
The matricial microparticles are constituted of safe, physiological
component or inhalation FDA authorized excipient wherein the active
ingredient is dispersed in a modified physical state. After
inhalation of those microparticles, after matrix dissolution or
erosion, the active ingredient will expose a higher surface area to
the pulmonary mucosa than the same dose of pure spray dried active
ingredient microparticles, resulting in an improved dissolution
rate.
[0079] The nature of the matricial agent directly influences the
dissolution profile of the active ingredient. The matricial agent
can be (i) hydrophilic to directly release the active ingredient
when in contact with the pulmonary mucosa (ii) hydrophobic to delay
the release of the active ingredient (iii) a mixture of hydrophilic
and hydrophobic (in different proportion) agent to obtain an
intermediate release profile.
[0080] Matricial agents are physiological component excipients,
GRAS excipients; FDA authorized excipients for inhalation therapy
to avoid as far as possible pulmonary or systemic toxicity. The
matricial agents can be combined together to confer to the dry
powder desired flow, aerodynamic and dissolution characteristics.
The matricial agent is necessary in the composition.
[0081] Matricial agent can be selected from the group consisting of
sugar alcohols, polyols such as sorbitol, mannitol and xylitol, and
crystalline sugars, including monosaccharides (glucose, arabinose)
and disaccharides (lactose, maltose, saccharose, dextrose) and
cholesterol.
[0082] In one embodiment of the invention the API is in majority in
amorphous state. The proportion of amorphous active ingredient (in
percentage of the total amount of active ingredient from the
invention is from 51% to 100%, preferably between 70% and 100%,
even more preferably 100%.
[0083] One way to obtain an amorphous compound is to spray dry it
from a solution because the rapid solvent evaporation during the
drying process do not let enough time to solid particles to
recrystallize. However azole compounds and particularly
itraconazole are only sparingly soluble in chloride solvent such as
dichloromethane and chloroform which are, due to their high
toxicity, not recommended for the preparation of pharmaceutical
formulations. This invention provides methods to obtain an
amorphous product by spray drying the API from a solution using
only a class 3 solvent. Those solvents are considered as low toxic
potential solvents and then offer a better safety profile in case
of residuals inhalation. This category of solvent includes acetic
acid, Heptane, Acetone, Isobutyl acetate, Anisole, Isopropyl
acetate,1-Butanol, Methyl acetate, 2-Butanol, 3-Methyl-1-butanol,
Butyl acetate, Methylethylketone, tert-Butylmethyl ether,
Methylisobutylketone, Cumene, 2-Methyl-1-propanol, Dimethyl
sulfoxide, Pentane, Ethanol, 1-Pentanol, Ethyl acetate, 1-Propanol,
Ethyl ether, 2-Propanol, Ethyl formate, Propyl acetate, formic acid
or the mixture thereof,
[0084] By spray drying an organic solution of active ingredient it
is possible to obtain it after the drying process in an amorphous
state with geometric size appropriated for inhalation therapy
(<5 .mu.m). This can be done from a drug saturated organic
solution. However solubility of azole derivates such as
itraconazole in class 3 solvents is extremely low. These low
concentrations could not be optimal for a good recovery of the dry
powder after spray drying In order to obtain a good recovery of the
dry powder after spray drying azole derivatives with a higher
solubility may be selected instead of itraconazole. A matricial
agent can be added before spray drying this kind of solutions to
enhance total solute concentration. An acid can be added into-a
preheated organic class 3 solvent under magnetic stirring in order
to enhance the solubility of poorly soluble azole compound such as
itraconazole. An organic solution comprising azole compound(s) can
also be heated to high temperature under magnetic stirring to
obtain enhanced solubility of the azole compound(s). Those options
only allow the dissolution of hydrophobic excipients in the
solution. A determinate quantity of water can be added to one of
those solutions type in order to allow dissolving both poorly
soluble active ingredients, hydrophilic and hydrophobic excipients.
This can be particularly interesting in order to modify active
ingredient's dissolution rate, particle size, aerodynamic behavior
and flow properties. Preferential ratio of water to organic solvent
(in volume to volume percentage) are from 0 to 50%, preferably
between 0% to 30%, more preferably between 10% and 30% and even
more preferably between 20% and 30%.
[0085] On a thermodynamic point of view, due to their unorganized
structure, amorphous compounds present the advantage to possess
higher solubility than the same crystalline compound. In practice,
during dissolution, amorphous compounds often recrystallize to
lower energy crystalline state presenting lower solubility than the
initial product. This invention provides formulations wherein an
active compound is in an amorphous state and formulated so that its
dissolution occurs before complete drug recrystallization leading
to an improved dissolution rate product. Indeed, the improvements
and enlargement of surface area of dry powder formulation arrived
at local site of a patient can be obtained by spray drying a
solution of an active ingredient together with a hydrophilic
maticial agent which provides particles comprising the active
ingredient in amorphous state dispersing in the matricial agent.
Such improvements in surface area can--accelerate the active
ingredient dissolution rate preventing from excessive
recrystallization prior dissolution.
[0086] Recrystallization of amorphous drugs also may happen during
storage leading to a decrease of the dissolution performance
product. One aspect of the present invention provide a stable
amorphous product when formulate as a solid dispersion of the
active ingredient in a matricial agent.
[0087] In a composition of the invention, the amount of azole
derivates that can be incorporated in the matricial agent(s) is
from 0.5 to 40%, preferably from 1 to 35%, more preferably from 10
to 35% by weight.
[0088] Surprisingly, it is possible by varying the concentration of
the spray dried solution or the matricial agent/API ratio to modify
aerodynamic behavior of generated particles. Varying the
concentration in solution or the matricial agent/API ratio can
directly modify the geometric diameter and the density of dried
particles thus their aerodynamic diameter which will also directly
modify their aerodynamic behavior. Modifying one of those
parameters would lead to formation of particles presenting
different aerodynamic behavior while presenting similar dissolution
rate. This can help to provide a dry powder with an optimized
dissolution rate that will penetrate the lung in a sufficient
quantity to provide appropriated antifungal dose from a
predetermined nominal dose. Variation of those parameters allows
then the optimization of the fine particle dose (FPD) of the spray
dried powder while keeping improved dissolution rate.
[0089] Preferably, the amount of the azole derivative added in the
liquid composition is between 0.1% and 5%, preferably between 0.5%
and 2% by weight of the azole derivative to the volume of the
liquid composition (g/100 mL).
[0090] A surfactant can be added in the matrix of particles
comprised in a dry powder formulation according to the present
invention in order to improve the dissolution rate enhancement of
the active ingredient. A surfactant is an amphiphilic compound with
both hydrophilic and hydrophobic characteristics. By spray drying a
solution containing both the active ingredient the matricial agent
and a surfactant it is possible to produce matricial microparticles
wherein the active ingredient and the surfactant are dispersed. The
surfactant will play a wetting enhancement effect on the active
ingredient resulting, in a reduction in particle agglomeration and
acceleration/improvement of its dissolution rate when compared to
matricial microparticles without surfactant.
[0091] The surfactant(s) can be selected from the group consisting
of physiological component, GRAS (generally recognized as save)
excipients, FDA authorized excipients for inhalation therapy to
avoid any pulmonary or systemic toxicity.
[0092] The quantity of added surfactant could influence azole
compound dissolution rate improvement. The preferred amount of
surfactant is comprised between 0.1 and 5% by weight in the dry
powder composition.
[0093] Preferentially surfactant can be phospholipids, lecithin,
lipids or GRAS modified vitamins, or combination of such
surfactant. Phospholipids that may use comprise phosphatic acids,
phosphatidyl choline (saturated and unsaturated), phoshpatidyl
ethanol amine, phosphatidyl glycerol, phosphatidyl serine,
phosphatidyl inositol. Examples of such phospholipids include,
dioleoylphosphatidylcholine, dimyristoyl phosphatidylcholine
(DMPC), dipalmitoylphosphatidylcholine (DPPC), distearoyl
phosphatidylcholine (DSPC), diarachidoyl phosphatidylcholine
(DAPC), dibenoyl phosphatidylcholine (DBPC), ditricosanoyl
phosphatidylcholine (DTPC), dilignoceroylphatidylcholine (DLPC),
dimiristoylphosphatidylethanolamine (DMPE),
dipalmitoylphosphatidylethanoalamine (DPPE),
pipalmitoleoylphasphatidylethanolamine,
distearoylphosphatidylethanolamine (DSPE),
dimyristoylphosphatidylglycerol (DMPG), dipalmitoylphosphatidyl
glycerol (DPPG), dipalmitolcoylphosphatidylglycerol and more
preferentially hydrogenated derivates. Examples of GRAS modified
vitamins comprise .alpha.-tochopherols derivates.
[0094] A too high quantity of surfactant in the formulation can
induce an important particle size increase during spray drying. Due
to their low melting point, surfactants could soft or melt during
spray drying increasing particle size. Dilution of the surfactant
in the matricial agent can mask this effect resulting in production
of smaller particles with appropriate characteristics.
[0095] One particular embodiment of the invention consists to
obtain the active ingredient in the form of crystalline
nanoparticles by a method described in the art.
[0096] The term "nanoparticles" used to describe the present
invention has a meaning of solid discrete particles ranging in size
from 1 nm to 1000 nm. The presence of the crystalline nanoparticles
of azole derivative in a spray dried particle and the weight ratio
of the crystalline nanoparticles comprised in the particle can be
determined by using powder X-ray diffraction, and differential
scanning calorimetry concomitantly with IIPLC drug quantification .
. . .
[0097] Those nanoparticles are then dispersed in a matricial agent
to confer to the formulation appropriated particle size, flow
properties, dissolution rate and aerodynamic behavior. The
dissolution rate of those nanoparticles is instantaneous (within 5
minutes) with a very pronounced burst effect that cannot be delayed
due to inherent dissolution rate of the nanoparticles.
[0098] The production of this formulation types (i.e., particles
containing crystalline nanoparticles of the active ingredient and
the matricial agent) includes two steps in the manufacturing
procedure. The first step being the production of drug
nanoparticles and the second step being the drying procedure. The
nanoparticles could be produced by a method described in the art.
Preferably nanoparticles are produced by high pressure
homogenization. The matricial agent can be added prior the size
reduction step or before the spray drying procedure.
[0099] In one particular embodiment of the invention the active
ingredient is dispersed in the matricial agent both in form of
crystalline nanoparticles and amorphous compound. This embodiment
can be the result of the spray drying of both matricial agent and
the active ingredient in solution together with nanoparticles of
the active in. Another aspect of this embodiment is that the dry
powder formulation according to the present invention is
manufactured by a simple blend of the nanoparticles of the active
ingredient, which are obtained by spray drying of a suspension
comprising its crystalline nanoparticles and a matricial agent or
by mechanical milling of the crystalline active ingredient, and an
amorphous matricial formulation obtained by spray drying of the
active ingredient in solution. This blend powder will be filled in
capsule, blister or multidose device.
[0100] The desired result is to confer to the formulation a
controlled dissolution profile by optimizing the proportion of
nanoparticles/amorphous compound in the formulation. This
dissolution profile could not be reach with only the nanoparticles
in the formulations. The modification of the proportion
nanoparticles/amorphous allow varying dissolution profile.
Preferably, the ratio (w/w) of amorphous matricial
particles/nanocrystalline matricial composition is comprised
between 100/0 to 80/20.
[0101] In another embodiment the active ingredient is dispersed as
nanoparticles or microparticles in a matrix of the same active
ingredient. The active ingredient matricial being in amorphous
state
[0102] Nanosuspension could be concomitantly spray dried with a
solution of active ingredient containing a matrix former. The
differences that exist between amorphous and nanoparticles
dissolution rate could allow modifying dissolution rate of the
formulation. The API in solution could either be used as matrix
former encapsulating the nanoparticles. This could provide
formulation presenting an interesting dissolution rate and optimal
aerodynamic characteristics.
EXAMPLES
Example 1
[0103] The starting material is constituted of crystalline
micronized itraconazole (ITZ) with a volume mean diameter of 3.5
.mu.m and 90% of particles below 6.2 .mu.m. Pure amorphous
itraconazole (Example 1A) and a hydrophilic matricial formulation
of itraconazole dry powder (Example 1B; invention) were produced at
laboratory scale by spray-drying using a Buchi Mini Spray Dryer
B-191a (Buchi laboratory-Techniques, Switzerland). Two feed stock
solutions were prepared then separately spray-dried in the
following conditions: spraying air flow, 800 l/h; drying air flow,
35 m.sup.3/h; solution feed rate, 2.7 g/min; nozzle size, 0.5 mm;
Inlet temperature, 90.degree. C.; resulting outlet temperature of
53.degree. C. The composition of the feedstock solutions is
summarized in Table 1. Each component were dissolved under magnetic
stirring (600 rpm) in a hydro-alcoholic solution (20 water-80
isopropanol) heated at 70.degree. c. During spray drying the
solutions were kept at a temperature between 60 and 70.degree.
C.
TABLE-US-00001 TABLE 1 Composition of spray dried solutions in
Example 1. liquid Isopropanol Water composition Itraconazole (g)
Mannitol (g) (ml) (ml) Example 1A 0.56 -- 80 20 (Comparative: Cex)
Example 1B 0.56 1 80 20 (Invention: INV)
[0104] Crystallinity profile of the dried samples was evaluated
using MDSC (modulate temperature differential scanning calorimetry)
and PXRD (powder x-ray diffraction). Those two techniques are
complementary and provide a maximum of information on sample's
polymorphism.
[0105] MDSC experiments were conducted using a Q 2000 DSC (TA
Instruments) equipped with cooling system. MDSC differs from
standard DSC in the possibility to apply two simultaneous heating
rates to the sample, a sinusoidal modulation is added to the linear
heating ramp. The total measured heat flow corresponds to the
standard heat flow in classic DSC. MDSC heating conditions offers
the possibility to make the deconvolution of reversing and non
reversing heat flow in which particular thermal event can be
singularly detected. Crystallizations phenomena were then observed
in the non-reversing heat flow, glass transitions were observed in
the reversing heat flow while melting were observed in total heat
flow All samples were analyzed in the same following conditions. A
2-3 mg sample was exactly weighted in a low mass aluminum hermetic
pan. A 5.degree.. C/min temperature rate with a modulation of
+/-0.8.degree. C. every 60 seconds was applied to the sample from
25.degree. C. to 185.degree. C. The instrument was calibrated for
temperature using indium as a standard. The heat flow and heat
capacity signals were calibrated using a standard sapphire sample.
The Universal Analysis 2000 software was used to integrate each
thermal event.
[0106] PXRD is a powerful tool widely used to evaluate the
crystalline form of various compounds. It can help to determine the
structural physical state of a product. At a given crystalline
lattice, will correspond a given PXRD spectra and inversely a given
chaotic system (as amorphous state) would not provide any
diffraction peak. This will therefore help to evaluate the
polymorphic form obtained after spray drying and in a second time
to estimate the proportion of amorphous phase within a sample. The
powders were analyzed by the Debye-Scherrer method. The samples
were submitted to the K.alpha. line of copper, monochromatic
radiation (.lamda.=1.540 .ANG.). The diffractometer (Siemens D5000,
Germany) equipped with a mounting said reflection Bragg-Brentano,
connected to the monochromator and a channel program Diffracplus.
The measures are determined to 40 KV, 40 mA in 2theta an angular
range from 2.degree. to 60.degree. in steps of 0.02.degree. through
a counting speed of 1.2 s per step and a rotation speed of sample
of 15 rpm. Each sample was stored in a hermetic plastic container
and placed at 8, 25, 40.degree. C. They were analyzed directly
after spray drying, and after 2 months storage at the different
temperatures.
[0107] It is possible to quantify the percentage of crystalline
phase in a given compound. Several techniques of calculation have
been developed In this case measuring the areas under the curves
was used to determine the percentage of amorphous phase in the
sample. Indeed, there is a proportional relationship between the
ratio of the area under the curve of the diffraction peaks above
the deviation from the baseline (A.sub.c) and the total area of the
diffractogram (A.sub.tot) with the amount of crystalline phase in
the sample. To calculate the degree of crystallinity within a
sample it suffices to measure the area under the curve of the
diffraction peaks (A.sub.c) without integrating the deviation from
the baseline because it comes from the noise and amorphous areas
present in the sample. Then integrate the total area under the
curve of the diffractogram (A.sub.T). The percentage of crystalline
phase will be expressed as in equation 1. The amorphous content
expressed in % was estimated as 100% minus the estimated
crystallinity degree.
% Crystailinity = ( A C A T ) .times. 100 Equation 1
##EQU00001##
[0108] MDSC analysis (FIG. 1) showed that amorphous itraconazole
(Example 1A) exhibited a glass transition at about 49.degree.
C.
[0109] An exothermic recrystallization peak was observed between
100.degree. C. and 125.degree. C., which was followed by an
endothermic peak around 164.degree. C. that corresponded to the
melting of early formed crystalline material. This crystalline
itraconazole melted at a temperature lower that the bulk material
when analyzed in the same conditions (about 168.degree. C.). Those
thermal events are characteristics of glassy itraconazole.
[0110] PDRX confirmed amorphous state of itraconazole in Examples
1A and 1B. At T 0 month no diffraction's peak appeared on
diffractogram of Example 1A. Approximated calculated amorphous
phase in this sample was equal to 100%. This traduced the lack of
any crystalline structure in the sample.
TABLE-US-00002 TABLE 2 DRX based estimated amorphous sample's
content Formulation T0 months T2 months 8.degree. C. Example 1A
(Cex) 100% 100% Example 1B (INV) 52% 52% 25.degree. C. Example 1A
(Cex) 100% 100% Example 1B (INV) 52% 55% 40.degree. C. Example 1A
(Cex) 100% 63% Example 1B (INV) 52% 55%
[0111] No recrystallization occurred after 2 months of storage at
8, and 25.degree. C. The percentage of amorphous phase stayed at
100% and no diffraction's peak characteristics of crystalline
itraconazole were observed in the diffractograms. When stored at
40.degree. C. amorphous itraconazole recrystallized and
approximated amorphous phase shifted to 63%. Recrystallization
peaks appeared at the originals diffraction's angles of bulk
crystalline itraconazole signifying that amorphous itraconazole
recrystallized to its original more stable form.
[0112] At T 0, Example 1B's diffractogram exhibited some
diffractions peaks. However none of those peaks corresponded to
crystalline itraconazole. Diffraction profiles of both .alpha.,
.beta. and .delta. mannitol were present. Total approximated amount
of amorphous phase within the sample was equal to 52%. This value
was higher than actual content of itraconazole in the sample. This
came probably from the proportion of mannitol that was amorphous
after spray drying. When stored at 8.degree. C., 25.degree. C. and
40.degree. C. only small variations in the approximated amorphous
phase in the sample was observed (see Table 2). Contrary to Example
1A, no recrystallization evidences of itraconazole were present at
its characteristics diffractions angles. Dispersing amorphous
itraconazole in mannitol (by spray drying a solution containing
both components) yielded to the stabilization of the amorphous
API.
[0113] Aerodynamic behavior of generated particles after dose
actuation from a dry powder inhaler was assessed using a multistage
liquid impinger (MsLI). The dry powder inhaler used was an
Axahaler.RTM. (SMB laboratories). A flow rate (adjusted to a
pressure drop of 4 kPa) of 100 L/min during 2.4 sec was applied
through the device for each actuation. The device was filled with
HPMC n.degree.3 capsules loaded with an approximate quantity of dry
powder corresponding to 2.5 mg of itraconazole. One test was
realized with three discharges. After the three dose actuations the
total deposited dry powder was quantified for each part of the
impactor with a suitable and validated HPLC method. Each test was
replicated three times. For each test the fine particle dose (FPD)
has been estimated by the method described in the European
Pharmacopea 7.2 for aerodynamic assessment of fine particle,
apparatus C (MsLI). The expressed results have been weighted to a
constant itraconazole nominal dose of 2.5 mg. The fine particle
fraction (FPF) is the FPD expressed in % of the nominal dose.
[0114] A Malvern Spraytec.RTM. laser diffraction equipment was used
to measure particle size distribution (PSD) during the aerodynamic
fine particle assessment test. The laser beam was directly placed
between the throat and the impactor to measure the PSD of generated
dry powder cloud, which was then split along its aerodynamic
diameter in the MsLI during simulated inhalation conditions. The
average PSD was measured from three replicates of each sample.
Results were expressed in terms of D[4.3], d(0.5) and d(0.9) which
are, respectively, the volume mean diameter and the size in microns
at which 50% and 90% of the particles are smaller than the rest of
the distribution. Results are expressed in Table 3.
TABLE-US-00003 TABLE 3 Size and aerodynamic characteristics of the
different formulations: Particle Size Characteristics (Mean .+-.
SD, n = 3) Measured with the the Spraytec .RTM. and fine particles
fractions (% of particle with d.sub.ac <5 .mu.m) expressed in
function of nominal dose (FPF; Mean .+-. SD, n = 3) measured by
impaction test (MsLI). Spraytec .RTM. MsLI Formulation d(0.5)
(.mu.m) D[4.3] (.mu.m) d(0.9) (.mu.m) FPF (%) Example 1B 2.22 .+-.
0.11 2.75 .+-. 0.39 3.38 .+-. 0.28 46.9 .+-. 1.9 (INV)
[0115] Particle size analysis revealed that the volume mean
diameter of the invention was below 5 .mu.m which is the first
criteria for deep lung deposition. This was confirmed by the
aerodynamic fine particle assessment test. The invention presented
a high FPF equal to 46.9.+-.1.9%.
[0116] Dissolution tests were performed using USP 33 type 2 paddle
apparatus (Distek Dissolution System 2100C, Distek Inc., USA). The
dissolution media was constituted of deionized water set at pH 1.2
(HCl 0.063N) containing 0.3% of sodium lauryl sulfate. This
dissolution allowed maintaining SINK conditions throughout the
test. The medium was heated to 37.degree. C. and kept at this
temperature during the test. The paddle speed was set at 50 rpm and
the dissolution vessel was filled with 900 ml of dissolution media.
An exactly weighted amount of dry powder corresponding to 10 mg of
itraconazole was spread on the dissolution media (=T0).
Itraconazole was quantified at pre-determined intervals (0, 2, 5,
10, 20, 30, 60, and 120 minutes) using a suitable validated HPLC
method. Five milliliters of dissolution media was removed from the
dissolution vessel and directly replaced by fresh dissolution
medium. These five milliliters were directly filtered through 0.2
.mu.m diameter filters to avoid quantification of undissolved
particles at the determinate time interval. The cumulative amount
of drug release was calculated and expressed in percentage of
initial drug load and plotted versus time. Each test was replicated
three times.
[0117] Dissolution profiles are shown in FIG. 2. Comparison of the
dissolution curves of crystalline micronized (bulk ITZ) and pure
amorphous ITZ (Example 1A) suggested no difference in the drug
release curves. This observation was interesting, since amorphous
ITZ would be expected to have a faster dissolution profile compared
to the crystalline ITZ. This may come from the fact that the highly
hydrophobic nature of the drug substance could lead to poor
wettability by the aqueous dissolution media impeding drug
dissolution improvement.
[0118] Progressive re-crystallization of amorphous ITZ could also
have occurred during dissolution, delaying dissolution of the
amorphous form. However, it was surprisingly discovered that the
formulation of Example 1B according to the present invention
wherein ITZ is dispersed in mannitol microparticles provided a
significant improvement of the dissolution rate of ITZ, i.e., 11.4%
at 10 min, 15.2% at 20 min and 46.7% at 60 min, compared to bulk
micronized crystalline ITZ and pure amorphous ITZ. The increase in
surface area available to the dissolution media of amorphous ITZ
when dispersed in mannitol microparticles could explain this
significant acceleration (FIG. 2) of dissolution rate. Mannitol
being dissolved quasi instantly, it was supposed that remaining ITZ
particles exposed a higher surface area to the dissolution media
that pure spray dried amorphous particles. Mannitol formed
spherical matrix wherein amorphous ITZ is dispersed. Once the
mannitol is dissolved, porous amorphous ITZ particles are released
in the dissolution vessel whit, due to numerous pores formed by the
mannitol dissolution. The increased surface area available to the
dissolution media increases dissolution rate and prevents excessive
re-crystallization which enhance solubility therefore dissolution
rate.
Example 2
[0119] The purpose of this example was to demonstrate the ability
of the invention to modify aerodynamic behavior of the dry powder
without modifying its dissolution rate by modifying excipient/API
ratio and the total solute in the liquid composition for spray
drying.
[0120] Four formulations were prepared at laboratory scale by
spray-drying using a Buchi Mini Spray Dryer B-191a (Buchi
laboratory-Techniques, Switzerland). Four feed stock solutions were
separately prepared and spray dried. A determined quantity of
itraconazole and mannitol (see Table 4) were dissolved in 100 ml of
a hydro-alcoholic solution (20 water-80 isopropanol) heated at
70.degree. C. under magnetic stirring (600 rpm). The total dry
product amount in solution for Examples 2A and 2B are similar (1.56
g). The only difference between the two formulations is the ratio
of itraconazole/mannitol. For formulation 2A, 2C and 2D the ratio
of itraconazole/mannitol was constant but the total amount of
solute in solution in the liquid composition was different. The
spray drying conditions are the same that in Example 1.
TABLE-US-00004 TABLE 4 Amount of itraconazole and mannitol in the
liquid compositions for spray drying in Example 2 Liquid
composition Composition (for 100 ml) Example 2A (INV) Itraconazole
0.56 g Mannitol 1 g Example 2B (INV) Itraconazole 0.234 g Mannitol
1.326 g Example 2C (INV) Itraconazole 0.28 g Mannitol 0.5 g Example
2D (INV) Itraconazole 0.84 g Mannitol 1.5 g
[0121] Cristallinity profile of samples was assessed using PXRD
(powder x-ray diffraction) at the same condition that those
described in Example 1.
[0122] The diffractograms of the four formulation presented some
diffraction's peaks. However none of those diffraction's peaks
corresponded to crystalline itraconazole. That means that
itraconazole, in those formulations, was in an amorphous state.
Mannitol was in majority in crystalline state. Its three different
polymorphic forms (.alpha., .beta. and .delta.) were present in all
samples but in different proportions, the .delta. form being in
majority.
[0123] Powder flowability was evaluated by Carr's compressibility
index (CI) as described in Example 1. A Can's index values of above
40% are generally related to poor powder flowability whereas value
under 20% are related to extremely good powder flowability. The
four present a CI value ranging from 20.9% to 28.8%. Those values
indicate good powder flowability for both formulations.
[0124] Particle size distribution of powders was evaluated by laser
scattering using a Malvern Mastersizer 2000.RTM. (Malvern
instrument) via a Sirocco 2000.RTM. (Malvern instrument) thy feeder
dispersion unit. Particle size measurement was done on a sample of
+/-50 mg at a pressure of 4 Bar with a feed rate vibration set at
40%. Those conditions allow to measure particle size distribution
of practically, totally desagglomerated powder due to very drastic
dispersion conditions. Particle refractive index with a real part
equaling 1.48 and imaginary part of 0.1 were chosen. Those values
ensure low weighted residual (<2%) which traduces result's
integrity.
[0125] A Malvern Spraytec.RTM. was used as describe in example 1.
For both techniques, the average PSDs was measured from three
replicates of each sample. Results were expressed in terms of
D[4.3], d(0.5) and d(0.9) which are, respectively, the volume mean
diameter and the size in microns at which 50% and 90% of the
particles are smaller than the rest of the distribution. Results
are expressed in Table 5.
[0126] Aerodynamic behavior of generated particles was evaluated by
impaction test as described in Example 1. The fine particle
fraction is the FPD expressed in % of the nominal dose (FPF) having
an aerodynamic diameter inferior to 5 .mu.m. The emitted doses have
been calculated and correspond to the recovered dose from the
induction port and five stages of the MsLI during the tests. The
emitted dose is express in percentage of the nominal dose and
corresponds to the percent of the nominal dose that effectively
leaved the device and capsule. Results are expressed in Table 6 and
represented in FIG. 3.
[0127] Malvern Sirocco.RTM. measurements showed that the four
formulations exhibited similar mass median diameter d(0.5), and the
volume mean diameter values (D[4.3]) of the formulations 2B and 2C
were higher than those of the two other formulations as expressed
in Table 5. The formation of slightly larger particles seemed
occurred in those two formulations. In addition their
deagglomeration seemed to be more difficult regarding higher d(0.5)
and D[4.3] values obtained for the 2B and 2C formulations with
Spraytec.RTM. analysis in simulated breath conditions.
TABLE-US-00005 TABLE 5 Size characteristics of the different
formulations of Example 2: Particle Size Characteristics (Mean .+-.
SD, n = 3) were Measured with the Malvern Masterzizer2000 .RTM. and
Spraytec .RTM. Malvern Sirocco* Spraytec* d(0.5) D[4.3] d(0.9)
d(0.5) D[4.3] d(0.9) Formulation (.mu.m) .mu.m (.mu.m) (.mu.m)
(.mu.m) (.mu.m) Example 2A (INV) 0.74 .+-. 0.01 1.00 .+-. 0.04 1.78
.+-. 0.09 2.22 .+-. 0.11 2.75 .+-. 0.39 3.38 .+-. 0.28 Example 2B
(INV) 0.73 .+-. 0.03 1.2 .+-. 0.46 1.89 .+-. 0.49 2.99 .+-. 0.11
6.45 .+-. 1.78 14.91 .+-. 9.94 Example 2C (INV) 0.76 .+-. 0.03 1.54
.+-. 0.18 3.08 .+-. 0.75 2.70 .+-. .05 4.60 .+-. 0.62 7.12 .+-.
2.20 Example 2D (INV) 0.76 .+-. 0.01 1.01 .+-. 0.04 1.86 .+-. 0.12
2.16 .+-. 0.04 2.31 .+-. 0.04 2.90 .+-. 0.03
[0128] Despite their higher particle size and their lower
deagglomeration efficiency, the 2B and 2C formulations have higher
FPF than formulations 2A and 2D. This is directly related to higher
emitted dose for those two formulations (2B and 2C). Because of
extremely fine granulometry, despite lower deagglomeration tendency
and slightly larger particle size those two formulations penetrated
deeper in the impactor than formulation 2A and 2D which result in
higher FPF.
TABLE-US-00006 TABLE 6 Particle deposition, FPD and FPF (mean .+-.
SD) and emitted dose (% nominal dose) obtained during impaction
test (MSLI, 100 l/min, 2.4 sec, 3 discharges per test, nominal dose
weighted at 2.5 mg, n = 3). Example 2A Example 2B Example 2C
Example 2D Mean FPD 1.17 .+-. 0.05 1.40 .+-. 0.01 1.36 .+-. 0.09
1.19 .+-. 0.04 (mg) Mean FPF (%) 49.6 .+-. 1.9 56 .+-. 0.4 54.4
.+-. 1.8 47.6 .+-. 1.6 Emitted 53.3 .+-. 1.9 71 .+-. 0.5 73.5 .+-.
6.3 53.3 .+-. 1.5 dose.sub.nom (%)
[0129] Dissolution tests were conducted as described in Example 1.
Obtained dissolution profiles are shown in FIG. 4. The four
formulations exhibited different and faster dissolution's rate than
bulk micronized crystalline itraconazole (FIG. 4). The dissolution
profiles of Examples 2A, 2B, 2C and 2D were similar.
[0130] Regarding those results it is possible to modify aerodynamic
behavior of generated particles by modifying active
ingredient/matrix former ratio, the total amount of solute or the
concentration of the active ingredient in solution of the spray
dried solution while keeping similar dissolution profile. The
modification of the aerodynamic behavior was done without varying
excipient type or spray drying parameters. This shows the
possibility of this flexible one step process to vary aerodynamic
behavior of particles without modify API dissolution rate. All
excipients used were GRAS. The four formulations presented good
powder flowability.
Example 3
[0131] The purpose of this example was to show the ability of the
invention to modify dissolution rate's acceleration of a
formulation while keeping good flow properties and aerodynamic
characteristics.
[0132] Three formulations were produced at laboratory scale by
spray drying feed stock solutions using a Buchi Mini Spray Dryer
B-191a (Buchi laboratory-Techniques, Switzerland). For the five
examples a determined quantity of itraconazole, mannitol and
hydrogenated soy-lecithin with more than 90% of hydrogenated
phosphatidylcholine (Phospholipon 90H), (see Table 7) were
dissolved in 100 ml of an hydro-alcoholic solution (20 water:80
isopropanol) heated at 70.degree. c. under magnetic stirring (600
rpm). The spray drying conditions are the same that in Example
1.
TABLE-US-00007 TABLE 7 Theoretical composition of spray dried
solutions, dry formulations ns used during the spray drying process
in Example 3. Liquid composition Dry powder composition ITZ %
Mannitol PL90H % ITZ Mannitol PL90H Formulation (w/v) %(w/v)
(m/m.sub.ITZ) (% w/w) (% w/w) (% w/w) Example 3A (INV) 0.56 1 --
35.9 64.1 -- Example 3B (INV) 0.1 0.9 -- 10 90 -- Example 3C (INV)
0.56 1 1 35.77 63.87 0.36 Example 3D (INV) 0.56 1 10 34.65 61.88
3.47 Example 3E (INV) 0.1 0.9 10 9.90 89.11 0.99 Example 3F (Cex)
0.56 -- -- 100 -- --
[0133] Determination of drug content was used in order to compare
expected and actual drug content. For that a determined quantity of
dry powder was dissolved in a dilution phase and sonicated during
20 min. Those solutions were analyzed by HPLC-UV from which the
drug content (wt %) was determined. Average content (wt %) and
standard deviations were calculated from five analysis.
Itraconazole content measurements results for the different
formulations are summarized in Table 8. The measured values were
very close to the expected one with relative errors ranged between
-3.9% and 3.0%. Lower itraconazole content as well as introduction
of phospholipids in the formulations induced a reduction of this
relative error. The active ingredient seemed to be uniformly
distributed within particles since samples have been selected
randomly and that variation coefficient for all five test samples
were not greater than 3.25%. Those exact contents values were used
during aerodynamic particle size analysis to determine exact
nominal doses. No ITZ degradation seemed to occur during the spray
drying process. The relative error between the measured and
expected ITZ content for pure spray dried itraconazole (Example 3F)
was equal to 0.7%.
TABLE-US-00008 TABLE 8 ITZ content measured by HPLC determination
of spray dried powder of Example 3 (mean +/- SD; n = 5) Coefficent
Expected Relative Measured ITZ variation ITZ content error
Formulation content (wt %) (%) (wt %) (%) Example 3A (INV) 34.5
.+-. 0.6 1.64 35.9 -3.9 Example 3B (INV) 9.99 .+-. 0.3 3.25 10 -0.1
Example 3C (INV) 35.6 .+-. 0.7 1.82 35.8 -0.6 Example 3D (INV) 33.6
.+-. 0.7 2.01 34.65 -3.1 Example 3E (INV) 10.2 .+-. 0.2 1.98 9.9
3.0 Example 3F (Cex) 100.7 .+-. 1.6 1.61 100 0.7
[0134] Qualitative morphological evaluations were conducted by
scanning electron microscopy using a Philips XL30 ESEM-FEG (FEI,
The Netherlands). The samples were spread on a carbon adhesive band
then coated with gold at 40 mA for 90 sec at 6.10-2 mbar under
argon. Observations were done at acceleration between 5 and 25 KV
depending on the sample.
[0135] Regarding the quantitative composition of the spray dried
formulations, mannitol was the major component and was therefore
subject to forming matricial particles within which were dispersed
the ITZ and, if applicable, the PL. The morphological evaluation
showed that very small spherical particles (.about.1-2 .mu.m with
presence of submicron size particles) with smooth surfaces were
formed from the spray dried solution containing mannitol and
itraconazole without PL (Examples 3A and 3B; FIG. 5). No
morphological differences were observed between these formulations
despite the different proportions of amorphous content and mannitol
polymorphs. However Example 3B seems to be constituted of slightly
larger spherical particles. The presence of PL induces the
formation of larger particles with a granular appearance. For the
formulation presenting the highest PL content (Example 3D), this
granular appearance was the more pronounced and interparticular
links were observed (FIG. 5). Those links were probably formed
during the spray drying process because of the softening or melting
of PL inducing particle aggregation. The reduction of the PL
content (Examples 3C and 3E) considerably reduced this grainy
aspect.
[0136] The residual moisture and solvent content of the different
dry powders was assessed using thermogravimetric analysis (TGA)
with a Q500 apparatus (TA instruments, New Castle, USA) and
Universal Analysis 2000 version 4.4A software (TA Instruments,
Zellik, Belgium). The residual water and solvent content was
calculated as the weight loss between 25.degree. C. and 125.degree.
C. and expressed as a percentage of the initial sample mass. Run
were set from 25.degree. C. to 300.degree. C. at a heating rate of
10.degree. C./min on sample mass of about 10 mg and performed in
triplicate. Weight loss measured during heating the samples between
25.degree. C. and 125.degree. C. were very low (<0.5%) for each
formulations.
[0137] MDSC were realized as described in Example 1 and results are
show in FIG. 6. As previously described (Example 1A), spray dried
in those conditions MTDSC analysis showed that itraconazole was
retrieved in its particular amorphous glassy state after the spray
drying process (here Example 3F). This particular profile was also
observed again on MDSC thermograms for the formulations containing
the highest proportion of itraconazole (Examples 3A, 3C and 3D;
FIG. 6). The glass transition at about 49.degree. C. was present in
the reversing heat flow as was the cold crystallization exotherm at
around 100.degree. C. in the non-reversing heat flow. Those thermal
events were not detected in the formulations containing the
smallest proportion of itraconazole (.about.10%; Examples 3B and
3E), probably due to lack of sensitivity of the thermal detection
for diluted compositions. Spray-dried mannitol and itraconazole
melted (total heat flow) at around the same temperature. One single
melting point at about 164.degree. C. was observed for all
formulations. One supplementary endothermic peak followed by an
exothermic peak around 150.degree. C. was observed for Example 3E.
These transitions correspond to the melting of .delta.-mannitol
followed by crystallization into the .beta. polymorph. The other
formulations did not exhibit this thermal event probably because
mannitol was only almost totally (98.5%) in the .delta. form in
this formulation (see PXRD results).
[0138] PXRD analyses were conducted on all spray dried powders as
described in Example 1. Amorphous contents calculated using the
area under the diffractograms are summarized in Table 9.
Formulation with higher ITZ content exhibited higher amorphous
content. A good correlation was obtained between calculated
amorphous content and itraconazole measured content by
HPLC(R.sup.2>0.9).
[0139] The proportion of participation of each mannitol polymorph
to the formation of the total crystalline network was evaluated
using the reference intensity ratio methodology. Calculations were
made on Diffracplus EVA software. This semi-quantitative method of
estimation consists of the identification of the different phases
in a specimen by comparison with references patterns (from ICDD
data base) and the relative estimation of the proportions of the
different phases in the multiphase specimens by comparing peak
intensities attributed to the identified phases.
TABLE-US-00009 TABLE 9 PXRD based estimated amorphous content and
.alpha. .beta. and .DELTA. mannitol .beta. .DELTA. Amorphous
.alpha. mannitol mannitol mannitol Formulation content (%) (%) (%)
(%) Example 3A (INV) 55 42 2.5 55.1 Example 3B (INV) 34.5 38.3 1.3
60.3 Example 3C (INV) 53 31.4 2.9 65.7 Example 3D (INV) 57 1.1 0.4
98.5 Example 3E (INV) 37 20.5 0.9 78.8 Example 3F (Cex) 100 -- --
--
[0140] One specific diffraction peak was chosen for each polymorph
were no other crystalline structure that could be present in the
dry powder diffracted. Specific diffraction peaks at 43.92, 16.81
and 22.09.degree. 2.theta. were used for .alpha., .beta. and
.delta.-mannitol, respectively and their respective ICDD spectrum
were adjusted to those diffractions ray for calculation. The
results are expressed as an estimation of the percentage of each
polymorph in the formulations and are summarized in Table 9.
[0141] Flow properties were evaluated by determining the Carr's
index compressibility index (CI) as described in Example 2. Good
powder flowability is a necessary characteristic for an eventually
easy processing at an industrial scale. Moreover, more specifically
to dry powder for inhalation, a good flowability has already been
related to generate an adequate metering, dispersion and
fluidization of a dry powder from an inhaler device. All
formulations exhibited CI values ranged between 15.6% and 26.4%
(see Table 10) which indicated good potential in flow properties
for this formulations type.
[0142] Particle size analyses were conducted using two different
methods. The first method (using a Malvern Mastersizer 2000.RTM.)
provided size results corresponding to totally individualized
particles. The second method (using a Malvern Spraytec.RTM.)
allowed evaluating the size of particles in a deagglomeration rate
that is produced after dispersion form an inhaler device.
[0143] Malvern Mastersizer 2000.RTM. results showed that all
formulations presented a very fine granulometry with a volume mean
diameter ranged from 1.00 .mu.m to 2.04 .mu.m and a mass volume
median diameter comprised between 034 .mu.m and 1.81 .mu.m (Table
10). The PSD of formulations without PL, Examples 3A and 3B, were
very close with a d(0.5) value of 0.74 .mu.m and 0.88 .mu.m,
respectively. However, as observed by SEM a small proportion of
larger particles were formed for Example 3B, which was traduced by
an increase in the D[4.3] and d(0.5).
TABLE-US-00010 TABLE 10 Size, aerodynamic and flow characteristics
of formulations obtained from the different solutions: Particle
Size Characteristics (Mean .+-. SD, n = 3) Measured with the
Mastersizer 2000 .RTM. and the Spraytec .RTM., Emitted dose
(expressed in % of nominal dose) and fine particles fractions (% of
particle with dae <5 .mu.m) measured by impaction test (Mean
.+-. SD, n = 3, Carr's index value (CI) (Mean .+-. SD, n = 3).
Laser light scattering Aerodynamic Mastersizer 2000 .RTM. Spraytec
.RTM. evaluation d(0.5) D[4.3] d(0.5) D[4.3] ED FPF CI Formulation
(.mu.m) (.mu.m) (.mu.m) (.mu.m) (%.sub.nom) (%.sub.nom) (%) Ex. 3A
0.74 .+-. 0.01 1.00 .+-. 0.04 2.2 .+-. 0.1 2.8 .+-. 0.4 53.3 .+-.
1.9 46.9 .+-. 1.9 26.4 .+-. 0.1 Ex. 3B 0.88 .+-. 0.07 1.15 .+-.
0.05 2.71 .+-. 0.08 3.66 .+-. 0.07 81.9 .+-. 0.6 67.0 .+-. 1.0 20.6
.+-. 0.8 Ex. 3C 1.35 .+-. 0.01 1.59 .+-. 0.01 2.97 .+-. 0.04 3.14
.+-. 0.08 68.3 .+-. 7.8 52.5 .+-. 4.9 18.1 .+-. 2.1 Ex. 3D 1.81
.+-. 0.05 2.04 .+-. 0.05 4.63 .+-. 0.01 5.27 .+-. 0.07 75.2 .+-.
4.6 43.0 .+-. 5.2 24.9 .+-. 0.9 Ex. 3E 0.93 .+-. 0.01 1.23 .+-.
0.04 3.14 .+-. 0.09 3.93 .+-. 0.40 84.9 .+-. 5.3 66.4 .+-. 3.6 15.6
.+-. 1.9
[0144] Aerodynamic fine particle assessment was done as described
in Example 2. Results are shown in Table 10. For all formulation
the FPF was calculated to be up to 40% and even up to 60% for the
Examples 3B and 3E. In other words, more than 40% of loaded
formulations into the device would be deposited in the potential
deposition site of inhaled fungal spores after emission from the
device. Deposition pattern are exposed in FIG. 7.
[0145] Dissolution tests were conducted in the conditions described
in Example 1. Every formulations presented different and faster
dissolution rate than amorphous spray dried itraconazole (Example
3F) and crystalline bulk ITZ (FIG. 8). As shown in FIG. 9, all
dissolution rates of ITZ according to the present invention, 3A to
3E, are at least 5% within 10 minute, 10% within 20 minutes and 40%
within 60 minutes when tested in the dissolution apparatus type 2
of the United States Pharmacopoeia at 50 rotation per minute,
37.degree. C. in 9000 milliliters of an aqueous dissolution medium
adjusted at pH 1.2 and containing 0.3% of sodium laurylsulfate,
namely these dissolution rates are found in the upper area of the
curve A which defines the dissolution rate of 5% within 10 minute,
10% within 20 minutes and 40% within 60 minutes. As shown in FIG.
10, the dissolution rates of ITZ according to 3A to 3E are also
included in an area between curves B and B', which defines the
dissolution rate of 5% within 5 minute, 10% within 10 minute, 15%
within 20 minutes and 40% within 60 minutes, and the one of 50%
within 5 minute, 60% within 10 minute, 90% within 20 minutes and
100% within 60 minutes, respectively, when tested in the
dissolution apparatus type 2 of the United States Pharmacopoeia at
50 rotation per minute, 37.degree. C. in 9000 milliliters of an
aqueous dissolution medium adjusted at pH 1.2 and containing 0.3%
of sodium laurylsulfate.
[0146] The addition of phospholipids induced an acceleration of the
dissolution rate of itraconazole, i.e., >20% of the dissolution
ratio at 5 min, >35% at 10 min, >60% at 20 min, >90% at 60
min. Result are shown in Table 11.
TABLE-US-00011 TABLE 11 Dissolution rate of ITZ Dissolution rate of
ITZ (%) Formulation 5 min 10 min 20 min 60 min Example 3A (INV) 7.9
11.4 15.2 46.7 Example 3B (INV) 8.1 11.7 16.8 47.3 Example 3C (INV)
6.8 12.7 34.1 98 Example 3D (INV) 24.7 37.2 64.6 96.4 Example 3E
(INV) 19.8 36.7 68.3 96.9
[0147] Increasing quantity of incorporated phospholipids in the
formulation induced acceleration of API's dissolution rate. Indeed,
as an example, Example 3C contained 1% (w/w) of phospholipids
(expressed by weight of itraconazole) whereas Example 3D contained
10% (w/w). Formulation 3E containing also 10% (w/w) of
phospholipids expressed by weigh of itraconazole exhibited a
similar dissolution profile than Example 3D, which also contained
10% (w/w) of phospholipids. Although the total amount of
phospholipids in the final dry form was much lower for Example 3E
(0.99% for Example 3E) this formulation did not show a different
dissolution profile than Example 3D which contained a higher total
quantity of phospholipids in the final dry form (3.47%).
[0148] This indicates that, when evaluated in those conditions, the
itraconazole/phospholipids ratio seemed to be the key factor for
the API dissolution rate enhancement. It is therefore possible to
make vary, to modulate dissolution velocity within this range by
varying this ratio. This could be an advantage in vivo to offer
different possibility of drug intrapulmonary pharmacokinetic.
[0149] Regarding this it is possible to produce a formulation,
possessing high fine particle fraction, with a faster dissolution
rate than bulk material. But it is also possible to
control/modulate this acceleration by varying the quantity of
incorporated surfactant.
Example 4
[0150] The purpose of this example was to show the ability of the
invention to produce matricial dry powders with high fine particle
fractions, improved wettability, different dissolution profile and
good flow properties using high potentially healthy safe
hydrophobic matrix forming agents.
[0151] The formulation was prepared at laboratory scale by
spray-drying using a Buchi Mini Spray Dryer B-191a (Buchi
laboratory-Techniques, Switzerland). A determined quantity of
itraconazole, cholesterol and hydrogenated soy-lecithin with more
than 90% of hydrogenated phosphatidylcholine (Phosphohpon 90H) (see
Table 12) were dissolved in 100 ml of isopropanol heated at
70.degree. c. under magnetic stirring (600 rpm). The solution was
spray-dried in the following conditions: spraying air flow, 800 l/h
heated at 50.degree. C.; drying air flow, 35 m.sup.3/h; solution
feed rate, 2.7 g/min; nozzle size, 0.5 mm; Inlet temperature,
70.degree. C.; resulting outlet temperature, 45.degree. C.
TABLE-US-00012 TABLE 12 Composition of the spray-dried solutions in
Example 4 Liquid composition Composition (g/100 ml) Example 4
Itraconazole 0.525 g (INV) Cholesterol 1.5 g Phospholipon 90H
0.0525 g
[0152] CI value was estimated, as described in Example 1, at 18.9%
indicating good powder flowability.
[0153] Particle size measurement (Table 13) analysis showed that
formulation 4 presented a volume median particle diameter of about
1.1 .mu.m with the Mastersizer 2000.RTM. and 2.9 .mu.m with the
Spraytec.RTM.. Some agglomerates seemed to be present in the
formulation with higher d(0.9) values. They were probably formed by
a certain softening of the phospholipid during the spray drying
process due to outlet temperature close of its glass
transition.
TABLE-US-00013 TABLE 13 Size distribution parameters measured by
laser diffraction methods for the formulation of Example 4
Mastersizer Sirocco 2000 .RTM. Malvern Spraytec .RTM. Formulation
d(0.5) d(0.9) d(0.5) d(0.9) N = 3 (.mu.m) (.mu.m) (.mu.m) .mu.m
Example 4 1.13 .+-. 0.03 7.20 .+-. 1.57 2.94 .+-. 0.07 9.35 .+-.
0.19
[0154] This presence of agglomerates influenced particles
deposition evaluated during aerodynamic assessment of fine
particles test realized as described in Example 1. However, 44% of
the loaded dose for Example 4 reached the three lower stages of the
impactor (table 14).
TABLE-US-00014 TABLE 14 Particle deposition in mg (mean .+-. SD)
and FPF obtained during impaction test (MSLI, 100 l/min, 2.4 sec, 3
discharges per test, nominal dose weighted at 2.5 mg, n = 3).
Example 4 Device (mg) 0.73 .+-. 0.05 Throat (mg) 0.15 .+-. 0.03
Stage 1 (mg) 0.26 .+-. 0.14 Stage 2 (mg) 0.17 .+-. .08 Stage 3 (mg)
0.31 .+-. 0.03 Stage 4 (mg) 0.50 .+-. 0.05 Stage 5 (mg) 0.28 .+-.
0.03 Mean FPD (mg) 1.1 .+-. 0.1 Mean FPF (%) 44 .+-. 4
[0155] Dissolution test were performed as described in Example 1
but the dissolution media was constituted of deionized water set at
pH 1.2 (HCl 0.063N) containing 1% of sodium lauryl sulfate (FIG.
11). Formulation 4 presented a faster dissolution rate than
crystalline micronized bulk itraconazole.
[0156] The use of a hydrophobic GRAS matrix former directly
modified the release profile of the dispersed API while providing
good aerodynamic characteristics and flow properties.
Example 5
[0157] The purpose of this example is to show the influence of
API's physical state (amorphous Vs crystalline nanoparticles) in
the formulation. Two formulations presenting the same quantitative
composition were produced and characterized. However the API was in
a different physical state in each formulation.
[0158] The formulations 5A and 5B were obtained by spray drying a
solution or a nanosuspension, respectively, using a Buchi Mini
Spray Dryer B-191a (Buchi laboratory-Techniques, Switzerland).
[0159] For Example 5A the dry powder was produced by spray drying a
feed stock solution of both excipient and API. 0.10 g of
itraconazole, 0.9 g of mannitol and 0.01 g of TPGS 1000 were
dissolved in 100 ml of an hydro-alcoholic solution (20 water:80
isopropanol) heated at 70.degree. C. under magnetic stirring (600
rpm). This solution was spray-dried in the following conditions:
spraying air flow, 800 l/h; drying air flow, 35 m.sup.3/h; solution
feed rate, 2.7 g/min; nozzle size, 0.5 mm; Inlet temperature,
90.degree. C.; resulting outlet temperature of 53.degree. C.
[0160] For Example 5B the dry powder was produced by spray drying a
feed stock solution of excipients in which was re-suspended a
determined volume of API nanosuspension added prior spray drying.
This procedure was composed of two steps. The first one consisted
in size reduction of a micronized API suspension to a nanosize
range suspension. The second one consisted to re-suspend a
determined quantity of the produced nanoparticles in a feed stock
solution containing the matricial agent in order to spray-dry
it.
[0161] The nanosuspension was prepared as following. In 75 ml of a
hydro-alcoholic solution (isopropanol 25:water 50) 75 mg of TPGS
1000 were dissolved under magnetic stirring (600 rp). 750 mg of
micronized itraconazole were suspended in this solution using a CAT
high speed homogenizer X620 (HSH) (CAT M. Zipperer, Staufen,
Germany) at 24,000 rpm during 5 min. The suspension was then
circulated in a high pressure homogenizer EmulsiFlex C5 (Avestin
Inc., Ottawa, Canada) at 24000 PSI until the particles presented a
d(0.5) under 300 nm and a d(0.9) under 2.5 .mu.m. Particle size
distribution analysis of the homogenized suspension was done by
laser diffraction with a wet sampling system (Mastersizer, Hydro
2000, Malvern instruments, UK). For measurements samples were
dispersed in deionized water saturated in itraconazole containing
2% of poloxamer 407 to avoid particle dissolution and aggregation.
A refractive index of 1.61 and an absorption index of 0.01 were
used for measurements. The high pressure homogenization was done
using a heat exchanger, placed ahead of the homogenizing valve to
maintain sample temperature below 10.degree. C. 270 ml of a
hydro-alcoholic solution composed of 200 ml of isopropanol and 70
ml of water, wherein 2.7 g of mannitol was dissolved under magnetic
stirring, was prepared. This solution was kept in an ice bath and
30 ml of the produced nanosuspension was added under magnetic
stirring (200 rpm). This final suspension was spray-dried. The
following conditions were used during spray-drying: spraying air
flow, 800 l/h; drying air flow, 35 m.sup.3/h; solution feed rate,
2.7 g/min; nozzle size, 0.5 mm; Inlet temperature, 80.degree. C.;
resulting outlet temperature, 45.degree. C.
[0162] The composition of final dry products is shown in Table
15.
TABLE-US-00015 TABLE 15 Quantitative composition of final dry
products of Example 5 Quantitative composition Formulation of the
dry product Example 5A Itraconazole 9.9% (INV) Mannitol 89.1% TPGS
1000 0.9% Example 5B Itraconazole 9.9% (INV) Mannitol 89.1% TPGS
1000 0.9%
[0163] Particle size distribution measurement of the prepared
nanosuspension was done. The suspension presented a d(0.5) and a
d(0.9) of 0.257+/-0.005 .mu.m and 1.784+/-0.010 .mu.m,
respectively. The two dry sample presented good powder flowability.
Carr's index values were 19.9% and 24.7% for Examples 5A and 5B,
respectively.
[0164] PDRX analysis showed that for formulation 5A no
characteristics diffraction's peak of crystalline itraconazole were
present while the diffractogram of Example 5B exhibited it clearly.
Itraconazole was then present in formulation 5A in an amorphous
state while it was in a nano-crystalline state in formulation
5B.
[0165] Malvern Sirocco.RTM. particle size analysis revealed very
close size distributions values for both formulations. Results are
shown in Table 16. In contrast with those results, Spraytec
measurement revealed that after discharge from an inhaler device
formulation 5B exhibited a totally different size distribution
profile (see in Tables 16). Indeed, the presence of severe
agglomerates was observed graphically and traduced by a severe
increase of the d(0.9) value to 64.50.+-.19.9 .mu.m.
TABLE-US-00016 TABLE 16 Size distributions parameters measured by
laser diffraction with a Malvern Sirocco .RTM. and Spraytec .RTM.
for the formulation of Example 5 Mastersizer Sirocco 2000 .RTM.
Malvern Spraytec .RTM. Formulation d(0.5) d(0.9) d(0.5) d(0.9) N =
3 (.mu.m) (.mu.m) (.mu.m) (.mu.m) Example 1.60 .+-. 0.14 3.59 .+-.
0.25 4.33 .+-. 0.63 9.12 .+-. 0.74 5A (INV) Example 1.72 .+-. 0.07
3.61 .+-. 0.15 6.30 .+-. 1.1 64.50 .+-. 19.9 5B (INV)
[0166] Formulation 5B seemed to present lower deagglomeration
efficiency than formulation 5A in simulated breath condition.
However, despite this presence of severe agglomerates formulation
5B presented the higher fine particle fraction determined as
described in Example 1 (see Table 17).
TABLE-US-00017 TABLE 17 Particle deposition in mg (mean .+-. SD)
and fine particle fraction expressed in % of nominal dose (FPF)
obtained during impaction test (MSLI, 100 l/min, 2.4 sec, 3
discharges per test, nominal dose weighted at 2.5 mg, n = 3)
Example 5A Example 5B Device (mg) 0.27 .+-. 0.01 0.44 .+-. 0.02
Throat (mg) 0.49 .+-. 0.02 0.28 .+-. 0.01 Stage 1 (mg) 0.24 .+-.
0.01 0.13 .+-. 0.03 Stage 2 (mg) 0.37 .+-. 0.01 0.25 .+-. 0.04
Stage 3 (mg) 0.62 .+-. 0.01 0.68 .+-. 0.03 Stage 4 (mg) 0.31 .+-.
0.0 0.47 .+-. 0.02 Stage 5 (mg) 0.04 .+-. 0.0 0.08 .+-. 0.0 Mean
FPD (mg) 0.95 +/- 0.1 1.19 +/- 0.03 Mean FPF (%) 38 +/- 4 48 +/-
1.2
[0167] Dissolution tests were conducted using the method described
in Example 1. The two formulations presented different dissolution
rates. Formulation 5B exhibited a faster dissolution rate than
formulation 5A but the two formulations presented faster
dissolution rate than bulk itraconazole.
Example 6
[0168] The invention can also consist in a blend of crystalline
nanoparticles matricial formulation and the amorphous matricial
formulations to vary the dissolution profile of the active
ingredient in the desire range. The blend can be realized before or
during capsule filling. The burst effect that would be provided by
the nanoparticles will induce a determined concentration of ITZ
that could be enhanced at a desired velocity by dissolution of the
amorphous matricial formulation for which the dissolution rate
could be optimized. The proportion of matrixial nanoparticle
formulation in the final blend will determine to which extend the
burst effect (rapid initial dissolution of the drug) would be
pronounced.
* * * * *