U.S. patent application number 14/428530 was filed with the patent office on 2015-09-10 for method for coating pharmaceutical substrates.
This patent application is currently assigned to NovaldMedical Ltd Oy. The applicant listed for this patent is NovaldMedical Ltd Oy. Invention is credited to Pekka Hoppu, Tommi Kaariainen, Marja-Leena Kaarianen, Aimo Turunen.
Application Number | 20150250731 14/428530 |
Document ID | / |
Family ID | 50340624 |
Filed Date | 2015-09-10 |
United States Patent
Application |
20150250731 |
Kind Code |
A1 |
Hoppu; Pekka ; et
al. |
September 10, 2015 |
METHOD FOR COATING PHARMACEUTICAL SUBSTRATES
Abstract
The present invention relates to the field of coating
pharmaceutical substrates. In particular, the invention relates to
methods of coating of pharmaceutical substances, pharmaceutical
ingredients or a blend of them. The invention also provides a
method of making a pharmaceutical formulation which maybe processed
into a pharmaceutical dosage form, which utilizes solid
pharmaceutical particles and a pharmaceutical formulation obtained
by the method. The methods of the invention utilize atomic layer
deposition technology. The novel methods allow difficult, moisture
sensitive and electrically charged pharmaceutical substrates to be
easily processable.
Inventors: |
Hoppu; Pekka; (Kitee,
FI) ; Kaariainen; Tommi; (Mikkeli, FI) ;
Kaarianen; Marja-Leena; (Mikkeli, FI) ; Turunen;
Aimo; (Kitee, FI) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
NovaldMedical Ltd Oy |
Kitee |
|
FI |
|
|
Assignee: |
NovaldMedical Ltd Oy
Kitee
FI
|
Family ID: |
50340624 |
Appl. No.: |
14/428530 |
Filed: |
September 17, 2013 |
PCT Filed: |
September 17, 2013 |
PCT NO: |
PCT/FI2013/050896 |
371 Date: |
March 17, 2015 |
Current U.S.
Class: |
424/490 ;
427/2.14; 514/629 |
Current CPC
Class: |
A61P 29/00 20180101;
A61K 9/2081 20130101; A61K 9/501 20130101; A61K 9/2095 20130101;
C23C 16/45555 20130101; A61K 9/2018 20130101; C23C 16/403 20130101;
A61K 9/5015 20130101; A61K 9/2077 20130101; C23C 16/45525 20130101;
A61K 9/2009 20130101; C23C 16/405 20130101; A61K 31/167
20130101 |
International
Class: |
A61K 9/20 20060101
A61K009/20; A61K 31/167 20060101 A61K031/167 |
Foreign Application Data
Date |
Code |
Application Number |
Sep 18, 2012 |
FI |
20125962 |
Claims
1. A method of coating a pharmaceutical substrate, characterized
by: providing a pharmaceutical substrate, which is a particle in a
solid form; and depositing a coating layer over the pharmaceutical
substrate by atomic layer deposition method (ALD method).
2. The method of claim 1, characterized in that the pharmaceutical
substrate comprises at least one active pharmaceutical substance,
pharmaceutical ingredient, or a blend of them.
3. A method of claim 1 or 2, characterized in that the coating
layer comprises of one or more different inorganic or organic
materials or a combination of them.
4. A method of claim 3, characterized in that the inorganic
material comprises a metal oxide, preferably aluminum oxide
Al.sub.2O.sub.3 or titanium oxide TiO.sub.2.
5. A method of claim 3, characterized in that the organic material
comprises of taste-masking agents.
6. A method of claim 5, characterized in that the tastemasking
agent is a sweetener.
7. A method of claim 6, characterized in that the tastemasking
agent is a sugar alcohol.
8. A method of making a pharmaceutical formulation, the method
comprising: coating a pharmaceutical substrate by ALD; optionally
forming a mixture of the coated pharmaceutical substrate with
excipients; and processing the mixture into a dosage form, which
utilizes solid pharmaceutical particles.
9. A method of claim 8, wherein processing of the mixture is
performed by compressing.
10. A method of claim 9, wherein the mixture is compressed into a
tablet.
11. A pharmaceutical formulation, wherein a pharmaceutical
substrate is distributed as particles, and wherein a coating layer
is deposited by ALD and the coating layer conformally coats over
the individual particles of the pharmaceutical substrate.
12. A pharmaceutical formulation of claim 11, which is in a dosage
form, which utilizes solid pharmaceutical particles.
13. A pharmaceutical formulation of claim 12, which is a
tablet.
14. Use of the ALD method for coating a pharmaceutical substrate,
which is a particle.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to the field of coating
pharmaceutical substrates. In particular, the invention relates to
a method of coating of pharmaceutical substrates and a method of
making a pharmaceutical formulation.
BACKGROUND OF THE INVENTION
[0002] Many tablets today are coated after being pressed. Coating
is used to surround or coat a pharmaceutically active ingredient or
drug by at least one layer of a surface. Coating is used for
recognition, for purposes of masking the taste, or for controlled
release purposes to change dissolution properties of active agent.
Coating can also been used to work as a barrier against atmospheric
stress e.g. humidity, UV-light and oxygen to increase physical and
chemical stability of the active agent.
[0003] Various methods of coating pharmaceuticals or medical
devices are known. Modern tablet coatings are polymer and
polysaccharide based, with plasticizers and pigments included. The
tablet coating process is complex, and involves parameters such as
the spray pattern, drop size, and nozzle spacing, in addition to
multiple other non-spray related parameters which must all be
precisely controlled in order to ensure uniform distribution of the
coating material.
[0004] Prior art discloses several methods for coating or
encapsulating pharmaceuticals. WO9002546 discloses
microencapsulated pharmaceuticals, which are formed by vapor
depositing a polymeric film around a core comprising an active
pharmaceutical agent to provide effective controlled release
activity. DE 10307568 discloses membranes useful in pharmaceutical
industry, which have reduced diameter micro- or nanopores produced
by coating film with etched or laser produced openings. US
2010/0297251 discloses a method of encapsulating an active
pharmaceutical agent with a controlled release coating layer using
a gas phase chemical vapor deposition process. The coating
materials used are monomers or carbonaceous compounds that upon
polymerization yield polymers or polymer films that are degradable
or nondegradable. US2009/0186968 discloses atomic plasma deposited
coatings over a drug attached to a porous metal substrate. The
method is applicable on drugs attached or adhering to a stent
surface.
[0005] Pharmaceutical industry has a great desire to reduce costs
and find new approaches for drug manufacturing and drug delivery.
Current approaches of preparing pharmaceutical formulations and
pharmaceutical dosage forms are complex, involve a number of
technical steps, require special additives or treatments and result
in pharmaceutical products with poor stability. In addition, most
methods result in low product yields, due, in part, to the limited
tolerance of the starting materials to industrial operating
conditions and the numerous technical difficulties associated with
the coating process. Especially challenging is the dissolution and
controlled delivery of poorly soluble pharmaceuticals. Undoubtedly,
there is a need for more efficient methods which improve processing
techniques and processability of drugs which have poor flow
properties and lack of compressibility. Moreover, there remains a
need of developing a robust process of preparing pharmaceutical
formulations which can be directly processed into the final dosage
forms.
BRIEF DESCRIPTION OF THE INVENTION
[0006] An object of the present invention is thus to provide a
method so as to solve the above problems. In particular, the object
of the present invention is to provide an advantageous method for
coating pharmaceuticals, which improves processability of drugs
having poor flow properties and lack of compressibility. In
addition, the object of the present invention is to provide an
effective method for making a pharmaceutical formulation.
[0007] The objects of the application are achieved by a method
wherein a layer of protective material is applied on the surface of
a pharmaceutical substrate using an ALD (Atomic Layer Deposition)
method or other corresponding technology. The objects of the
application are further achieved by a method of making a
pharmaceutical formulation, wherein the pharmaceutical substrate is
first coated by ALD, an optional mixture of the coated substrate
and excipients is formed and thereafter processed into a desired
dosage form in which solid pharmaceutical particles are utilized.
The present invention also relates to a pharmaceutical formulation
obtained by the method. Additionally, the objects of the
application are achieved by a pharmaceutical formulation consisting
of individual pharmaceutical particles wherein each individual
particle comprises an active pharmaceutical agent and wherein each
individual particle is coated by ALD method. The present invention
also relates to the use of the ALD method or other corresponding
technology for coating a pharmaceutical substrate.
[0008] The preferred embodiments of this invention are disclosed in
the dependent claims.
[0009] The inventors of the present application surprisingly
noticed that when coating of pharmaceutical substrates is performed
before the processing into a solid dosage form a significant
improvement in the manufacturing process of pharmaceutical
formulations can be obtained. The ALD coating layer coats the
individual pharmaceutical particles allowing obtaining dosage forms
composed of coated individual particles, without any obligatory
need to use excipients such as fillers, binders, disintegrants or
lubricants. The properties of such a coated material are
considerably better in the further processing of the pharmaceutical
formulation into a suitable dosage form.
[0010] An advantage to the method of the invention is that
difficult, moisture sensitive, electrically charged pharmaceutical
substrates can be made more easily processable. The coating
generated by the method is thin, dense and smooth; moreover the
coating layers deposited by ALD are pinhole-free and very
conformal. The pharmaceutical formulations obtained by the methods
of the present invention are uniform in the content, which ensures
that the same active pharmaceutical ingredient dose is delivered
within each dosage form. In addition, the pharmaceutical
formulations of the present invention have good protection against
moisture, oxygen and light. Furthermore, poor drug solubility may
be overcome with an individually tailored coating to allow for
modified or sustained release in a specific environment. The
consumption of the coating material is low, and thus coating costs
may be reduced. In addition, the coated components reduce dosing
and administration of associated agents or particles.
[0011] The thickness of the coating layer may be controlled by
varying the number of molecule layers in the coating. The term thin
layer means in this context a layer that may have any thickness
between 1 nm and 500 .mu.m, the thickness depends on the
pharmaceutical agent, pharmaceutical ingredients and the desired
final dosage form.
[0012] The coating process of the invention is not sensitive to
minor changes in the process parameters, and thus the repeatability
of the method is good. Such a uniform layer is not possible to be
provided on a three dimensional object for example with CVD method
(Chemical Vapor Deposition) or PVD (Physical Vapor Deposition)
method, since the coating process may not be controlled in such a
detail as with the ALD method. CVD and other similar methods also
require that the coated object have to be rotated for providing
coating material over the whole surface of the three dimensional
object.
[0013] One of the advantages of present invention is the ability to
individually coat particles on both the micro and nano scales. The
processing of nanoparticles has been extremely laborious due to
electricity, physical interactions and their natural tendency for
aggregation.
[0014] Another advantage of the present invention is that the
process is solvent free, which allows highly soluble as well as
highly insoluble drug particles to be easily coated in dry form.
The invention overcomes the difficulties of using standard wet
chemistry techniques with aqueous solutions wherein highly soluble
particles dissolve before they can be coated or the pharmaceutical
ingredient or drug substance changes the polymorphic form during
processing. Likewise the use of organic and sometimes toxic
solvents and plasticizers to apply a coating is not required and
hence the chance of incorporation of these undesirable compounds is
eliminated.
DETAILED DESCRIPTION OF THE INVENTION
[0015] The present invention relates to a method, wherein
pharmaceutical substrates are coated by Atomic Layer Deposition
(ALD) or other corresponding technology before processing into a
final dosage form in which solid pharmaceutical particles are
utilized.
[0016] A pharmaceutical substrate to be coated in the present
invention may be any active pharmaceutical substance,
pharmaceutical ingredient, or a blend of them which is in a solid
form and capable of being deposited without changing structure and
losing efficacy. The pharmaceutical substrate may contain one or
more active pharmaceutical substances or pharmaceutical
ingredients. The substrate may be, for example, a particle,
granule, pellet, tablet or powder. Preferably it is a particle. A
pharmaceutical formulation is a medicinal composition, including
the active pharmaceutical substance, administered in a specific
dosage form.
[0017] The term "pharmaceutical", "pharmaceutical substance",
"therapeutic agent" or "drug" as used herein, refers to a
medicinally administered composition or compositions as a whole.
The terms refers to the active medicament which has a therapeutic
effect intended to cure, alleviate, treat or prevent a disease or a
symptom or condition suffered by the patient.
[0018] The pharmaceutical substrate to be coated may also be a
biomolecule, a small molecule, or cells. The biomolecules may be,
for example, peptides, polypeptides, oligonucleotides; nucleic
acids and genes. The small molecules may be, for example,
nucleotides, amino acids, sugars, carbohydrates, lipids and
compounds which have a molecular weight of less than 100 kD.
[0019] Atomic layer deposition (ALD) is a generally known coating
method in which surfaces of a substrate are subjected to
alternating surface reactions of at least a first and second
gaseous precursor. One ALD-cycle is completed when the surfaces of
the substrate are subjected once to both or all gaseous precursors.
Each time the surface of the substrate is subjected to a precursor,
a monolayer of material is formed on the surfaces of the substrate.
These ALD-surface reactions are normally substantially saturated
surface reactions, meaning that the only one monolayer of material
is formed on the surfaces of the substrate when the substrate is
subjected to a precursor. One basic characteristic of ALD method is
the conformality of the surfaces reactions. This means that the ALD
growth layers of material grow on all the surfaces which are
subjected to the precursors. Thus the coating is formed on all
surfaces. In the present context the term atomic layer deposition
covers also atomic layer epitaxy (ALE) and other corresponding
coating methods in which the material growth is based on successive
substantially self-limiting surface reactions of at least two
gaseous precursors.
[0020] One corresponding coating method is molecular layer
deposition (MLD). MLD is also based on sequential, self-limiting
surface reactions. However, a "molecular" fragment, which is
organic and can contain inorganic constituents, is deposited during
MLD. The deposition of purely organic polymer MLD films can be
achieved using step-wise condensation reactions. Hybrid
organic-inorganic films can be deposited by simply mixing organic
and inorganic reactants.
[0021] Only one atomic layer is produced on the surface of the
substrate during one ALD cycle. This self-controlled growth mode
contributes several advantages. The thickness of the films can be
controlled in a straightforward manner by controlling the number of
reaction cycles, therefore enabling the controlled growth of
sub-nanometer thin layers. The precursors form stoichiometric films
with large area uniformity and conformity even on complex surfaces
with deformities and on particles. Layer-by-layer growth allows one
to change the material abruptly after each step. This gives the
possibility of depositing multicomponent films, so called
nanolaminates or mixed oxides. It is also possible to develop the
dissolution characteristics.
[0022] In the present application pharmaceutical particle
formulations are loaded into the ALD reactor and pumped down to the
operating pressure of around 2 mbar. The ALD precursors are
introduced into the reactor from the inlet port after which they
are forced to travel through all the cells before exhausted from
the exhaust port connected to the uppermost cell. During this
process the desired precursor chemicals will be diffused into the
matter on the cell and consequently react with its active surface
groups forming a chemical bonding between the substrate surface and
precursor molecule. In the present invention the substrate to be
coated is the individual particle within the pharmaceutical
formulation. While the coating will be formed on the surface with
molecular layer accuracy the bulk properties of particle will not
be changed.
[0023] In one embodiment of the present application, paracetamol is
coated with one or more molecule layers of aluminum oxide
Al.sub.2O.sub.3. Trimethyl aluminum (CH.sub.3).sub.3Al is used as a
precursor and water H.sub.2O as an oxygen source. In the present
invention also other compounds, such as hydrogen peroxide
H.sub.2O.sub.2 or ozone O.sub.3 may be used as the oxygen source
instead of water.
[0024] In other embodiment of the present invention, a
pharmaceutical substrate is coated with titanium dioxide
(TiO.sub.2). An advantage of selecting titanium as a coating layer
is titanium's well known compatibility in vivo and its track record
of use in medical implants. Titanium is nontoxic and not associated
with immune response.
[0025] The coating deposited by ALD may be used to mask the taste
of bitter drugs. In one embodiment of the present invention, a
pharmaceutical substrate is coated with a taste-improving agent,
typically a sweetener, such as xylitol or sorbitol or their
mixture. The coating problems previously associated with
sweeteners, such a long coating times and moisture sensitive
sweetener material can be overcome with the present method. Typical
sweetener or other small molecule can be mixed with other chemicals
according to the ALD coating procedure.
[0026] Precursor chemistry, process parameters and used substrates
define the coating material characteristics. The coating layer may
alternatively comprise one or more of various types of inorganic,
organic and hybrid organic-inorganic polymer materials. The
inorganic materials include nitrides, carbides, oxides, metals,
sulfides, fluorides, etc. Inorganic oxides include, for example,
silicon oxide or zinc oxide, or material such as CaO, CuO,
Er.sub.2O.sub.3, La.sub.2O, ZrO.sub.2, HfO.sub.2, Ta.sub.2O.sub.5,
Nb.sub.2O.sub.5, MgO, SC.sub.2O.sub.3, Ga.sub.2O.sub.3, ZnO,
Y.sub.2O.sub.3 and Yb.sub.2O.sub.3 without limiting to these.
[0027] Also biomaterials, such as hydroxyapatite, polymers, sugar,
nanolaminates etc. are possible materials to be deposited. ALD
enables a vast array of material combinations. Molecular layer
deposition makes possible the deposition of organic polymers and
hybrid organic-inorganic polymers. For a review of ALD process and
its exploitation we refer to Puurunen R. L. J., Appl. Phys 97
(2005), pp. 1-52. An overview of the surface chemistry for the MLD
of organic and hybrid organic-inorganic polymers can be seen e.g.
in George, S. M. et al, (2009), ACC. Chem. Res., 42, pp.
498-508.
[0028] A coating layer in accordance with the present invention may
have various thicknesses, depending upon the particular
application. In the coating process usually a coating that is as
thin as possible is desirable such that it will be sufficiently
thick in order to have the desired properties. ALD layer thickness
can also be used to control the release of pharmaceutical substance
and consequently control the drug dissolution time. The layer
thickness can be defined by ALD cycles. For example, one ALD cycle
of TMA and water results 0,1 nm thick Al.sub.2O.sub.3 coating. In
one embodiment of the present invention, wherein trimethyl aluminum
(CH.sub.3).sub.3Al is used as a precursor, the thickness of the
coating is within the range of 1 nm to 500 nm, more preferably in
the range of 1 of 100 nm, most preferably from 5 to 15 nm. However,
the coating layer may have any thickness between 1 nm and 500
.mu.m. The thickness of the coating layer depends on the
pharmaceutical substance, pharmaceutical ingredients and the
desired final dosage form.
[0029] The temperature used in the coating process depends on the
substrate properties and on the chosen precursor chemistry. In most
common ALD methods it is advantageous to use relatively high
temperature, because it allows molecules to evaporate readily and a
coating having a sufficiently good quality is obtained. In the
present invention a coating layer is deposited over a
pharmaceutical substrate and therefore heat degradation of the
pharmaceutical substrate is to be avoided or reduced. For example,
the melting point of ibuprofen is around 74-77.degree. C., whereas
the melting point of paracetamol is around 169-172.degree. C. The
coating temperature may be from room temperature (RT) up to
350.degree. C. Preferably the temperature for pharmaceuticals is
below 200.degree. C. In general, the present invention utilizes
relatively low temperature ranges in contrast to vapor deposition
methods, which are conducted at much higher temperatures.
[0030] The present invention may utilize any suitable ALD reactor.
In one embodiment of the present invention, a static particle bed
reactor is used. In this type of a reactor the particles are
stationary on the reactor surface and overall and uniform coverage
of each particles is depending e.g. on effective aspect ratio that
particles are forming. One of the main obstacles in coating
pharmaceuticals or nanoparticles is their natural tendency for
aggregation. Among several factors, aggregation of cohesive
particles is dependent on flow conditions as well as the external
energy that is transferred to the particles during processing.
Therefore, pharmaceuticals in different reactor configurations will
show diverse aggregation patterns. Processing an ALD coating of
pharmaceutical substrates in a fluidized bed reactor is preferred.
Fluidized bed reactors offer advantages like higher heat and
mass-transfer co-efficients and easy scalability. In addition due
to the superior level of solids mixing in a fluidized bed
conformally coated individual pharmaceutical particles are
obtained. Also roll-to-roll ALD reactors may be utilized in the
context of the present invention for depositing thin films on
flexible pharmaceutical substrates, such as for example on
transdermal patches.
[0031] The ALD coating according to the present invention may be
used to influence on the particle release to the environment. For
example, a poorly soluble coating allows for sustained release.
Such poorly soluble coatings are e.g. aluminum oxide and titanium
oxide. The coating on the pharmaceutical substance may comprise a
plurality of inorganic coating layers or organic layers, or a
combination of inorganic and organic layers to modify drug release
rate. The use of multiple coating layers may allow for an
additional degree of control in elution of a pharmaceutical
substance. A greater number of deposited layers increasingly
hinders elution of the drug and allows customization of time
release.
[0032] Different coating layers may be used to produce different
pharmaceutical dosage forms, such as immediate release, controlled
release, and/or combinations of both immediate and controlled
release dosage forms. Controlled release dosage forms, may include
particles or beads containing a drug or active agent, where the
particles or beads are coated with a release- controlling polymer.
Controlled release beads may comprise an inert core, coated with an
inner drug-containing layer and an outer membrane layer controlling
drug release from the inner layer. The inert core may be a sphere
or bead of sugar, a hydrophilic cellulosic polymer, or a
crosslinked hydrophilic synthetic polymer.
[0033] The ALD coating according to the present invention may also
be a responsive coating. Such a coating has a component such as a
nanoparticle, responsive polymer or molecule incorporated in the
coating. A responsive coating is able to give an appropriate and
predictable response to outside condition changes and thus can
enhance the performance of the pharmaceutical substance.
[0034] A pharmaceutical dosage form is a form in which a
pharmaceutical formulation is presented in the medicinal product
package as supplied by the marketing authorization holder,
manufacturer, or distributor. The key defining characteristics of
the pharmaceutical dosage form are the state of matter, delivery
method, release characteristics, and the administration site or
route for which the product is formulated. Pharmaceutical dosage
forms are a mixture of active drug components and nondrug
components. Depending on the method of administration they come in
several types. These are liquid dosage form, solid dosage form and
semisolid dosage forms. Solid dosage forms, such as tablets and
capsules, are the most established and preferred administration
route. In the present invention a dosage form may be any dosage
form which utilizes solid pharmaceutical particles. Such a dosage
form may be, in addition to tablets and capsules, suppository,
vaginary, liquid preparations, transdermal patches (transdermal
drug delivery), medical ointments and emulsions (topical drug
delivery, wound dressings), injection (parental drug delivery) and
pulmonary drug delivery, without limiting to them. These can be
administrated via nasal, rectal, vaginal, ear, eye, parenteral, per
oral drug delivery route, without limiting to them.
[0035] A tablet is usually a compressed preparation that contains
active substance, fillers, disintegrants, lubricants, glidants,
binders and compounds which ensure disintegration, disaggregation,
dissolution of the tablet in the stomach and intestine.
[0036] In common tableting processes, the material which is to be
tableted is deposited into a cavity and one or more punch members
are then advanced into the cavity and brought into intimate contact
with the material to be pressed, whereupon a compression force is
applied.
[0037] Three basic compression methods are common in most tableting
operations, i.e., the wet granulation method, the
double-compression method (also known as dry granulation) and the
direct compression method. In each of these methods, there are
blending steps which can promote agglomeration of fine particles of
the drug into larger.
[0038] In the wet granulation method, pre-weighed drug and one or
more other ingredients, like a diluent, are blended. The blend is
then mixed with a liquid such as water or ethanol which causes the
particles to agglomerate into a damp mass. Sometimes the liquid
contains a binder. The damp mass is screened to produce granules
which are then dried. The dry granules are screened to produce
granules of a predetermined size. Then, the granules are typically
blended with a solid lubricant and possibly other ingredients.
Lastly, the lubricated granules and any other extra-granular
ingredients are compressed into a tablet, which may subsequently be
coated.
[0039] The double-compression or dry granulation method has fewer
steps than wet granulation and does not require contact with a
liquid or drying, which makes it well suited for formulating water
sensitive and heat sensitive drugs. In the double-compression
method, the drug and other ingredients, such as a lubricant, are
blended and then compressed in a first compression step. There are
two conventional first compression techniques. One is roller
compaction where the blend is fed between rollers which press it
into sheets and the other is slugging where the blend is compressed
into slugs, which are tablet-like forms that are typically larger
than tablets intended for human consumption. The resulting sheets
or slugs are then comminuted into granules, mixed with a solid
lubricant and compressed in a second compression step to produce
the final tablet.
[0040] The direct compression method is the simplest of the three
well known methods for making compressed solid dosage forms. In the
direct compression method, the drug and any other ingredients are
blended together and directly compressed into the final tablet. For
various reasons, however, not all components which can be employed
for the formulation of tablets are suitable for use in this process
due to poor compressibility, flowability and stability under
conventional tableting conditions.
[0041] The present invention relates to a procedure for preparing a
pharmaceutical formulation and to a pharmaceutical formulation
obtained by the process. In accordance with the present invention
the pharmaceutical substrates are first coated by ALD after which
all of the components, i.e., the coated active pharmaceutical
substance, optionally any additional excipient(s) and other
ingredient(s), are mixed together and processed into the final
pharmaceutical dosage form. The final dosage form may be any dosage
form which utilizes solid pharmaceutical particles. The present
invention allows compression of the pharmaceutical substances
directly after coating. In accordance with the present invention it
is also possible to first coat the pharmaceutical substance and the
excipient together and then proceed in manufacturing the dosage
form. Alternatively, the excipient may be coated alone before
making the pharmaceutical formulation.
[0042] The ingredients in the pharmaceutical formulation are mixed
together using techniques well known in the art until the mixture
is homogenous with respect to the drug. It is important that all
ingredients are fairly dry, powdered or granular, somewhat uniform
in particle size, and freely flowing. The pharmaceutical particles
may be reduced in a particle size using conventional milling
techniques, such as air jet milling, ball milling, cad milling,
multi milling and other suitable size reduction techniques.
[0043] In a preferred embodiment the processing into the final
dosage form is done by compressing. The term "compressing" includes
any known process performed by applying compression forces. These
methods include, but are not limited to, compression, compaction,
extrusion and injection molding.
[0044] In one embodiment of the present invention the
pharmaceutical dosage form is a tablet. Some active pharmaceutical
agents may be tableted as pure substances, but this is rarely the
case; most formulations include excipients, which are
pharmacologically inactive ingredients added to help holding the
tablet together and giving it strength. The pharmaceutically
acceptable excipients may be selected from the group of diluents,
surfactants, antioxidants, disintegrants, binders, lubricants,
glidants, and chelating agents. Pharmaceutically accepted
excipients are well known in the art and in this context we refer
to e.g. Handbook of Pharmaceutical Excipients, 6th edition,
Pharmaceutical Press and American Pharmacist's Association by Ray
C. Rowe, Paul J. Sheskey and Marian Quinn. It should be noted that
a tablet obtained by the method of the present invention may be
further coated after being pressed to get for example a
sugar-coated tablet or a film-coated tablet.
[0045] After making the final tableting blend for the
pharmaceutical formulation, a lubrication step is used to ensure
that the tableting blend does not stick to the equipment during the
tableting process. This usually involves low shear blending of the
pharmaceutical ingredients with a powdered lubricant, such as
magnesium stearate or stearic acid.
[0046] Any conventional tablet presses, also called tableting
machines, may be used from a hand-operated press or a single
station tableting press to a multi-station rotary press. The
operation of such machinery is well within the ordinary skill in
the art.
[0047] The present invention relates also to a pharmaceutical
formulation, wherein the pharmaceutical substrate is distributed as
particles, and wherein the coating layer is deposited by ALD and
the coating layer conformally coats over the individual particles
of the pharmaceutical substrate. In one embodiment of the
invention, the pharmaceutical formulation is in a dosage form which
utilizes solid pharmaceutical particles, preferably it is a
tablet.
[0048] The present invention also relates to the use of the ALD
method or other corresponding technology for coating a
pharmaceutical substrate.
[0049] It will be obvious to a person skilled in the art that as
the technology advances, the inventive concept can be implemented
in various ways. The invention and its embodiments are not limited
to the examples described below but may vary within the scope of
the claims.
EXAMPLES
Example 1. Pharmaceutical Substrate Coating
[0050] Pharmaceutical particles (as shown in Table 1) were coated
by Beneq TFS 500 ALD tool, equipped with static particle bed
reactor. This type of particle reactor is suitable for small amount
of particles. The reactor is built up from five cells top of each
other. Each cell is 200 mm of its diameter and 20 mm of its height.
Paracetamol powder was loaded on the bottom of the reactor cells
without any pretreatment and the reactor cells were then loaded
into the reactor and pumped down to the operating pressure of
around 2 mbar. Al.sub.2O.sub.3 and TiO.sub.2 were deposited on
paracetamol particles with average particle size of approximately
50 .mu.m at temperature of 100 to 140.degree. C. Al.sub.2O.sub.3
films were grown from trimethylaluminum (TMA) and water vaporized
from the source at a temperature of 20.degree. C. TiO.sub.2 films
were grown from tetrakis(dimethylamido)titanium (TDMAT) vaporized
from the source at a temperature of 41.degree. C. and water
vaporized from the source at a temperature of 20.degree. C. One
deposition cycle for Al.sub.2O.sub.3 consisted of a 2 seconds metal
precursor (TMA) pulse, 2.5 seconds N.sub.2 purge, 0.5 second water
pulse and 1 second N.sub.2 purge. Similarly the timing sequence
used for TiO.sub.2 deposition was 1-5-1.5-2 seconds. The number of
ALD cycles deposited for both oxides was 500.
[0051] Paracetamol (USP) was purchased from Hawkins Inc. (Hawkins
Inc., MN, USA), mannitol was purchased from Roquette Freres,
Lestrem, France, D-sorbitol from Sigma Aldrich and xylitol was
commercial foodstuff.
Example 2. Tableting Study
[0052] The material obtained from Example 1 was tableted using an
instrumented eccentric tableting machine (Korsch EK-0, Erweka
Apparatebau, Heusenstamm, Germany) Flat-faced 9 mm punches were
used and the die wall was lubricated using 5% (w/V) magnesium
stearate in acetone before each compression. The target weights of
tablets were 300 mg. Compression forces during the compression
process were measured and the crushing strength of each tablet was
measured using Scleuninger-E apparatus (Switzerland) (Table 1).
TABLE-US-00001 TABLE 1 Compression forces and the crushing strength
of the resulting tablets Upper punch force Crushing strength
Material (kN) (N) Neat paracetamol * 8 kN No tablet, no measurable
crushing strength Paracetamol + Al.sub.2O.sub.3 3.6 kN 62N coating
Paracetamol + TiO.sub.2 8.7 kN 10N coating Paracetamol + Xylitol
7.4 kN 5N 50%/Sorbitol coating 50% (w/w) .sup.a) * no coating
.sup.a) amorphous blend deposited using ALD equipment
[0053] The results presented in Table 1 show that flowability and
processability of the ALD coated pharmaceuticals is better than in
pure paracetamol.
* * * * *