U.S. patent application number 14/631999 was filed with the patent office on 2015-07-23 for dry powder pharmaceutical composition, its preparation process and stable aqueous suspension obtained from such composition.
The applicant listed for this patent is ERATECH S.R.L.. Invention is credited to Mariella Artusi, Giovanni Caponetti, Loretta Maggi, Paolo Corvi Mora.
Application Number | 20150202156 14/631999 |
Document ID | / |
Family ID | 34956435 |
Filed Date | 2015-07-23 |
United States Patent
Application |
20150202156 |
Kind Code |
A1 |
Caponetti; Giovanni ; et
al. |
July 23, 2015 |
DRY POWDER PHARMACEUTICAL COMPOSITION, ITS PREPARATION PROCESS AND
STABLE AQUEOUS SUSPENSION OBTAINED FROM SUCH COMPOSITION
Abstract
Pharmaceutical composition in a dry powder form comprising at
least one hydrophobic active principle, at least one water-soluble
excipient and at least one surfactant, wherein the particles in
said dry powder state have a Volume Mean Diameter VMD.sub.d greater
than the Volume Mean Diameter VMD.sub.w of particles in a
suspension obtained from said pharmaceutical composition at
standard conditions of dispersion in a water-medium. It is also
disclosed a process to prepare such dry composition and an
extemporaneous suspension for inhalation therapy obtainable from
said dry composition.
Inventors: |
Caponetti; Giovanni;
(Piacenza, IT) ; Artusi; Mariella; (Parma, IT)
; Maggi; Loretta; (Piacenza, IT) ; Mora; Paolo
Corvi; (Piacenza, IT) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
ERATECH S.R.L. |
Milano |
|
IT |
|
|
Family ID: |
34956435 |
Appl. No.: |
14/631999 |
Filed: |
February 26, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13558566 |
Jul 26, 2012 |
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14631999 |
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11578661 |
Oct 18, 2006 |
8252334 |
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PCT/EP05/04277 |
Apr 21, 2005 |
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13558566 |
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Current U.S.
Class: |
424/489 ; 264/12;
514/174; 514/180; 514/182; 514/570 |
Current CPC
Class: |
A61K 9/14 20130101; A61K
31/58 20130101; A61K 9/0078 20130101; A61K 31/192 20130101; A61K
9/0075 20130101; A61K 31/573 20130101; A61K 9/145 20130101; A61K
9/143 20130101 |
International
Class: |
A61K 9/14 20060101
A61K009/14; A61K 31/573 20060101 A61K031/573; A61K 31/192 20060101
A61K031/192; A61K 31/58 20060101 A61K031/58 |
Foreign Application Data
Date |
Code |
Application Number |
Apr 23, 2004 |
IT |
MI2004 A 000795 |
Claims
1. Process for the preparation of a dry powder pharmaceutical
composition comprising at least one hydrophobic active principle,
at least one water-soluble excipient, and at least one surfactant,
in which the Volume Mean Diameter VMD.sub.d of the particles in
said solid dry composition is greater than the Volume Mean Diameter
VMD.sub.w of the particles in a suspension obtained from said
pharmaceutical composition at standard conditions of dispersion in
a water-medium, said process comprising the following steps: a)
preparing a first phase (A) which is a solution of said hydrophobic
active principle in an organic solvent; b) preparing a second phase
(B) in which one or more water-soluble excipients are dissolved in
an aqueous medium; c) dissolving the surfactants in either one of
phase (A) or phase (B); d) mixing said phases (A) and (B) to obtain
a phase (C) in which the liquid medium is homogeneous; e) drying
said phase (C) in order to obtain a dry powder with particle size
between 0.1 and 17.5 .mu.m; f) collecting said dry powder; wherein
said surfactant and active principle have a weight-to-weight ratio
in said particles comprised between 0.6 and 40.
2. Process according to claim 1, wherein said organic solvent is
miscible with water.
3. Process according to claim 2, wherein said organic solvent is an
alcohol.
4. Process according to claim 3, wherein said alcohol is ethyl
alcohol.
5. Process according to claim 1, wherein said step d) of drying
said phase (C) is a spray drying process.
6. Process according to claim 1, wherein said particle size,
expressed as VMD.sub.d, is comprised between 0.1 and 175 .mu.m.
Description
[0001] The present invention relates to a pharmaceutical
composition in the form of dry powder, to its preparation process,
to a stable aqueous suspension obtained from said pharmaceutical
composition and to a kit designed for an extemporaneous preparation
of said suspension.
[0002] A distinctive aspect of the invention is directed to a
pharmaceutical composition in the form of powder, granulate,
tablets or similar, capable of generating--through an
extemporaneous preparation--a fine suspension of a drug or active
principle, or particles containing said drug or active principle,
in an aqueous medium. Said fine suspension of the drug is intended,
preferably, but not exclusively, for an inhalation therapy.
BACKGROUND OF THE INVENTION
[0003] In case of an inhalation therapy, the particles of any drug
must be deposited in the deepest pulmonary region, where the most
important pharmacological actions occur. For this to happen, said
particles must be fine and such as to avoid a premature deposition
in the upper respiratory tract. It is indeed known that the
respiratory tract operates against aerosolized particles as a
filter, along which said particles are captured and deposited
according to their size. The particle size range useful for
inhalation, to achieve optimal deposition of the drug, usually lies
between 0.1 and 10 .mu.m, ideally between 0.5 and 5 .mu.m. It is
also reported that particles below 0.1 .mu.m can be exhaled by the
patient instead of being deposited in the deepest pulmonary
region.
[0004] The preparation of fine pharmaceutical suspensions, even if
widely common, can present some inherent difficulties that can
ultimately affect their physical stability. In particular, the
critical aspect influencing the physical stability of a fine
suspension is related to the formation at rest of a sediment of
drug which, due to the presence of surfactants and proper salts in
the medium, should allow for rapid dispersion of the sediment and
reconstitution of the original homogeneous suspension. A difficult
re-dispersion of this sediment in the suspension, however, can
cause the patient to withdraw an incorrect dosage of drug from the
container, either exceeding or lacking the correct one. FIG. 1
shows the dimensional distribution of a commercial inhalation
suspension, from which it is clear that the particles have a very
strong tendency to aggregate, leading to sediments of large size
aggregated particles and bi-modal size distributions. In the common
practice of fine suspensions preparations, such as inhalation
suspensions, the drug in a coarse dry powder state, is previously
micronized to reduce its particle size below 5 .mu.m. This
dimensional reduction, performed in the dry state, leads to an
initial aggregation of the drug particles. In order to break these
initial aggregates and to maintain primary drug particles
individually separated for the entire life of the product, the
preparation of the inhalatory suspension is normally carried out by
"wetting" the drug in advance with surfactants, suspending it in an
aqueous solution containing salts and using high-energy mixers to
mechanically break the aggregations of the drug particles. In such
case, the physical stability is theoretically assured by the
formation at rest of a weakly flocculated sediment that the patient
would re-suspend shaking the container before its use. However, the
formation of these weak floccules is not guaranteed, and the
majority of inhalation products in suspension show drug sediments
made of strongly aggregated particles that cannot be re-dispersed,
causing irregularities in the administered dosage.
[0005] A further difficulty in the preparation of pharmaceutical
suspensions relates to the chemical instability of certain drugs in
an aqueous medium, which remarkably limits the shelf-life of the
product. In these cases the drug is preferably administered, when
possible, in the powder form.
[0006] Another problem of pharmaceutical suspensions relates to the
control of microbial proliferation in inhalation products in
aqueous form. The simplest approach has been, until now, the use of
preservatives, which in some cases can lead to allergic reactions
in the patient and sometimes do not guarantee the preservation of
the product against certain microorganisms. The microbial
contamination of a pharmaceutical composition can be better
controlled by using a dry, powder form composition.
[0007] An example of the complexity of the preparation of
inhalation pharmaceutical suspensions--concerning both the process
and the required ingredients--is described in the U.S. Pat. No.
6,187,765. Moreover, FIG. 1 shows the size distribution of the
particles in a freshly prepared suspension, that appears to be
bi-modal, with a first peak around 1.2-1.3 .mu.m and a second peak
around 3 .mu.m. The suspension therefore does not consist of
homogeneous particles. As previously indicated, it is known that in
these types of suspensions the particles have the tendency to
aggregate over time and to originate multi-modal size
distributions, with proportionally significant fractions of large
size aggregates. The result is a reduction of the effective
administered drug dosage during the inhalation therapy.
[0008] U.S. Pat. No. 6,001,336 describes a method to prepare drugs
in powder form for inhalation therapy via spray drying of
suspensions of said drugs. Considering that the final goal of the
method is the production of fine powders for inhalation, lower than
5 .mu.m in diameter, the method is rather expensive and not so much
efficient. For example, the spray drying phase has to be performed
in a way to generate about 20 .mu.m drops and the collection and
separation of the dry particles can require different treatments
and the use of non-conventional equipments. Dry particles are
characterized by the absence of surfactant or the presence of a low
amount of surfactant compared to that of the drug, with a
weight-to-weight surfactant/drug ratio never greater than about
0.5.
[0009] An aspect of the invention is therefore to provide a dry
powder pharmaceutical composition that can be prepared using a
relatively simple method and is able to generate--by an
extemporaneous dispersion in an aqueous medium performed in mild
conditions--a stable pharmaceutical suspension in which the
dispersed drug or active ingredient particles have size such as to
optimize the actually administrable dosage.
[0010] This and other objects and advantages of the invention,
which will appear from the following description, are achieved by a
pharmaceutical composition in a dry powder form containing a
hydrophobic active principle, one or more water-soluble excipients,
and one or more surfactants, characterized by particles with a
Volume Mean Diameter (VMD.sub.d) greater than the Volume Mean
Diameter (VMD.sub.w) of particles of a suspension obtained from
said pharmaceutical composition in an aqueous medium under standard
conditions of dispersion.
[0011] Another aspect of the invention consists in a preparation
process of a dry powder pharmaceutical composition including a
hydrophobic active principle, one or more water-soluble excipients
and one or more surfactants, wherein the Volume Mean Diameter
(VMD.sub.d) of the particles of said dry solid composition is
greater than the Volume Mean Diameter (VMD.sub.w) of the particles
of a suspension obtained from said composition in aqueous--medium
under standard conditions of dispersion, said process including:
[0012] a) preparing a first phase (A) in which said hydrophobic
active principle is present in a suitable liquid medium; [0013] b)
preparing a second phase (B) in which one or more water-soluble
excipients are dissolved in an aqueous medium; [0014] c) dissolving
the surfactants in either one of phase (A) or phase (B) above,
depending on the surfactant preferential solubility; [0015] d)
mixing said phases (A) and (B) to obtain a phase (C) in which the
liquid medium is homogeneous; [0016] e) drying said phase (C) in
controlled conditions in order to obtain a dry powder with particle
size between 0.1 and 175 .mu.m; [0017] f) collecting said dry
powder and shaping it in a suitable form for an extemporaneous
preparation of a suspension.
[0018] Another aspect of the invention refers to a stable aqueous
suspension of particles comprising a hydrophobic active principle,
obtained by an extemporaneous dispersion of a dry powder
pharmaceutical composition in an aqueous medium, comprising a
hydrophobic active principle, at least one water-soluble excipient
and at least one surfactant, characterized by the fact that the.
Volume Mean Diameter (VMD.sub.w) of the particles in said
suspension is lower than the Volume Mean Diameter (VMD.sub.d) of
the particles of said dry powder composition, wherein said Volume
Mean Diameter (VMD.sub.w) is determined under standard conditions
of dispersion in an aqueous medium.
[0019] A further aspect of the invention consists of a kit
comprising a predetermined amount of the dry powder composition of
the invention and a known volume of an aqueous dispersing medium,
such as the contact of said composition and said dispersing medium
generates said stable aqueous suspension of said hydrophobic active
principle, ready to use.
BRIEF DESCRIPTION OF THE DRAWINGS
[0020] FIG. 1 shows the dimensional distribution of a commercial
inhalation suspension.
[0021] FIG. 2 is a graph showing particle size evaluated by light
scattering in humid state conditions plotted against time of
complete sedimentation evaluated with the Lumifuge centrifuge.
[0022] FIG. 3 shows the dry state (curve A) and wet state (curve B)
particle size distribution related to Example 4.
[0023] FIG. 4 shows the dry state (curve A) and wet state (curve B)
particle size distribution related to Example 6.
[0024] FIG. 5 shows the dry state (curve A) and wet state (curve B)
particle size distribution related to Example 8.
[0025] FIG. 6 shows the dry state (curve A) and wet state (curve B)
particle size distribution related to Example 17.
DETAILED DESCRIPTION OF THE INVENTION
[0026] The term "standard conditions of dispersion in aqueous
medium" means those conditions at which an amount of dry powder
composition, variable with respect to its active principle content,
is dispersed under stirring for 3 minutes in a Sucell SVA (Small
Volume Adapter) dispersion cell of a light scattering Sympatec
Oasis analyzer for humid state--analysis, such as to detect,
through the light scattering analyzer, an optimal light
obscuration. The analysis is conducted generally using a lens for
the dimensional range 0.10-35.0 .mu.m or if necessary a lens for
the range 0.5-175.0 .mu.m. Data are calculated and expressed on a
volume distribution basis.
[0027] The dry powder composition according to the invention
includes a drug or hydrophobic active principle, one or more
water-soluble excipients, one or more surfactants and possibly
other ingredients.
[0028] According to the invention, the term "drug or hydrophobic
active principle" is referred to any substance with a therapeutic
or biological activity which is insoluble or slightly soluble in
water. More in particular, the term hydrophobic is referred to
substances whose water-solubility is below 10 g/l, usually below 1
g/l and in some cases below 0.01 g/l. If possible, such drug or
hydrophobic active principle is soluble in organic solvents such as
ethanol or other low molecular weight aliphatic alcohols.
[0029] The active principle can include two or more substances in
the same form, for example one coating the other, or one dispersed
in a matrix of the other, or a mixture of two or more active
principles. Common examples of such formulations include active
drugs coated with excipients or encapsulated into them, or solid
dispersions of the active principles with excipients, with the
excipient present to modify the release velocity or to actuate the
"targeting" of the active principle.
[0030] Examples of pharmacological active principles that can be
administered by inhalation include: .beta..sub.2-agonists; steroids
such as glycocorticosteroids (preferably anti-inflammatory drugs);
anticholynergic drugs; leukotriene antagonists and agonists,
inhibitors of leukotriene synthesis; pain relievers in general such
as analgesic and antiinflammatory drugs (including steroids and
non-steroid anti-inflammatory drugs); cardiovascular drugs such as
glycosides; respiratory drugs; antiasthma agents; bronchodilators;
anticancer agents; alkaloids (e.g. ergot alkaloids) or triptans
such as sumatriptan or rizatriptan that can be used against
migraine; drugs (e.g. sulphonylurea) used against diabetes and
related dysfunctions; hypnotic and sedative drugs; general
anesthetics, psychic energizers; appetite inhibitors; antiarthritic
drugs; antimalaria drugs; antiepileptic drugs; antithrombotic
drugs; antihypertensive drugs; antiarrhythmia drugs; antioxidant
drugs; antidepressive drugs; antipsychotic drugs; anxiolytic drugs;
antiseizure drugs; antiemetic drugs; antiinfective drugs;
antihistaminic drugs; antifungus and antiviral drugs; drugs against
neurological dysfunctions such as anti-Parkinson drugs (dopamine
agonists); drugs against alcoholism and other addiction forms;
vasodilators used against erectile dysfunction; muscle relaxants;
muscle contractors; opioids; stimulant drugs; relaxant drugs;
antibiotics such as macrolides; aminoglycosides; quinolones and
.beta.-lactam drugs, vaccines; cytokines; growth factors, hormones,
including birth-control drugs; sympathomimetic drugs; diuretics;
lipid regulator agents; antiandrogen agents, antiparasitical drugs;
blood thinners; neoplastic drugs; antineoplastic drugs;
hypoglycemia drugs; nutrient and integrator agents; growth
integrators; antienteric agents; vaccines; antibodies, diagnostic
and radio-opaque agents; or mixtures of above mentioned substances
(e.g., combinations against asthma including steroids and .beta.
agonists), anesthetics and general anesthetic drugs.
[0031] Said active principles belong to one or more structural
classes, including, but not limited to, small molecules (preferably
small insoluble molecules), peptides, polypeptides, proteins,
polysaccharides, steroids, nucleotides, oligonucleotides,
polynucleotides, fats, electrolytes and similar substances.
[0032] Specific examples include .beta..sub.2 agonists salbutamol,
salmeterol (as salmeterol xinafoate or other form), formoterol (as
formoterol fumarate or other forms), fenoterol and isoproterenol,
steroids such as beclomethasone (as beclomethasone dipropionate or
other forms), budesonide, mometasone (as mometasone furoate or
other forms), fluticasone (as fluticasone propionate or other
forms), triamcinolone (as triamcinolone acetonide or other forms),
prednisone, prednisolone, methylprednisolone, betamethasone,
hydrocortisone, dexamethasone and cortisone. With respect to
peptides and proteins, the present invention includes the
synthetic, recombinant, native, glycosylated and non-glycosylated
ones and active biological fragments and similar substances.
[0033] Active principles for which an immediate release in the
blood stream in order to have a rapid pharmacological effect is
particularly beneficial include the ones used against migraine,
nausea, insomnia, allergic reactions (including anaphylactic
reactions), neurological and psychiatric disorders (in particular
panic attacks and other psychic or nervous disorders), erectile
dysfunction, diabetes and related diseases and cardiac diseases,
anti-seizures drugs, bronchodilators and pain relievers and
anti-inflammatory drugs.
[0034] Examples of such substances are steroids and their salts,
such as budesonide, testosterone, progesterone, flunisolide,
triamcinolone, beclomethasone, betamethasone, dexamethasone,
fluticasone, methylprednisolone, prednisone, hydrocortisone and
similar; peptides such as cyclosporine and other water-insoluble
peptides; retinoids such as cis--retinoic acid, 13-trans-retinoic
acid and other vitamin A and .beta.-carotene derivatives; vitamins
D, E and K and their water-insoluble precursors and derivatives;
prostaglandins, leukotriene and their activators and inhibitors,
included prostacyclin, prostaglandins E.sub.1 and E.sub.2,
tetrahydrocannabinol, pulmonary surfactant lipids, hydrophobic
antioxidants, hydrophobic antibiotics and chemotherapy drugs such
as amphotericin B, adriamycin and similar substances.
[0035] The water solubility of the soluble excipient or excipients
of the present invention is greater than 5 g/l and often greater
than 100 g/l or more. They are preferably chosen among sugars,
salts and aminoacids and have the twofold function to minimize the
effects of the inhaled composition on the cellular fluids balance,
and to stabilize the aqueous suspension obtained from the dry
composition. With respect to the composition in its dry powder
form, the excipient constitutes also the solid matrix in which the
drug or active principle is dispersed. Examples of soluble
excipients used in the composition according to the invention are:
alitame, acesulfame potassium, aspartame, sodium saccharin, sodium
cyclamate, sucralose, trehalose, xylitol, citric acid, tartaric
acid, natural or synthetic aminoacids, peptides and proteins,
cyclodextrins, dextrins, hydroxyethylcellulose, gelatin, malic
acid, maltitol, maltodextrins, maltose, polydextrose, tartaric
acid, sodium or potassium bicarbonate, sodium or potassium
chloride, phospholipids, lactose, saccharose, glucose, fructose,
mannitol, sorbitol.
[0036] Among the favorite soluble excipients are alkaline metals
salts such as sodium chloride or potassium chloride, and sugars
such as lactose.
[0037] The surfactant of the pharmaceutical composition according
to the invention may be chosen among different classes of
pharmaceutical use surfactants.
[0038] Among those substances which may be considered usable
surfactants of this invention are all those substances
characterized by having a medium-to-low molecular weight and
containing a hydrophobic portion, which is usually readily soluble
in an organic solvent but weakly soluble or completely insoluble in
water, and a hydrophilic (or polar) portion, which is weakly
soluble or completely insoluble in an organic solvent but readily
soluble in water.
[0039] Surfactants are classified based on their polar portion.
Therefore surfactants with a negatively charged polar portion are
called anionic surfactants while cationic surfactants have a
positively charged polar portion. Non-charged surfactants are
generally called non-ionic surfactants while surfactants with both
negatively and positively charged groups are called
zwitterions.
[0040] Examples of anionic surfactants are the salts of fatty acids
(better known as soaps), sulphates, sulphate ethers and phosphate
esters. Cationic surfactants are frequently based on polar groups
containing amine groups. The most common non-ionic surfactants are
based on polar groups containing oligo-(ethylene-oxide) groups.
Zwitterions are usually characterized by a polar group consisting
of a quaternary amine and a sulphoric or carboxylic group.
[0041] Examples of invention surfactants belonging to the class
above are: benzalkonium chloride, cetrimide, sodium docusate,
glyceryl monooleate, sorbitan esters, sodium lauryl sulphate,
polysorbates, phospholipids, biliary salts.
[0042] Surfactants belonging to the family of lecithins are widely
used in the food, cosmetic and pharmaceutical industry to improve
dispersibility and wettability of poorly soluble compounds. The
designation "lecithin" is used for natural mixtures of various
phospholipids and their accompanying substances. Lecithins are
generally derived from Egg or Soybean eventually leading to
lecithins with different compositions. Preferred lecithins for the
present inventions are those derived from egg and commercially
known as Lipoid E PC-3 as they are characterized by approximately
99% of saturated phosphocholines with palmitic acid content of 34%
and stearic acid content of 57%. Also synthetic phospholipids or
mixtures of phospholipids can be used in the composition of the
invention, in particular those belonging to the families of
phosphatidyl choline, phopshatidyl glycerol, phosphatidic acid and
phosphatidyl ethanolamine.
[0043] Non-ionic surfactants such as polysorbates and
polyoxyethylene and polyoxypropylene block copolymers, known as
"Poloxamers", are preferred. Among the Poloxamer family of
surfactants the commercially known "Pluronic F68", a poloxamer with
average molecular weight of 8400, is preferred. Polysorbates are
described in the CTFA International Cosmetic Ingredient Dictionary
as mixtures of sorbitol fatty acids and esters and sorbitol
anhydride condensed with ethylene oxide, known as "Span".
Particularly preferred are non-ionic surfactants of the series
known as "Tween", more particularly the surfactant known as "Tween
80", a polyoxyethylene sorbitan monooleate available on the
market.
[0044] The pharmaceutical composition according to the invention
may include other components, such as pH buffers and preservatives,
but said components are usually not necessary because the
composition is stored in dry powder state and the related aqueous
suspension is prepared extemporaneously before use.
[0045] The term "dry powder composition" refers to a powder,
granules, tablet or any other solid state composition with such
humidity content to assure a chemically stable composition. More in
particular, the term "dry" refers to a solid composition containing
less than 10% water (w/w), usually less than 5% and if possible
less than 3% (w/w).
[0046] The amount of surfactant in the dry powder composition of
the invention may vary in a wide range. Usually, the
surfactant/active principle weigh-to-weight ratio ranges between
0.1 and 100, preferably between 0.3 and 80, more preferably 0.6 and
40.
[0047] The particle size in the dry powder composition of the
invention ranges between 0.1 and 175 .mu.m, preferably between 0.5
and 30 .mu.m, and more preferably between 1 and 10 .mu.m, expressed
as volume mean diameter VMD.
[0048] Preferably the size distribution of the particles in the dry
powder composition is concentrated around one peak, which means it
is substantially mono-modal.
[0049] The preparation process of the dry powder composition
according to the invention comprises the following steps: [0050] a)
preparing a first phase (A) in which said hydrophobic active
principle is present in a suitable liquid medium; [0051] b)
preparing a second phase (B) in which one or more water-soluble
excipients are dissolved in an aqueous medium; [0052] c) dissolving
the surfactants in either one of phase (A) or phase (B) above,
depending on the surfactant preferential solubility; [0053] d)
mixing said phases (A) and (B) to obtain a phase (C) in which the
liquid medium is homogeneous; [0054] e) drying said phase (C) in
controlled conditions in order to obtain a dry powder with particle
size between 0.1 and 175 .mu.m; [0055] f) collecting said dry
powder and shaping it in a suitable form for an extemporaneous.
[0056] Phase (A) can be a suspension of the hydrophobic active
principle in an aqueous or non-aqueous medium or a solution of the
hydrophobic active principle in a suitable non-aggressive organic
solvent.
[0057] The preparation of a solution is preferred, and the organic
solvent is chosen among those miscible with water. In this case,
also phase (C) is a solution of all components of the desired
composition.
[0058] When instead phase (A) is a suspension of the hydrophobic
active principle in an aqueous medium, phase (C) too is a
suspension in an aqueous medium, and will contain the soluble
components, such as excipients and surfactants. Step e) consists of
removing the solvent or dispersing liquid medium from phase (C), in
order to obtain a dry powder with desired particle size. This
removal of solvent or dispersing medium is preferably obtained by
spray drying. The nozzle features and the operation parameters are
chosen in order to evaporate the liquid medium from the solution or
suspension (C) and to obtain a powder with desired properties. If
possible, said particle size, expressed as VMD, ranges between 0.1
and 175 .mu.m.
[0059] Preferably the size distribution of the particles is
substantially mono-modal.
[0060] The obtained powder is partitioned as it is in tablets or
other suitable form. The relatively large particle size of the dry
composition according to the invention is particularly beneficial
for various reasons. As already indicated, larger particles have a
lower tendency to aggregate compared to fine ones. Moreover, the
spray drying process yield could be greater than the one achieved
with commercially known processes used to manufacture fine dry
inhalation powders. Also, the collection and manipulation of such
powder is improved.
[0061] The above described dry powder pharmaceutical composition is
intended for preparing a stable extemporaneous suspension of the
hydrophobic drug or active principle in a proper volume of
dispersing fluid, preferably water or physiological solution.
[0062] As already indicated, an extemporaneous preparation of a
suspension is one performed at the time of use, which is right
before the administration of the drug to the patient. In the
present description, the term "extemporaneous preparation" also
includes a preparation done by a pharmacist or other healthcare
practitioner and administered to a patient in a relatively short
period of time after the preparation. More in general, an
extemporaneous preparation is considered a suspension not directly
prepared by the pharmaceutical industry and put on the market to be
used as it is, but prepared at a time following the preparation of
the dry powder composition, usually at a time close to the
administration to the patient.
[0063] The suspension according to the invention can be
administered to a patient in various ways. Though the suspension is
particularly suitable for an inhalation administration, it can also
be administered in other parenteral (i.e. non-enteral or non-oral)
or oral way.
[0064] According to an aspect of the present invention, the Volume
Mean Diameter (VMD.sub.w) of the powder particles in the suspension
is lower than the Volume Mean Diameter (VMD.sub.d) of the particles
in the dry powder composition. It is to be considered that the
lower diameter of the particles in suspension is just partially due
to the solubilization of the excipients and surfactant in the
aqueous medium. It was indeed surprisingly found that the
solubilization effect alone is not sufficient to explain this
characteristic feature of the invention, since soluble excipients
are also present in powder formulations where the VMD.sub.d is
greater than the VMD.sub.w, as shown in examples that will
follow.
[0065] Such feature, expressed by the relationship
VMD.sub.w<VMD.sub.d, shows three benefits: a) to provide an
easier manipulation of the dry composition, since it can be
prepared with larger particle size than the one required for an
optimal administration, to eliminate or reduce the typical problems
related to fine powders, b) to provide a stable suspension, c) to
optimize the actual administrable drug dosage in an inhalation
therapy.
[0066] According to another aspect of the invention, extemporaneous
suspensions prepared from a dry powder composition according to the
invention, are very stable.
[0067] It is known from the literature that a suspension is
considered stable if rapid phase separations due to sedimentation
do not occur when the density of the particle is greater than the
one of the dispersing liquid medium. Therefore the suspension
stability is referred to the tendency that said suspension shows to
act against the formation of large particle aggregates which
separate from the medium. Said stability of the suspension was
studied to assess the sedimentation tendency using a Lum GmbH
Lumifuge centrifuge working at 300 rpm. Said instrument is able to
measure the variation of transmittance of an opaque suspension
under centrifugation against time. The variation of the
transmittance over time was therefore used to evaluate the tendency
to sediment of the suspension. The effect of the centrifugation
accelerates the sedimentation, allowing for a rapid evaluation of
the physical stability of the suspension. The effect of a 300 rpm
centrifugation corresponds indeed to a 12-times increase of the
gravity acceleration impressed on the sample. Said gravity increase
has been considered useful to accelerate sedimentation in
pharmaceutical suspensions in such a way that the acceleration
impressed on the sample would not alter the physico-chemical
interactions between the particles and the dispersing medium.
[0068] Through the Lumifuge centrifuge, the transmittance of a 2 ml
suspension sample in a test tube is measured in several spots of
said tube along a definite length of the portion of tube where the
liquid is confined by the centrifugation action. Said measurements
help drawing the transmittance profile of the sample, which is then
integrated in order to calculate the % transmittance of the sample.
The values of % transmittance, recorded every 10 seconds, are
plotted against time. It is therefore possible to draw a
transmittance profile, typically a straight line, indicating the
variation of the % transmittance over time. The slope of said
transmittance profile describes the sedimentation velocity of the
tested sample, since the transmittance of a sample is a function of
the presence of particles in suspension.
[0069] In case of samples that do not reach complete sedimentation
(100% transmittance) during the measurement time, the slope is
calculated using every available data. The value of sedimentation
velocity (K) is used to calculate the time of complete
sedimentation (100% of transmittance) of the tested sample through
the following equation:
T 100 = ( 100 K ) 6 ##EQU00001##
[0070] where:
[0071] T.sub.100=time of complete sedimentation
[0072] K=slope of the transmittance line
[0073] According to another aspect of the invention, the time of
complete sedimentation of extemporaneous suspensions according to
the invention, calculated with the above described method, is
greater than 40 minutes, preferably greater than 60 minutes, more
preferably greater than 100 minutes.
[0074] Referring to the extemporaneous suspensions prepared
according to the invention, it was moreover surprisingly found that
the behavior of the particles in suspension is distinctive of
particles with a lower diameter compared to the actually measured
one and expressed as VMD.sub.w. The diameter evaluated based on
particles in suspension was called Theoretical Mean Diameter TMD.
It is evaluated using the following described method.
[0075] Sedimentation of a spherical particle in a liquid medium is
essentially driven by the Stokes Equation, here reported in a form
that shows sedimentation time:
.tau. = 9 .alpha. .eta. 2 gr 2 ( .rho. s - .rho. l )
##EQU00002##
[0076] where:
[0077] .tau.=sedimentation time (minutes)
[0078] .alpha.=sedimentation deepness (mm)
[0079] .eta.=dynamic viscosity of the medium (mPas)
[0080] g=acceleration gravity (9.81 m/s.sup.2)
[0081] r=solid particles radius
[0082] .rho..sub.s=solid particle density (g/cm.sup.3)
[0083] .rho..sub.l=liquid medium density (g/cm.sup.3)
[0084] Such equation is minimally modified in case sedimentation
occurs due to centrifugation. In this case, in fact, the gravity
force is substituted by .omega..sup.2, the square of the angular
speed, and r.sub.0, the radius of the centrifuge. The equation
becomes:
.tau. = 9 .alpha. .eta. 2 .omega. 2 r 0 r 2 ( .rho. s - .rho. l )
##EQU00003##
[0085] Using the equation above it is possible to compare, through
the time of complete sedimentation, different suspensions, by
preparing the samples in a way such as to reproduce the same
operative conditions in terms of liquid viscosity and
centrifugation parameters. In these operative conditions it is
possible to compare the behavior of particles of the same material
but different size, using the following equation:
.tau..sub.refr.sub.ref.sup.2=.tau.r.sup.2
[0086] where
[0087] .tau..sub.ref=sedimentation time of the reference
[0088] r.sub.ref=mean radius of a reference particle
[0089] .tau.=sedimentation time of the unknown sample
[0090] r=mean radius of an unknown particle sample
[0091] Such equation has been set up to compare the sedimentation
time evaluated for suspensions obtained from dry powder
compositions according to the invention, against the sedimentation
time of suspensions of each active principle, suspended in a
solution with the same final composition of the suspension of the
invention. Therefore starting from T.sub.ref (sedimentation time of
the standard suspension of each active principle), r.sub.ref (mean
radius of the standard particles of each active ingredient) and
.tau. (sedimentation time of the extemporaneous suspensions
prepared according to the invention), it is possible to calculate r
and from this it is possible to calculate TMD, which is 2r,
according to the formula:
TMD = 2 .tau. ref r ref 2 .tau. ##EQU00004##
[0092] Another aspect of the invention is therefore consisting of
the fact that extemporaneous suspensions prepared according to the
invention are characterized by a theoretical mean diameter TMD
lower than VMD.sub.w, that is TMD<VMD.sub.w, preferably
TMD.ltoreq.0.5 VMD.sub.w.
[0093] It is important to underline that some insoluble active
principles, when tested for reference sedimentation measurement by
dispersing them in the mixture of surfactant and soluble excipient
equivalent to the extemporaneous preparation, did not disperse at
all in the aqueous medium making impossible to measure their
sedimentation time. In this case it is indeed very clear the
benefit provided by the invention as it allows for the formation of
stable suspensions with these active principles.
[0094] The effect of the formation of stable suspensions, though
not completely clarified, could be due to a series of occurrences
which, during the extemporaneous dispersion of the dry powder in
the liquid medium, lead to the dissolution of the soluble
excipients and the formation of insoluble drug particles
characterized by having greater suspension stability.
[0095] In order to deeply investigate such occurrences, the diagram
reported in FIG. 2 2 has been drawn, in which the particle size
evaluated by light scattering in humid state conditions is plotted
against time of complete sedimentation evaluated with the Lumifuge
centrifuge.
[0096] The graph shows a direct relationship between the particle
size and the evaluated sedimentation time. The trend is hyperbolic,
with fine particles tending to high sedimentation times and coarse
particles for which the sedimentation time tends to be zero. The
graph also shows that a crystalline powder like budesonide with a
1.59 .mu.m, although dispersed in substantially the same liquid
medium and kept in dispersion by a surfactant, has a sedimentation
time much lower than that of a suspension of the invention with
particles of about the same size.
[0097] According to a preferential aspect of the invention, the
size distribution of the solid particles in the suspension
maintains the substantial mono-modality of the dry powder
composition precursor of the suspension, therefore avoiding the
undesired aggregation occurrences of the particles, typical of
known commercial pharmaceutical suspensions.
[0098] Another aspect of the invention consists of a kit of
products for the extemporaneous preparation of a stable aqueous
suspension of a hydrophobic active principle, comprising: [0099] a)
an effective amount of a dry pharmaceutical composition comprising
said hydrophobic active principle, at least one water soluble
excipient and at least one surfactant, as previously described;
[0100] b) a predetermined volume of a dispersing liquid medium;
wherein said products are filled in physically separated
containers, in order to be mixed extemporaneously to form a
suspension in which the Volume Mean Diameter VMD, of the particles
in suspension is lower than the Volume Mean Diameter VMD.sub.d of
the particles of said dry powder composition.
[0101] Preferably, the dispersing medium is water or a
physiological solution, and its contact with the dry powder
composition allows to prepare a suspension of the active principle
according to the invention ready to be administered.
[0102] The invention will now be illustrated referring to the
following examples, given as an illustrative but not limitative
basis.
EXAMPLES
Preparation of the Solid Dry Composition
[0103] A) Preparation Based on a Solution
Examples from 1 to 14 and Comparative Examples 1 to 6
[0104] The preparation of the composition was carried out by mixing
an aqueous solution of excipients with an organic solution of the
active principle and dissolving the surfactants in either one of
the two phases, according to the surfactant preferential
solubility. The two solutions were then mixed to form a final clear
solution. Said final solution was dried by spray drying using a
Labplant SD 06 spray dryer according to the operative conditions
indicated in table 1.
TABLE-US-00001 TABLE 1 Aqueous solution Organic solution Example
Phase (B) Phase (A) Operative conditions 1 Lactose 43.65 g
Budesonide 0.45 g Inlet temp. (.degree. C.) 120 Tween 80 0.9 g
Ethyl alcohol 90 ml Feed rate (ml/min) 3.0 Distilled water 210 ml
Nozzle (diameter) 0.5 2 Lactose 95.5 g Budesonide 0.5 g Inlet temp.
(.degree. C.) 120 Tween 80 4 g Ethyl alcohol 300 ml Feed rate
(ml/min) 3.0 Distilled water 700 ml Nozzle (diameter) 1.0 3 Lactose
49.25 g Budesonide 0.25 g Inlet temp. (.degree. C.) 120 Tween 80
0.5 g Ethyl alcohol 150 ml Feed rate (ml/min) 3.0 Distilled water
350 ml Nozzle (diameter) 1.0 4 Lactose 38.75 g Budesonide 0.25 g
Inlet temp. (.degree. C.) 120 Saccharose 10.0 g Ethyl alcohol 150
ml Feed rate (ml/min) 3.0 Tween 80 1.0 g Nozzle (diameter) 1.0
Distilled water 350 ml 5 Lactose 48.75 g Budesonide 0.25 g Inlet
temp. (.degree. C.) 120 Tween 80 1.0 g Ethyl alcohol 150 ml Feed
rate (ml/min) 3.0 Distilled water 350 ml Nozzle (diameter) 1.0 6
Lactose 32.5 g Budesonide 0.25 g Inlet temp. (.degree. C.) 120
Saccharose 16.25 g Ethyl alcohol 150 ml Feed rate (ml/min) 3.0
Tween 80 1.0 g Nozzle (diameter) 1.0 Distilled water 350 ml 7
Lactose 9.75 g Beclomethasone 0.05 g Inlet temp. (.degree. C.) 120
Tween 80 0.2 g dipropionate Feed rate (ml/min) 5.0 Distilled water
300 ml Ethyl alcohol 700 ml Nozzle (diameter) 1.0 8 Lactose 8.705 g
Beclomethasone 0.05 g Inlet temp. (.degree. C.) 120 NaCl 1.125 g
dipropionate Feed rate (ml/min) 5.0 Tween 20 0.1 g Ethyl alcohol
700 ml Nozzle (diameter) 1.0 Span 20 0.02 g Distilled water 300 ml
9 Lactose 22.375 g Budesonide 0.125 g Inlet temp. (.degree. C.) 130
Pluronic F68 2.5 g Ethyl Alcool 250 ml Feed rate (ml/min) 3.0
Distilled water 250 ml Nozzle (diameter) 0.5 10 Lactose 9.7 g
Ursodiol 0.1 g Inlet temp. (.degree. C.) 130 Tween 80 0.2 g Ethyl
alcool 250 ml Feed rate (ml/min) 3.0 Distilled water 250 ml Nozzle
(diameter) 0.5 11 Lactose 14.1 g Ketoprofen 0.45 g Inlet temp.
(.degree. C.) 130 Tween 80 0.45 g Ethyl alcool 250 ml Feed rate
(ml/min) 3.0 Distilled water 250 ml Nozzle (diameter) 0.5 12
Lactose 9.3 g Ketoprofen 0.3 g Inlet temp. (.degree. C.) 130
Pluronic F68 0.4 g Ethyl alcool 250 ml Feed rate (ml/min) 4.0
Distilled water 250 ml Nozzle (diameter) 2.0 13 Lactose 9.4 g
Ursodiol 0.2 g Inlet temp. (.degree. C.) 130 Pluronic F68 0.4 g
Ethyl alcool 250 ml Feed rate (ml/min) 3.0 Distilled water 250 ml
Nozzle (diameter) 2.0 14 Lactose 8.95 g Beclomethasone 0.05 g Inlet
temp. (.degree. C.) 130 Tween 20 0.1 g dipropionate Feed rate
(ml/min) 5.0 Distilled water 300 ml Lipoid E-PC3 0.9 g Nozzle
(diameter) 1.0 Ethyl alcool 700 ml Comp. 1 Lactose 3.45 g
Budesonide 0.375 g Inlet temp. (.degree. C.) 140 Benzalkonium 0.2 g
Ethyl alcohol 5 ml Feed rate (ml/min) 5.0 Chloride Nozzle
(diameter) 1.0 NaCl 3.45 g Distilled water 495 ml Comp. 2 Lactose
22.5 g Budesonide 0.45 g Inlet temp. (.degree. C.) 120 NaCl 22.05 g
Ethyl alcohol 90 ml Feed rate (ml/min) 3.0 Distilled water 210 ml
Nozzle (diameter) 0.5 Comp. 3 Lactose 24.75 g Budesonide 0.25 g
Inlet temp. (.degree. C.) 130 Distilled water 350 ml Ethyl alcohol
150 ml Feed rate (ml/min) 3.0 Nozzle (diameter) 0.5 Comp. 4 Lactose
9.95 g Beclomethasone 0.05 g Inlet temp. (.degree. C.) 130
Distilled water 300 ml dipropionate Feed rate (ml/min) 5.0 Ethyl
alcohol 700 ml nozzle (diameter) 1.0 Comp. 5 Lactose 9.9 g Ursodiol
0.1 g Inlet temp. (.degree. C.) 130 Distilled water 250 ml Ethyl
alcohol 250 ml Feed rate (ml/min) 3.0 nozzle (diameter) 0.5 Comp. 6
Lactose 14.55 g Ketoprofen 0.45 g Inlet temp. (.degree. C.) 130
Distilled water 250 ml Ethyl alcool 250 ml Feed rate (ml/min) 3.0
Nozzle (diameter) 0.5
[0105] B) Preparation Based on a Suspension
Examples from 15 to 17 and reference example 7
[0106] The suspension was been prepared by using a homogenizer and
by dispersing the micronized active principle in an aqueous
solution including surfactant and excipient according to the
amounts indicated in Table 2 in order to form a homogeneous aqueous
suspension.
[0107] The obtained suspension was dried using a Labplant SD 06
spray dryer according to the operative conditions indicated in
Table 2 and by keeping the suspension under continuous stirring
during the drying process.
TABLE-US-00002 TABLE 2 Aqueous suspension Example Phase (C)
Operative conditions 15 Lactose 20.0 g Inlet temp (.degree. C.) 120
Sodium Chloride 4.25 g Feed rate (ml/min) 3.0 Tween 80 0.1 g Nozzle
(diameter mm) 0.5 Budesonide 0.25 g Distilled water 500 ml 16
Lactose 72.75 g Inlet temp (.degree. C.) 120 Tween 80 1.5 g Feed
rate (ml/min) 3.0 Budesonide 0.75 g Nozzle (diameter mm) 0.5
Distilled water 500 ml 17 Lactose 37.5 g Inlet temp (.degree. C.)
120 Sodium Chloride 35.25 g Feed rate (ml/min) 3.0 Tween 80 1.5 g
Nozzle (diameter mm) 0.5 Budesonide 0.75 g Distilled water 500 ml
Comp. Sodium Chloride 8.42 g Inlet temp (.degree. C.) 120 7 Sodium
Citrate 0.5 g Feed rate (ml/min) 3.0 Citric acid 0.28 g Nozzle
(diameter mm) 0.5 Sodium EDTA 0.1 g Tween 80 0.2 g Budesonide 0.5 g
Distilled water 1000 ml
Dry State Particle Size Distribution
[0108] The obtained powder was characterized in terms of dry state
size distribution using a Sympatec Oasis light scattering
instrument equipped with a Rodos dry disperser working at a 3 bar
dispersing pressure and appropriate measuring lens able to analyze
over the dimensional range 0.10-35.0 .mu.m or alternatively
measuring lens for the dimensional range 0.5-175.0 .mu.m.
Determination of the Wet State Particle Size Distribution of the
Particls of the Extemporaneous Suspension
[0109] For the wet state particle size distribution an amount of
powder, variable in relation of the amount of active principle, was
dispersed in 50 ml of distilled water, corresponding to the
capacity of a light scattering Sympatec Oasis wet state analyzer
dispersion cell Sucell SVA (Small Volume Adapter), under stirring
for at least 3 minutes, such as to detect, through the light
scattering analyzer, an optimal stable light obscuration. The
analysis was conducted using a lens in the dimensional range
0.10-35.0 .mu.m or alternatively a lens in the dimensional range
0.5-175.0 .mu.m.
[0110] Characteristics of Dry Powder Compositions and of
Suspensions Prepared Extremporaneously
[0111] Table 3 shows some data referred to dry powders,
extemporaneous suspensions obtained from them, and also some
comparative example data. Data reported in the table have the
following meaning: [0112] The number of the example is that of
tables 1 and 2, except for comparative examples 8 and 9; [0113] The
composition in comparative example 9 is the following: NaCl 84.2 g;
Sodium citrate 5.0 g; citric acid 2.8 g; Sodium EDTA 1.0 g;
surfactant "Tween 80" 2.0 g; Budesonide 5.0 g. [0114] The column
"Surfactant ratio/Active principle" indicates the weight-to-weight
ratio of these two species of the composition; [0115] VMD.sub.d is
the diameter of the particles in the dry composition (powder);
[0116] VMD.sub.w is the diameter of the particles in the
extemporaneous suspension; [0117] VMD.sub.w/VMD.sub.d is the
diameters ratio in the wet state and dry state.
[0118] The time of complete clarification of the extemporaneous
suspension is calculated using the transmittance variation line, as
previously indicated.
TABLE-US-00003 TABLE 3 Time of complete Surfac- sedimen-
tant/active Dry Humid tation T.sub.100 principle state state
VMD.sub.w/ (min) @ Example ratio VMD.sub.d VMD.sub.w VMD.sub.d K
300 rpm PREPARATIONS BASED ON SOLUTIONS 1 2 5.3 3.52 0.66 0.1608
103.65 2 8 5.22 2.17 0.41 0.0178 936.3 3 2 5.03 2.56 0.51 0.0522
319.28 4 4 4.60 1.63 0.35 0.0114 1461.99 5 4 5.13 1.78 0.35 0.0212
786.16 6 4 4.87 1.63 0.33 0.0095 1754.4 7 4 4.88 3.39 0.69 0.0803
207.55 8 2.4 4.11 2.53 0.61 0.0253 658.76 9 20 6.02 2.03 0.34
0.1009 165.18 10 2 3.36 2.32 0.69 0.0169 986.19 11 1 6.74 4.38 0.65
0.1588 104.95 12 1.33 17.17 11.05 0.64 0.2199 75.79 13 2 24.58 5.25
0.21 0.1368 121.83 14 20 3.67 3.60 0.98 0.0288 578.7 PREPARATIONS
BASED ON SUSPENSIONS 15 0.4 4.51 2.32 0.51 0.2272 73.36 16 2 6.09
2.29 0.37 0.1798 92.69 17 2 5.99 2.01 0.33 0.2413 69.07 Comp. 7 0.4
2.82 5.63 1.99 0.4188 39.79 PREPARATIONS WITHOUT SURFACTANT OR WITH
AN INSUFFICIENT AMOUNT OF SURFACTANT Comp. 2 -- 4.81 5.28 1.09
2.5144 6.63 Comp. 1 0.53 3.70 8.55 2.31 0.6134 27.17 Comp. 3 --
3.21 9.62 3.00 0.2719 61.00 Comp. 4 -- 3.18 22.75 3.75 -- -- Comp.
5 -- 4.01 7.70 1.92 0.2273 73.32 Comp. 6 -- 5.05 9.81 1.94 -- --
SUSPENSIONS OF COMPARISON Comp. 8 -- 1.59 -- -- 0.264 63.0 Comp. 9
0.40 -- 3.67 NA 2.094 7.96
[0119] Comparative example 1 relates to a composition with the same
components and amounts of example B-44 of U.S. Pat. No. 6,001,336
to Inhale Therapeutic Systems. It appears from Table 3 that when a
suspension is made from said composition, the VMD.sub.w is greater
than the VMD.sub.d, differently from the compositions of the
invention.
[0120] Comparative examples 2 and 3 are examples of Budesonide
compositions without surfactant.
[0121] Comparative example 4 is an example of a Beclomethasone
dipropionate composition without surfactant.
[0122] Comparative example 5 is an example of a Ursodeoxycholic
Acid (Ursodiol) composition without surfactant
[0123] Comparative example 6 is an example of a Ketoprofen
composition without surfactant Comparative example 7 is an example
of a composition with surfactant and excipients but with a
VMD.sub.w/VMD.sub.d ratio >1.
[0124] Comparative example 8 is referred to a suspension of just
the active principle budesonide.
[0125] Comparative example 9 is referred to a composition similar
to the commercial suspension Pulmaxan.
[0126] As table 3 demonstrates, examples 1-17 according to the
invention refer to compositions which generate very stable
extemporaneous suspensions with times of complete sedimentation
greater than 60 minutes. Comparative examples 1,2,3,4,5,6,7 and 9,
instead, refer to less stable suspensions, that means with complete
sedimentation times firmly less than their corresponding
extemporaneous suspensions. A particular case is comparative
example 8, related to budesonide alone, not prepared using the
spray drying process of the invention but obtained just suspending
the active ingredient budesonide in a crystalline state. This is a
low particle size active principle (VMD.sub.d=1.59), therefore
liable to the previously described dry-state handling problems.
Where said suspensions are prepared by extemporaneous re-suspending
of powders obtained from solutions (examples Cl to C6) or
suspensions (example C7), Table 3 shows that they do not fulfil the
relation VMD.sub.w/VMD.sub.d<1.
Determinationof the Theoretical Mean Diameter of the Particles of
the Active Principle in an Extemporaneious Suspension
[0127] Using the previously described Stokes Equation which governs
the sedimentation of a spherical particle in a liquid medium, the
Theoretical Mean Diameter of the particles in the extemporaneous
suspensions of the examples 1-14 was evaluated, using as a
reference a suspension of micronized particles of the relevant
active principle suspended in a solution having the same final
composition of the corresponding suspension according to the
invention. The obtained results are shown in the following Table
4.
TABLE-US-00004 TABLE 4 VMD.sub.w .tau. VMD.sub.wref .tau..sub.ref
TMD/ Example (.mu.m) (min) (.mu.m) (min) TMD VMD.sub.w 1 3.52
103.65 1.97 86.27 1.80 0.51 2 2.17 936.30 2.03 150.83 0.81 0.38 3
2.56 319.28 1.97 111.56 1.16 0.45 4 1.63 1461.99 2.16 50.67 0.40
0.25 5 1.78 786.16 2.34 118.29 0.91 0.51 6 1.63 1754.40 2.09 57.0
0.38 0.23 7 3.39 207.55 7.65 32.73 3.04 0.90 8 2.53 658.76 5.56
94.86 2.11 0.83 9 2.03 165.18 2.53 59.25 1.52 0.75 10 2.32 986.19
NA* NA* -- -- 11 4.38 104.95 22.10 NA** -- -- 12 11.05 75.79 24.96
NA** -- -- 13 5.25 121.83 NA* NA* -- -- 14 3.60 578.7 NA* NA* -- --
16 2.29 92.69 1.97 86.27 1.90 0.82 *Drug particles could not be
dispersed efficiently in the liquid medium making impossible to
measure VMD.sub.wref and .tau..sub.ref for these preparations.
**Drug particles were too large and sedimented so fast that it was
impossible to measure .tau..sub.ref
[0128] Table 4 shows that all reported compositions, prepared by
spray drying, surprisingly behave in suspension as particles with a
lower diameter than the actually evaluated one and are consistent
with the relation TMD<VMD.sub.w
[0129] FIG. 1 shows the particles size and the particles size
distribution of a commercial suspension of beclomethasone
dipropionate, evaluated using an Oasis Sympatec Light Scattering
instrument equipped with a wet--state Sucell dispersion cell,
previously mentioned. Said suspension appears to be bi-modal, with
an important peak around 21 .mu.m. Therefore the majority of the
suspended particles have a size, expressed as VMD, greater than 5
.mu.m.
[0130] It is obvious that the actually administrable drug dose in
said suspensions, for an inhalation therapy, is heavily reduced due
to evident particle aggregation, and consequent sedimentation
phenomena.
[0131] FIGS. 3, 4, 5 and 6 show the dry state (curve A) and wet
state (curve B) particle size distribution related to examples 4,
6, 8 and 17, respectively. More in particular, in each figure curve
A shows the size distribution of the dry powder composition whose
diameter is VMD.sub.d, and curve B shows the size distribution of
the particles in suspension whose diameter is VMD.sub.w. It is
noticeable that particles in suspension are always very fine and
size distributions are always substantially mono-modal, that means
that the particle size is substantially distributed around one
peak.
[0132] Therefore, suspensions according to the invention are
stable, they do not lead to aggregation or sedimentation and may be
used to administer degradable drugs throughout prolonged contact
with water, due to their extemporaneous preparation. Moreover,
making available and putting on the market a dry powder composition
allows for a simplification of the sterilization process and
minimizing its microbial contamination, without necessarily using
preservatives, like it is instead necessary with non-extemporaneous
suspensions, stored for a long time.
[0133] Determination of the Aerosol Properties of Extemporaneous
Suspensions Delivered Out of a Nebulizer.
[0134] In order to evaluate the aerosol properties of
extemporaneous suspensions prepared from the dry pharmaceutical
compositions described, an Apparatus C--Multi Stage Liquid Impinger
(MSLI) as described in the European Pharmacopoeia was used.
[0135] The Multi Stage Liquid Impinger consists of 4 impaction
stages and an integral filter stage (stage 5). A standard induction
port was utilized with a suitable mouthpiece adapter to provide
airtight seal between the nebulizer and the induction port.
[0136] According to its directions for use, 20 ml of an appropriate
solvent mixture were introduced in each of stages 1 to 4.
[0137] The outlet of the Multi Stage Liquid Impinger was connected
to a suitable vacuum pump and the flow adjusted to 30.+-.1.5 litres
per minute in order to determine a lower cut-off aerodynamic
diameter corresponding to 9.62 .mu.m for stage 2, 4.38 .mu.m for
stage 3 and 2.40 .mu.m for stage 4.
[0138] The mouthpiece adapter was placed in position at the end of
the induction port so that the mouthpiece end of the nebulizer,
when inserted lined up along the horizontal axis of the induction
port and the nebulizer was positioned in the same orientation
intended for use.
[0139] The nebulizer utilized was the Clenny (marketed by Medel,
Italy) loaded with 2 ml of suspension to be tested.
[0140] The pump was then switched on for 10 sec. before activating
the nebulizer, aerosolizing for 5 consecutive minutes its content
inside the impinger.
[0141] At the end of the 5 minutes the nebulizer had been turned
off and 5 sec. later the pump was switched off.
[0142] The Multi Stage Liquid lmpinger had been dismantled,
carefully collecting the amount of active principle into aliquots
of solvent and subsequently analyzing for active content deposited
in each stage, in the induction port, on the mouthpiece adapter and
residual in the nebulizer.
[0143] The total mass of active principle collected was within the
range of 75 to 125 per cent of the nominal drug dosage introduced
in the nebulizer.
[0144] The compositions tested were: commercial budesonide and
beclomethasone dipropionate products, budesonide and beclomethasone
dipropionate suspensions prepared by mixing micronized active
principles in a dispersing medium equivalent to the one of the
commercial products and tested in order to evaluated the aerosol
performance of a freshly prepared suspension in comparison to a
commercial product whose manufacturing date can only be estimated
through expiration date.
[0145] The compositions according to Example 1 and Example 8
represented extemporaneous suspensions containing budesonide and
beclomethasone dipropionate.
[0146] The test performed was used to calculate for each
preparation the Fine Particle Fraction (or FPF%) corresponding to
the percentage of active drug that was delivered inside the
impinger whose aerodynamic diameter was below 5.0 .mu.m, the Mass
Median Aerodynamic Diameter (MMAD) which corresponds to the
calculated aerodynamic diameter that divides the particles of an
aerosol (a gaseous suspension of fine liquids or solid particles)
in half, based on the weight of the particles. 50% by weight of the
particles will be larger than the MMAD and 50% will be smaller than
the MMAD and the Geometric Standard Deviation (GSD) of the
distribution corresponding to a dimensionless number equal to the
ratio between the MMAD and either 84% or 16% of the particle size
distribution.
[0147] MMAD and GSD together describe the particle size
distribution of an aerosol.
[0148] To perform the calculations for MMAD and GSD the cumulative
fraction of active ingredient versus cut-off diameter were plotted
on log probability paper and the plot was used to calculate MMAD
and GSD. The results are reported in Table 5.
[0149] The data reported in Table 5 indicate a substantial
improvement in FPF and MMAD for Budesonide and Beclomethasone
corresponding to Examples 1 and 8.
TABLE-US-00005 TABLE 5 Example FPF (%) MMAD (.mu.m) GSD Commercial
budesonide 27.3 .+-. 5.5 7.25 .+-. 1.38 2.57 .+-. 0.17 suspension
(Pulmaxan) Budesonide suspension 29.3 .+-. 0.3 7.16 .+-. 0.06 2.33
.+-. 0.05 Example 1 52.4 .+-. 0.6 4.14 .+-. 0.05 2.73 .+-. 0.01
Commercial BDP 29.1 .+-. 0.5 6.99 .+-. 0.04 2.13 .+-. 0.01
suspension (Clenil A) BDP suspension 35.4 .+-. 1.4 6.16 .+-. 0.19
2.22 .+-. 0.02 Example 8 48.3 .+-. 2.0 4.75 .+-. 0.23 2.48 .+-.
0.04
* * * * *