U.S. patent application number 14/824207 was filed with the patent office on 2015-12-03 for production of inorganic-organic composite materials by reactive spray-drying.
The applicant listed for this patent is BASF SE. Invention is credited to Heidrun Debus, Andreas Kempter, Max Siebert.
Application Number | 20150342887 14/824207 |
Document ID | / |
Family ID | 51297855 |
Filed Date | 2015-12-03 |
United States Patent
Application |
20150342887 |
Kind Code |
A1 |
Kempter; Andreas ; et
al. |
December 3, 2015 |
Production Of Inorganic-Organic Composite Materials By Reactive
Spray-Drying
Abstract
A composite material comprising at least one amorphous
hydrophobic active ingredient in an amorphous salt matrix with a
solubility in the neutral aqueous medium of less than 0.02 mol/l,
obtained by a reactive spray-drying process, where a liquid phase
A, which comprises inorganic cations, and a liquid phase B, which
comprises anions which, with the inorganic cations, form a salt
that is insoluble in the mixture of the liquid phases are sprayed
together using at least one multi-substance nozzle, and where at
least one hydrophobic active ingredient is present in dissolved
form in at least one liquid spraying phase, and where the salt
formed from the cations of phase A and the anions of phase B has a
solubility of less than 0.02 mol/l in the neutral aqueous
medium.
Inventors: |
Kempter; Andreas; (Neustadt,
DE) ; Siebert; Max; (Ludwigshafen, DE) ;
Debus; Heidrun; (Eisenberg, DE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
BASF SE |
Ludwigshafen |
|
DE |
|
|
Family ID: |
51297855 |
Appl. No.: |
14/824207 |
Filed: |
August 12, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
14175635 |
Feb 7, 2014 |
9138381 |
|
|
14824207 |
|
|
|
|
61762350 |
Feb 8, 2013 |
|
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Current U.S.
Class: |
514/176 ;
514/182; 514/254.07; 514/406; 514/569 |
Current CPC
Class: |
A61K 31/58 20130101;
B01D 1/18 20130101; A61K 9/1682 20130101; A61K 31/565 20130101;
A61K 31/496 20130101; A61J 3/005 20130101; B01J 2/04 20130101; A61K
9/145 20130101; A61J 3/02 20130101; A61K 31/192 20130101; A61K
9/1617 20130101; A61K 31/415 20130101; A61K 9/143 20130101; A61K
9/1611 20130101 |
International
Class: |
A61K 9/16 20060101
A61K009/16; A61K 31/415 20060101 A61K031/415; A61K 31/496 20060101
A61K031/496; A61K 31/192 20060101 A61K031/192; A61K 31/58 20060101
A61K031/58; A61K 31/565 20060101 A61K031/565 |
Claims
1. A composite material comprising at least one amorphous
hydrophobic active ingredient in an amorphous salt matrix with a
solubility in the neutral aqueous medium of less than 0.02 mol/l,
obtained by a reactive spray-drying process, where a liquid phase
A, which comprises inorganic cations, and a liquid phase B, which
comprises anions which, with the inorganic cations, form a salt
that is insoluble in the mixture of the liquid phases are sprayed
together using at least one multi-substance nozzle, and where at
least one hydrophobic active ingredient is present in dissolved
form in at least one liquid spraying phase, and where the salt
formed from the cations of phase A and the anions of phase B has a
solubility of less than 0.02 mol/l in the neutral aqueous
medium.
2. The composite material of claim 1, comprising at least one
amorphous hydrophobic active ingredient in an amorphous salt matrix
of at least one salt selected from the group of calcium, magnesium
and zinc salts.
3. The composite material of claim 1, comprising at least one
amorphous hydrophobic active ingredient in an amorphous salt matrix
of calcium carbonate.
4. The composite material of claim 1, further comprising a
surfactant.
5. The composite material of claim 4, comprising a surfactant
selected from the group of polyoxyethylenated esters of castor oil
or hydrogenated castor oil.
6. The composite material of claim 4, comprising sodium
laurylsulfate as surfactant.
7. The composite material of claim 1, wherein the inorganic cations
of phase A are selected from the group consisting of magnesium
ions, calcium ions and zinc ions.
8. The composite material of claim 7, wherein the inorganic cations
of phase A used are calcium ions.
9. The composite material of claim 1, wherein the liquid phase A is
a solution of salts of the inorganic cations and the salts are
selected from the group consisting of calcium chloride, calcium
nitrate, calcium acetate, magnesium chloride, magnesium nitrate,
magnesium acetate, magnesium citrate, magnesium lactate, zinc
chloride, zinc nitrate and zinc acetate.
10. The composite material of claim 1, wherein the liquid phase B
used is a solution of salts selected from the group consisting of
ammonium, alkali metal or magnesium salts of carbonates,
hydrogencarbonates, sulfates, phosphates and
hydrogenphosphates.
11. The composite material of claim 10, wherein the liquid phase B
used is a solution of salts selected from the group consisting of
ammonium, alkali metal or magnesium salts of citric acid, lactic
acid and oxalic acid.
12. The composite material of claim 1, wherein the salt formed from
the cations of phase A and the anions of phase B that is used is a
calcium salt selected from the group consisting of carbonates,
phosphates, sulfates, hydroxylapatites, citrates, lactates and
oxalates.
13. The composite material of claim 1, wherein the hydrophobic
active ingredient is used in the form of an ethanolic or
aqueous-ethanolic solution.
14. The composite material of claim 4, wherein the surfactant is
present in amounts of from 2 to 50% by weight, based on the amount
of active ingredient.
15. The composite material of claim 4, wherein the surfactant is
selected from the group consisting of polyoxyalkylated fatty acid
esters and polyoxyalkylated fatty alcohol ethers.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a divisional application and claims the
benefit of priority of U.S. application Ser. No. 14/175,635, filed
Feb. 7, 2014, which claims the benefit of priority under 35 U.S.C.
.sctn.119(e) to U.S. Provisional Application No. 61/762,350, filed
Feb. 8, 2013, the entire content of which is incorporated herein by
reference in its entirety.
TECHNICAL FIELD
[0002] The present invention relates to a process for producing
inorganic-organic composite materials by reactive spray-drying,
where the organic phase in the composite materials constitutes at
least one organic active ingredient and the inorganic phase
constitutes an inorganic salt that is sparingly soluble under
standard conditions. Furthermore, the invention relates to
corresponding composite materials and to the use thereof.
BACKGROUND
[0003] Inorganic-organic materials based on calcium carbonate in
which biomolecules can be embedded are known per se, where the
materials are obtained by precipitation processes, and where the
active ingredients embedded in the calcium carbonate matrix are
water-soluble substances. For example, A. Elabbadi et al., Journal
of Microencapsulation, 2011; 28(1):1-9, describe the
microencapsulation of green tea extracts into microparticles of
calcium carbonate and phosphates. M. Fujiwara et al, Chemical
Engineering Journal 137 (2008) 14-22, describe the encapsulation of
water-soluble biomolecules such as bovine serum albumin into
calcium carbonate microcapsules. A. I. Petrov et al., Biotechnol.
Prog. 2005, 21, 918-925 also describe the embedding or adsorption
of water-soluble biomolecules such as, for example, bovine serum
albumin into calcium carbonate by coprecipitation.
[0004] US 2009/0104275 describes the production of
microencapsulated insulin, where the microencapsulation can take
place by coprecipitation.
[0005] US 2009029902 describes complexes of calcium carbonate and
proteins with calcium carbonate binding domains. The complexes can
be obtained by precipitation from aqueous slurries.
[0006] WO 2008000042 describes nanoparticulate formulations of
sparingly water-soluble active ingredients, where the formulations
are obtained by grinding the active ingredients with water-soluble
inorganic salts.
[0007] In WO 0105731, amorphous glass-like products obtained by
melting inorganic salt mixtures are mechanically mixed with active
ingredients and granulated.
[0008] WO 2009077147 describes pharmaceutical formulations which
are obtained by mixing an active ingredient with a particulate
basic solid, where the basic particulate solid is an alkali metal
or alkaline earth metal salt.
[0009] EP-A 1905427 describes the embedding of active ingredients
into an inorganic matrix, where only readily water-soluble
inorganic salts such as, for example, sodium carbonate are
described as inorganic matrix.
[0010] WO 2012/027378 describes the production of particulate
active ingredient preparations, where an inorganic carrier
substance such as, for example, calcium carbonate and a hydrophobic
pharmaceutical active ingredient are precipitated together in a
mixing chamber.
[0011] However, it is a disadvantage of the precipitation processes
in a mixing chamber that the mixing chambers tend to rapidly block.
Furthermore, the coprecipitates have a tendency toward
recrystallization of the active ingredient, which results in poorer
release of the active ingredient and therefore deterioration in
bioavailability.
[0012] One aspect of the present invention provides a simple and
economically feasible process for producing inorganic-organic
composite materials comprising biologically active ingredients
which avoids the disadvantages of the prior art.
SUMMARY
[0013] Therefore, the present invention relates to a process for
producing composite materials by reactive spray-drying, where a
liquid phase A, which comprises inorganic cations, and a liquid
phase B, which comprises anions which, with the inorganic cations,
form a salt that is insoluble in the mixture of the liquid phases
are sprayed together using at least one multi-substance nozzle, and
where at least one hydrophobic active ingredient is present in
dissolved form in at least one liquid spraying phase, and where the
salt formed from the cations of phase A and the anions of phase B
has a solubility of less than 0.02 mol/l in the neutral aqueous
medium.
[0014] In one or more embodiments, the inorganic cations of phase A
are selected from the group consisting of magnesium ions, calcium
ions and zinc ions. In a preferred embodiment, the inorganic
cations of phase A used are calcium ions.
[0015] In one or more embodiments, the liquid phase A is a solution
of salts of the inorganic cations and the salts are selected from
the group consisting of calcium chloride, calcium nitrate, calcium
acetate, magnesium chloride, magnesium nitrate, magnesium acetate,
magnesium citrate, magnesium lactate, zinc chloride, zinc nitrate
and zinc acetate.
[0016] In one or more embodiments, the liquid phase B used is a
solution of salts selected from the group consisting of ammonium,
alkali metal or magnesium salts of carbonates, hydrogencarbonates,
sulfates, phosphates and hydrogenphosphates.
[0017] In yet another embodiment, the liquid phase B used is a
solution of salts selected from the group consisting of ammonium,
alkali metal or magnesium salts of citric acid, lactic acid and
oxalic acid.
[0018] In one or more embodiments, the salt formed from the cations
of phase A and the anions of phase B that is used is a calcium salt
selected from the group consisting of carbonates, phosphates,
sulfates, hydroxylapatites, citrates, lactates and oxalates.
[0019] In one or more embodiments, the liquid phases are solutions
and the solvents present are water or organic solvents or mixtures
thereof. In one or more preferred embodiments, the organic solvent
used is ethanol.
[0020] In one or more embodiments, the hydrophobic active
ingredient is used in the form of an ethanolic or aqueous-ethanolic
solution.
[0021] In one or more embodiments, a surfactant may be added to the
liquid phase which comprises the hydrophobic active ingredient. In
one or more embodiments, the surfactant is added in amounts of from
2 to 50% by weight, based on the amount of active ingredient, to
the liquid phase which comprises the hydrophobic active ingredient.
The surfactant may be selected from the group consisting of
polyoxyalkylated fatty acid esters and polyoxyalkylated fatty
alcohol ethers.
[0022] In one or more embodiments, the multi-substance nozzle used
is an ultrasonic nozzle. An atomization gas is used during the
spray-drying. In one or more embodiments, spraying drops with a
median diameter of 10 to 200 .mu.m .mu.m are produced.
[0023] In one or more embodiments, the hydrophobic active
ingredient is present in phase A. In yet another embodiment, the
hydrophobic active ingredient is present in phase B. In one
embodiment, phase A comprises a calcium salt and phase B comprises
ammonium carbonate or sodium carbonate. In another embodiment,
phase A comprises a calcium salt and phase B comprises ammonium
acetate or sodium acetate.
[0024] Further, the present invention relates to a composite
material comprising at least one amorphous hydrophobic active
ingredient in an amorphous salt matrix with a solubility in the
neutral aqueous medium of less than 0.02 mol/l, obtained by a
spraying process according to one or more embodiments of the
present invention. In one or more preferred embodiments, the
composite material comprises at least one amorphous hydrophobic
active ingredient in an amorphous salt matrix of at least one salt
selected from the group of calcium, magnesium and zinc salts. In
yet another preferred embodiment, the at least one amorphous
hydrophobic active ingredient in an amorphous salt matrix is
calcium carbonate.
[0025] In one or more embodiments, the composite material further
comprises a surfactant. In one or more embodiments, the surfactant
may be selected from the group consisting of polyoxyethylenated
esters of castor oil or hydrogenated castor oil. In yet another
embodiment, the surfactant is sodium laurylsulfate.
BRIEF DESCRIPTION OF THE DRAWINGS
[0026] FIG. 1 shows the plasma level of the composite materials
according to Examples 1, 2 and Comparative Example I.
DETAILED DESCRIPTION
[0027] A process has been found for producing composite materials
by reactive spray-drying, where a liquid phase A, which comprises
inorganic cations, and a liquid phase B, which comprises anions
which, with the inorganic cations, form a salt that is insoluble in
the mixture of the liquid phases, are sprayed together using a
multi-substance nozzle, and where at least one hydrophobic active
ingredient is present in dissolved form in at least one liquid
phase, and the salt formed from the cations of phase A and the
anions of phase B has a solubility of less than 0.02 mol/l in the
neutral aqueous medium. Neutral aqueous medium means a pH of
7+/-0.5. In one or more embodiments, aqueous medium means a purely
aqueous medium without the presence of further solvents. The
solubility refers to the solubility under standard conditions at
20.degree. C. and 0.101325 MPa.
[0028] The hydrophobic active ingredient can be present in
dissolved form in one of the liquid phases A or B or be introduced
into the process in dissolved form in a further liquid phase.
[0029] Within the context of the present invention, composite
materials are those materials in which one component is embedded
into a matrix of another component. In the composite materials
obtained by the process according to the invention, a hydrophobic
organic active ingredient is present in embedded form in a matrix
of a salt of inorganic cations (the "salt matrix"), with the salt
matrix being present in amorphous form. In one preferred
embodiment, the hydrophobic active ingredient is also in the
amorphous state. Amorphous state in this connection means that not
more than 5% by weight of the active ingredient or of the salt
matrix are present in crystalline form, this state being determined
by means of XRD (X-ray diffraction).
[0030] A suitable salt matrix according to the invention is salts
which can be obtained under certain conditions by bringing at least
two liquid phases into contact, of which one phase comprises
inorganic cations and a second or further phase comprises anions
which form sparingly water-soluble salts with the cations of the
other liquid phase. As defined, the resulting salts are only
sparingly soluble in water, but readily soluble in an acidic
medium, sometimes with decomposition.
[0031] According to the invention, inorganic cations of the salt
matrix are metallic cations which are preferably physiologically
well tolerated. In particular, suitable cations are calcium ions,
magnesium ions or zinc ions or mixtures thereof. Particular
preference is given to calcium ions.
[0032] Suitable counterions of the salt matrix are both inorganic
and organic anions, the intention being for the resulting salts as
described to be insoluble in the neutral aqueous medium. Which
anions are suitable is also governed by the type of cation. Thus,
for example, some calcium salts are sparingly soluble in water
whereas the corresponding magnesium salts are readily soluble in
water. For all of the anions specified below, the solubility of the
possible salts should thus be ascertained. This is possible for the
person skilled in the art in a simple manner since these are known
in the literature.
[0033] Suitable inorganic anions of the resulting sparingly
water-soluble salt matrix are selected from the group consisting of
carbonate, phosphate, sulfate or mixed anions such as, for example,
hydroxylapatite.
[0034] According to one embodiment, suitable organic anions of the
sparingly water-soluble salt matrix are anions of physiologically
compatible organic mono- or polybasic acids. This embodiment refers
to a salt matrix which comprises calcium salts as salts that are
sparingly soluble in water. Suitable calcium salts are selected
from the group consisting of calcium citrate, calcium lactate and
calcium oxalate.
[0035] The liquid phase A which comprises the cations of the
sparingly water-soluble salt matrix to be formed is obtained by
dissolving corresponding salts that are readily soluble in the
selected medium. Suitable salts are calcium chloride, calcium
nitrate, calcium acetate, magnesium chloride, magnesium nitrate,
magnesium acetate, magnesium citrate, magnesium lactate, zinc
chloride, zinc nitrate or zinc acetate. The salts can, if
applicable, also be used in the form of their mono-, di- or
semihydrates.
[0036] The salts with which the cations of the sparingly
water-soluble salt matrix to be formed in the liquid phase A are
introduced as solution into the process are those which are
preferably readily water-soluble or are readily soluble in organic
solvents or organic-aqueous mixtures.
[0037] The salts with which the anions of the sparingly
water-soluble salt matrix to be formed in the liquid phase A are
introduced as solution into the process are ammonium salts or
alkali metal salts that are readily water-soluble or readily
soluble in a hydrophilic organic solvent or readily soluble in
aqueous-organic mixtures. Furthermore, also of suitability are
correspondingly readily soluble magnesium salts. Suitable salts are
in particular readily water-soluble carbonates, hydrogencarbonates,
sulfates, phosphates, hydrogenphosphates. Furthermore, organic
salts such as ammonium, alkali metal or magnesium salts of citric
acid, lactic acid or oxalic acid are suitable. In one preferred
embodiment, the liquid phase B via which the anion component of the
sparingly water-soluble salt matrix is introduced is purely
aqueous. Optionally, phase B can also comprise organic
solvents.
[0038] How the salt components of the liquid phases A and B are
combined depends on the type of desired sparingly water-soluble
salt matrix. It is obvious that a cation which is introduced in
liquid phase A as cation-supplying component for the sparingly
water-soluble salt matrix cannot simultaneously serve as cation of
an anion-supplying component dissolved in liquid phase B.
[0039] The cations of liquid phase A must in any case be able to
form with the anions of liquid phase B a sparingly water-soluble
salt with a solubility of less than 0.02 mol/l (at 20.degree. C.
and 0.1 MPa).
[0040] Thus, for example, a magnesium salt such as magnesium
chloride can be reacted as cation-supplying salt of phase A with an
ammonium carbonate or alkali metal carbonate salt dissolved in
phase B to give a corresponding sparingly soluble magnesium
carbonate. Similarly, for example, a calcium salt such as calcium
chloride can be reacted as cation-supplying salt of phase A with a
magnesium salt such as magnesium citrate dissolved in phase B to
give a corresponding sparingly soluble calcium citrate.
[0041] Suitable solvents for the different liquid phases to be
sprayed are, besides water, also hydrophilic organic solvents which
have unlimited miscibility with water, such as methanol, ethanol,
glycerol, 1,2-propylene glycol, low molecular weight polyethylene
glycols such as PEG 200, PEG 300, PEG 600 or acetone, acetonitrile,
dimethyl sulfoxide, dimethylformamide, N-methylpyrrolidone,
2-methoxyethanol or tetrahydrofuran. In one preferred embodiment,
the hydrophilic organic solvent used is ethanol.
[0042] The respective concentration of the feed materials in the
solvent is case-specific and arises from the particular
solubilities of the components used. However, in the liquid phases,
preference is given to concentrations of 0.1 to 10 mol/l for the
salt components to be used. In one preferred embodiment, a
concentration of 0.5 to 2 mol/l for the salt components is
used.
[0043] The concentration of the hydrophobic active ingredients in
the liquid phase can be 1 to 100 g/l. In one preferred embodiment,
the concentration of the hydrophobic active ingredients in the
liquid phase can be 10 to 40 g/l.
[0044] The salt matrix as target substance of the reactive
spray-drying is no longer soluble in the mixture of the solvents of
the fluid phases and is also sparingly soluble in water (less than
0.02 mol/l).
[0045] According to one embodiment, the hydrophobic active
ingredient component is introduced into the process via an organic
solution, and the mixture of all liquid phases constitutes an
aqueous-organic solvent mixture.
[0046] For all of the embodiments specified below, when using an
organic solvent, preference is given to using ethanol.
[0047] According to one embodiment, phase A comprises a mixture of
water and an organic solvent and also the hydrophobic active
ingredient, and phase B is a purely aqueous phase which comprises
no further solvent. According to a further embodiment, phases A and
B are purely aqueous phases and the hydrophobic active ingredient
is introduced into the spraying process in a further liquid phase,
dissolved in an organic solvent. According to another embodiment,
the phase is a purely aqueous phase and phase B is an
aqueous-organic phase which also comprises the hydrophobic active
ingredient.
[0048] According to a further embodiment, different hydrophobic
active ingredients can also be introduced into the process. These
can be dissolved together in one phase or introduced via different
phases.
[0049] According to a further preferred embodiment of the
invention, at least one surfactant is added to one of the liquid
phases A or B or optionally to a further liquid phase. According to
one embodiment of the invention, the hydrophobic active ingredient
component is accordingly introduced into the spraying process via
an aqueous or aqueous-organic phase which additionally comprises at
least one surfactant. According to a further embodiment of the
invention, the hydrophobic active ingredient component is present
together with the surfactant in phase A. According to one
embodiment of the invention, the hydrophobic active ingredient
component is present together with the surfactant in phase B.
According to a further embodiment of the invention, the hydrophobic
active ingredient component is present together with the surfactant
in an additional liquid phase. According to a particularly
preferred embodiment, the liquid phase comprising surfactant and
hydrophobic active ingredient is a purely aqueous phase.
[0050] Suitable surfactants are selected from the group of anionic,
cationic, nonionic and amphiphilic surfactants.
[0051] Suitable anionic surfactants are inter alia, sodium,
potassium, magnesium and calcium salts of fatty acids and food
fatty acids. Suitable anionic surfactants are for example sodium
lauryl sulfate, ammonium lauryl sulfate, sodium cetylstearyl
sulfate, docusate sodium, docusate potassium or docusate
calcium.
[0052] A suitable cationic surfactant is for example
cetylpyridinium chloride.
[0053] In principle, suitable surfactants are mono- and
diglycerides of fatty acids and food fatty acids, acetic acid
esters, lactic acid esters such as sodium or calcium stearoyl
2-lactate, citric acid esters such as, for example, triethyl
citrate, tartaric acid esters, for example, stearyl tartrate,
diacetyltartaric acid esters, mixed acetic and tartaric acid
esters, sugar esters of fatty acids and food fatty acids, sugar
glycerides, propylene glycol esters of food fatty acids,
polyglycerol polyricinoleate or propylene glycol esters of food
fatty acids.
[0054] Suitable nonionic surfactants are for example fatty alcohols
and sterols such as cetyl alcohol, stearyl alcohol, cetylstearyl
alcohol or cholesterol.
[0055] Suitable nonionic surfactants are for example sorbitan
esters, which may also be polyoxyalkylated, for example sorbitan
monostearate, sorbitan stearate, sorbitan monolaurate, sorbitan
monooleate, sorbitan monopalmitate, polysorbate 20
(polyoxyethylene-(20) sorbitan monolaurate), polysorbate 21
(polyoxyethylene-(4) sorbitan monolaurate), polysorbate 40
(polyoxyethylene-(20) sorbitan monopalmitate), polysorbate 60
(polyoxyethylene-(20) sorbitan monostearate), polysorbate 61
(polyoxyethylene-(4) sorbitan monostearate), polysorbate 65
(polyoxyethylene-(20) sorbitan tristearate), polysorbate 80
(polyoxyethylene-(20) sorbitan monooleate), polysorbate 81
(polyoxyethylene-(5) sorbitan monooleate), polysorbate 85
(polyoxyethylene-(20) sorbitan trioleate) or polysorbate 120
(polyoxyethylene-(20) sorbitan monoisostearate)
[0056] Suitable nonionic surfactants are also sucrose fatty acid
esters such as, for example, sucrose stearate, sucrose Iaurate,
sucrose palmitate, sucrose oleate, sucrose caprylate, sucrose
decanoate, sucrose myristate, sucrose pelargonate, sucrose
undecanoate, sucrose tridecanoate, sucrose pentadecanoate or
sucrose heptadecanoate.
[0057] Also suitable are polyoxyethylene fatty acid glycerides such
as Macrogol-1500 glycerol triricinoleate, Macrogol glycerol
hydroxystearate Ph. Eur. (Kolliphor.TM. RH40), Macrogol glycerol
ricinoleate Ph. eur. (Kolliphor.TM. EL), Macrogol-1000 glycerol
monolaurate, Macrogol-1000 glycerol monostearate, Macrogol-1000
glycerol monooleate.
[0058] Also suitable are polyoxyethylene fatty acid esters such as
Macrogol-15 hydroxystearate (Kolliphor.TM. HS15), Macrogol stearate
400 (Ph. Eur.), polyoxyl-40 stearate or polyoxyl-50 stearate.
[0059] Also suitable are polyoxyethylene fatty alcohol ethers such
as Macrogol lauryl ether, polyoxyethylene-23 lauryl ether or
polyoxyl-10 oleyl ether.
[0060] Likewise suitable are glycerol fatty acid esters such as
glycerol monostearate.
[0061] Suitable amphiphilic surfactants are for example poloxamers
such as poloxamer 188, poloxamer 237, poloxamer 338 or poloxamer
407. In one preferred embodiment, the amphiphilic surfactant is
poloxamer 188. Also suitable as amphiphilic surfactants are
solubilizing polymers such as Soluplus, a copolymer of PEG 6000,
N-vinylcaprolactam and vinyl acetate and in the weight ratio
13/57/30. A suitable amphiphilic surfactant is also lecithin.
[0062] According to one embodiment of the invention, sodium lauryl
sulfate is a preferred surfactant.
[0063] According to a further preferred embodiment, the surfactants
used are polyoxyethylenated castor oils and hydrogenated castor
oils such as Macrogol glycerol hydroxystearate Ph. Eur. or Macrogol
glycerol ricinoleate Ph. Eur.
[0064] According to a further preferred embodiment, the surfactant
used is tocopherol polyethylene glycol succinate with PEG 1000,
1500 or 2000.
[0065] The surfactants can be added in amounts of from 2 to 50% by
weight based on the amount of active ingredient. In one preferred
embodiment, the surfactants can be added in amounts of from 5 to
45% by weight, based on the amount of active ingredient.
[0066] Hydrophobic organic active ingredients can be pharmaceutical
or cosmetic active ingredients, crop protection agents, nutritional
supplements or pigments. Hydrophobic active ingredients have a
solubility in water of less than 0.1 g/l at 20.degree. C. and a
pressure of 0.101325 MPa.
[0067] Pharmaceutical hydrophobic active ingredients can be for
example: benzodiazepines, antihypertensives, vitamins,
cytostatics--in particular taxol, anesthetics, neuroleptics,
antidepressants, antivirals, such as, for example, anti-HIV drugs,
antibiotics, antimycotics, antidementia agents, fungicides,
chemotherapeutics, urologics, thrombocyte aggregation inhibitors,
tyrosine kinase inhibitors, sulfonamides, spasmolytics, hormones,
immunoglobulins, sera, thyroid therapeutics, psychopharmaceuticals,
Parkinson's drugs and other antihyperkinetics, ophthalmics,
neuropathy preparations, calcium metabolism regulators, muscle
relaxants, narcotics, lipid-lowering drugs, liver therapeutics,
coronary drugs, cardiac drugs, immunotherapeutics, regulatory
peptides and their inhibitors, hypnotics, sedatives, gynecological
drugs, gout remedies, fibrinolytics, enzyme preparations and
transport proteins, enzyme inhibitors, emetics, blood-flow
stimulators, diuretics, diagnostics, corticoids, cholinergics,
biliary therapeutics, antiasthmatics, broncholytics, beta-receptor
blockers, calcium antagonists, ACE inhibitors, arteriosclerosis
drugs, antiphlogistics, anticoagulants, antihypertensives,
antihypoglycemics, antihypertonics, antifibrinolytics,
antiepileptics, antiemetics, antidotes, antidiabetics,
antiarrhythmics, antianemics, antiallergics, anthelmintics,
analgesics, analeptics, aldosterone antagonists, slimming aids.
[0068] To produce the spray solutions, the individual components
are dissolved in the solvents suitable in each case. The different
liquid phases are supplied to the spraying nozzles separately.
[0069] All conventional spraying devices are suitable for carrying
out the process according to the invention.
[0070] Suitable spraying nozzles are multi-substance nozzles such
as two-substance nozzles, three-substance nozzles or four-substance
nozzles. Such nozzles can also be configured as so-called
"ultrasonic nozzles". Such nozzles are commercially available per
se.
[0071] Furthermore, depending on the type of nozzle, an atomization
gas can also be supplied. The atomization gas used can be air or an
inert gas such as nitrogen or argon. The gas pressure of the
atomization gas can be up to 1 MPa absolute. In one preferred
embodiment, the gas pressure of the atomization gas is within the
range of 0.12 to 0.5 MPa absolute.
[0072] According to one embodiment, special nozzles in which the
different liquid phases are mixed within the nozzle body and then
atomized are also suitable.
[0073] One embodiment of the invention relates, as mentioned, to
ultrasonic nozzles. Ultrasonic nozzles can be operated with or
without atomization gas. In ultrasonic nozzles, the atomization
takes place in that the phase to be atomized is set vibrating.
Depending on the nozzle size and design, the ultrasonic nozzles can
be operated with a frequency of 16 to 120 kHz.
[0074] The throughput of liquid phase to be sprayed per nozzle is
governed by the nozzle size. The throughput can be 500 g/h to 1000
kg/h. When producing commercial amounts, the throughput is
preferably in the range from 10 to 1000 kg/h.
[0075] If no atomization gas is used, then the liquid pressure can
be 0.2 to 20 MPa absolute. If an atomization gas is used, then the
liquid can be supplied without pressure.
[0076] Furthermore, a drying gas such as air or one of the
mentioned inert gases is supplied to the spray-drying device. The
drying gas can be supplied cocurrently or countercurrently to the
sprayed liquid. In one preferred embodiment, the drying gas is
supplied cocurrently to the sprayed liquid. The entry temperature
of the drying gas can be 120 to 220.degree. C. the exit temperature
50 to 90.degree. C. In one preferred embodiment, the entry
temperature of the drying gas can be 150 to 200.degree. C., and the
exit temperature can be 50 to 90.degree. C.
[0077] As already mentioned, the orders of magnitude of the
spraying parameters to be used such as throughput, gas pressure or
nozzle diameter are decisively governed by the size of the devices.
The devices are commercially available and corresponding orders of
magnitude are usually recommended by the manufacturer.
[0078] According to one or more preferred embodiments of the
invention, the spraying process is operated such that the average
drop size of the sprayed phases is 10 to 200 .mu.m. The average
drop size can be determined by means of laser diffraction or
high-speed camera coupled with image evaluation.
[0079] The statements above relating to the spraying process can be
applied to all of the preferred and particularly preferred
embodiments described below. Preferred spraying parameters are also
preferred in connection with the embodiments below.
[0080] According to a preferred embodiment, the invention relates
to a process for producing composite materials by reactive
spray-drying, where a liquid phase A which comprises inorganic
cations and constitutes a solution of salts of the inorganic
cations, where the salts are selected from the group consisting of
calcium chloride, calcium nitrate, calcium acetate, magnesium
chloride, magnesium nitrate, magnesium acetate, magnesium citrate,
magnesium lactate, zinc chloride, zinc nitrate and zinc acetate,
and a liquid phase B which comprises anions which form with the
inorganic cations a salt that is insoluble in the mixture of the
liquid phases and constitutes a solution of salts selected from the
group consisting of ammonium, alkali metal or magnesium salts of
acetates, carbonates, hydrogencarbonates, sulfates, phosphates,
hydrogenphosphates and hydroxides, are sprayed together using at
least one multi-substance nozzle, and where at least one
hydrophobic active ingredient is present in at least one liquid
spraying phase, in dissolved form, and where the salt formed from
the cations of phase A and the anions of phase B has a solubility
of less than 0.02 mol/l in the neutral aqueous medium. According to
one or more preferred embodiments of the invention, the solvents of
the liquid phases used are water or ethanol or water/ethanol
mixtures. According to a further preferred embodiment, the
invention relates to a process for producing composite materials by
reactive spray-drying, where a liquid phase A which comprises
inorganic cations and constitutes a solution of salts of the
inorganic cations and the salts are selected from the group of
calcium chloride, calcium nitrate, calcium acetate, magnesium
chloride, magnesium nitrate, magnesium acetate, magnesium citrate,
magnesium lactate, zinc chloride, zinc nitrate and zinc acetate,
and a liquid phase B which comprises anions which form with the
inorganic cations a salt that is insoluble in the mixture of the
liquid phases and constitutes a solution of salts selected from the
group consisting of ammonium, akali metal or magnesium salts of
acetates, carbonates, hydrogencarbonates, sulfates, phosphates,
hydrogenphosphates and hydroxides, are sprayed together using at
least one multi-substance nozzle, and where at least one
hydrophobic active ingredient is present in dissolved form together
with a surfactant in at least one liquid spraying phase, and where
the salt formed from the cations of phase A and the anions of phase
B has a solubility of less than 0.02 mol/l in the neutral aqueous
medium. According to one or more preferred embodiments of the
invention, the solvents of the liquid phases used are water or
ethanol or water/ethanol mixtures.
[0081] According to one or more preferred embodiments of the
invention, the surfactants used are nonionic surfactants.
[0082] According to a particularly preferred embodiment, the
invention relates to a process for producing composite materials by
reactive spray-drying, where a liquid phase A which comprises
inorganic cations is used and where the liquid phase A constitutes
a solution of salts of the inorganic cations, and the salts are
selected from the group consisting of calcium chloride and calcium
acetate, and a liquid phase B which comprises anions which, with
the inorganic cations, form a salt that is insoluble in the mixture
of the liquid phases, and where the liquid phase B used is a
solution of salts selected from the group consisting of ammonium or
alkali metal salts of acetates, carbonates, hydrogencarbonates,
sulfates, phosphates, hydrogenphosphates and hydroxides, and where
the liquid phases A and B and optionally further liquid phases are
sprayed together using at least one multi-substance nozzle, and
where at least one hydrophobic active ingredient is present in
dissolved form in at least one liquid spraying phase, and where the
salt formed from the cations of phase A and the anions of phase B
has a solubility of less than 0.02 mol/l in the neutral aqueous
medium. According to one or more preferred embodiments of the
invention, the solvents of the liquid phases used may be water,
ethanol or water/ethanol mixtures. According to one or more
preferred embodiments of the invention, the active ingredient is
dissolved in ethanol, optionally in the presence of a surfactant,
which is preferably a nonionic surfactant, and can be added to
phase A or to phase B. According to one or more preferred
embodiments of the invention, the ammonium or alkali metal salts of
phase B are acetates or carbonates.
[0083] If, according to one of the preferred or particularly
preferred embodiments described above, a nonionic surfactant is
used in the liquid phase which comprises the hydrophobic active
ingredient, then preference is given to using a polyoxyalkylated
fatty acid ester, in particular Macrogol hydroxystearate, Macrogol
glycerol hydroxystearate or Macrogol glycerol ricinoleate.
[0084] The resulting composite materials constitute an amorphous
sparingly water-soluble salt matrix in which at least one active
ingredient present in amorphous form is embedded. Furthermore, the
composite material comprises water-soluble salt components.
[0085] The composite materials according to the invention which are
produced using the reactive spraying technology have particular
advantages over known technologies. Surprisingly, the reaction time
can be considerably reduced by the reactive spray-drying compared
to precipitation. The spraying process produces a powder which can
be further processed without complicated work-up (filtration,
downstream drying).
[0086] Compared with the described processes, the reactive
spray-drying has the advantage that it is based on a technology
which is scalable and is easy to realize under GMP conditions. The
composites are particularly suitable for the formulation of
sparingly soluble active ingredients which have a high melting
point (>180.degree. C.) and an inadequate thermal stability
(decomposition at high temperatures, decomposition in the melt) and
are therefore less suitable for conventional processes such as melt
extrusion.
[0087] The composites exhibit a significantly more rapid and more
complete active ingredient release in synthetic gastric juice
compared to the crystalline substance.
[0088] Being spray-dried powders, the composite materials are
suitable for processing in solid administration forms.
[0089] For example, they are suitable for producing adhesive
granules by wet granulation (mixer or fluidized bed) by adding
binders such as carboxymethylcellulose Na,
hydroxypropylmethylcellulose, homo- and copolymers of
N-vinylpyrrolidone such as PVP or copolymers of N-vinylpyrrolidone
and vinyl acetate, starches or gelatin.
[0090] They are also suitable for producing dry granules with or
without the addition of dry binders such as e.g. Kollidon.RTM. VA
64 Fine, for example using a roller compactor.
[0091] Furthermore, the powders or granules can be mixed with other
auxiliaries or active ingredients and be packaged in sachets for
taking as redispersible powders.
[0092] Furthermore, the powders or granules can be packaged into
hard capsules.
[0093] Furthermore, the powders or granules can be compressed to
give tablets, for example with addition of flow regulators (Aerosil
200=highly disperse SiO2), lubricants such as Mg stearate, Ca
stearate, stearic acid, sodium stearyl fumarate, PEG with average
molecular weights M.sub.W of 1000-8000, disintegrants such as
crospovidone or sodium starch glycolate). Furthermore, wetting
agents such as poloxamer 188 or sodium lauryl sulfate can also be
added to the tableting mixture.
[0094] The composite materials according to the invention are also
suitable for producing effervescent tablets. Here, an effervescent
mixture which consists of sodium bicarbonate and an acid (citric
acid or tartaric acid) is usually added to the tableting mixture.
In the case of the composite materials according to the invention,
it is possible, depending on the composition, to dispense with the
addition of sodium bicarbonate, for example if the matrix consists
of calcium carbonate. In this case, the amount of acid is adapted
to the amount of calcium carbonate.
EXAMPLES
Analytical Methods
[0095] The active ingredient release was determined in accordance
with the USP, chapter <711>, Dissolution, paddle apparatus at
100 rpm. The amount of sample was standardized to 100 mg of active
ingredient.
[0096] Release medium A: 0.08 m HCl, pH 1.1
[0097] Release medium B: as release medium A, but additionally 0.1%
by weight polysorbate 80 were added to the release medium.
[0098] The determination is carried out at 20+/-5.degree. C. and
atmospheric pressure (0.101325 MPa).
[0099] The amorphous state was determined by means of XRD.
[0100] Measuring instrument: diffractometer D 8 Advance with 9-fold
sample changer (Bruker/AXS)
[0101] Measurement type: .theta.-.theta. geometry in reflection
[0102] Angle range 2 theta: 2-80.degree.
[0103] Interval: 0.02.degree.
[0104] Measuring time per angle interval: 4.8 s
[0105] Divergence slit: Gobel mirror with 0.4 mm orifice plate
[0106] Antiscattering slit: Soller slit
[0107] Detector: Sol-X detector
[0108] Temperature: room temperature
Example 1
Danazol-Calcium Carbonate Composite
[0109] Phase A: CaCl.sub.2, danazol
[0110] 0.5 mol/l CaCl.sub.2 dissolved in ethanol, concentration of
danazol in the solution: 10 g/1
[0111] Phase B: solution of 0.5 mol/l Na.sub.2CO.sub.3 in deionized
water
[0112] The spraying device was a device from Buchi, B290, equipped
with a three-substance nozzle of the type 0465555
[0113] Spraying Parameters:
[0114] Spraying device: Buchi B290; nozzle: outer channel 2.0 mm
diameter, inner channel 0.7 mm diameter, gas channel 2.8 mm
diameter
[0115] Atomization gas: nitrogen, 819 l/h
[0116] Pump throughput of spraying liquid: 15 ml/min
[0117] Drying gas: nitrogen, throughput: 65 m.sup.3/h
[0118] Tower entry temperature: 180.degree. C.
[0119] Tower exit temperature: 62-65.degree. C.
[0120] Release test: after 120 min in a release medium B, 10% by
weight of the danazol were released.
[0121] According to determination with XRD, the composites were
amorphous.
Example 2
Danazol-Calcium Carbonate Composite with Surfactant
[0122] Phase A: calcium acetate 0.25 mol/l in deionized water
[0123] Phase B: ammonium acetate 0.25 mol/l, danazol 5 g/l,
Kolliphor.TM. RH40 5% by weight, based on active ingredient
[0124] A corresponding amount of ammonium carbonate was dissolved
in 150 g of deionized water and admixed with 300 g of the ethanolic
active ingredient solution. The resulting mixture was stirred at
40.degree. C. until a clear solution was formed.
[0125] The nozzle used was a 120 kHz ultrasonic spray-dryer nozzle
type 06-04-00445, equipped with a micropore capillary for two-fold
liquid introduction type 06-05-00290.
[0126] Spraying Parameters:
[0127] Spraying device: Buchi B290; ultrasound nozzle:
two-substance nozzle, Sonotek, power 5 W cooling ultrasonic nozzle
with 60%, gas passage, cooling gas nitrogen, nozzle temperature
63.degree. C.
[0128] Pump throughput of spraying liquid: 4 ml/min
[0129] Drying gas: nitrogen, throughput: 65 m.sup.3/h, tower entry
temperature: 130.degree. C.,
[0130] Tower exit temperature: 68.degree. C.
[0131] Release test: after 120 min in release medium A, 35% by
weight of the danazol were released.
[0132] According to XRD, the composites were amorphous.
Example 3
Danazol-Calcium Carbonate Composite with Surfactant
[0133] A composite with Kolliphor.TM. EL as surfactant was obtained
analogously to Example 2. Release test: after 120 min in release
medium A, 35% by weight of the danazol were released.
[0134] According to XRD, the composites were amorphous.
Example 4
Estradiol-Calcium Carbonate Composite
[0135] Phase A: solution of 0.5 mol/l calcium chloride and 10 g/l
estradiol in ethanol. Phase B: solution of 0.5 mol/l CaCO.sub.3 in
deionized water
[0136] The spraying device used was a device from Buchi, B290,
equipped with a three-substance nozzle of the type 0465555.
[0137] Spraying Parameters:
[0138] Spraying device: Buchi B290; nozzle: outer channel 2.0 mm
diameter, inner channel 0.7 mm diameter, gas channel 2.8 mm
diameter
[0139] Atomization gas: nitrogen, 819 l/h
[0140] Pump throughput of spraying liquid: 15 ml/min
[0141] Drying gas: nitrogen, throughput: 65 m.sup.3/h
[0142] Tower entry temperature: 170.degree. C.
[0143] Tower exit temperature: 48-52.degree. C.
[0144] Release test: after 120 min in release medium B, 30% by
weight of the estradiol were released.
[0145] According to determination with XRD, the composites were
amorphous.
Example 5
Itraconazole-Calcium Carbonate Composite
[0146] Phase A: calcium acetate
[0147] 0.25 mol/l calcium acetate dissolved in ethanol. 5 g/l
itraconazole dissolved in THF, then both solutions were mixed.
Ethanol/THF solvent mixture after mixing: 60/40 (ethanol/THF) 60/40
Phase B: solution of 0.25 mol/l (NH.sub.4).sub.2CO.sub.3 in
deionized water.
[0148] The spraying device used was a device from Buchi, B290,
equipped with a three-substance nozzle of the type 0465555
[0149] Spraying Parameters:
[0150] Spraying device: Buchi B290; nozzle: outer channel 2.0 mm
diameter, inner channel 0.7 mm diameter, gas channel 2.8 mm
diameter
[0151] Atomization gas: nitrogen, 819 l/h
[0152] Pump throughput of spraying liquid: 15 ml/min
[0153] Drying gas: nitrogen, throughput: 65 m.sup.3/h
[0154] Tower entry temperature: 210.degree. C.
[0155] Tower exit temperature: 68-72.degree. C.
[0156] Release test: after 120 min in release medium A, 30% by
weight of the itraconazole were released.
[0157] According to determination with XRD, the composites were
amorphous.
Example 6
Naproxen-Calcium Carbonate Composite
[0158] Phase A: calcium acetate
[0159] 0.25 mol/l calcium acetate dissolved in deionized water.
[0160] Phase B: solution of 0.25 mol/l (NH.sub.4).sub.2CO.sub.3 in
deionized water/acetone (60/40) and 10 g/1 naproxen
[0161] The spraying device was a device from Buchi, B290, equipped
with a three-substance nozzle of the type 0465555.
[0162] Spraying Parameters:
[0163] Spraying device: Buchi B290; nozzle: outer channel 2.0 mm
diameter, inner channel 0.7 mm diameter, gas channel 2.8 mm
diameter
[0164] Atomization gas: nitrogen, 819 l/h
[0165] Pump throughput of spraying liquid: 12 ml/min
[0166] Drying gas: nitrogen, throughput: 65 m.sup.3/h
[0167] Tower entry temperature: 220.degree. C.
[0168] Tower exit temperature: 68-70.degree. C.
[0169] Release test: after 120 min in release medium A, 45% by
weight of the naproxen were released.
[0170] According to determination with XRD, the composites were
amorphous.
Example 7
Celecoxib-Calcium Carbonate Composite
[0171] Phase A: calcium acetate 0.25 mol/l in deionized water
[0172] Phase B: ammonium acetate 0.25 mol/l, celecoxib 5 g/l, 5% by
weight Kolliphor.TM. RH40, based on active ingredient, in a mixture
of deionized water and EtOH 1:2 (weight ratio).
[0173] A corresponding amount of ammonium carbonate was dissolved
in 150 g of deionized water and admixed with 300 g of the ethanolic
active ingredient solution. The resulting mixture was stirred at
40.degree. C. until a clear solution was formed.
[0174] The nozzle used was a 120 kHz ultrasonic spray-dryer nozzle
type 06-04-00445, SonoTek, USA, equipped with a micropore capillary
for two-fold liquid introduction type 06-05-00290.
[0175] Spraying Parameters:
[0176] Spraying device: Buchi B290; ultrasonic nozzle:
two-substance nozzle, Sonotek, power 5 W cooling ultrasonic nozzle
with 60% gas passage, cooling gas nitrogen, nozzle temperature
52.degree. C.
[0177] Pump throughput of spraying liquid: 4 ml/min
[0178] Drying gas: nitrogen, throughput: 65 m.sup.3/h, tower entry
temperature: 132.degree. C., tower exit temperature: 68-70.degree.
C.
[0179] Release test: after 120 min in release medium A, 20% by
weight of the celecoxib were released.
[0180] According to XRD, the composites were amorphous.
Comparative Example I
Spraying of Pure Danazol
[0181] As spraying solution, a solution obtained analogously to
Example 2, phase B was sprayed under the spraying conditions given
in Example 2.
[0182] Release test: after 120 min in release medium A comprising
0.1% by weight polysorbate 80, 5 to 6.5% by weight of danazol were
released.
Comparative Example II
Danazol-Calcium Carbonate Composite Produced by Precipitation in a
Mixing Chamber in Accordance with WO 2012/027378
[0183] Release test: after 120 min in release medium A comprising
0.1% by weight polysorbate 80, 8% by weight of the danazol were
released.
[0184] According to XRD, the products had considerable fractions of
crystalline calcium carbonate.
[0185] FIG. 1 shows the plasma level of the composite materials
according to Examples 1, 2 and Comparative Example I.
[0186] The plasma levels were determined as follows:
[0187] Each of 5 dogs (average weight 16 kg) was given the test
substances in the same order with a break of 14 days after each
application. The formulations were administered as a physical
mixture of 70% test substance, 15% Avicel PH 101 (FMC BioPolymer)
and 15% Kollidon CL (BASF SE) in hard gelatin capsules (Torpac
Inc., USA #11). The dose was 30 mg/kg and was based individually
for each animal and each application time on the actual body
weight. The dogs were given the capsules on an empty stomach. Blood
was taken at 3, 60, 90 min and 2, 4, 8 and 24 hours after
application. Water was available ad libitum, and feeding was 4
hours after application. The plasma samples were frozen and later
analyzed ((ESI(+)-LC-MS/MS) (column: Ascentis Express C18/2.7
.mu.m/100 mm.times.2.1 mm/Supelco) mobile phase: acetonitrile/water
(50:50 v/v) with 0.01% formic acid; detection limit (limit of
quantification (LoQ)): 2-5 ng/ml)
[0188] The plasma concentration of the active ingredient is given
in the FIGURE in ng/ml.
* * * * *